Francois Haddad

All Publications

• High and intermediate risk pulmonary embolism in the ICU. Intensive care medicine Millington, S. J., Aissaoui, N., Bowcock, E., Brodie, D., Burns, K. E., Douflé, G., Haddad, F., Lahm, T., Piazza, G., Sanchez, O., Savale, L., Vieillard-Baron, A. 2023

  Abstract

  Pulmonary embolism (PE) is a common and important medical emergency, encountered by clinicians across all acute care specialties. PE is a relatively uncommon cause of direct admission to the intensive care unit (ICU), but these patients are at high risk of death. More commonly, patients admitted to ICU develop PE as a complication of an unrelated acute illness. This paper reviews the epidemiology, diagnosis, risk stratification, and particularly the management of PE from a critical care perspective. Issues around prevention, anticoagulation, fibrinolysis, catheter-based techniques, surgical embolectomy, and extracorporeal support are discussed.

  View details for DOI 10.1007/s00134-023-07275-6

  View details for PubMedID 38112771

  View details for PubMedCentralID 5804676

• The Echocardiographic Evaluation of the Right Heart: Current and Future Advances. Current cardiology reports O'Donnell, C., Sanchez, P. A., Celestin, B., McConnell, M. V., Haddad, F. 2023

  Abstract

  PURPOSE OF REVIEW: To discuss physiologic and methodologic advances in the echocardiographic assessment of right heart (RH) function, including the emergence of artificial intelligence (AI) and point-of-care ultrasound.RECENT FINDINGS: Recent studies have highlighted the prognostic value of right ventricular (RV) longitudinal strain, RV end-systolic dimensions, and right atrial (RA) size and function in pulmonary hypertension and heart failure. While RA pressure is a central marker of right heart diastolic function, the recent emphasis on venous excess imaging (VExUS) has provided granularity to the systemic consequences of RH failure. Several methodological advances are also changing the landscape of RH imaging including post-processing 3D software to delineate the non-longitudinal (radial, anteroposterior, and circumferential) components of RV function, as well as AI segmentation- and non-segmentation-based quantification. Together with recent guidelines and advances in AI technology, the field is shifting from specific RV functional metrics to integrated RH disease-specific phenotypes. A modern echocardiographic evaluation of RH function should focus on the entire cardiopulmonary venous unit-from the venous to the pulmonary arterial system. Together, a multi-parametric approach, guided by physiology and AI algorithms, will help define novel integrated RH profiles for improved disease detection and monitoring. Advances in right heart echocardiography will incorporate a physiologic, multi-parametric approach that is augmented by deep learning to develop integrated right heart phenotypes. Ao Aorta, LV left ventricle, RA right atria, RV right ventricle, PA pulmonary artery.

  View details for DOI 10.1007/s11886-023-02001-6

  View details for PubMedID 38041726

• Strength training is more effective than aerobic exercise for improving glycaemic control and body composition in people with normal-weight type 2 diabetes: a randomised controlled trial. Diabetologia Kobayashi, Y., Long, J., Dan, S., Johannsen, N. M., Talamoa, R., Raghuram, S., Chung, S., Kent, K., Basina, M., Lamendola, C., Haddad, F., Leonard, M. B., Church, T. S., Palaniappan, L. 2023

  Abstract

  AIMS/HYPOTHESIS: Type 2 diabetes in people in the healthy weight BMI category (<25 kg/m2), herein defined as 'normal-weight type 2 diabetes', is associated with sarcopenia (low muscle mass). Given this unique body composition, the optimal exercise regimen for this population is unknown.METHODS: We conducted a parallel-group RCT in individuals with type 2 diabetes (age 18-80 years, HbA1c 47.5-118.56 mmol/mol [6.5-13.0%]) and BMI <25 kg/m2). Participants were recruited in outpatient clinics or through advertisements and randomly assigned to a 9 month exercise programme of strength training alone (ST), aerobic training alone (AER) or both interventions combined (COMB). We used stratified block randomisation with a randomly selected block size. Researchers and caregivers were blinded to participants' treatment group; however, participants themselves were not. Exercise interventions were conducted at community-based fitness centres. The primary outcome was absolute change in HbA1c level within and across the three groups at 3, 6 and 9 months. Secondary outcomes included changes in body composition at 9 months. Per adherence to recommended exercise protocol (PP) analysis included participants who completed at least 50% of the sessions.RESULTS: Among 186 individuals (ST, n=63; AER, n=58; COMB, n=65) analysed, the median (IQR) age was 59 (53-66) years, 60% were men and 83% were Asian. The mean (SD) HbA1c level at baseline was 59.6 (13.1) mmol/mol (7.6% [1.2%]). In intention-to-treat analysis, the ST group showed a significant decrease in HbA1c levels (mean [95% CI] -0.44 percentage points [-0.78, -0.12], p=0.002), while no significant change was observed in either the COMB group (-0.35 percentage points, p=0.13) or the AER group (-0.24 percentage points, p=0.10). The ST group had a greater improvement in HbA1c levels than the AER group (p=0.01). Appendicular lean mass relative to fat mass increased only in the ST group (p=0.0008), which was an independent predictor of HbA1c change (beta coefficient -7.16, p=0.01). Similar results were observed in PP analysis. Only one adverse event, in the COMB group, was considered to be possibly associated with the exercise intervention.CONCLUSIONS/INTERPRETATION: In normal-weight type 2 diabetes, strength training was superior to aerobic training alone, while no significant difference was observed between strength training and combination training for HbA1c reduction. Increased lean mass relative to decreased fat mass was an independent predictor of reduction in HbA1c level.TRIAL REGISTRATION: ClinicalTrials.gov NCT02448498.FUNDING: This study was funded by the National Institutes of Health (NIH; R01DK081371).

  View details for DOI 10.1007/s00125-023-05958-9

  View details for PubMedID 37493759

• Right Ventricular Dysfunction Patterns Among Patients with COVID-19 in the Intensive Care Unit - a Retrospective Cohort Analysis. Annals of the American Thoracic Society Sanchez, P. A., O'Donnell, C. T., Francisco, N., Santana, E. J., Moore, A. R., Pacheco-Navarro, A., Roque, J., Lebold, K. M., Parmer, C. M., Pienkos, S. M., Celestin, B. E., Levitt, J. E., Collins, W. J., Lanspa, M. J., Ashley, E. A., Wilson, J. G., Haddad, F., Rogers, A. J. 2023

  Abstract

  Right ventricular (RV) dysfunction is common among patients hospitalized with COVID-19; however, its epidemiology may depend on the echocardiographic parameters used to define it.To evaluate the prevalence of abnormalities in three common echocardiographic parameters of RV function among COVID-19 patients admitted to the intensive care unit, as well as the effect of RV dilatation on differential parameter abnormality and the association of RV dysfunction with 60-day mortality.Retrospective cohort study of COVID-19 ICU patients between March 4th,2020 to March 4th, 2021, who received a transthoracic echocardiogram within 48 hours before to at most 7 days after ICU admission. RV dysfunction and dilatation respectively defined by guideline thresholds for tricuspid annular plane systolic excursion (TAPSE), RV fractional area change (RVFAC), RV free wall longitudinal strain (RVFWS), and RV basal dimension or RV end-diastolic area. Association of RV dysfunction with 60-day mortality assessed through logistic regression adjusting for age, prior history of congestive heart failure, invasive ventilation at time of TTE and APACHE II score.116 patients were included, of which 69% had RV dysfunction by > 1 parameter and 36.3% of these had RV dilatation. The three most common patterns of RV dysfunction included: Presence of 3 abnormalities, the combination of abnormal RVFWS and TAPSE, and isolated TAPSE abnormality. Patients with RV dilatation had worse RVFAC (24% vs 36%, p = 0.001), worse RVFWS (16.3% vs 19.1%, p = 0.005), higher RVSP (45mmHg vs 31mmHg, p = 0.001) but similar TAPSE (13mm vs 13mm, p = 0.30) compared to those with normal RV size. After multivariable adjustment, 60-day mortality was significantly associated with RV dysfunction (OR 2.91, 95% CI 1.01 - 9.44), as was the presence of at least 2 parameter abnormalities.ICU patients with COVID-19 had significant heterogeneity in RV function abnormalities present with different patterns associated with RV dilatation. RV dysfunction by any parameter was associated with increased mortality. Therefore, a multiparameter evaluation may be critical in recognizing RV dysfunction in COVID-19.

  View details for DOI 10.1513/AnnalsATS.202303-235OC

  View details for PubMedID 37478340

• Automation for Right Heart Analysis: The Start of a New Era. JACC. Cardiovascular imaging Haddad, F., Gomes, B. 2023

  View details for DOI 10.1016/j.jcmg.2023.03.018

  View details for PubMedID 37227331

• Improved Right Ventricular Energy Efficiency by 4-Dimensional Flow Magnetic Resonance Imaging After Harmony Valve Implantation. JACC. Advances Woo, J. P., Dong, M. L., Kong, F., McElhinney, D. B., Schiavone, N., Chan, F., Lui, G. K., Haddad, F., Bernstein, D., Marsden, A. 2023; 2 (3)

  View details for DOI 10.1016/j.jacadv.2023.100284

  View details for PubMedID 37691969

  View details for PubMedCentralID PMC10487049

• Clinical and echocardiographic diversity associated with physical fitness in the Project Baseline Health Study: implications for heart failure staging. Journal of cardiac failure Cauwenberghs, N., Haddad, F., Daubert, M. A., Chatterjee, R., Salerno, M., Mega, J. L., Heidenreich, P., Hernandez, A., Amsallem, M., Kobayashi, Y., Mahaffey, K. W., Shah, S. H., Bloomfield, G. S., Kuznetsova, T., Douglas, P. S. 2023

  Abstract

  Clinical and echocardiographic features may carry diverse information on the development of heart failure (HF). Therefore, we determined heterogeneity in clinical and echocardiographic phenotypes and its association with exercise capacity.In 2036 community-dwelling individuals, we defined echocardiographic profiles of left and right heart remodeling and dysfunction. We subdivided the cohort based on presence (+) or absence (-) of HF risk factors and echocardiographic abnormalities (RF-/Echo-, RF-/Echo+, RF+/Echo-, RF+/Echo+). Multivariable-adjusted associations between RF/Echo subgroups and physical performance metrics from 6-minute walk and treadmill exercise testing were assessed.Prevalence was: 35.3% for RF-/Echo-, 4.7% for RF-/Echo+, 39.3% for RF+/Echo- and 20.6% for RF+/Echo+. We observed large diversity in echocardiographic profiles in the Echo+ group. Participants with RF-/Echo+ (18.6% of Echo+) predominantly had echocardiographic abnormalities other than left ventricular (LV) diastolic dysfunction, hypertrophy and reduced ejection fraction, while their physical performance was similar to RF-/Echo-. In contrast, participants with RF+/Echo+ mostly presented LV hypertrophy or dysfunction, features that related to lower 6-minute walking distance and lower exercise capacity.Subclinical echocardiographic abnormalities suggest HF pathogenesis, but the presence of HF risk factors and type of echo abnormality should be considered to distinguish adverse from benign adaptation and stratify HF risk.

  View details for DOI 10.1016/j.cardfail.2023.04.008

  View details for PubMedID 37116641

• Accelerated Epigenetic Aging Is Associated With Multiple Cardiometabolic, Hematologic, and Renal Abnormalities: A Project Baseline Health Substudy. Circulation. Genomic and precision medicine Uchehara, B., Coulter Kwee, L., Regan, J., Chatterjee, R., Eckstrand, J., Swope, S., Gold, G., Schaack, T., Douglas, P., Mettu, P., Haddad, F., Shore, S., Hernandez, A., Mahaffey, K. W., Pagidipati, N., Shah, S. H., Project Baseline Health Study Group 2023: e003772

  Abstract

  BACKGROUND: Epigenetic clocks estimate chronologic age using methylation levels at specific loci. We tested the hypothesis that accelerated epigenetic aging is associated with abnormal values in a range of clinical, imaging, and laboratory characteristics.METHODS: The Project Baseline Health Study recruited 2502 participants, including 1661 with epigenetic age estimates from the Horvath pan-tissue clock. We classified individuals with extreme values as having epigenetic age acceleration (EAA) or epigenetic age deceleration. A subset of participants with longitudinal methylation profiling was categorized as accelerated versus nonaccelerated. Using principal components analysis, we created phenoclusters using 122 phenotypic variables and compared individuals with EAA versus epigenetic age deceleration, and at one year of follow-up, using logistic regression models adjusted for sex (false discovery rate [Q] <0.10); in secondary exploratory analyses, we tested individual clinical variables.RESULTS: The EAA (n=188) and epigenetic age deceleration (n=195) groups were identified as having EAA estimates ≥5 years or ≤-5 years, respectively. In primary analyses, individuals with EAA had higher values for phenoclusters summarizing lung function and lipids, and lower values for a phenocluster representing physical function. In secondary analyses of individual variables, neutrophils, body mass index, and waist circumference were significantly higher in individuals with EAA (Q<0.10). No phenoclusters were significantly different between participants with accelerated (n=148) versus nonaccelerated (n=112) longitudinal aging.CONCLUSIONS: We report multiple cardiometabolic, hematologic, and physical function features characterizing individuals with EAA. These highlight factors that may mediate the adverse effects of aging and identify potential targets for study of mitigation of these effects.REGISTRATION: URL: https://www.CLINICALTRIALS: gov; Unique identifier: NCT03154346.

  View details for DOI 10.1161/CIRCGEN.122.003772

  View details for PubMedID 37039013

• The heart of the matter: Right heart imaging indicators for treatment escalation in pulmonary arterial hypertension. Pulmonary circulation Forfia, P., Benza, R., D'Alto, M., De Marco, T., Elwing, J. M., Frantz, R., Haddad, F., Oudiz, R., Preston, I. R., Rosenkranz, S., Ryan, J., Schilz, R., Shlobin, O. A., Vachiery, J., Vizza, C. D., Noordegraaf, A. V., Sketch, M. R., Broderick, M., McLaughlin, V. 2023; 13 (2): e12240

  Abstract

  Right heart (RH) structure and function are major determinants of symptoms and prognosis in pulmonary arterial hypertension (PAH). RH imaging provides detailed information, but evidence and guidelines on the use of RH imaging in treatment decisions are limited. We conducted a Delphi study to gather expert opinion on the role of RH imaging in decision-making for treatment escalation in PAH. A panel of 17 physicians with expertise in PAH and RH imaging used three surveys in a modified Delphi process to reach consensus on the role of RH imaging in PAH. Survey 1 used open-ended questions to gather information. Survey 2 contained Likert scale and other questions intended to identify consensus on topics identified in Survey 1. Survey 3 contained Likert scale questions derived from Survey 2 and summary information on the results of Survey 2. The Delphi panel reached consensus that RH imaging is likely to improve the current risk stratification algorithms and help differentiate risk levels in patients at intermediate risk. Tricuspid annular plane systolic excursion, right ventricular fractional area change, right atrial area, tricuspid regurgitation, inferior venae cavae diameter, and pericardial effusion should be part of routine echocardiography in PAH. Cardiac magnetic resonance imaging is valuable but limited by cost and access. A pattern of abnormal RH imaging results should prompt consideration of hemodynamic evaluation and possible treatment escalation. RH imaging is an important tool for decisions about treatment escalation in PAH, but systematically collected evidence is needed to clarify its role.

  View details for DOI 10.1002/pul2.12240

  View details for PubMedID 37222992

• Challenging obesity and sex based differences in resting energy expenditure using allometric modeling, a sub-study of the DIETFITS clinical trial. Clinical nutrition ESPEN Haddad, F., Li, X., Perelman, D., Santana, E. J., Kuznetsova, T., Cauwenberghs, N., Busque, V., Contrepois, K., Snyder, M. P., Leonard, M. B., Gardner, C. 2023; 53: 43-52

  Abstract

  BACKGROUND & AIMS: Resting energy expenditure (REE) is a major component of energy balance. While REE is usually indexed to total body weight (BW), this may introduce biases when assessing REE in obesity or during weight loss intervention. The main objective of the study was to quantify the bias introduced by ratiometric scaling of REE using BW both at baseline and following weight loss intervention.DESIGN: Participants in the DIETFITS Study (Diet Intervention Examining The Factors Interacting with Treatment Success) who completed indirect calorimetry and dual-energy X-ray absorptiometry (DXA) were included in the study. Data were available in 438 participants at baseline, 340at 6 months and 323at 12 months. We used multiplicative allometric modeling based on lean body mass (LBM) and fat mass (FM) to derive body size independent scaling of REE. Longitudinal changes in indexed REE were then assessed following weight loss intervention.RESULTS: A multiplicative model including LBM, FM, age, Black race and the double product (DP) of systolic blood pressure and heart rate explained 79% of variance in REE. REE indexed to [LBM0.66*FM0.066] was body size and sex independent (p=0.91 and p=0.73, respectively) in contrast to BW based indexing which showed a significant inverse relationship to BW (r=-0.47 for female and r=-0.44 for male, both p<0.001). When indexed to BW, significant baseline differences in REE were observed between male and female (p<0.001) and between individuals who are overweight and obese (p<0.001) while no significant differences were observed when indexed to REE/[LBM0.66*FM0.066], p>0.05). Percentage predicted REE adjusted for LBM, FM and DP remained stable following weight loss intervention (p=0.614).CONCLUSION: Allometric scaling of REE based on LBM and FM removes body composition-associated biases and should be considered in obesity and weight-based intervention studies.

  View details for DOI 10.1016/j.clnesp.2022.11.015

  View details for PubMedID 36657929

• Defining left ventricular remodeling using lean body mass allometry: a UK Biobank study. European journal of applied physiology Gomes, B., Hedman, K., Kuznetsova, T., Cauwenberghs, N., Hsu, D., Kobayashi, Y., Ingelsson, E., Oxborough, D., George, K., Salerno, M., Ashley, E., Haddad, F. 2023

  Abstract

  PURPOSE: The geometric patterns of ventricular remodeling are determined using indexed left ventricular mass (LVM), end-diastolic volume (LVEDV) and concentricity, most often measured using the mass-to-volume ratio (MVR). The aims of this study were to validate lean body mass (LBM)-based allometric coefficients for scaling and to determine an index of concentricity that is independent of both volume and LBM.METHODS: Participants from the UK Biobank who underwent both CMR and dual-energy X-ray absorptiometry (DXA) during 2014-2015 were considered (n=5064). We excluded participants aged≥70years or those with cardiometabolic risk factors. We determined allometric coefficients for scaling using linear regression of the logarithmically transformed ventricular remodeling parameters. We further defined a multiplicative allometric relationship for LV concentricity (LVC) adjusting for both LVEDV and LBM.RESULTS: A total of 1638 individuals (1057 female) were included. In subjects with lower body fat percentage (<25% in males,<35% in females, n=644), the LBM allometric coefficients for scaling LVM and LVEDV were 0.85±0.06 and 0.85±0.03 respectively (R2=0.61 and 0.57, P<0.001), with no evidence of sex-allometry interaction. While the MVR was independent of LBM, it demonstrated a negative association with LVEDV in (females: r=-0.44, P<0.001; males: -0.38, P<0.001). In contrast, LVC was independent of both LVEDV and LBM [LVC=LVM/(LVEDV0.40*LBM0.50)] leading to increased overlap between LV hypertrophy and higher concentricity.CONCLUSIONS: We validated allometric coefficients for LBM-based scaling for CMR indexed parameters relevant for classifying geometric patterns of ventricular remodeling.

  View details for DOI 10.1007/s00421-022-05125-9

  View details for PubMedID 36617359

• 4D flow cardiovascular magnetic resonance recovery profiles following pulmonary endarterectomy in chronic thromboembolic pulmonary hypertension. Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance Dong, M. L., Azarine, A., Haddad, F., Amsallem, M., Kim, Y., Yang, W., Fadel, E., Aubrege, L., Loecher, M., Ennis, D., Pavec, J. L., Vignon-Clementel, I., Feinstein, J. A., Mercier, O., Marsden, A. L. 2022; 24 (1): 59

  Abstract

  BACKGROUND: Four-dimensional flow cardiovascular magnetic resonance imaging (4D flow CMR) allows comprehensive assessment of pulmonary artery (PA) flow dynamics. Few studies have characterized longitudinal changes in pulmonary flow dynamics and right ventricular (RV) recovery following a pulmonary endarterectomy (PEA) for patients with chronic thromboembolic pulmonary hypertension (CTEPH). This can provide novel insights of RV and PA dynamics during recovery. We investigated the longitudinal trajectory of 4D flow metrics following a PEA including velocity, vorticity, helicity, and PA vessel wall stiffness.METHODS: Twenty patients with CTEPH underwent pre-PEA and >6 months post-PEA CMR imaging including 4D flow CMR; right heart catheter measurements were performed in 18 of these patients. We developed a semi-automated pipeline to extract integrated 4D flow-derived main, left, and right PA (MPA, LPA, RPA) volumes, velocity flow profiles, and secondary flow profiles. We focused on secondary flow metrics of vorticity, volume fraction of positive helicity (clockwise rotation), and the helical flow index (HFI) that measures helicity intensity.RESULTS: Mean PA pressures (mPAP), total pulmonary resistance (TPR), and normalized RV end-systolic volume (RVESV) decreased significantly post-PEA (P<0.002). 4D flow-derived PA volumes decreased (P<0.001) and stiffness, velocity, and vorticity increased (P<0.01) post-PEA. Longitudinal improvements from pre- to post-PEA in mPAP were associated with longitudinal decreases in MPA area (r=0.68, P=0.002). Longitudinal improvements in TPR were associated with longitudinal increases in the maximum RPA HFI (r=-0.85, P<0.001). Longitudinal improvements in RVESV were associated with longitudinal decreases in MPA fraction of positive helicity (r=0.75, P=0.003) and minimum MPA HFI (r=-0.72, P=0.005).CONCLUSION: We developed a semi-automated pipeline for analyzing 4D flow metrics of vessel stiffness and flow profiles. PEA was associated with changes in 4D flow metrics of PA flow profiles and vessel stiffness. Longitudinal analysis revealed that PA helicity was associated with pulmonary remodeling and RV reverse remodeling following a PEA.

  View details for DOI 10.1186/s12968-022-00893-x

  View details for PubMedID 36372884

• Reference change value of global longitudinal strain in clinical practice: A test-rest quality implementation project. Echocardiography (Mount Kisco, N.Y.) Tuzovic, M., Tang, X., Francisco, N., Sell, A., Drew, R., Paloma, A., Chow, J., Liang, D., Heidenreich, P., Salerno, M., Schnittger, I., Haddad, F. 2022

  Abstract

  BACKGROUND: Reference change value (RCV) is used to assess the significance of the difference between two measurements after accounting for pre-analytic, analytic, and within-subject variability. The objective of the current study was to define the RCV for global longitudinal strain (GLS) using different semi-automated software in standard clinical practice.METHODS: Using a test-retest study design, we quantified the median coefficient of variation (CV) for GLS using AutoStrain and Automated Cardiac Motion Quantification (aCMQ) by Philips. Triplane left-ventricular ejection fraction (LVEF) was measured for comparison. Multivariable regression analysis was performed to determine factors influencing test-retest CV including image quality and the presence of segmental wall motion abnormalities (WMA). RCV was reported using a standard formula assuming two standard deviations for repeated measurements; results were also translated into Bayesian probability. Total measurement variation was described in terms of its three different components: pre-analytic (acquisition), analytic (measuring variation), and within-subject (biological) variation.RESULT: Of the 44 individuals who were screened, 41 had adequate quality for strain quantification. The mean age of the cohort was 56.4±16.8 years, 41% female, LVEF was 55.8±9.8% and the median and interquartile range for LV GLS was -17.2 [-19.3 to -14.8]%. Autostrain was more time efficient (80% less analysis time) and had a lower total median CV than aCMQ (CV=7.4%vs. 17.6%, p <.001). The total CV was higher in patients with WMA (6.4%vs. 13.2%, p=.035). In non-segmental disease, the CV translates to a RCV of 15% (corresponding to a probability of real change of 80%). Assuming a within-subject variability of 4.0%, the component analysis identified that inter-reader variability accounts for 3.7% of the CV, while acquisition variability accounts for 4.0%.CONCLUSION: Using test-retest analysis and CVs, we find that an RCV of 15% for GLS represents an optimistic estimate in routine clinical practice. Based on our results, a higher RCV of 17%-21% is needed in order to provide a high probability of clinically meaningful change in GLS in all comers. The methodology presented here for determining measurement reproducibility and RCVs is easily translatable into clinical practice for any imaging parameter.

  View details for DOI 10.1111/echo.15482

  View details for PubMedID 36376263

• Association of left ventricular diastolic function with coronary artery calcium score: A Project Baseline Health Study. Journal of cardiovascular computed tomography Haddad, F., Cauwenberghs, N., Daubert, M. A., Kobayashi, Y., Bloomfield, G. S., Fleischman, D., Koweek, L., Maron, D. J., Rodriguez, F., Liao, Y. J., Moneghetti, K., Amsallem, M., Mega, J., Hernandez, A., Califf, R., Mahaffey, K. W., Shah, S. H., Kuznetsova, T., Douglas, P. S., Project Baseline Health Study Investigators 2022

  Abstract

  BACKGROUND: Coronary artery calcium (CAC) and left ventricular diastolic dysfunction (LVDD) are strong predictors of cardiovascular events and share common risk factors. However, their independent association remains unclear.METHODS: In the Project Baseline Health Study (PBHS), 2082 participants underwent cardiac-gated, non-contrast chest computed tomography (CT) and echocardiography. The association between left ventricular (LV) diastolic function and CAC was assessed using multidimensional network and multivariable-adjusted regression analyses. Multivariable analysis was conducted on continuous LV diastolic parameters and categorical classification of LVDD and adjusted for traditional cardiometabolic risk factors. LVDD was defined using reference limits from a low-risk reference group without established cardiovascular disease, cardiovascular risk factors or evidence of CAC, (n​=​560). We also classified LVDD using the American Society of Echocardiography recommendations.RESULTS: The mean age of the participants was 51​±​17 years with 56.6% female and 62.6% non-Hispanic White. Overall, 38.1% had hypertension; 13.7% had diabetes; and 39.9% had CAC >0. An intertwined network was observed between diastolic parameters, CAC score, age, LV mass index, and pulse pressure. In the multivariable-adjusted analysis, e', E/e', and LV mass index were independently associated with CAC after adjustment for traditional risk factors. For both e' and E/e', the effect size and statistical significance were higher across increasing CAC tertiles. Other independent correlates of e' and E/e' included age, female sex, Black race, height, weight, pulse pressure, hemoglobin A1C, and HDL cholesterol. The independent association with CAC was confirmed using categorical analysis of LVDD, which occurred in 554 participants (26.6%) using population-derived thresholds.CONCLUSION: In the PBHS study, the subclinical coronary atherosclerotic disease burden detected using CAC scoring was independently associated with diastolic function.CLINICALTRIALS: GOV IDENTIFIER: NCT03154346.

  View details for DOI 10.1016/j.jcct.2022.06.003

  View details for PubMedID 35872137

• Elucidating tricuspid Doppler signal interpolation and its implication for assessing pulmonary hypertension PULMONARY CIRCULATION Dual, S. A., Verdonk, C., Amsallem, M., Pham, J., Obasohan, C., Nataf, P., McElhinney, D. B., Arunamata, A., Kuznetsova, T., Zamanian, R., Feinstein, J. A., Marsden, A., Haddad, F. 2022; 12 (3): e12125

  Abstract

  Doppler echocardiography plays a central role in the assessment of pulmonary hypertension (PAH). We aim to improve quality assessment of systolic pulmonary arterial pressure (SPAP) by applying a cubic polynomial interpolation to digitized tricuspid regurgitation (TR) waveforms. Patients with PAH and advanced lung disease were divided into three cohorts: a derivation cohort (n = 44), a validation cohort (n = 71), an outlier cohort (n = 26), and a non-PAH cohort (n = 44). We digitized TR waveforms and analyzed normalized duration, skewness, kurtosis, and first and second derivatives of pressure. Cubic polynomial interpolation was applied to three physiology-driven phases: the isovolumic phase, ejection phase, and "shoulder" point phase. Coefficients of determination and a Bland-Altman analysis was used to assess bias between methods. The cubic polynomial interpolation of the TR waveform correlated strongly with expert read right ventricular systolic pressure (RVSP) with R 2 > 0.910 in the validation cohort. The biases when compared to invasive SPAP measured within 24 h were 6.03 [4.33; 7.73], -2.94 [1.47; 4.41], and -3.11 [-4.52; -1.71] mmHg, for isovolumic, ejection, and shoulder point interpolations, respectively. In the outlier cohort with more than 30% difference between echocardiographic estimates and invasive SPAP, cubic polynomial interpolation significantly reduced underestimation of RVSP. Cubic polynomial interpolation of the TR waveform based on isovolumic or early ejection phase may improve RVSP estimates.

  View details for DOI 10.1002/pul2.12125

  View details for Web of Science ID 000843054900001

  View details for PubMedID 36016669

  View details for PubMedCentralID PMC9395694

• Temporal shift and predictive performance of machine learning for heart transplant outcomes. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Miller, R. J., Sabovcik, F., Cauwenberghs, N., Vens, C., Khush, K. K., Heidenreich, P. A., Haddad, F., Kuznetsova, T. 2022

  Abstract

  BACKGROUND: Outcome prediction following heart transplant is critical to explaining risks and benefits to patients and decision-making when considering potential organ offers. Given the large number of potential variables to be considered, this task may be most efficiently performed using machine learning (ML). We trained and tested ML and statistical algorithms to predict outcomes following cardiac transplant using the United Network of Organ Sharing (UNOS) database.METHODS: We included 59,590 adult and 8,349 pediatric patients enrolled in the UNOS database between January 1994 and December 2016 who underwent cardiac transplantation. We evaluated 3 classification and 3 survival methods. Algorithms were evaluated using shuffled 10-fold cross-validation (CV) and rolling CV. Predictive performance for 1 year and 90 days all-cause mortality was characterized using the area under the receiver-operating characteristic curve (AUC) with 95% confidence interval.RESULTS: In total, 8,394 (12.4%) patients died within 1 year of transplant. For predicting 1-year survival, using the shuffled 10-fold CV, Random Forest achieved the highest AUC (0.893; 0.889-0.897) followed by XGBoost and logistic regression. In the rolling CV, prediction performance was more modest and comparable among the models with XGBoost and Logistic regression achieving the highest AUC 0.657 (0.647-0.667) and 0.641(0.631-0.651), respectively. There was a trend toward higher prediction performance in pediatric patients.CONCLUSIONS: Our study suggests that ML and statistical models can be used to predict mortality post-transplant, but based on the results from rolling CV, the overall prediction performance will be limited by temporal shifts inpatient and donor selection.

  View details for DOI 10.1016/j.healun.2022.03.019

  View details for PubMedID 35568604

• An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging. Nature aging Sayed, N., Huang, Y., Nguyen, K., Krejciova-Rajaniemi, Z., Grawe, A. P., Gao, T., Tibshirani, R., Hastie, T., Alpert, A., Cui, L., Kuznetsova, T., Rosenberg-Hasson, Y., Ostan, R., Monti, D., Lehallier, B., Shen-Orr, S. S., Maecker, H. T., Dekker, C. L., Wyss-Coray, T., Franceschi, C., Jojic, V., Haddad, F., Montoya, J. G., Wu, J. C., Davis, M. M., Furman, D. 2021; 1: 598-615

  Abstract

  While many diseases of aging have been linked to the immunological system, immune metrics capable of identifying the most at-risk individuals are lacking. From the blood immunome of 1,001 individuals aged 8-96 years, we developed a deep-learning method based on patterns of systemic age-related inflammation. The resulting inflammatory clock of aging (iAge) tracked with multimorbidity, immunosenescence, frailty and cardiovascular aging, and is also associated with exceptional longevity in centenarians. The strongest contributor to iAge was the chemokine CXCL9, which was involved in cardiac aging, adverse cardiac remodeling and poor vascular function. Furthermore, aging endothelial cells in human and mice show loss of function, cellular senescence and hallmark phenotypes of arterial stiffness, all of which are reversed by silencing CXCL9. In conclusion, we identify a key role of CXCL9 in age-related chronic inflammation and derive a metric for multimorbidity that can be utilized for the early detection of age-related clinical phenotypes.

  View details for DOI 10.1038/s43587-021-00082-y

  View details for PubMedID 34888528

• Donor and Recipient Size Matching in Heart Transplantation with Predicted Heart and Lean Body Mass. Seminars in thoracic and cardiovascular surgery Miller, R. J., Hedman, K. n., Amsallem, M. n., Tulu, Z. n., Kent, W. n., Fatehi, A. n., Clarke, B. n., Heidenreich, P. n., Hiesinger, W. n., Khush, K. K., Teuteberg, J. n., Haddad, F. n. 2021

  Abstract

  Donor and recipient size matching during heart transplant can be assessed using weight or predicted heart mass (PHM) ratios. We developed sex-specific allomteric equations for PHM and predicted lean body mass (PLBM) using the United Kingdom Biobank (UKB) and evaluated their predictive value in the United Network of Organ Sharing (UNOS) database. Donor and recipient size matching was based on weight, PHM and PLBM ratios. PHM was calculated using the Multi-ethnic Study of Atherosclerosis and UKB equations. PLBM was calculated using the UKB and National Health and Nutrition Examination Survey (NHANES) equations. Relative prognostic utility was compared using multivariable Cox analysis, adjusted for predictors of one-year survival in the Scientific Registry of Transplant Recipients (SRTR) model. Of 53,648 adult patients in the UNOS database between 1996 and 2016, 6528 (12.2%) died within the first year. In multivariable analysis, undersized matches by any metric were associated with increased one-year mortality (all p<0.01). Oversized matches were at increased risk using PHM or PLBM (all p<0.01), but not weight ratio. There were significant differences in classification of size matching by weight or PHM in sex-mismatched donor-recipient pairs. A significant interaction was observed between pulmonary hypertension and donor undersizing (hazard ratio 1.15, p=0.026) suggesting increased risk of undersizing in pulmonary hypertension. Donor and recipient size matching with simplified PHM and PLBM offered an advantage over total body weight and may be more important for sex-mismatched donor-recipient pairs. Donor undersizing is associated with worse outcomes in patients with pulmonary hypertension.

  View details for DOI 10.1053/j.semtcvs.2021.01.001

  View details for PubMedID 33444763

• The Right Heart Network and Risk Stratification in Pulmonary Arterial Hypertension. Chest Haddad, F., Contrepois, K., Amsallem, M., Denault, A. Y., Bernardo, R. J., Jha, A., Taylor, S., Arthur Ataam, J., Mercier, O., Kouznetsova, T., Vonk Noordegraaf, A., Zamanian, R. T., Sweatt, A. J. 2021

  Abstract

  Prognosis in pulmonary arterial hypertension (PAH) is closely related to indexes of right ventricular function. A better understanding of their relationship may provide important implications for risk stratification in PAH.Can clinical network graphs inform risk stratification in PAH?The study cohort consisted of 231 patients with PAH followed up for a median of 7.1 years. An undirected, correlation network was used to visualize the relationship between clinical features in PAH. This network was enriched for right heart parameters and included N-terminal pro-hormone B-type natriuretic peptide (NT-proBNP), comprehensive echocardiographic parameters, and hemodynamics, as well as 6-min walk distance (6MWD), vital signs, laboratory data, and diffusing capacity for carbon monoxide (Dlco). Connectivity was assessed by using eigenvector and betweenness centrality to reflect global and regional connectivity, respectively. Cox proportional hazards regression was used to model event-free survival for the combined end point of death or lung transplantation.A network of closely intertwined features centered around NT-proBNP with 6MWD emerging as a secondary hub were identified. Less connected nodes included Dlco, systolic BP, albumin, and sodium. Over the follow-up period, death or transplantation occurred in 92 patients (39.8%). A strong prognostic model was achieved with a Harrell's C-index of 0.81 (0.77-0.85) when combining central right heart features (NT-proBNP and right ventricular end-systolic remodeling index) with 6MWD and less connected nodes (Dlco, systolic BP, albumin, sodium, sex, connective tissue disease etiology, and prostanoid therapy). When added to the baseline risk model, serial change in NT-proBNP significantly improved outcome prediction at 5 years (increase in C-statistic of 0.071 ± 0.024; P = .003).NT-proBNP emerged as a central hub in the intertwined PAH network. Connectivity analysis provides explainability for feature selection and combination in outcome models.

  View details for DOI 10.1016/j.chest.2021.10.045

  View details for PubMedID 34774527

• Cardiopulmonary Exercise Testing With Echocardiography to Assess Recovery in Patients With Ventricular Assist Devices. ASAIO journal (American Society for Artificial Internal Organs : 1992) Christle, J. W., Moneghetti, K. J., Duclos, S., Mueller, S., Moayedi, Y., Khush, K. K., Haddad, F., Hiesinger, W., Myers, J., Ashley, E. A., Teuteberg, J. J., Wheeler, M. T., Banerjee, D. 2021; 67 (10): 1134-1138

  Abstract

  The left ventricular assist device (LVAD) is an established treatment for select patients with end-stage heart failure. Some patients recovered and are considered for explantation. Assessing recovery involves exercise testing and echo ramping on full and minimal LVAD support. Combined cardiopulmonary exercise testing with simultaneous echo ramping (CPET-R) has not been well studied. Patients were included if they had CPET within the previous 6 months, were clinically stable, and had an INR >2.0 on the day of examination. Patients had CPET-R on two occasions within 14 days: (a) with LVAD at therapeutic speed and (b) with LVAD at the lowest speed possible. Six patients were between 29 and 75 years (two female). One patient did not complete a turn-down test due to evidence of ischemia on initial CPET-R subsequently confirmed as a significant coronary artery stenosis on angiography. There were no significant differences in CPET or echo metrics between LVAD speeds. Two patients were explanted due to presumed LV recovery and remained event free for 30 and 47 months, respectively. Serial CPET-R seems safe and feasible for the evaluation of LV and global function and may result in improved clinical decision making for LVAD explantation.

  View details for DOI 10.1097/MAT.0000000000001383

  View details for PubMedID 34570726

• Association of Subclinical Heart Maladaptation With the Pooled Cohort Equations to Prevent Heart Failure Risk Score for Incident Heart Failure. JAMA cardiology Cauwenberghs, N., Haddad, F., Kuznetsova, T. 2020

  Abstract

  Importance: The Pooled Cohort Equations to Prevent Heart Failure (PCP-HF) estimate the 10-year risk for symptomatic heart failure (HF) from routine clinical data. The PCP-HF score should detect asymptomatic individuals with cardiac maladaptation preceding HF symptoms for it to be a useful HF prediction tool in primary prevention.Objective: To assess the concordance between PCP-HF risk scoring and the presence of subclinical cardiac maladaptation in the community.Design, Setting, and Participants: This cross-sectional analysis included participants enrolled in the Flemish Study on Environment, Genes and Health Outcomes who underwent a clinical examination including echocardiography between May 2005 and January 2015. Participants younger than 30 years, older than 79 years, had prevalent cardiovascular disease, and/or had suboptimal echocardiographic imaging quality were excluded. Analysis began February 2020 and ended April 2020.Exposures: Ten-year HF risk as calculated from routine clinical data using the PCP-HF. Based on tertile limits, participants were categorized as having low (≤0.4%), intermediate (0.4%-2.4%), and high (≥2.4%) 10-year HF risk score.Main Outcomes and Measures: Echocardiographic profiles of subclinical heart remodeling and dysfunction.Results: A total of 1020 individuals were analyzed (mean [SD] age, 52.8 [11.4] years; 541 female [53.0%]). The prevalence of left ventricular (LV) remodeling and dysfunction was significantly higher from low to intermediate and high 10-year HF risk score. A doubling in 10-year HF risk score was associated with higher odds for LV concentric remodeling (odds ratio [OR], 1.48; 95% CI, 1.36-1.61; P<.001), LV hypertrophy (OR, 1.66; 95% CI, 1.51-1.83; P<.001), abnormal LV longitudinal strain (OR, 1.12; 95% CI, 1.05-1.19; P<.001), and LV diastolic dysfunction (OR, 2.28; 95% CI, 1.94-2.69; P<.001). Moreover, the PCP-HF score detected echocardiographic abnormalities with an accuracy of 74% (LV concentric remodeling), 78% (LV hypertrophy), 59% (abnormal LV longitudinal strain), and 87% (LV diastolic dysfunction). The likelihood of LV concentric remodeling, hypertrophy, and diastolic dysfunction were 3.1, 3.8, and 9.4 times higher in participants with high 10-year HF risk score than the average population risk, respectively (P<.001). Of all PCP-HF score components, age, body mass index, and systolic blood pressure were key correlates of echocardiographic abnormalities in multivariable-adjusted analysis.Conclusions and Relevance: PCP-HF risk scoring adequately detected individuals with subclinical heart maladaptation that precedes HF symptoms by years. Thus, it may be a valuable HF prediction tool in primary prevention.

  View details for DOI 10.1001/jamacardio.2020.5599

  View details for PubMedID 33175083

• Are pressure-volume loops relevant for hemodynamic assessment during ex vivo heart perfusion? JOURNAL OF HEART AND LUNG TRANSPLANTATION Guihaire, J., Haddad, F., Mercier, O. 2020; 39 (10): 1165–66

  View details for Web of Science ID 000574747400025

• Trends in Left Ventricular Ejection Fraction for Patients With a New Diagnosis of Heart Failure. Circulation. Heart failure Tisdale, R. L., Haddad, F., Kohsaka, S., Heidenreich, P. A. 2020: CIRCHEARTFAILURE119006743

  Abstract

  BACKGROUND: The left ventricular ejection fraction (LVEF) guides treatment of heart failure, yet this data has not been systematically collected in large data sets. We sought to characterize the epidemiology of incident heart failure using the initial LVEF.METHODS: We identified 219 537 patients in the Veterans Affairs system between 2011 and 2017 who had an LVEF documented within 365 days before and 30 days after the heart failure diagnosis date. LVEF was obtained from natural language processing from imaging and provider notes. In multivariate analysis, we assessed characteristics associated with having an initial LVEF <40%.RESULTS: Most patients were male and White; a plurality were within the 60 to 69 year age decile. A majority of patients had ischemic heart disease and a high burden of co-morbidities. Over time, presentation with an LVEF <40% became slightly less common, with a nadir in 2015. Presentation with an initial LVEF <40% was more common in younger patients, men, Black and Hispanic patients, an inpatient presentation, lower systolic blood pressure, lower pulse pressure, and higher heart rate. Ischemic heart disease, alcohol use disorder, peripheral arterial disease, and ventricular arrhythmias were associated with an initial LVEF <40%, while most other comorbid conditions (eg, atrial fibrillation, chronic obstructive pulmonary disease, malignancy) were more strongly associated with an initial LVEF >50%.CONCLUSIONS: For patients with heart failure, particularly at the extremes of age, an initial preserved LVEF is common. In addition to clinical characteristics, certain races (Black and Hispanic) were more likely to present with a reduced LVEF. Further studies are needed to determine if racial differences are due to patient or health systems issues such as access to care.

  View details for DOI 10.1161/CIRCHEARTFAILURE.119.006743

  View details for PubMedID 32867526

• The Project Baseline Health Study: a step towards a broader mission to map human health. NPJ digital medicine Arges, K., Assimes, T., Bajaj, V., Balu, S., Bashir, M. R., Beskow, L., Blanco, R., Califf, R., Campbell, P., Carin, L., Christian, V., Cousins, S., Das, M., Dockery, M., Douglas, P. S., Dunham, A., Eckstrand, J., Fleischmann, D., Ford, E., Fraulo, E., French, J., Gambhir, S. S., Ginsburg, G. S., Green, R. C., Haddad, F., Hernandez, A., Hernandez, J., Huang, E. S., Jaffe, G., King, D., Koweek, L. H., Langlotz, C., Liao, Y. J., Mahaffey, K. W., Marcom, K., Marks, W. J., Maron, D., McCabe, R., McCall, S., McCue, R., Mega, J., Miller, D., Muhlbaier, L. H., Munshi, R., Newby, L. K., Pak-Harvey, E., Patrick-Lake, B., Pencina, M., Peterson, E. D., Rodriguez, F., Shore, S., Shah, S., Shipes, S., Sledge, G., Spielman, S., Spitler, R., Schaack, T., Swamy, G., Willemink, M. J., Wong, C. A. 2020; 3 (1): 84

  Abstract

  The Project Baseline Health Study (PBHS) was launched to map human health through a comprehensive understanding of both the health of an individual and how it relates to the broader population. The study will contribute to the creation of a biomedical information system that accounts for the highly complex interplay of biological, behavioral, environmental, and social systems. The PBHS is a prospective, multicenter, longitudinal cohort study that aims to enroll thousands of participants with diverse backgrounds who are representative of the entire health spectrum. Enrolled participants will be evaluated serially using clinical, molecular, imaging, sensor, self-reported, behavioral, psychological, environmental, and other health-related measurements. An initial deeply phenotyped cohort will inform the development of a large, expanded virtual cohort. The PBHS will contribute to precision health and medicine by integrating state of the art testing, longitudinal monitoring and participant engagement, and by contributing to the development of an improved platform for data sharing and analysis.

  View details for DOI 10.1038/s41746-020-0290-y

  View details for PubMedID 33597683

• Quantifying the Influence of Wedge Pressure, Age, and Heart Rate on the Systolic Thresholds for Detection of Pulmonary Hypertension. Journal of the American Heart Association Amsallem, M., Tedford, R. J., Denault, A., Sweatt, A. J., Guihaire, J., Hedman, K., Peighambari, S., Kim, J. B., Li, X., Miller, R. J., Mercier, O., Fadel, E., Zamanian, R., Haddad, F. 2020: e016265

  Abstract

  Background The strong linear relation between mean (MPAP) and systolic (SPAP) pulmonary arterial pressure (eg, SPAP=1.62*MPAP) has been mainly reported in precapillary pulmonary hypertension. This study sought to quantify the influence of pulmonary arterial wedge pressure (PAWP), heart rate, and age on the MPAP-SPAP relation. Methods and Results An allometric equation relating invasive MPAP and SPAP was developed in 1135 patients with pulmonary arterial hypertension, advanced lung disease, chronic thromboembolic pulmonary hypertension, or left heart failure. The equation was validated in 60885 patients from the United Network for Organ Sharing (UNOS) database referred for heart and/or lung transplant. The MPAP/SPAP longitudinal stability was assessed in pulmonary arterial hypertension with repeated right heart catheterization. The equation obtained was SPAP=1.39*MPAP*PAWP-0.07*(60/heart rate)0.12*age0.08 (P<0.001). It was validated in the UNOS cohort (R2=0.93, P<0.001), regardless of the type of organ(s) patients were listed for (mean bias [-1.96SD; 1.96SD] was 0.94 [-8.00; 9.88] for heart, 1.34 [-7.81; 10.49] for lung and 0.25 [-16.74; 17.24] mmHg for heart-lung recipients). Thresholds of SPAP for MPAP=25 and 20mmHg were lower in patients with higher PAWP (37.2 and 29.8mmHg) than in those with pulmonary arterial hypertension (40.1 and 32.0mmHg). In 186 patients with pulmonary arterial hypertension, the predicted MPAP/SPAP was stable over time (0.63±0.03 at baseline and follow-up catheterization, P=0.43). Conclusions This study quantifies the impact of PAWP, and to a lesser extent heart rate and age, on the MPAP-SPAP relation, supporting lower SPAP thresholds for pulmonary hypertension diagnosis in patients with higher PAWP for echocardiography-based epidemiological studies.

  View details for DOI 10.1161/JAHA.119.016265

  View details for PubMedID 32419583

• Are pressure-volume loops relevant for hemodynamic assessment during ex vivo heart perfusion? The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Guihaire, J., Haddad, F., Mercier, O. 2020

  View details for DOI 10.1016/j.healun.2020.04.023

  View details for PubMedID 32418863

• Subclinical left atrial dysfunction profiles for prediction of cardiac outcome in the general population. Journal of hypertension Cauwenberghs, N. n., Haddad, F. n., Sabovčik, F. n., Kobayashi, Y. n., Amsallem, M. n., Morris, D. A., Voigt, J. U., Kuznetsova, T. n. 2020

  Abstract

  Echocardiographic definitions of subclinical left atrial dysfunction based on epidemiological data remain scarce. In this population study, we derived outcome-driven thresholds for echocardiographic left atrial function parameters discriminating between normal and abnormal values.In 1306 individuals (mean age, 50.7 years; 51.6% women), we echocardiographically assessed left atrial function and LV global longitudinal strain. We derived cut-off values for left atrial emptying fraction (LAEF), left atrial function index (LAFI) and left atrial reservoir strain (LARS) to define left atrial dysfunction using receiver-operating curve threshold analysis. Main outcome was the incidence of cardiac events and atrial fibrillation (AFib) on average 8.5 years later.For prediction of new-onset AFib, left atrial cut-offs yielding the best balance between sensitivity and specificity (highest Youden index) were: LAEF less than 55%, LAFI less than 40.5 and LARS less than 23%. Applying these cut-offs, abnormal LAEF, LAFI and LARS were, respectively, present in 27, 37.1 and 18.1% of the cohort. Abnormal LARS (<23%) was independently associated with higher risk for cardiac events and new-onset AFib (P ≤ 0.012). Participants with both abnormal LAEF and LARS presented a significantly higher risk to develop cardiac events (hazard ratio: 2.10; P = 0.014) and AFib (hazard ratio: 6.45; P = 0.0036) than normal counterparts. The concomitant presence of an impaired LARS and LV global longitudinal strain improved prognostic accuracy beyond a clinical risk model for cardiac events and the CHARGE-AF Risk Score for AFib.Left atrial dysfunction based on outcome-driven thresholds predicted cardiac events and AFib independent of conventional risk factors. Screening for subclinical left atrial and LV systolic dysfunction may enhance cardiac disease prediction in the community.

  View details for DOI 10.1097/HJH.0000000000002572

  View details for PubMedID 32649644

• Targeted Proteomics of Right Heart Adaptation to Pulmonary Arterial Hypertension. The European respiratory journal Amsallem, M. n., Sweatt, A. J., Arthur Ataam, J. n., Guihaire, J. n., Lecerf, F. n., Lambert, M. n., Ghigna, M. R., Ali, M. K., Mao, Y. n., Fadel, E. n., Rabinovitch, M. n., de Jesus Perez, V. n., Spiekerkoetter, E. n., Mercier, O. n., Haddad, F. n., Zamanian, R. T. 2020

  Abstract

  No prior proteomic screening study has centered on the right ventricle (RV) in pulmonary arterial hypertension (PAH). This study investigates the circulating proteomic profile associated with right heart maladaptive phenotype (RHMP) in PAH.Plasma proteomic profiling was performed using multiplex immunoassay in 121 PAH patients (discovery cohort) and 76 patients (validation cohort). The association between proteomic markers and RHMP (defined by the Mayo right heart score [combining RV strain, New York Heart Association NYHA class and NT-proBNP] and Stanford score [RV end-systolic remodelling index, NYHA and NT-proBNP]) was assessed by partial least squares regression. Biomarkers expressions were measured in RV samples from PAH patients and controls, and pulmonary artery banding (PAB) mice.High levels of hepatic growth factor (HGF), stem cell growth factor beta, nerve growth factor and stromal derived factor-1 were associated with worse Mayo and Stanford scores independently from pulmonary resistance or pressure in both cohorts (the validation cohort had more severe disease features: lower cardiac index and higher NT-proBNP). In both cohorts, HGF added value to the REVEAL score in the prediction of death, transplant, or hospitalisation at 3 years. RV expression levels of HGF and its receptor c-Met were higher in end-stage PAH patients than controls, and in PAB mice than shams.High plasma HGF levels are associated with RHMP and predictive of 3-year clinical worsening. Both HGF and c-Met RV expression levels are increased in PAH. Assessing plasma HGF levels might identify patients at risk for heart failure who warrant closer follow-up and intensified therapy.

  View details for DOI 10.1183/13993003.02428-2020

  View details for PubMedID 33334941

• The impact of prescribed fire versus wildfire on the immune and cardiovascular systems of children ALLERGY Prunicki, M., Kelsey, R., Lee, J., Zhou, X., Smith, E., Haddad, F., Wu, J., Nadeau, K. 2019; 74 (10): 1989–91

  View details for DOI 10.1111/all.13825

  View details for Web of Science ID 000493013400015

• Outcomes in patients undergoing cardiac retransplantation: A propensity matched cohort analysis of the UNOS Registry. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Miller, R. J., Clarke, B. A., Howlett, J. G., Khush, K. K., Teuteberg, J. J., Haddad, F. 2019

  Abstract

  BACKGROUND: Cardiac retransplantation accounts for approximately 3% of cardiac transplantation and is considered a risk factor for increased mortality. However, factors inherent to retransplantation including previous sternotomy, sensitization, and renal dysfunction may account for the increased mortality. We assessed whether retransplantation was associated with all-cause mortality after adjusting for such patient risk factors.METHODS: We conducted a retrospective cohort study of adult and pediatric patients enrolled in the United Network for Organ Sharing database. We identified patients undergoing cardiac retransplantation based on transplant listing diagnosis and history of previous transplant. We used propensity-score matching to identify a matched cohort undergoing initial heart transplantation.RESULTS: In total, 62,112 heart transplant recipients were identified, with a mean age 46.6 ± 19.1 years. Of these, 2,202 (3.4%) underwent late cardiac retransplantation (>1 year after initial transplant and not for acute rejection). Compared with a matched group of patients undergoing initial heart transplantation, patients undergoing late retransplantation had comparable rates of all-cause mortality at 1 year (13.6% vs 13.8%, p = 0.733). In addition, overall mortality was not significantly different after matching (unadjusted hazard ratio [HR] 1.08, p = 0.084). In contrast, patients undergoing retransplantation within 1 year of initial transplant or for acute rejection remained at increased risk of mortality post-transplant after similar matching (unadjusted HR 1.79, p < 0.001).CONCLUSIONS: After matching for comorbidities, late retransplantation in the adult population was not associated with an increase in all-cause mortality. Our findings highlight the importance of assessing indication acuity and comorbid conditions when considering retransplant candidacy.

  View details for DOI 10.1016/j.healun.2019.07.001

  View details for PubMedID 31378576

• Blood pressure in athletic preparticipation evaluation and the implication for cardiac remodelling. Heart (British Cardiac Society) Hedman, K., Moneghetti, K. J., Christle, J. W., Bagherzadeh, S. P., Amsallem, M., Ashley, E., Froelicher, V., Haddad, F. 2019

  Abstract

  OBJECTIVES: To explore blood pressure (BP) in athletes at preparticipation evaluation (PPE) in the context of recently updated US and European hypertension guidelines, and to determine the relationship between BP and left ventricular (LV) remodelling.METHODS: In this retrospective study, athletes aged 13-35 years who underwent PPE facilitated by the Stanford Sports Cardiology programme were considered. Resting BP was measured in both arms; repeated once if ≥140/90mm Hg. Athletes with abnormal ECGs or known hypertension were excluded. BP was categorised per US/European hypertension guidelines. In a separate cohort of athletes undergoing routine PPE echocardiography, we explored the relationship between BP and LV remodelling (LV mass, mass/volume ratio, sphericity index) and LV function.RESULTS: In cohort 1 (n=2733, 65.5% male), 34.3% of athletes exceeded US hypertension thresholds. Male sex (B=3.17, p<0.001), body mass index (BMI) (B=0.80, p<0.001) and height (B=0.25, p<0.001) were the strongest independent correlates of systolic BP. In the second cohort (n=304, ages 17-26), systolic BP was an independent correlate of LV mass/volume ratio (B=0.002, p=0.001). LV longitudinal strain was similar across BP categories, while higher BP was associated with slower early diastolic relaxation.CONCLUSION: In a large contemporary cohort of athletes, one-third presented with BP levels above the current US guidelines' thresholds for hypertension, highlighting that lowering the BP thresholds at PPE warrants careful consideration as well as efforts to standardise measurements. Higher systolic BP was associated with male sex, BMI and height and with LV remodelling and diastolic function, suggesting elevated BP in athletes during PPE may signify a clinically relevant condition.

  View details for DOI 10.1136/heartjnl-2019-314815

  View details for PubMedID 31142598

• A longitudinal big data approach for precision health NATURE MEDICINE Rose, S., Contrepois, K., Moneghetti, K. J., Zhou, W., Mishra, T., Mataraso, S., Dagan-Rosenfeld, O., Ganz, A. B., Dunn, J., Hornburg, D., Rego, S., Perelman, D., Ahadi, S., Sailani, M., Zhou, Y., Leopold, S. R., Chen, J., Ashland, M., Christle, J. W., Avina, M., Limcaoco, P., Ruiz, C., Tan, M., Butte, A. J., Weinstock, G. M., Slavich, G. M., Sodergren, E., McLaughlin, T. L., Haddad, F., Snyder, M. P. 2019; 25 (5): 792-+

  View details for DOI 10.1038/s41591-019-0414-6

  View details for Web of Science ID 000468247800023

• Right ventricular mitochondrial respiratory function in a piglet model of chronic pulmonary hypertension. The Journal of thoracic and cardiovascular surgery Noly, P., Piquereau, J., Coblence, M., Ataam, J. A., Guihaire, J., Rucker-Martin, C., Decante, B., Haddad, F., Fadel, E., Mercier, O. 2019

  Abstract

  OBJECTIVE: We aimed to assess the mitochondrial respiratory capacities in the right ventricle in the setting of ventricular remodeling induced by pressure overload.METHODS: Chronic thromboembolic pulmonary hypertension was induced in 8 piglets over a 12-week period (chronic thromboembolic pulmonary hypertension model). Right ventricular remodeling, right ventricular function, and mitochondrial respiratory function were assessed at 3, 6, and 12weeks after induction of pulmonary hypertension and were compared with sham animals (n=5). Right ventricular cardiomyocytes and mitochondrial structure were studied in transmission electronic microscopy after 12weeks.RESULTS: As of 3weeks, chronic pressure overload induced right ventricular dilatation, right ventricular hypertrophy, and right ventricular dysfunction. Maladaptive remodeling in the chronic thromboembolic pulmonary hypertension model was confirmed by the decrease of right ventricular pulmonary artery coupling and right fractional area change. Mitochondrial functional assays in permeabilized right ventricular myocardial fibers revealed that oxidative phosphorylation capacities (complex I, complex II, and IV of the mitochondrial respiratory chain) were degraded. Furthermore, no change in substrate preference of mitochondria was found in the overloaded right ventricle. There was a good correlation between maximal mitochondrial oxygen consumption rate and right ventricular pulmonary artery coupling (Pearson coefficient r=0.83). Transmission electronic microscopy analysis showed that the composition of cardiomyocytes was no different between the chronic thromboembolic pulmonary hypertension group and the sham group. However, mitochondrial structure anomalies were significantly increased in the chronic thromboembolic pulmonary hypertension group.CONCLUSIONS: Mitochondrial respiratory function impairment is involved early in the development of right ventricular dysfunction in a piglet model of chronic thromboembolic pulmonary hypertension. Underlying mechanisms remain to be elucidated.

  View details for PubMedID 30979421

• Circulating Biomarkers Predicting Longitudinal Changes in Left Ventricular Structure and Function in a General Population. Journal of the American Heart Association Cauwenberghs, N., Ravassa, S., Thijs, L., Haddad, F., Yang, W., Wei, F., Lopez, B., Gonzalez, A., Diez, J., Staessen, J. A., Kuznetsova, T. 2019; 8 (2): e010430

  Abstract

  Background Serial imaging studies in the general population remain important to evaluate the usefulness of pathophysiologically relevant biomarkers in predicting progression of left ventricular (LV) remodeling and dysfunction. Here, we assessed in a general population whether these circulating biomarkers at baseline predict longitudinal changes in LV structure and function. Methods and Results In 592 participants (mean age, 50.8years; 51.4% women; 40.5% hypertensive), we derived echocardiographic indexes reflecting LV structure and function at baseline and after 4.7years. At baseline, we measured alkaline phosphatase, markers of collagen turnover (procollagen type I, C-terminal telopeptide, matrix metalloproteinase-1) and high-sensitivity cardiac troponin T. We regressed longitudinal changes in LV indexes on baseline biomarker levels and reported standardized effect sizes as a fraction of the standard deviation of LV change. After full adjustment, a decline in LV longitudinal strain (-14.2%) and increase in E/e' ratio over time (+18.9%; P≤0.019) was associated with higher alkaline phosphatase activity at baseline. Furthermore, longitudinal strain decreased with higher levels of collagen I production and degradation at baseline (procollagen type I, -14.2%; C-terminal telopeptide, -16.4%; P≤0.029). An increase in E/e' ratio over time was borderline associated with lower matrix metalloproteinase-1 (+9.8%) and lower matrix metalloproteinase-1/tissue inhibitor of metalloproteinase-1 ratio (+11.9%; P≤0.041). Higher high-sensitivity cardiac troponin T levels at baseline correlated significantly with an increase in relative wall thickness (+23.1%) and LV mass index (+18.3%) during follow-up ( P≤0.035). Conclusions We identified a set of biomarkers predicting adverse changes in LV structure and function over time. Circulating biomarkers reflecting LV stiffness, injury, and collagen composition might improve the identification of subjects at risk for subclinical cardiac maladaptation.

  View details for PubMedID 30638123

• Discovery of Distinct Immune Phenotypes Using Machine Learning in Pulmonary Arterial Hypertension. Circulation research Sweatt, A. J., Hedlin, H. K., Balasubramanian, V. n., Hsi, A. n., Blum, L. K., Robinson, W. H., Haddad, F. n., Hickey, P. M., Condliffe, R. A., Lawrie, A. n., Nicolls, M. R., Rabinovitch, M. n., Khatri, P. n., Zamanian, R. T. 2019

  Abstract

  Accumulating evidence implicates inflammation in pulmonary arterial hypertension (PAH) and therapies targeting immunity are under investigation, though it remains unknown if distinct immune phenotypes exist.Identify PAH immune phenotypes based on unsupervised analysis of blood proteomic profiles.In a prospective observational study of Group 1 PAH patients evaluated at Stanford University (discovery cohort, n=281) and University of Sheffield (validation cohort, n=104) between 2008-2014, we measured a circulating proteomic panel of 48 cytokines, chemokines, and factors using multiplex immunoassay. Unsupervised machine learning (consensus clustering) was applied in both cohorts independently to classify patients into proteomic immune clusters, without guidance from clinical features. To identify central proteins in each cluster, we performed partial correlation network analysis. Clinical characteristics and outcomes were subsequently compared across clusters. Four PAH clusters with distinct proteomic immune profiles were identified in the discovery cohort. Cluster 2 (n=109) had low cytokine levels similar to controls. Other clusters had unique sets of upregulated proteins central to immune networks- cluster 1 (n=58)(TRAIL, CCL5, CCL7, CCL4, MIF), cluster 3 (n=77)(IL-12, IL-17, IL-10, IL-7, VEGF), and cluster 4 (n=37)(IL-8, IL-4, PDGF-β, IL-6, CCL11). Demographics, PAH etiologies, comorbidities, and medications were similar across clusters. Non-invasive and hemodynamic surrogates of clinical risk identified cluster 1 as high-risk and cluster 3 as low-risk groups. Five-year transplant-free survival rates were unfavorable for cluster 1 (47.6%, CI 35.4-64.1%) and favorable for cluster 3 (82.4%, CI 72.0-94.3%)(across-cluster p<0.001). Findings were replicated in the validation cohort, where machine learning classified four immune clusters with comparable proteomic, clinical, and prognostic features.Blood cytokine profiles distinguish PAH immune phenotypes with differing clinical risk that are independent of World Health Organization Group 1 subtypes. These phenotypes could inform mechanistic studies of disease pathobiology and provide a framework to examine patient responses to emerging therapies targeting immunity.

  View details for PubMedID 30661465

• Pathophysiology of the right ventricle andof the pulmonary circulation in pulmonary hypertension: an update. The European respiratory journal Vonk Noordegraaf, A., Chin, K. M., Haddad, F., Hassoun, P. M., Hemnes, A. R., Hopkins, S. R., Kawut, S. M., Langleben, D., Lumens, J., Naeije, R. 2018

  Abstract

  The function of the right ventricle determines the fate of patients with pulmonary hypertension. Since right heart failure is the consequence of increased afterload, a full physiological description of the cardiopulmonary unit consisting of both the right ventricle and pulmonary vascular system is required to interpret clinical data correctly. Here, we provide such a description of the unit and its components, including the functional interactions between the right ventricle and its load. This physiological description is used to provide a framework for the interpretation of right heart catheterisation data as well as imaging data of the right ventricle obtained by echocardiography or magnetic resonance imaging. Finally, an update is provided on the latest insights in the pathobiology of right ventricular failure, including key pathways of molecular adaptation of the pressure overloaded right ventricle. Based on these outcomes, future directions for research are proposed.

  View details for PubMedID 30545976

• The Incremental Value of Right Ventricular Size and Strain in the Risk Assessment of Right Heart Failure Post - Left Ventricular Assist Device Implantation. Journal of cardiac failure Aymami, M., Amsallem, M., Adams, J., Sallam, K., Moneghetti, K., Wheeler, M., Hiesinger, W., Teuteberg, J., Weisshaar, D., Verhoye, J., Woo, Y. J., Ha, R., Haddad, F., Banerjee, D. 2018; 24 (12): 823–32

  Abstract

  BACKGROUND: Right heart failure (RHF) after left ventricular assist device (LVAD) implantation is associated with high morbidity and mortality. Existing risk scores include semiquantitative evaluation of right ventricular (RV) dysfunction. This study aimed to determine whether quantitative evaluation of both RV size and function improve risk stratification for RHF after LVAD implantation beyond validated scores.METHODS AND RESULTS: From 2009 to 2015, 158 patients who underwent implantation of continuous-flow devices who had complete echocardiographic and hemodynamic data were included. Quantitative RV parameters included RV end-diastolic (RVEDAI) and end-systolic area index, RV free-wall longitudinal strain (RVLS), fractional area change, tricuspid annular plane systolic excursion, and right atrial area and pressure. Independent correlates of early RHF (<30 days) were determined with the use of logistic regression analysis. Mean age was 56 ± 13 years, with 79% male; 49% had INTERMACS profiles ≤2. RHF occurred in 60 patients (38%), with 20 (13%) requiring right ventricular assist device. On multivariate analysis, INTERMACS profiles (adjusted odds ratio 2.38 [95% confidence interval [CI] 1.47-3.85]), RVEDAI (1.61 [1.08-2.32]), and RVLS (2.72 [1.65-4.51]) were independent correlates of RHF (all P < .05). Both RVLS and RVEDAI were incremental to validated risk scores (including the EUROMACS score) for early RHF after LVAD (all P < .01).CONCLUSIONS: RV end-diastolic and strain are complementary prognostic markers of RHF after LVAD implantation.

  View details for PubMedID 30539717

• Forgotten No More: A Focused Update on the Right Ventricle in CardiovascularDisease. JACC. Heart failure Amsallem, M., Mercier, O., Kobayashi, Y., Moneghetti, K., Haddad, F. 2018

  Abstract

  In the last decade, there has been renewed interest in the study of the right ventricle. It is now well established that right ventricular function is a strong predictor of mortality, not only in heart failure but also in pulmonary hypertension, congenital heart disease, and cardiothoracic surgery. The right ventricle is part of a cardiopulmonary unit with connections to the pulmonary circulation, venous return, atria, and left ventricle. In this context, ventriculoarterial coupling, interventricular interactions, and pericardial constraint become important to understand right ventricular adaptation to injury or abnormal loading conditions. This state-of-the-art review summarizes major advances that occurred in the field of right ventricular research over the last decade. The first section focuses on right ventricular physiology and pulmonary circulation. The second section discusses the emerging data on right ventricular phenotyping, highlighting the importance of myocardial deformation (strain) imaging and assessment of end-systolic dimensions. The third section reviews recent clinical trials involving patients at risk for or with established right ventricular failure, focusing on beta blockade, phosphodiesterase inhibition, and mechanical support of the failing right heart. The final section presents a perspective on active areas of research that are most likely to translate in clinical practice in the next decade.

  View details for PubMedID 30316939

• Right ventricular load adaptability metrics in patients undergoing left ventricular assist device implantation. The Journal of thoracic and cardiovascular surgery Amsallem, M., Aymami, M., Hiesinger, W., Zeigler, S., Moneghetti, K., Marques, M., Teuteberg, J., Ha, R., Banerjee, D., Haddad, F. 2018

  Abstract

  OBJECTIVE: Several right load adaptability metrics have been proposed as predictors of right heart failure (RHF) following left ventricular assist device implantation. This study sought to validate and compare the prognostic value of these indices.METHODS: This retrospective study included 194 patients undergoing continuous-flow left ventricular assist device implantation. The primary end point was unplanned right atrial assist device (RVAD) need within 30days after left ventricular assist device implantation; the secondary end points included clinical RHF syndrome without RVAD need and the composite of RHF or RVAD need. Load adaptability indices or interventricular ratios were divided into surrogates of ventriculoarterial coupling (RV area change:end-systolic area), indices reflecting adaptation proportionality (Dandel's index=tricuspid regurgitation velocity-time integral normalized for average RV radius in diastole or systole), and simple ratios (eg, pulse pressure:right atrial pressure or right arterial pressure:pulmonary arterial wedge pressure).RESULTS: Mean age was 55±13years with 77% of men. RHF occurred in 75 patients with 30 patients requiring RVAD implantation. Among right heart metrics, right arterial pressure (normalized odd ratio, 1.62; 95% confidence interval, 1.15-2.38), right arterial pressure:pulmonary arterial wedge pressure (normalized odds ratio, 1.59; 95% confidence interval, 1.08-2.32) and pulse pressure:right arterial pressure<2.0 (normalized odds ratio, 2.56; 95% confidence interval, 1.16-5.56) were associated with RVAD need (all P values<.02). These 3 metrics significantly added incremental prognostic value to the Interagency Registry for Mechanically Assisted Circulatory Support classification score in a similar range, whereas only RAP was incremental to the Michigan score. Correlates of RHF not requiring RVAD included RV end-systolic area index and the Dandel indices, which provided similar incremental value to the Interagency Registry for Mechanically Assisted Circulatory Support, Michigan, and European Registry for Patients with Mechanical Circulatory Support scores.CONCLUSIONS: Although associated with outcome, right load adaptability indices do not appear to provide strong incremental value when compared with simple metrics.

  View details for PubMedID 30482529

• Optimizing right ventricular focused four-chamber views using three-dimensional imaging, a comparative magnetic resonance based study. The international journal of cardiovascular imaging Amsallem, M., Lu, H., Tang, X., Do Couto Francisco, N. L., Kobayashi, Y., Moneghetti, K., Shiran, H., Rogers, I., Schnittger, I., Liang, D., Haddad, F. 2018

  Abstract

  Obtaining focused right ventricular (RV) apical view remains challenging using conventional two-dimensional (2D) echocardiography. This study main objective was to determine whether measurements from RV focused views derived from three-dimensional (3D) echocardiography (3D-RV-focused) are closely related to measurements from magnetic resonance (CMR). A first cohort of 47 patients underwent 3D echocardiography and CMR imaging within 2h of each other. A second cohort of 25 patients had repeat 3D echocardiography to determine the test-retest characteristics; and evaluate the bias associated with unfocused RV views. Tomographic views were extracted from the 3D dataset: RV focused views were obtained using the maximal RV diameter in the transverse plane, and unfocused views from a smaller transverse diameter enabling visualization of the tricuspid valve opening. Measures derived using the 3D-RV-focused view were strongly associated with CMR measurements. Among functional metrics, the strongest association was between RV fractional area change (RVFAC) and ejection fraction (RVEF) (r=0.92) while tricuspid annular plane systolic excursion moderately correlated with RVEF (r=0.47), all p<0.001. Among RV size measures, the strongest association was found between RV end-systolic area (RVESA) and volume (r=0.87, p<0.001). RV unfocused views led on average to 10% underestimation of RVESA. The 3D-RV-focused method had acceptable test-retest characteristics with a coefficient of variation of 10% for RVESA and 11% for RVFAC. Deriving standardized RV focused views using 3D echocardiography strongly relates to CMR-derived measures and may improve reproducibility in RV 2D measurements.

  View details for PubMedID 29654480

• Long-term prognostic value of invasive and non-invasive measures early after heart transplantation. International journal of cardiology Kobayashi, Y. n., Kobayashi, Y. n., Yang, H. M., Bouajila, S. n., Luikart, H. n., Nishi, T. n., Choi, D. H., Schnittger, I. n., Valantine, H. A., Khush, K. K., Yeung, A. C., Haddad, F. n., Fearon, W. F. 2018; 260: 31–35

  Abstract

  Invasively assessed coronary microvascular resistance early after heart transplantation predicts worse long-term outcome; however, little is known about the relationship between microvascular resistance, left ventricular function and outcomes in this setting.A total of 100 cardiac transplant recipients had fractional flow reserve (FFR) and the index of microcirculatory resistance (IMR) measured in the left anterior descending artery and echocardiographic assessment of left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) at 1 year after heart transplantation. The primary endpoint was the composite of death and retransplantation occurring beyond the first post-operative year.The mean FFR, IMR, LVEF, and GLS values at 1 year were 0.87 ± 0.06, 21.3 ± 17.3, 60.4 ± 5.4%, and 14.2 ± 2.4%, respectively. FFR and IMR had no significant correlation with LVEF and GLS. During a mean follow-up of 6.7 ± 4.2 years, the primary endpoint occurred in 24 patients (24.0%). By ROC curve analysis, IMR = 19.3 and GLS = 13.3% were the best cutoff values for predicting death or retransplantation. Cumulative event-free survival was significantly lower in patients with higher IMR (log-rank p = 0.02) and lower GLS (log-rank p < 0.001). Cumulative event-free survival can be further stratified by the combination of IMR and GLS (long-rank p < 0.001). By multivariable Cox proportional hazards model, higher IMR and lower GLS were independently associated with long-term death or retransplantation (elevated IMR, hazard ratio = 2.50, p = 0.04 and reduced GLS, hazard ratio = 3.79, p = 0.003, respectively).Invasively assessed IMR does not correlate with GLS at 1 year after heart transplantation. IMR and GLS determined at 1 year may be used as independent predictors of late death or retransplantation.

  View details for PubMedID 29622448

• Early Development of Right Ventricular Ischemic Lesions in a Novel Large Animal Model of Acute Right Heart Failure in Chronic Thromboembolic Pulmonary Hypertension. Journal of cardiac failure Boulate, D. n., Arthur Ataam, J. n., Connolly, A. J., Giraldeau, G. n., Amsallem, M. n., Decante, B. n., Lamrani, L. n., Fadel, E. n., Dorfmuller, P. n., Perros, F. n., Haddad, F. n., Mercier, O. n. 2017

  Abstract

  Our aim was to develop a model of acute right heart failure (ARHF) in the setting of pulmonary hypertension and to characterize acute right ventricular lesions that develop early after hemodynamic restoration.We used a described piglet model of chronic pulmonary hypertension (cPH) induced by pulmonary artery occlusions. We induced ARHF in animals with cPH (ARHF-cPH group, n = 9) by volume loading and iterative acute pulmonary embolism until hemodynamic compromise followed by dobutamine infusion for hemodynamic restoration before sacrifice for right ventricular tissue evaluation. The median duration of ARHF before sacrifice was 162 (135-189) minutes. Although ventriculoarterial coupling (measured with multibeat pressure-volume loops) and stroke volume decreased after iterative pulmonary embolism and improved with dobutamine, relative pulmonary to systemic pressure increased by 2-fold and remained similarly increased with dobutamine. Circulating high-sensitivity troponin I increased after hemodynamic restoration. We found an increase in right ventricular subendocardial and subepicardial focal ischemic lesions and in expression of autophagy-related protein LC3-II (Western blot) in the ARHF-cPH group compared with the cPH (n = 5) and control (n = 5) groups.We developed and phenotyped a novel large animal model of ARHF on cPH in which right ventricular ischemic lesions were observed early after hemodynamic restoration.

  View details for PubMedID 28801076

• Noninvasive Imaging in the Assessment of the Cardiopulmonary Vascular Unit CIRCULATION Noordegraaf, A. V., Haddad, F., Bogaard, H. J., Hassoun, P. M. 2015; 131 (10): 899-913

  View details for DOI 10.1161/CIRCULATI0NAHA.114.006972

  View details for Web of Science ID 000350771700013

• Experimental Models of Right Heart Failure: A Window for Translational Research in Pulmonary Hypertension SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE Guihaire, J., Bogaard, H. J., Flecher, E., Noly, P., Mercier, O., Haddad, F., Fadel, E. 2013; 34 (5): 689-699

  Abstract

  The right ventricle (RV) faces major changes in loading conditions associated with cardiovascular and pulmonary vascular disorders. Despite major pharmacological advances since the last decade, pulmonary arterial hypertension remains a deadly disease mainly secondary to the development of right ventricular failure (RVF). Several experimental models of RVF have been developed over the past three decades providing a particular insight in RV pathophysiology. Mechanisms involved in the transition from RV adaptive hypertrophy to maladaptive remodeling and failure in conditions of chronic RV pressure or volume overload are of a great interest but not yet completely understood. Further investigations are needed to find new therapeutic approaches for RVF. Current animal models and emerging concepts of translational RV research will be detailed in this review.

  View details for DOI 10.1055/s-0033-1355444

  View details for Web of Science ID 000324401900013

  View details for PubMedID 24037635

• Effects of Intracoronary CD34(+) Stem Cell Transplantation in Nonischemic Dilated Cardiomyopathy Patients 5-Year Follow-Up CIRCULATION RESEARCH Vrtovec, B., Poglajen, G., Lezaic, L., Sever, M., Domanovic, D., Cernelc, P., Socan, A., Schrepfer, S., Torre-Amione, G., Haddad, F., Wu, J. C. 2013; 112 (1): 165-173

  Abstract

  CD34+ transplantation in dilated cardiomyopathy was associated with short-term improvement in left ventricular ejection fraction and exercise tolerance.We investigated long-term effects of intracoronary CD34+ cell transplantation in dilated cardiomyopathy and the relationship between intramyocardial cell homing and clinical response.Of 110 dilated cardiomyopathy patients, 55 were randomized to receive CD34+ stem cell transplantation (SC group) and 55 received no cell therapy (controls). In the SC group, CD34+ cells were mobilized by granulocyte colony-stimulating factor and collected via apheresis. Patients underwent myocardial scintigraphy and cells were injected in the artery supplying segments with the greatest perfusion defect. At baseline, 2 groups did not differ in age, sex, left ventricular ejection fraction, or N-terminal B-type natriuretic peptide levels. At 5 years, stem cell therapy was associated with increased left ventricular ejection fraction (from 24.3 ± 6.5% to 30.0 ± 5.1%; P=0.02), increased 6-minute walk distance (from 344 ± 90 m to 477 ± 130 m; P<0.001), and decreased N-terminal B-type natriuretic peptide (from 2322 ± 1234 pg/mL to 1011 ± 893 pg/mL; P<0.01). Left ventricular ejection fraction improvement was more significant in patients with higher myocardial homing of injected cells. During follow-up, 27 (25%) patients died and 9 (8%) underwent heart transplantation. Of the 27 deaths, 13 were attributed to pump failure and 14 were attributed to sudden cardiac death. Total mortality was lower in the SC group (14%) than in controls (35%; P=0.01). The same was true of pump failure (5% vs. 18%; P=0.03), but not of sudden cardiac death (9% vs. 16%; P=0.39).Intracoronary stem cell transplantation may be associated with improved ventricular function, exercise tolerance, and long-term survival in patients with dilated cardiomyopathy. Higher intramyocardial homing is associated with better stem cell therapy response.

  View details for DOI 10.1161/CIRCRESAHA.112.276519

  View details for Web of Science ID 000313053000021

  View details for PubMedID 23065358

• Sudden death in myotonic dystrophy NEW ENGLAND JOURNAL OF MEDICINE Vrtovec, B., Haddad, F. 2008; 359 (15): 1628-1628

  View details for Web of Science ID 000259903100022

  View details for PubMedID 18846683

• Twenty-year survivors of heart transplantation at Stanford University AMERICAN JOURNAL OF TRANSPLANTATION Deuse, T., Haddad, F., Pham, M., Hunt, S., Valantine, H., BATES, M. J., Mallidi, H. R., Oyer, P. E., Robbins, R. C., Reitz, B. A. 2008; 8 (9): 1769-1774

  Abstract

  Human heart transplantation started 40 years ago. Medical records of all cardiac transplants performed at Stanford were reviewed. A total of 1446 heart transplantations have been performed between January 1968 and December 2007 with an increase of 1-year survival from 43.1% to 90.2%. Sixty patients who were transplanted between 1968 and 1987 were identified who survived at least 20 years. Twenty-year survivors had a mean age at transplant of 29.4 +/- 13.6 years. Rejection-free and infection-free 1-year survivals were 14.3% and 18.8%, respectively. At their last follow-up, 86.7% of long-term survivors were treated for hypertension, 28.3% showed chronic renal dysfunction, 6.7% required hemodialysis, 10% were status postkidney transplantation, 13.3% were treated for diabetes mellitus, 36.7% had a history of malignancy and 43.3% had evidence of allograft vasculopathy. The half-life conditional on survival to 20 years was 28.1 years. Eleven patients received a second heart transplant after 11.9 +/- 8.0 years. The most common causes of death were allograft vasculopathy (56.3%) and nonlymphoid malignancy (25.0%). Twenty-year survival was achieved in 12.5% of patients transplanted before 1988. Although still associated with considerable morbidity, long-term survival is expected to occur at much higher rates in the future due to major advances in the field over the past decade.

  View details for DOI 10.1111/j.1600-6143.2008.02310.x

  View details for Web of Science ID 000258401700004

  View details for PubMedID 18557718

• The changing face of heart transplantation JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Hunt, S. A., Haddad, F. 2008; 52 (8): 587-598

  Abstract

  It has been 40 years since the first human-to-human heart transplant performed in South Africa by Christiaan Barnard in December 1967. This achievement did not come as a surprise to the medical community but was the result of many years of early pioneering experimental work by Alexis Carrel, Frank Mann, Norman Shumway, and Richard Lower. Since then, refinement of donor and recipient selection methods, better donor heart management, and advances in immunosuppression have significantly improved survival. In this article, we hope to give a perspective on the changing face of heart transplantation. Topics that will be covered in this review include the changing patient population as well as recent advances in transplantation immunology, organ preservation, allograft vasculopathy, and immune tolerance.

  View details for DOI 10.1016/j.jacc.2008.05.020

  View details for Web of Science ID 000258394000001

  View details for PubMedID 18702960

• Right ventricular function in cardiovascular disease, Part II - Pathophysiology, clinical importance, and management of right ventricular failure CIRCULATION Haddad, F., Doyle, R., Murphy, D. J., Hunt, S. A. 2008; 117 (13): 1717-1731

  View details for DOI 10.1161/CIRCULATIONAHA.107.653584

  View details for Web of Science ID 000254576500013

  View details for PubMedID 18378625

• Right ventricular function in cardiovascular disease, part I - Anatomy, physiology, aging, and functional assessment of the right ventricle CIRCULATION Haddad, F., Hunt, S. A., Rosenthal, D. N., Murphy, D. J. 2008; 117 (11): 1436-1448

  View details for DOI 10.1161/CIRCULATIONAHA.107.653576

  View details for Web of Science ID 000254065200011

  View details for PubMedID 18347220

• Right ventricular myocardial performance index predicts perioperative mortality or circulatory failure in high-risk valvular surgery JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY Haddad, F., Denault, A. Y., Couture, P., Cartier, R., Pellerin, M., Levesque, S., Lambert, J., Tardif, J. 2007; 20 (9): 1065-1072

  Abstract

  The prognostic value of right ventricular myocardial performance index (RVMPI) and right ventricular fractional area change (RVFAC) in mitral or aortic valve surgery has not been well described. The main objective of this study is to assess the prognostic value of RVMPI and RVFAC in predicting postoperative mortality or circulatory failure.RVMPI and RVFAC were prospectively measured after induction of anesthesia using transesophageal echocardiography in 50 consecutive patients undergoing corrective mitral or aortic valve surgery. Univariate and multivariate analyses were performed for the primary clinical end point of in-hospital mortality or circulatory failure.In the study population, the mean age was 67 +/- 9 years. The primary end point occurred in 17 patients (34%); three patients died, and 14 patients presented signs of circulatory failure. Multivariate regression analysis identified RVMPI and RVFAC as variables of prognostic significance.Preoperative RVMPI and RVFAC could have an incremental value in predicting postoperative mortality and morbidity in valvular heart surgery. Future studies are needed to validate these results in a larger population.

  View details for DOI 10.1016/j.echo.2007.02.017

  View details for Web of Science ID 000249454900006

  View details for PubMedID 17566702

• Relationship between body mass index and cardiometabolic health in a multi-ethnic population: A project baseline health study. American journal of preventive cardiology Shah, N. P., Lu, R., Haddad, F., Shore, S., Schaack, T., Mega, J., Pagidipati, N. J., Palaniappan, L., Mahaffey, K., Shah, S. H., Rodriguez, F. 2024; 18: 100646

  Abstract

  Obesity is associated with a higher risk of cardiovascular disease. Understanding the associations between comprehensive health parameters and body mass index (BMI) may lead to targeted prevention efforts.Project Baseline Health Study (PBHS) participants were divided into six BMI categories: underweight (BMI <18.5 kg/m2), normal weight (BMI 18.5-24.9 kg/m2), overweight (BMI 25-29.9 kg/m2), class I obesity (30-34.9 kg/m2), class II obesity (35-39.9 kg/m2), and class III obesity (BMI ≥40 kg/m2). Demographic, cardiometabolic, mental health, and physical health parameters were compared across BMI categories, and multivariable logistic regression models were fit to evaluate associations.A total of 2,493 PBHS participants were evaluated. The mean age was 50±17.2 years; 55 % were female, 12 % Hispanic, 16 % Black, and 10 % Asian. The average BMI was 28.4 kg/m2±6.9. The distribution of BMI by age group was comparable to the 2017-2018 National Health and Nutrition Examination Survey (NHANES) dataset. The obesity categories had higher proportions of participants with CAC scores >0, hypertension, diabetes, lower HDL-C, lower vitamin D, higher triglycerides, higher hsCRP, lower mean step counts, higher mean PHQ-9 scores, and higher mean GAD-7 scores.We identified associations of cardiometabolic and mental health characteristics with BMI, thereby providing a deeper understanding of cardiovascular health across BMI.

  View details for DOI 10.1016/j.ajpc.2024.100646

  View details for PubMedID 38550633

  View details for PubMedCentralID PMC10966449

• Quantifying assumptions underlying peak oxygen consumption equations across the body mass spectrum. Clinical obesity Busque, V., Christle, J. W., Moneghetti, K. J., Cauwenberghs, N., Kouznetsova, T., Blumberg, Y., Wheeler, M. T., Ashley, E., Haddad, F., Myers, J. 2024: e12653

  Abstract

  The goal of this study is to quantify the assumptions associated with the Wasserman-Hansen (WH) and Fitness Registry and the Importance of Exercise: A National Database (FRIEND) predictive peak oxygen consumption (pVO2 ) equations across body mass index (BMI). Assumptions in pVO2 for both equations were first determined using a simulation and then evaluated using exercise data from the Stanford Exercise Testing registry. We calculated percent-predicted VO2 (ppVO2 ) values for both equations and compared them using the Bland-Altman method. Assumptions associated with pVO2 across BMI categories were quantified by comparing the slopes of age-adjusted VO2 ratios (pVO2 /pre-exercise VO2 ) and ppVO2 values for different BMI categories. The simulation revealed lower predicted fitness among adults with obesity using the FRIEND equation compared to the WH equations. In the clinical cohort, we evaluated 2471 patients (56.9% male, 22% with BMI >30 kg/m2 , pVO2 26.8 mlO2 /kg/min). The Bland-Altman plot revealed an average relative difference of -1.7% (95% CI: -2.1 to -1.2%) between WH and FRIEND ppVO2 values with greater differences among those with obesity. Analysis of the VO2 ratio to ppVO2 slopes across the BMI spectrum confirmed the assumption of lower fitness in those with obesity, and this trend was more pronounced using the FRIEND equation. Peak VO2 estimations between the WH and FRIEND equations differed significantly among individuals with obesity. The FRIEND equation resulted in a greater attributable reduction in pVO2 associated with obesity relative to the WH equations. The outlined relationships between BMI and predicted VO2 may better inform the clinical interpretation of ppVO2 values during cardiopulmonary exercise test evaluations.

  View details for DOI 10.1111/cob.12653

  View details for PubMedID 38475989

• Deep Learning-Derived Myocardial Strain. JACC. Cardiovascular imaging Kwan, A. C., Chang, E. W., Jain, I., Theurer, J., Tang, X., Francisco, N., Haddad, F., Liang, D., Fábián, A., Ferencz, A., Yuan, N., Merkely, B., Siegel, R., Cheng, S., Kovács, A., Tokodi, M., Ouyang, D. 2024

  Abstract

  Echocardiographic strain measurements require extensive operator experience and have significant intervendor variability. Creating an automated, open-source, vendor-agnostic method to retrospectively measure global longitudinal strain (GLS) from standard echocardiography B-mode images would greatly improve post hoc research applications and may streamline patient analyses.This study was seeking to develop an automated deep learning strain (DLS) analysis pipeline and validate its performance across multiple applications and populations.Interobserver/-vendor variation of traditional GLS, and simulated effects of variation in contour on speckle-tracking measurements were assessed. The DLS pipeline was designed to take semantic segmentation results from EchoNet-Dynamic and derive longitudinal strain by calculating change in the length of the left ventricular endocardial contour. DLS was evaluated for agreement with GLS on a large external dataset and applied across a range of conditions that result in cardiac hypertrophy.In patients scanned by 2 sonographers using 2 vendors, GLS had an intraclass correlation of 0.29 (95% CI: -0.01 to 0.53, P = 0.03) between vendor measurements and 0.63 (95% CI: 0.48-0.74, P < 0.001) between sonographers. With minor changes in initial input contour, step-wise pixel shifts resulted in a mean absolute error of 3.48% and proportional strain difference of 13.52% by a 6-pixel shift. In external validation, DLS maintained moderate agreement with 2-dimensional GLS (intraclass correlation coefficient [ICC]: 0.56, P = 0.002) with a bias of -3.31% (limits of agreement: -11.65% to 5.02%). The DLS method showed differences (P < 0.0001) between populations with cardiac hypertrophy and had moderate agreement in a patient population of advanced cardiac amyloidosis: ICC was 0.64 (95% CI: 0.53-0.72), P < 0.001, with a bias of 0.57%, limits of agreement of -4.87% to 6.01% vs 2-dimensional GLS.The open-source DLS provides lower variation than human measurements and similar quantitative results. The method is rapid, consistent, vendor-agnostic, publicly released, and applicable across a wide range of imaging qualities.

  View details for DOI 10.1016/j.jcmg.2024.01.011

  View details for PubMedID 38551533

• Being fit in the COVID-19 era and future epidemics prevention: Importance of cardiopulmonary exercise test in fitness evaluation. Progress in cardiovascular diseases de la Guía-Galipienso, F., Palau, P., Berenguel-Senen, A., Perez-Quilis, C., Christle, J. W., Myers, J., Haddad, F., Baggish, A., D'Ascenzi, F., Lavie, C. J., Lippi, G., Sanchis-Gomar, F. 2024

  Abstract

  Endurance and resistance physical activity have been shown to stimulate the production of immunoglobulins and boost the levels of anti-inflammatory cytokines, natural killer cells, and neutrophils in the bloodstream, thereby strengthening the ability of the innate immune system to protect against diseases and infections. Coronavirus disease 19 (COVID-19) greatly impacted people's cardiorespiratory fitness (CRF) and health worldwide. Cardiopulmonary exercise testing (CPET) remains valuable in assessing physical condition, predicting illness severity, and guiding interventions and treatments. In this narrative review, we summarize the connections and impact of COVID-19 on CRF levels and its implications on the disease's progression, prognosis, and mortality. We also emphasize the significant contribution of CPET in both clinical evaluations of recovering COVID-19 patients and scientific investigations focused on comprehending the enduring health consequences of SARS-CoV-2 infection.

  View details for DOI 10.1016/j.pcad.2024.03.001

  View details for PubMedID 38452909

• Defining the Role of Imaging in Heart Failure Risk Stratification. JACC. Heart failure Daubert, M. A., Haddad, F. 2024; 12 (2): 287-289

  View details for DOI 10.1016/j.jchf.2023.11.011

  View details for PubMedID 38325999

• Clinical and biochemical predictors of longitudinal changes in left atrial structure and function: A general population study. Echocardiography (Mount Kisco, N.Y.) Kuznetsova, T., Daels, Y., Ntalianis, E., Santana, E. J., Sabovčik, F., Haddad, F., Cauwenberghs, N. 2024; 41 (2): e15780

  Abstract

  There is a need for better understanding the factors that modulate left atrial (LA) dysfunction. Therefore, we determined associations of clinical and biochemical biomarkers with serial changes in echocardiographic indexes of LA function in the general population.We measured LA maximal and minimal volume indexes (LAVImax and LAVImin) by echocardiography and LA reservoir strain (LARS) by two-dimensional speckle-tracking in 627 participants (mean age 50.8 years, 51.2% women) at baseline and after 4.8 years.During follow-up, LARS decreased significantly in men (-.90%, P = .033) but not in women (-.23%, P = .60). In stepwise regression analysis, stronger decrease in LARS over time was associated with male sex, a higher age, body mass index (BMI), mean arterial pressure (MAP) and serum insulin at baseline and with a greater increase in BMI and MAP over time (P ≤ .018). Similarly, an increased risk of developing or retaining abnormal LARS was observed in older participants, in subjects with a higher baseline BMI, MAP, heart rate (HR), troponin T and ΔMAP, and in those who used β-blockers at baseline. Both LAVImax and LAVImin increased significantly over time (P ≤ .0007). This increase was associated with a higher baseline age, pulse pressure and a lower HR at baseline and a greater increase in pulse pressure over time (P ≤ .029). Higher serum insulin and D-dimer were independently associated with a stronger increase in LAVImin (P ≤ .0034).Subclinical worsening in LA dysfunction was associated with older age, hypertension, obesity, insulin resistance and troponin T levels. Cardiovascular risk management strategies may delay LA deterioration.

  View details for DOI 10.1111/echo.15780

  View details for PubMedID 38372342

• Improving Reporting of Exercise Capacity Across Age Ranges Using Novel Workload Reference Equations. The American journal of cardiology Santana, E. J., Christle, J. W., Cauwenberghs, N., Peterman, J. E., Busque, V., Gomes, B., Bagherzadeh, S. P., Moneghetti, K., Kuznetsova, T., Wheeler, M., Ashley, E., Harber, M. P., Arena, R., Kaminsky, L. A., Myers, J., Haddad, F. 2024

  Abstract

  Exercise capacity (EC) is an important predictor of survival in the general population as well as in individuals with cardiopulmonary disease. Despite its relevance, considering percent-predicted workload (%pWL) given by current equations may overestimate EC in older adults. Therefore, to improve the reporting of EC in clinical practice, our main objective was to develop workload reference equations (pWL) that better reflect the relation between workload and age. Using the Fitness Registry and the Importance of Exercise National Database (FRIEND), we analyzed a reference group of 6,966 apparently healthy participants and 1,060 participants with HF who underwent graded treadmill cardiopulmonary exercise testing. For the first group, the mean age was 44 years [18-79]; 56.5% of individuals were male and 15.4% had obesity. Peak VO2 was 11.6 ± 3.0 METs in males and 8.5±2.4 METs in females. After partition analysis, we first developed sex-specific pWL equations to allow comparisons to a healthy weight reference. For males, pWL (METs) = 14.1 - 0.9 × 10-3 × age2 and for female 11.5 - 0.87 × 10-3 × age2. We used those equations as denominators of %pWL and, based on their distribution, we determined thresholds for EC classification, with average EC defined by the range corresponding to 85-115%pWL. Compared to %pWL using current equations, the new equations yielded better-calibrated %pWL across different age ranges. We also derived body mass index-adjusted pWL equations that better assessed EC in individuals with HF. In conclusion, the novel pWL equations have the potential to impact the report of EC in practice.

  View details for DOI 10.1016/j.amjcard.2024.01.022

  View details for PubMedID 38301753

• Identifying a stable and generalizable factor structure of major depressive disorder across three large longitudinal cohorts. Psychiatry research Tseng, V. W., Tharp, J. A., Reiter, J. E., Ferrer, W., Hong, D. S., Doraiswamy, P. M., Nickels, S. 2023; 333: 115702

  Abstract

  The Patient Health Questionnaire 9 (PHQ-9) is the current standard outpatient screening tool for measuring and tracking the nine symptoms of major depressive disorder (MDD). While the PHQ-9 was originally conceptualized as a unidimensional measure, it has become clear that MDD is not a monolithic construct, as evidenced by high comorbidities with other theoretically distinct diagnoses and common symptom overlap between depression and other diagnoses. Therefore, identifying reliable and temporally stable subfactors of depressive symptoms could allow research and care to be tailored to different depression phenotypes. This study improved on previous factor analysis studies of the PHQ-9 by leveraging samples that were clinical (participants with depression only), large (N = 1483 depressed individuals in total), longitudinal (up to 5 years), and from three diverse (matching racial distribution of the United States) datasets. By refraining from assuming the number of factors or item loadings a priori, and thus utilizing a solely data-driven approach, we identified a ranked list of best-fitting models, with the parsimonious one achieving good model fit across studies at most timepoints (average TLI >= 0.90). This model categorizes the PHQ-9 items into four factors: (1) Affective (Anhedonia + Depressed Mood), (2) Somatic (Sleep + Fatigue + Appetite), (3) Internalizing (Worth/Guilt + Suicidality), (4) Sensorimotor (Concentration + Psychomotor), which may be used to further precision psychiatry by testing factor-specific interventions in research and clinical settings.

  View details for DOI 10.1016/j.psychres.2023.115702

  View details for PubMedID 38219346

• Quantitative metrics of the LV trabeculated layer by cardiac CT and cardiac MRI in patients with suspected noncompaction cardiomyopathy. European radiology Manohar, A., Vigneault, D. M., Kwon, D. H., Caliskan, K., Budde, R. P., Hirsch, A., Lee, S. P., Lee, W., Owens, A., Litt, H., Haddad, F., Mistelbauer, G., Wheeler, M., Rubin, D., Tang, W. H., Nieman, K. 2023

  Abstract

  To compare cardiac computed tomography (CCT) and cardiac magnetic resonance (CMR) for the quantitative assessment of the left ventricular (LV) trabeculated layer in patients with suspected noncompaction cardiomyopathy (NCCM).Subjects with LV excessive trabeculation who underwent both CMR and CCT imaging as part of the prospective international multicenter NONCOMPACT clinical study were included. For each subject, short-axis CCT and CMR slices were matched. Four quantitative metrics were estimated: 1D noncompacted-to-compacted ratio (NCC), trabecular-to-myocardial area ratio (TMA), trabecular-to-endocardial cavity area ratio (TCA), and trabecular-to-myocardial volume ratio (TMV). In 20 subjects, end-diastolic and mid-diastolic CCT images were compared for the quantification of the trabeculated layer. Relationships between the metrics were investigated using linear regression models and Bland-Altman analyses.Forty-eight subjects (49.9 ± 12.8 years; 28 female) were included in this study. NCC was moderately correlated (r = 0.62), TMA and TMV were strongly correlated (r = 0.78 and 0.78), and TCA had excellent correlation (r = 0.92) between CMR and CCT, with an underestimation bias from CCT of 0.3 units, and 5.1, 4.8, and 5.4 percent-points for the 4 metrics, respectively. TMA, TCA, and TMV had excellent correlations (r = 0.93, 0.96, 0.94) and low biases (- 3.8, 0.8,  - 3.8 percent-points) between the end-diastolic and mid-diastolic CCT images.TMA, TCA, and TMV metrics of the LV trabeculated layer in patients with suspected NCCM demonstrated high concordance between CCT and CMR images. TMA and TCA were highly reproducible and demonstrated minimal differences between mid-diastolic and end-diastolic CCT images.The results indicate similarity of CCT to CMR for quantifying the LV trabeculated layer, and the small differences in quantification between end-diastole and mid-diastole demonstrate the potential for quantifying the LV trabeculated layer from clinically performed coronary CT angiograms.• Data on cardiac CT for quantifying the left ventricular trabeculated layer are limited. • Cardiac CT yielded highly reproducible metrics of the left ventricular trabeculated layer that correlated well with metrics defined by cardiac MR. • Cardiac CT appears to be equivalent to cardiac MR for the quantification of the left ventricular trabeculated layer.

  View details for DOI 10.1007/s00330-023-10526-1

  View details for PubMedID 38114847

  View details for PubMedCentralID 10317841

• Genetic architecture of cardiac dynamic flow volumes. Nature genetics Gomes, B., Singh, A., O'Sullivan, J. W., Schnurr, T. M., Goddard, P. C., Loong, S., Amar, D., Hughes, J. W., Kostur, M., Haddad, F., Salerno, M., Foo, R., Montgomery, S. B., Parikh, V. N., Meder, B., Ashley, E. A. 2023

  Abstract

  Cardiac blood flow is a critical determinant of human health. However, the definition of its genetic architecture is limited by the technical challenge of capturing dynamic flow volumes from cardiac imaging at scale. We present DeepFlow, a deep-learning system to extract cardiac flow and volumes from phase-contrast cardiac magnetic resonance imaging. A mixed-linear model applied to 37,653 individuals from the UK Biobank reveals genome-wide significant associations across cardiac dynamic flow volumes spanning from aortic forward velocity to aortic regurgitation fraction. Mendelian randomization reveals a causal role for aortic root size in aortic valve regurgitation. Among the most significant contributing variants, localizing genes (near ELN, PRDM6 and ADAMTS7) are implicated in connective tissue and blood pressure pathways. Here we show that DeepFlow cardiac flow phenotyping at scale, combined with genotyping data, reinforces the contribution of connective tissue genes, blood pressure and root size to aortic valve function.

  View details for DOI 10.1038/s41588-023-01587-5

  View details for PubMedID 38082205

  View details for PubMedCentralID 7612636

• Segmenting computed tomograms for cardiac ablation using machine learning leveraged by domain knowledge encoding. Frontiers in cardiovascular medicine Feng, R., Deb, B., Ganesan, P., Tjong, F. V., Rogers, A. J., Ruipérez-Campillo, S., Somani, S., Clopton, P., Baykaner, T., Rodrigo, M., Zou, J., Haddad, F., Zahari, M., Narayan, S. M. 2023; 10: 1189293

  Abstract

  Segmentation of computed tomography (CT) is important for many clinical procedures including personalized cardiac ablation for the management of cardiac arrhythmias. While segmentation can be automated by machine learning (ML), it is limited by the need for large, labeled training data that may be difficult to obtain. We set out to combine ML of cardiac CT with domain knowledge, which reduces the need for large training datasets by encoding cardiac geometry, which we then tested in independent datasets and in a prospective study of atrial fibrillation (AF) ablation.We mathematically represented atrial anatomy with simple geometric shapes and derived a model to parse cardiac structures in a small set of N = 6 digital hearts. The model, termed "virtual dissection," was used to train ML to segment cardiac CT in N = 20 patients, then tested in independent datasets and in a prospective study.In independent test cohorts (N = 160) from 2 Institutions with different CT scanners, atrial structures were accurately segmented with Dice scores of 96.7% in internal (IQR: 95.3%-97.7%) and 93.5% in external (IQR: 91.9%-94.7%) test data, with good agreement with experts (r = 0.99; p < 0.0001). In a prospective study of 42 patients at ablation, this approach reduced segmentation time by 85% (2.3 ± 0.8 vs. 15.0 ± 6.9 min, p < 0.0001), yet provided similar Dice scores to experts (93.9% (IQR: 93.0%-94.6%) vs. 94.4% (IQR: 92.8%-95.7%), p = NS).Encoding cardiac geometry using mathematical models greatly accelerated training of ML to segment CT, reducing the need for large training sets while retaining accuracy in independent test data. Combining ML with domain knowledge may have broad applications.

  View details for DOI 10.3389/fcvm.2023.1189293

  View details for PubMedID 37849936

  View details for PubMedCentralID PMC10577270

• Epicardial fat and Stage B heart failure among overweight/obese and normal weight individuals with diabetes mellitus. The international journal of cardiovascular imaging Kobayashi, Y., Nishi, T., Christle, J. W., Cauwenberghs, N., Kuznetsova, T., Palaniappan, L., Haddad, F. 2023

  Abstract

  Although up to 20% of people with type 2 diabetes (DM) have normal BMI (< 25 kg/m2), it remains unclear whether there is a difference in the development of cardiac dysfunction between those with normal and higher BMI. Furthermore, little is known about the relationship of visceral fat with BMI or fitness in asymptomatic patients with DM.We prospectively enrolled asymptomatic patients with DM and divided into two groups: BMI ≥ 25kg/m2 (overweight/obese group) versus < 25kg/m2(normal-weight group). Resting echocardiogram followed by exercise stress echocardiogram and exercise gas exchange analysis (in a subgroup) was performed. Cardiac function was evaluated using left ventricular longitudinal strain (LVLS), E/e', and relative wall thickness (RWT). In addition, epicardial fat thickness (EFT) was measured to estimate visceral fat.Normal-weight patients with DM had more EFT compared with overweight/obese patients (0.66 ± 0.17 cm vs. 0.59 ± 0.22 cm, p < 0.05), despite the overlap between the groups. There was no significant difference in the prevalence of LV remodeling (p = 0.49), impaired LVLS (p = 0.22), or increased E/e' (p = 0.26), and these were consistently observed when matched for race. The majority of patients (63%) achieved ≥ 85% of percent peak-predicted VO2. At peak, there was no significant difference in peak VO2 normalized by eLBM (36.4 ± 7.7 vs. 37.8 ± 7.1 ml/kg eLBM/min, p = 0.43) while VO2 normalized by weight (23.6 ± 6.5 vs. 29.6 ± 6.7 ml/kg/min, p < 0.001) and VO2 ratio (5.7 ± 1.7 vs. 7.3 ± 2.4 METs, p = 0.001) were significantly lower in patients with obese/overweight group. There was no significant difference between patients with higher and lower EFT.Patients with DM and normal BMI have excess epicardial fat compared to those with overweight/obese. Epicardial fat was not directly linked to prevalence of subclinical dysfunction.

  View details for DOI 10.1007/s10554-023-02944-5

  View details for PubMedID 37695438

  View details for PubMedCentralID 1352345

• A Precision Approach to Family Screening in ARVC. Journal of the American College of Cardiology Heidenreich, P. A., Haddad, F., Parikh, V. N. 2023; 82 (3): 226-227

  View details for DOI 10.1016/j.jacc.2023.05.020

  View details for PubMedID 37438008

• Respiratory gas kinetics in patients with congestive heart failure during recovery from peak exercise. Clinics (Sao Paulo, Brazil) Patti, A., Blumberg, Y., Hedman, K., Neunhäuserer, D., Haddad, F., Wheeler, M., Ashley, E., Moneghetti, K. J., Myers, J., Christle, J. W. 2023; 78: 100225

  Abstract

  Cardiopulmonary Exercise Testing (CPX) is essential for the assessment of exercise capacity for patients with Chronic Heart Failure (CHF). Respiratory gas and hemodynamic parameters such as Ventilatory Efficiency (VE/VCO2 slope), peak oxygen uptake (peak VO2), and heart rate recovery are established diagnostic and prognostic markers for clinical populations. Previous studies have suggested the clinical value of metrics related to respiratory gas collected during recovery from peak exercise, particularly recovery time to 50% (T1/2) of peak VO2. The current study explores these metrics in detail during recovery from peak exercise in CHF.Patients with CHF who were referred for CPX and healthy individuals without formal diagnoses were assessed for inclusion. All subjects performed CPX on cycle ergometers to volitional exhaustion and were monitored for at least five minutes of recovery. CPX data were analyzed for overshoot of respiratory exchange ratio (RER=VCO2/VO2), ventilatory equivalent for oxygen (VE/VO2), end-tidal partial pressure of oxygen (PETO2), and T1/2 of peak VO2 and VCO2.Thirty-two patients with CHF and 30 controls were included. Peak VO2 differed significantly between patients and controls (13.5 ± 3.8 vs. 32.5 ± 9.8 mL/Kg*min-1, p < 0.001). Mean Left Ventricular Ejection Fraction (LVEF) was 35.9 ± 9.8% for patients with CHF compared to 61.1 ± 8.2% in the control group. The T1/2 of VO2, VCO2 and VE was significantly higher in patients (111.3 ± 51.0, 132.0 ± 38.8 and 155.6 ± 45.5s) than in controls (58.08 ± 13.2, 74.3 ± 21.1, 96.7 ± 36.8s; p < 0.001) while the overshoot of PETO2, VE/VO2 and RER was significantly lower in patients (7.2 ± 3.3, 41.9 ± 29.1 and 25.0 ± 13.6%) than in controls (10.1 ± 4.6, 62.1 ± 17.7 and 38.7 ± 15.1%; all p < 0.01). Most of the recovery metrics were significantly correlated with peak VO2 in CHF patients, but not with LVEF.Patients with CHF have a significantly blunted recovery from peak exercise. This is reflected in delays of VO2, VCO2, VE, PETO2, RER and VE/VO2, reflecting a greater energy required to return to baseline. Abnormal respiratory gas kinetics in CHF was negatively correlated with peak VO2 but not baseline LVEF.

  View details for DOI 10.1016/j.clinsp.2023.100225

  View details for PubMedID 37356413

• Integrative Interpretation of Cardiopulmonary Exercise Tests for Cardiovascular Outcome Prediction: A Machine Learning Approach. Diagnostics (Basel, Switzerland) Cauwenberghs, N., Sente, J., Van Criekinge, H., Sabovčik, F., Ntalianis, E., Haddad, F., Claes, J., Claessen, G., Budts, W., Goetschalckx, K., Cornelissen, V., Kuznetsova, T. 2023; 13 (12)

  Abstract

  Integrative interpretation of cardiopulmonary exercise tests (CPETs) may improve assessment of cardiovascular (CV) risk. Here, we identified patient phenogroups based on CPET summary metrics and evaluated their predictive value for CV events. We included 2280 patients with diverse CV risk who underwent maximal CPET by cycle ergometry. Key CPET indices and information on incident CV events (median follow-up time: 5.3 years) were derived. Next, we applied unsupervised clustering by Gaussian Mixture modeling to subdivide the cohort into four male and four female phenogroups solely based on differences in CPET metrics. Ten of 18 CPET metrics were used for clustering as eight were removed due to high collinearity. In males and females, the phenogroups differed significantly in age, BMI, blood pressure, disease prevalence, medication intake and spirometry. In males, phenogroups 3 and 4 presented a significantly higher risk for incident CV events than phenogroup 1 (multivariable-adjusted hazard ratio: 1.51 and 2.19; p ≤ 0.048). In females, differences in the risk for future CV events between the phenogroups were not significant after adjustment for clinical covariables. Integrative CPET-based phenogrouping, thus, adequately stratified male patients according to CV risk. CPET phenomapping may facilitate comprehensive evaluation of CPET results and steer CV risk stratification and management.

  View details for DOI 10.3390/diagnostics13122051

  View details for PubMedID 37370946

  View details for PubMedCentralID PMC10297339

• Reduced Pulmonary Artery Distensibility Predicts Persistent Pulmonary Hypertension and 2-Year Mortality in Patients with Severe Aortic Stenosis Undergoing TAVR. Academic radiology Turner, V., Maret, E., Kim, J. B., Codari, M., Hinostroza, V., Mastrodicasa, D., Watkins, A. C., Fearon, W. F., Fischbein, M. P., Haddad, F., Willemink, M. J., Fleischmann, D. 2023

  Abstract

  RATIONALE AND OBJECTIVES: Post-TAVR persistent pulmonary hypertension (PH) is a better predictor of poor outcome than pre-TAVR PH. In this longitudinal study we sought to evaluate whether pulmonary artery (distensibility (DPA) measured on preprocedural ECG-gated CTA is associated with persistent-PH and 2-year mortality after TAVR.MATERIALS AND METHODS: Three hundred and thirty-six patients undergoing TAVR between July 2012 and March 2016 were retrospectively included and followed for all-cause mortality until November 2017. All patients underwent retrospectively ECG-gated CTA prior to TAVR. Main pulmonary artery (MPA) area was measured in systole and in diastole. DPA was calculated as: [(area-MPAmax-area-MPAmin)/area-MPAmax]%. ROC analysis was performed to assess the AUC for persistent-PH. Youden Index was used to determine the optimal threshold of DPA for persistent-PH. Two groups were compared based on a DPA threshold of 8% (specificity of 70% for persistent-PH). Kaplan-Meier, Cox proportional-hazard, and logistic regression analyses were performed. The primary clinical endpoint was defined as persistent-PH post-TAVR. The secondary endpoint was defined as all-cause mortality 2 years after TAVR.RESULTS: Median follow-up time was 413 (interquartiles 339-757) days. A total of 183 (54%) had persistent-PH and 68 (20%) patients died within 2-years after TAVR. Patients with DPA<8% had significantly more persistent-PH (67% vs 47%, p<0.001) and 2-year deaths (28% vs 15%, p=0.006), compared to patients with DPA>8%. Adjusted multivariable regression analyses showed that DPA<8% was independently associated with persistent-PH (OR 2.10 [95%-CI 1.3-4.5], p=0.007) and 2-year mortality (HR 2.91 [95%-CI 1.5-5.8], p=0.002). Kaplan-Meier analysis showed that 2-year mortality of patients with DPA<8% was significantly higher compared to patients with DPA≥8% (mortality 28% vs 15%; log-rank p=0.003).CONCLUSION: DPA on preprocedural CTA is independently associated with persistent-PH and two-year mortality in patients who undergo TAVR.

  View details for DOI 10.1016/j.acra.2023.03.014

  View details for PubMedID 37147161

• Multiparametric evaluation of right ventricular function in pulmonary arterial hypertension associated with congenital heart disease REVISTA ESPANOLA DE CARDIOLOGIA Fournier, E., Selegny, M., Amsallem, M., Haddad, F., Cohen, S., Valdeolmillos, E., Le Pavec, J., Humbert, M., Isorni, M., Azarine, A., Sitbon, O., Jais, X., Savale, L., Montani, D., Fadel, E., Zoghbi, J., Belli, E., Hascoet, S. 2023; 76 (5): 333-343

  View details for DOI 10.1016/j.recesp.2022.07.012

  View details for Web of Science ID 001042439400001

• Novel left ventricular mechanical index in pulmonary arterial hypertension. Pulmonary circulation Ichimura, K., Santana, E. J., Kuznetsova, T., Cauwenberghs, N., Sabovčik, F., Chun, L., Francisco, N. L., Kheyfets, V. O., Salerno, M., Zamanian, R. T., Spiekerkoetter, E., Haddad, F. 2023; 13 (2): e12216

  Abstract

  Ventricular interdependence plays an important role in pulmonary arterial hypertension (PAH). It can decrease left ventricular (LV) longitudinal strain (LVLS) and lead to a leftward displacement ("transverse shortening") of the interventricular septum (sTS). For this study, we hypothesized the ratio of LVLS/sTS would be a sensitive marker of systolic ventricular interactions in PAH. In a cross-sectional cohort of patients with PAH (n = 57) and matched controls (n = 57), we quantified LVLS and septal TS in the amplitude and time domain. We then characterized LV phenotypes using upset plots, ventricular interactions using network analysis, and longitudinal analysis in a representative cohort of 45 patients. We also measured LV metrics in mice subjected to pulmonary arterial banding (PAB) using a 7 T magnetic resonance imaging at baseline, Week 1, and Week 7 post-PAB (N = 9). Patients with PAH had significantly reduced absolute LVLS (15.4 ± 3.4 vs. 20.1 ± 2.3%, p < 0.0001), higher sTS (53.0 ± 12.2 vs. 28.0 ± 6.2%, p < 0.0001) and lower LVLS/sTS (0.30 ± 0.09 vs. 0.75 ± 0.16, p < 0.0001) compared to controls. Reduced LVLS/sTS was observed in 89.5% of patients, while diastolic dysfunction, impaired LVLS (<16%), and LV atrophy were observed in 73.7%, 52.6%, and 15.8%, respectively. In the longitudinal cohort, changes in LVLS/sTS were closely associated with changes in N-terminal pro B-type natriuretic peptide (r = 0.73, p < 0.0001) as well as survival. Mice subjected to PAB showed significant RV systolic dysfunction and decreased LVLS/sTS compared to sham animals. We conclude that in PAH, LVLV/sTS is a simple ratio that can reflect ventricular systolic interactions.

  View details for DOI 10.1002/pul2.12216

  View details for PubMedID 37063750

  View details for PubMedCentralID PMC10103585

• SOCIAL DETERMINANTS OF HEALTH AND CORONARY ARTERY CALCIUM: RESULTS FROM THE PROJECT BASELINE HEALTH STUDY Dudum, R., Ling, A., Short, S., Koweek, L. H., Carroll, M., Daubert, M. A., Haddad, F., Hernandez, A. F., Shah, S., Mahaffey, K. W., Douglas, P. S., Mega, J., Maron, D., Rodriguez, F. ELSEVIER SCIENCE INC. 2023: 1843

  View details for Web of Science ID 000990866101855

• Longitudinal Validation of Right Ventricular Pressure Monitoring for the Assessment of Right Ventricular Systolic Dysfunction in a Large Animal Ischemic Model. Critical care explorations Couture, E. J., Moses, K., Monge Garcia, M. I., Potes, C., Haddad, F., Gronlykke, L., Garcia, F., Paster, E., Pibarot, P., Denault, A. Y. 2023; 5 (1): e0847

  Abstract

  Right ventricular (RV) dysfunction is a major cause of morbidity and mortality in intensive care and cardiac surgery. Early detection of RV dysfunction may be facilitated by continuous monitoring of RV waveform obtained from a pulmonary artery catheter. The objective is to evaluate the extent to which RV pressure monitoring can detect changes in RV systolic performance assess by RV end-systolic elastance (Ees) following the development of an acute RV ischemic in a porcine model.HYPOTHESIS: RV pressure monitoring can detect changes in RV systolic performance assess by RV Ees following the development of an acute RV ischemic model.METHODS AND MODELS: Acute ischemic RV dysfunction was induced by progressive embolization of microsphere in the right coronary artery to mimic RV dysfunction clinically experienced during cardiopulmonary bypass separation caused by air microemboli. RV hemodynamic performance was assessed using RV pressure waveform-derived parameters and RV Ees obtained using a conductance catheter during inferior vena cava occlusions.RESULTS: Acute ischemia resulted in a significant reduction in RV Ees from 0.26mm Hg/mL (interquartile range, 0.16-0.32mm Hg/mL) to 0.14mm Hg/mL (0.11-0.19mm Hg/mL; p < 0.010), cardiac output from 6.3L/min (5.7-7L/min) to 4.5 (3.9-5.2L/min; p = 0.007), mean systemic arterial pressure from 72mm Hg (66-74mm Hg) to 51mm Hg (46-56mm Hg; p < 0.001), and mixed venous oxygen saturation from 65% (57-72%) to 41% (35-45%; p < 0.001). Linear mixed-effect model analysis was used to assess the relationship between Ees and RV pressure-derived parameters. The reduction in RV Ees best correlated with a reduction in RV maximum first derivative of pressure during isovolumetric contraction (dP/dtmax) and single-beat RV Ees. Adjusting RV dP/dtmax for heart rate resulted in an improved surrogate of RV Ees.INTERPRETATION AND CONCLUSIONS: Stepwise decreases in RV Ees during acute ischemic RV dysfunction were accurately tracked by RV dP/dtmax derived from the RV pressure waveform.

  View details for DOI 10.1097/CCE.0000000000000847

  View details for PubMedID 36699251

• Feature-based clustering of the left ventricular strain curve for cardiovascular risk stratification in the general population. Frontiers in cardiovascular medicine Ntalianis, E., Cauwenberghs, N., Sabovcik, F., Santana, E., Haddad, F., Claus, P., Kuznetsova, T. 2023; 10: 1263301

  Abstract

  Objective: Identifying individuals with subclinical cardiovascular (CV) disease could improve monitoring and risk stratification. While peak left ventricular (LV) systolic strain has emerged as a strong prognostic factor, few studies have analyzed the whole temporal profiles of the deformation curves during the complete cardiac cycle. Therefore, in this longitudinal study, we applied an unsupervised machine learning approach based on time-series-derived features from the LV strain curve to identify distinct strain phenogroups that might be related to the risk of adverse cardiovascular events in the general population.Method: We prospectively studied 1,185 community-dwelling individuals (mean age, 53.2 years; 51.3% women), in whom we acquired clinical and echocardiographic data including LV strain traces at baseline and collected adverse events on average 9.1 years later. A Gaussian Mixture Model (GMM) was applied to features derived from LV strain curves, including the slopes during systole, early and late diastole, peak strain, and the duration and height of diastasis. We evaluated the performance of the model using the clinical characteristics of the participants and the incidence of adverse events in the training dataset. To ascertain the validity of the trained model, we used an additional community-based cohort (n=545) as external validation cohort.Results: The most appropriate number of clusters to separate the LV strain curves was four. In clusters 1 and 2, we observed differences in age and heart rate distributions, but they had similarly low prevalence of CV risk factors. Cluster 4 had the worst combination of CV risk factors, and a higher prevalence of LV hypertrophy and diastolic dysfunction than in other clusters. In cluster 3, the reported values were in between those of strain clusters 2 and 4. Adjusting for traditional covariables, we observed that clusters 3 and 4 had a significantly higher risk for CV (28% and 20%, P≤0.038) and cardiac (57% and 43%, P≤0.024) adverse events. Using SHAP values we observed that the features that incorporate temporal information, such as the slope during systole and early diastole, had a higher impact on the model's decision than peak LV systolic strain.Conclusion: Employing a GMM on features derived from the raw LV strain curves, we extracted clinically significant phenogroups which could provide additive prognostic information over the peak LV strain.

  View details for DOI 10.3389/fcvm.2023.1263301

  View details for PubMedID 38099222

• Improved Right Ventricular Energy Efficiency by 4-Dimensional Flow Magnetic Resonance Imaging After Harmony Valve Implantation JACC:Advances Woo, J. P., Dong, M. L., Kong, F., McElhinney, D. B., Schiavone, N., Chan, F., Lui, G. K., Haddad, F., Bernstein, D., Marsden, A. 2023; 2 (3)

  View details for DOI 10.1016/j.jacadv.2023.100284

• Intrinsic Atrial Myopathy Precedes Left Ventricular Dysfunction and Predicts Atrial Fibrillation in Lamin A/C Cardiomyopathy. Circulation. Genomic and precision medicine Tremblay-Gravel, M., Ichimura, K., Picard, K., Kawano, Y., Dries, A. M., Haddad, F., Lakdawala, N. K., Wheeler, M. T., Parikh, V. N. 2022: e003480

  Abstract

  BACKGROUND: In Lamin A/C (LMNA) cardiomyopathy, atrial fibrillation (AF) commonly occurs before dilated cardiomyopathy, and the ability to predict its incidence is limited. We hypothesized that left atrial (LA) echocardiographic phenotyping can identify atrial myopathy and harbingers of AF.METHODS: Echocardiograms from patients with pathogenic or likely pathogenic variants in LMNA (n=77) with and without reduced left ventricular ejection fraction (LVEF, <50%) were compared to healthy individuals (n=70) and patients with Titin truncating variant cardiomyopathy (n=35) with similar LVEF, sex, and age distributions. Echocardiographic analysis, blinded to genotype, included strain and volumetric measures of left ventricular and atrial function. The primary outcome was incident AF.RESULTS: At baseline, 43% of the patients with pathogenic or likely pathogenic LMNA variants had a history of AF, including 26% of those with LVEF ≥50%. Compared with healthy subjects, the patients with pathogenic or likely pathogenic LMNA variants and LVEF ≥50% had reduced LA contractile strain (LMNA, 11.8±6.1% versus control, 15.0±4.2%; P=0.003). Compared to LVEF-matched Titin truncating variant cardiomyopathy patients, the patients with pathogenic or likely pathogenic LMNA variants and LVEF <50% displayed no difference in LA size, but a worse LA contractile dysfunction (6.4±4.7% versus 12.6±9.6%; P=0.02). Over a median follow-up of 2.8 (1.2-5.7) years, LA contractile strain was the only significant predictor of AF in multivariable Cox regression (hazard ratio, 4.0 [95% CI, 1.04-15.2]).CONCLUSIONS: LMNA cardiomyopathy is associated with early intrinsic atrial myopathy reflected by high AF prevalence and reduced LA contractile strain, even in the absence of LV dysfunction and LA dilation. Whether LA strain can be used as a monitoring strategy to detect and mitigate AF complications requires validation.

  View details for DOI 10.1161/CIRCGEN.121.003480

  View details for PubMedID 36548481

• Imaging the right atrium in pulmonary hypertension: A systematic review and meta-analysis. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Richter, M. J., Fortuni, F., Alenezi, F., D'Alto, M., Badagliacca, R., Brunner, N. W., van Dijk, A. P., Douschan, P., Gall, H., Ghio, S., Giudice, F. L., Grunig, E., Haddad, F., Howard, L., Rajagopal, S., Stens, N., Stolfo, D., Thijssen, D. H., Vizza, C. D., Zamanian, R. T., Zhong, L., Seeger, W., Ghofrani, H. A., Tello, K. 2022

  Abstract

  BACKGROUND: Right atrial (RA) imaging has emerged as a promising tool for the evaluation of patients with pulmonary hypertension (PH), albeit without systematic validation.METHODS: PubMed, Web of Science and the Cochrane library were searched for studies investigating the prognostic value of RA imaging assessment in patients with PH from 2000 to June 2021 (PROSPERO Identifier: CRD42020212850). An inverse variance-weighted meta-analysis of univariable hazard ratios (HRs) was performed using a random effects model.RESULTS: Thirty-five studies were included (3,476 patients with PH; 74% female, 86% pulmonary arterial hypertension). Risk of bias was low/moderate (Quality of Prognosis Studies checklist). RA area (HR 1.06; 95% confidence interval [CI] 1.04-1.08), RA indexed area (HR 1.09; 95% CI 1.04-1.14), RA peak longitudinal strain (PLS; HR 0.94; 95% CI 0.91-0.97) and RA total emptying fraction (HR 0.96; 95% CI 0.94-0.98) were significantly associated with combined end-points including death, clinical worsening and/or lung transplantation; RA volume and volume index showed marginal significant associations. RA area (HR 1.06; 95% CI 1.04-1.07), RA indexed area (HR 1.12; 95% CI 1.07-1.17) and RA PLS (HR 0.98; 95% CI 0.97-0.99) showed significant associations with mortality; RA total emptying fraction showed a marginal association.CONCLUSIONS: Imaging-based RA assessment qualifies as a relevant prognostic marker in PH. RA area reliably predicts composite end-points and mortality, which underscores its clinical utility. RA PLS emerged as a promising imaging measure, but is currently limited by the number of studies and different acquisition methods.

  View details for DOI 10.1016/j.healun.2022.11.007

  View details for PubMedID 36610927

• Effectiveness of a Community-Based Structured Physical Activity Program for Adults With Type 2 Diabetes: A Randomized Clinical Trial. JAMA network open Mukherji, A. B., Lu, D., Qin, F., Hedlin, H., Johannsen, N. M., Chung, S., Kobayashi, Y., Haddad, F., Lamendola, C., Basina, M., Talamoa, R., Myers, J., Palaniappan, L. 2022; 5 (12): e2247858

  Abstract

  The efficacy of physical activity interventions among individuals with type 2 diabetes has been established; however, practical approaches to translate and extend these findings into community settings have not been well explored.To test the effectiveness of providing varying frequencies of weekly structured exercise sessions to improve diabetes control.The IMPACT (Initiate and Maintain Physical Activity in Communities Trial) study was a controlled randomized clinical trial (randomization occurred from October 2016 to April 2019) that included a 6-month, structured exercise intervention either once or thrice weekly vs usual care (UC; advice only). The exercise intervention was conducted at community-based fitness centers. Follow-up visits were conducted in a university research clinic. Participants included adults with type 2 diabetes (hemoglobin A1c [HbA1c] 6.5%-13.0%, not taking insulin, and no precluding health issues). Data analysis was performed from January to April 2022.A once-weekly structured exercise group, a thrice-weekly structured exercise group, or UC.The primary outcome was HbA1c at 6 months.A total of 357 participants (143 women [40.1%]) with a mean (SD) age of 57.4 (11.1) years were randomized (119 each to the UC, once-weekly exercise, and thrice-weekly exercise groups). There was no significant difference in HbA1c change by study group in the intention-to-treat analysis at 6 months. Specifically, HbA1c changed by -0.23% (95% CI, -0.48% to 0.01%) in the thrice-weekly exercise group and by -0.16% (95% CI, -0.41% to 0.09%) in the once-weekly exercise group. A total of 62 participants (52.1%) in the once-weekly exercise group and 56 participants (47.1%) in the thrice-weekly exercise group were at least 50% adherent to the assigned structured exercise regimen and were included in the per-protocol analysis. Per-protocol analysis showed that HbA1c changed by -0.35% (95% CI, -0.60% to -0.10%; P = .005) at 3 months and by -0.38% (95% CI, -0.65% to -0.12%; P = .005) at 6 months in the thrice-weekly exercise group compared with UC. There was no significant decrease in HbA1c in the once-weekly exercise group. The exercise intervention was effective in improving self-reported minutes of metabolic equivalent tasks per week for participants in the thrice-weekly exercise group (both overall and per protocol).Although the intervention was not effective in the intention-to-treat analysis, participants in the thrice-weekly exercise group who attended at least 50% of the sessions during the 6-month exercise intervention program improved HbA1c levels at 6 months. Future efforts should focus on improving adherence to thrice-weekly structured exercise programs to meet exercise guidelines.ClinicalTrials.gov Identifier: NCT02061579.

  View details for DOI 10.1001/jamanetworkopen.2022.47858

  View details for PubMedID 36542382

• Correction: Immune biomarkers link air pollution exposure to blood pressure in adolescents. Environmental health : a global access science source Prunicki, M., Cauwenberghs, N., Ataam, J. A., Movassagh, H., Kim, J. B., Kuznetsova, T., Wu, J. C., Maecker, H., Haddad, F., Nadeau, K. 2022; 21 (1): 117

  View details for DOI 10.1186/s12940-022-00916-1

  View details for PubMedID 36443731

• Cardiac output assessment methods in left ventricular assist device patients: A problem of heteroscedasticity. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Azih, N. I., Read, J. M., Jackson, G. R., Inampudi, C., Witer, L., Kilic, A., Pope, N. H., Hajj, J., Haddad, F., Tedford, R. J., Houston, B. A. 2022

  Abstract

  Equipoise remains about how best to measure cardiac output (CO) in patients with left ventricular assist devices (LVAD). In this study, direct Fick CO was compared with thermodilution (TD) and indirect Fick (iFick) CO in 61 LVAD patients. TD and LaFarge iFick showed moderate correlation with direct Fick (R2 = 0.49 and R2 = 0.38, p < 0.001 for both), while Dehmer and Bergstra iFick showed poor correlation with direct Fick (R2 = 0.29 and R2 = 0.31, p < 0.001 for both). Absolute bias between all CO estimation techniques and direct Fick CO was lowest for TD compared to iFick methods but significant for all methods. All methods tended to overestimate CO compared to direct Fick, with greatest overestimation present in those with the lowest measured direct Fick CO. Bias and frequency of significant discrepancy were least using TD and Lafarge iFick CO estimation methods in this study, with TD CO demonstrating modestly better correlation and less heteroscedasticity compared to Lafarge.

  View details for DOI 10.1016/j.healun.2022.10.021

  View details for PubMedID 36481112

• Pulmonary Vasodilator Response of Combined Inhaled Epoprostenol and Inhaled Milrinone in Cardiac Surgical Patients. Anesthesia and analgesia Elmi-Sarabi, M., Jarry, S., Couture, E. J., Haddad, F., Cogan, J., Sweatt, A. J., Rousseau-Saine, N., Beaubien-Souligny, W., Fortier, A., Denault, A. Y. 2022

  Abstract

  BACKGROUND: Pulmonary hypertension (PH) and right ventricular (RV) dysfunction are major complications in cardiac surgery. Intraoperative management of patients at high risk of RV failure should aim to reduce RV afterload and optimize RV filling pressures, while avoiding systemic hypotension, to facilitate weaning from cardiopulmonary bypass (CPB). Inhaled epoprostenol and inhaled milrinone (iE&iM) administered in combination before CPB may represent an effective strategy to facilitate separation from CPB and reduce requirements for intravenous inotropes during cardiac surgery. Our primary objective was to report the rate of positive pulmonary vasodilator response to iE&iM and, second, how it relates to perioperative outcomes in cardiac surgery.METHODS: This is a retrospective cohort study of consecutive patients with PH or RV dysfunction undergoing on-pump cardiac surgery at the Montreal Heart Institute from July 2013 to December 2018 (n = 128). iE&iM treatment was administered using an ultrasonic mesh nebulizer before the initiation of CPB. Demographic and baseline clinical data, as well as hemodynamic, intraoperative, and echocardiographic data, were collected using electronic records. An increase of 20% in the mean arterial pressure (MAP) to mean pulmonary artery pressure (MPAP) ratio was used to indicate a positive response to iE&iM.RESULTS: In this cohort, 77.3% of patients were responders to iE&iM treatment. Baseline systolic pulmonary artery pressure (SPAP) (odds ratio [OR], 1.63; 95% confidence interval [CI], 1.24-2.16 per 5 mm Hg; P = .0006) was found to be a predictor of pulmonary vasodilator response, while a European System for Cardiac Operative Risk Evaluation (EuroSCORE II) score >6.5% was a predictor of nonresponse to treatment (≤6.5% vs >6.5% [reference]: OR, 5.19; 95% CI, 1.84-14.66; P = .002). Severity of PH was associated with a positive response to treatment, where a higher proportion of responders had MPAP values >30 mm Hg (42.4% responders vs 24.1% nonresponders; P = .0237) and SPAP values >55 mm Hg (17.2% vs 3.4%; P = .0037). Easier separation from CPB was also associated with response to iE&iM treatment (69.7% vs 58.6%; P = .0181). A higher proportion of nonresponders had a very difficult separation from CPB and required intravenous inotropic drug support compared to responders, for whom easy separation from CPB was more frequent. Use of intravenous inotropes after CPB was lower in responders to treatment (8.1% vs 27.6%; P = .0052).CONCLUSIONS: A positive pulmonary vasodilator response to treatment with a combination of iE&iM before initiation of CPB was observed in 77% of patients. Higher baseline SPAP was an independent predictor of pulmonary vasodilator response, while EuroSCORE II >6.5% was a predictor of nonresponse to treatment.

  View details for DOI 10.1213/ANE.0000000000006192

  View details for PubMedID 36121254

• Multiparametric evaluation of right ventricular function in pulmonary arterial hypertension associated with congenital heart disease. Revista espanola de cardiologia (English ed.) Fournier, E., Selegny, M., Amsallem, M., Haddad, F., Cohen, S., Valdeolmillos, E., Pavec, J. L., Humbert, M., Isorni, M. A., Azarine, A., Sitbon, O., Jais, X., Savale, L., Montani, D., Fadel, E., Zoghbi, J., Belli, E., Hascoët, S. 2022

  Abstract

  Outcome in patients with congenital heart diseases and pulmonary arterial hypertension (PAH) is closely related to right ventricular (RV) function. Two-dimensional echocardiographic parameters, such as strain imaging or RV end-systolic remodeling index (RVESRI) have emerged to quantify RV function.We prospectively studied 30 patients aged 48 ± 12 years with pretricuspid shunt and PAH and investigated the accuracy of multiple echocardiographic parameters of RV function (tricuspid annular plane systolic excursion, tricuspid annular peak systolic velocity, RV systolic-to-diastolic duration ratio, right atrial area, RV fractional area change, RV global longitudinal strain and RVESRI) to RV ejection fraction measured by cardiac magnetic resonance.RV ejection fraction < 45% was observed in 13 patients (43.3%). RV global longitudinal strain (ρ [Spearman's correlation coefficient] = -0.75; P = .001; R² = 0.58; P = .001), right atrium area (ρ = -0.74; P < .0001; R² = 0.56; P < .0001), RVESRI (ρ = -0.64; P < .0001; R² = 0.47; P < .0001), systolic-to-diastolic duration ratio (ρ = -0.62; P = .0004; R² = 0.47; P < .0001) and RV fractional area change (ρ = 0.48; P = .01; R² = 0.37; P < .0001) were correlated with RV ejection fraction. RV global longitudinal strain, RVESRI and right atrium area predicted RV ejection fraction < 45% with the greatest area under curve (0.88; 95%CI, 0.71-1.00; 0.88; 95%CI, 0.76-1.00, and 0.89; 95%CI, 0.77-1.00, respectively). RV global longitudinal strain > -16%, RVESRI ≥ 1.7 and right atrial area ≥ 22cm² predicted RV ejection fraction < 45% with a sensitivity and specificity of 87.5% and 85.7%; 76.9% and 88.3%; 92.3% and 82.4%, respectively.RVESRI, right atrial area and RV global longitudinal strain are strong markers of RV dysfunction in patients with pretricuspid shunt and PAH.

  View details for DOI 10.1016/j.rec.2022.07.010

  View details for PubMedID 35940550

• Multi-dimensional characterization of prediabetes in the Project Baseline Health Study. Cardiovascular diabetology Chatterjee, R., Kwee, L. C., Pagidipati, N., Koweek, L. H., Mettu, P. S., Haddad, F., Maron, D. J., Rodriguez, F., Mega, J. L., Hernandez, A., Mahaffey, K., Palaniappan, L., Shah, S. H., Project Baseline Health Study 2022; 21 (1): 134

  Abstract

  BACKGROUND: We examined multi-dimensional clinical and laboratory data in participants with normoglycemia, prediabetes, and diabetes to identify characteristics of prediabetes and predictors of progression from prediabetes to diabetes or reversion to no diabetes.METHODS: The Project Baseline Health Study (PBHS) is a multi-site prospective cohort study of 2502 adults that conducted deep clinical phenotyping through imaging, laboratory tests, clinical assessments, medical history, personal devices, and surveys. Participants were classified by diabetes status (diabetes [DM], prediabetes [preDM], or no diabetes [noDM]) at each visit based on glucose, HbA1c, medications, and self-report. Principal component analysis (PCA) was performed to create factors that were compared across groups cross-sectionally using linear models. Logistic regression was used to identify factors associated with progression from preDM to DM and for reversion from preDM to noDM.RESULTS: At enrollment, 1605 participants had noDM; 544 had preDM; and 352 had DM. Over 4 years of follow-up, 52 participants with preDM developed DM and 153 participants reverted to noDM. PCA identified 33 factors composed of clusters of clinical variables; these were tested along with eight individual variables identified a priori as being of interest. Six PCA factors and six a priori variables significantly differed between noDM and both preDM and DM after false discovery rate adjustment for multiple comparisons (q<0.05). Of these, two factors (one comprising glucose measures and one of anthropometry and physical function) demonstrated monotonic/graded relationships across the groups, as did three a priori variables: ASCVD risk, coronary artery calcium, and triglycerides (q<10-21 for all). Four factors were significantly different between preDM and noDM, but concordant or similar between DM and preDM: red blood cell indices (q=8*10-10), lung function (q=2*10-6), risks of chronic diseases (q=7*10-4), and cardiac function (q=0.001), along with a priori variables of diastolic function (q=1*10-10), sleep efficiency (q=9*10-6) and sleep time (q=6*10-5). Two factors were associated with progression from prediabetes to DM: anthropometry and physical function (OR [95% CI]: 0.6 [0.5, 0.9], q=0.04), and heart failure and c-reactive protein (OR [95% CI]: 1.4 [1.1, 1.7], q=0.02). The anthropometry and physical function factor was also associated with reversion from prediabetes to noDM: (OR [95% CI]: 1.9 [1.4, 2.7], q=0.02) along with a factor of white blood cell indices (OR [95% CI]: 0.6 [0.4, 0.8], q=0.02), and the a priori variables ASCVD risk score (OR [95% CI]: 0.7 [0.6, 0.9] for each 0.1 increase in ASCVD score, q=0.02) and triglycerides (OR [95% CI]: 0.9 [0.8, 1.0] for each 25mg/dl increase, q=0.05).CONCLUSIONS: PBHS participants with preDM demonstrated pathophysiologic changes in cardiac, pulmonary, and hematology measures and declines in physical function and sleep measures that precede DM; some changes predicted an increased risk of progression to DM. A factor with measures of anthropometry and physical function was the most important factor associated with progression to DM and reversion to noDM. Future studies may determine whether these changes elucidate pathways of progression to DM and related complications and whether they can be used to identify individuals at higher risk of progression to DM for targeted preventive interventions. Trial registration ClinicalTrials.gov NCT03154346.

  View details for DOI 10.1186/s12933-022-01565-x

  View details for PubMedID 35850765

• A PILOT CLINICAL TRIAL OF CELL THERAPY IN HEART FAILURE WITH PRESERVED EJECTION FRACTION. European journal of heart failure Vrtovec, B., Frljak, S., Poglajen, G., Zemljic, G., Cerar, A., Sever, M., Haddad, F., Wu, J. C. 2022

  Abstract

  AIMS: We investigated the effects of CD34+ cell therapy in patients with heart failure with preserved ejection fraction (HFpEF).METHODS AND RESULTS: In a prospective pilot study, we enrolled 30 patients with HFpEF. In Phase 1, patients were treated with medical therapy for 6 months. Thereafter, all patients underwent CD34+ cell transplantation. Using electroanatomical mapping, we measured local mechanical diastolic delay and myocardial viability to guide the targeting of cell injections. Patients were followed for 6 months after cell transplantation (Phase 2), and the primary end-point was the difference in change in E/e' between Phase 1 and Phase 2. In Phase 1, the decrease in E/e' was significantly less pronounced than in Phase 2. (-0.33±1.72 vs. -3.77±2.66, P=0.001). During Phase 1, there was no significant change in global systolic strain (GLS; from -12.5±2.4% to -12.8±2.6%, P=0.77), NT-proBNP (from 1463±1247 pg/mL to 1298±931 pg/mL, P=0.31), or 6-minute walk test distance (6MWT; from 391±75 m to 402±93 m, P=0.42). In Phase 2, an improvement was noted in NT-proBNP (from 1298±931 pg/ml to 887±809 pg/ml, P=0.02) and 6MWT (from 402±93 m to 438±72 m, P=0.02). Although GLS did not change significantly in Phase 2 (from -12.8±2.6% to -13.8±2.7%, P=0.36), we found improved local systolic strain at cell injection sites (-3.4±6.8%, P=0.005).CONCLUSIONS: In this non-randomized trial, transendocardial CD34+ cell therapy in HFpEF was associated with an improvement in E/e', NT-proBNP, exercise capacity, and local myocardial strain at the cell injection sites.CLINICAL TRIALS REGISTRATION: Clinicaltrials.gov NCT02923609 This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/ejhf.2596

  View details for PubMedID 35775390

• Endogenous Retroviral Elements Generate Pathologic Neutrophils in Pulmonary Arterial Hypertension. American journal of respiratory and critical care medicine Taylor, S., Isobe, S., Cao, A., Contrepois, K., Benayoun, B. A., Jiang, L., Wang, L., Melemenidis, S., Ozen, M. O., Otsuki, S., Shinohara, T., Sweatt, A. J., Kaplan, J., Moonen, J., Marciano, D. P., Gu, M., Miyagawa, K., Hayes, B., Sierra, R. G., Kupitz, C. J., Del Rosario, P. A., Hsi, A., Thompson, A. A., Ariza, M. E., Demirci, U., Zamanian, R. T., Haddad, F., Nicolls, M. R., Snyder, M. P., Rabinovitch, M. 2022

  Abstract

  RATIONALE: The role of neutrophils and their extracellular vesicles (EVs) in the pathogenesis of pulmonary arterial hypertension is unclear.OBJECTIVES: Relate functional abnormalities in pulmonary arterial hypertension neutrophils and their EVs to mechanisms uncovered by proteomic and transcriptomic profiling.METHODS: Production of elastase, release of extracellular traps, adhesion and migration were assessed in neutrophils from pulmonary arterial hypertension patients and control subjects. Proteomic analyses were applied to explain functional perturbations, and transcriptomic data were used to find underlying mechanisms. CD66b-specific neutrophil EVs were isolated from plasma of patients with pulmonary arterial hypertension and we determined whether they produce pulmonary hypertension in mice.MEASUREMENTS AND MAIN RESULTS: Neutrophils from pulmonary arterial hypertension patients produce and release increased neutrophil elastase, associated with enhanced extracellular traps. They exhibit reduced migration and increased adhesion attributed to elevated beta1integrin and vinculin identified on proteomic analysis and previously linked to an antiviral response. This was substantiated by a transcriptomic interferon signature that we related to an increase in human endogenous retrovirus k envelope protein. Transfection of human endogenous retrovirus k envelope in a neutrophil cell line (HL-60) increases neutrophil elastase and interferon genes, whereas vinculin is increased by human endogenous retrovirus k dUTPase that is elevated in patient plasma. Neutrophil EVs from patient plasma contain increased neutrophil elastase and human endogenous retrovirus k envelope and induce pulmonary hypertension in mice, mitigated by elafin, an elastase inhibitor.CONCLUSIONS: Elevated human endogenous retroviral elements and elastase link a neutrophil innate immune response to pulmonary arterial hypertension.

  View details for DOI 10.1164/rccm.202102-0446OC

  View details for PubMedID 35696338

• Wnt Signaling Interactor WTIP (Wilms Tumor Interacting Protein) Underlies Novel Mechanism for Cardiac Hypertrophy. Circulation. Genomic and precision medicine De Jong, H. N., Dewey, F. E., Cordero, P., Victorio, R. A., Kirillova, A., Huang, Y., Madhvani, R., Seo, K., Werdich, A. A., Lan, F., Orcholski, M., Robert Liu, W., Erbilgin, A., Wheeler, M. T., Chen, R., Pan, S., Kim, Y. M., Bommakanti, K., Marcou, C. A., Martijn Bos, J., Haddad, F., Ackerman, M., Vasan, R. S., MacRae, C., Wu, J. C., de Jesus Perez, V., Snyder, M., Parikh, V. N., Ashley, E. A. 2022: 101161CIRCGEN121003563

  Abstract

  BACKGROUND: The study of hypertrophic cardiomyopathy (HCM)-a severe Mendelian disease-can yield insight into the mechanisms underlying the complex trait of cardiac hypertrophy. To date, most genetic variants associated with HCM have been found in sarcomeric genes. Here, we describe a novel HCM-associated variant in the noncanonical Wnt signaling interactor WTIP (Wilms tumor interacting protein) and provide evidence of a role for WTIP in complex disease.METHODS: In a family affected by HCM, we used exome sequencing and identity-by-descent analysis to identify a novel variant in WTIP (p.Y233F). We knocked down WTIP in isolated neonatal rat ventricular myocytes with lentivirally delivered shRNAs and in Danio rerio via morpholino injection. We performed weighted gene coexpression network analysis for WTIP in human cardiac tissue, as well as association analysis for WTIP variation and left ventricular hypertrophy. Finally, we generated induced pluripotent stem cell-derived cardiomyocytes from patient tissue, characterized size and calcium cycling, and determined the effect of verapamil treatment on calcium dynamics.RESULTS: WTIP knockdown caused hypertrophy in neonatal rat ventricular myocytes and increased cardiac hypertrophy, peak calcium, and resting calcium in D rerio. Network analysis of human cardiac tissue indicated WTIP as a central coordinator of prohypertrophic networks, while common variation at the WTIP locus was associated with human left ventricular hypertrophy. Patient-derived WTIP p.Y233F-induced pluripotent stem cell-derived cardiomyocytes recapitulated cellular hypertrophy and increased resting calcium, which was ameliorated by verapamil.CONCLUSIONS: We demonstrate that a novel genetic variant found in a family with HCM disrupts binding to a known Wnt signaling protein, misregulating cardiomyocyte calcium dynamics. Further, in orthogonal model systems, we show that expression of the gene WTIP is important in complex cardiac hypertrophy phenotypes. These findings, derived from the observation of a rare Mendelian disease variant, uncover a novel disease mechanism with implications across diverse forms of cardiac hypertrophy.

  View details for DOI 10.1161/CIRCGEN.121.003563

  View details for PubMedID 35671065

• Cardiac Fibrosis in the Pressure Overloaded Left and Right Ventricle as a Therapeutic Target. Frontiers in cardiovascular medicine Schimmel, K., Ichimura, K., Reddy, S., Haddad, F., Spiekerkoetter, E. 2022; 9: 886553

  Abstract

  Myocardial fibrosis is a remodeling process of the extracellular matrix (ECM) following cardiac stress. "Replacement fibrosis" is a term used to describe wound healing in the acute phase of an injury, such as myocardial infarction. In striking contrast, ECM remodeling following chronic pressure overload insidiously develops over time as "reactive fibrosis" leading to diffuse interstitial and perivascular collagen deposition that continuously perturbs the function of the left (L) or the right ventricle (RV). Examples for pressure-overload conditions resulting in reactive fibrosis in the LV are systemic hypertension or aortic stenosis, whereas pulmonary arterial hypertension (PAH) or congenital heart disease with right sided obstructive lesions such as pulmonary stenosis result in RV reactive fibrosis. In-depth phenotyping of cardiac fibrosis has made it increasingly clear that both forms, replacement and reactive fibrosis co-exist in various etiologies of heart failure. While the role of fibrosis in the pathogenesis of RV heart failure needs further assessment, reactive fibrosis in the LV is a pathological hallmark of adverse cardiac remodeling that is correlated with or potentially might even drive both development and progression of heart failure (HF). Further, LV reactive fibrosis predicts adverse outcome in various myocardial diseases and contributes to arrhythmias. The ability to effectively block pathological ECM remodeling of the LV is therefore an important medical need. At a cellular level, the cardiac fibroblast takes center stage in reactive fibrotic remodeling of the heart. Activation and proliferation of endogenous fibroblast populations are the major source of synthesis, secretion, and deposition of collagens in response to a variety of stimuli. Enzymes residing in the ECM are responsible for collagen maturation and cross-linking. Highly cross-linked type I collagen stiffens the ventricles and predominates over more elastic type III collagen in pressure-overloaded conditions. Research has attempted to identify pro-fibrotic drivers causing fibrotic remodeling. Single key factors such as Transforming Growth Factor β (TGFβ) have been described and subsequently targeted to test their usefulness in inhibiting fibrosis in cultured fibroblasts of the ventricles, and in animal models of cardiac fibrosis. More recently, modulation of phenotypic behaviors like inhibition of proliferating fibroblasts has emerged as a strategy to reduce pathogenic cardiac fibroblast numbers in the heart. Some studies targeting LV reactive fibrosis as outlined above have successfully led to improvements of cardiac structure and function in relevant animal models. For the RV, fibrosis research is needed to better understand the evolution and roles of fibrosis in RV failure. RV fibrosis is seen as an integral part of RV remodeling and presents at varying degrees in patients with PAH and animal models replicating the disease of RV afterload. The extent to which ECM remodeling impacts RV function and thus patient survival is less clear. In this review, we describe differences as well as common characteristics and key players in ECM remodeling of the LV vs. the RV in response to pressure overload. We review pre-clinical studies assessing the effect of anti-fibrotic drug candidates on LV and RV function and their premise for clinical testing. Finally, we discuss the mode of action, safety and efficacy of anti-fibrotic drugs currently tested for the treatment of left HF in clinical trials, which might guide development of new approaches to target right heart failure. We touch upon important considerations and knowledge gaps to be addressed for future clinical testing of anti-fibrotic cardiac therapies.

  View details for DOI 10.3389/fcvm.2022.886553

  View details for PubMedID 35600469

  View details for PubMedCentralID PMC9120363

• Induction and Phenotyping of Acute Right Heart Failure in a Large Animal Model of Chronic Thromboembolic Pulmonary Hypertension. Journal of visualized experiments : JoVE Boulate, D., Amsallem, M., Menager, J., Dang Van, S., Dorfmuller, P., Connolly, A., Todesco, A., Decante, B., Fadel, E., Haddad, F., Mercier, O. 2022

  Abstract

  The development of acute right heart failure (ARHF) in the context of chronic pulmonary hypertension (PH) is associated with poor short-term outcomes. The morphological and functional phenotyping of the right ventricle is of particular importance in the context of hemodynamic compromise in patients with ARHF. Here, we describe a method to induce ARHF in a previously described large animal model of chronic PH, and to phenotype, dynamically, right ventricular function using the gold standard method (i.e., pressure-volume PV loops) and with a non-invasive clinically available method (i.e., echocardiography). Chronic PH is first induced in pigs by left pulmonary artery ligation and right lower lobe embolism with biological glue once a week for 5 weeks. After 16 weeks, ARHF is induced by successive volume loading using saline followed by iterative pulmonary embolism until the ratio of the systolic pulmonary pressure over systemic pressure reaches 0.9 or until the systolic systemic pressure decreases below 90 mmHg. Hemodynamics are restored with dobutamine infusion (from 2.5 g/kg/min to 7.5 g/kg/min). PV-loops and echocardiography are performed during each condition. Each condition requires around 40 minutes for induction, hemodynamic stabilization and data acquisition. Out of 9 animals, 2 died immediately after pulmonary embolism and 7 completed the protocol, which illustrates the learning curve of the model. The model induced a 3-fold increase in mean pulmonary artery pressure. The PV-loop analysis showed that ventriculo-arterial coupling was preserved after volume loading, decreased after acute pulmonary embolism and was restored with dobutamine. Echocardiographic acquisitions allowed to quantify right ventricular parameters of morphology and function with good quality. We identified right ventricular ischemic lesions in the model. The model can be used to compare different treatments or to validate non-invasive parameters of right ventricular morphology and function in the context of ARHF.

  View details for DOI 10.3791/58057

  View details for PubMedID 35377356

• ANALYZING PROGRESSION OF DISEASE IN HYPERTROPHIC CARDIOMYOPATHY UTILIZING SEQUENTIAL CARDIOPULMONARY EXERCISE TESTING Devareddy, A., Busque, V., Haddad, F., Myers, J. N., Christle, J., Ashley, E. A., Wheeler, M. ELSEVIER SCIENCE INC. 2022: 241

  View details for Web of Science ID 000781026600242

• Evaluation of diastole by echocardiography for detecting early cardiac dysfunction: an outcome study. ESC heart failure Kuznetsova, T., Cauwenberghs, N., Sabovcik, F., Kobayashi, Y., Haddad, F. 2022

  Abstract

  AIMS: Timely detection of subclinical left ventricular diastolic dysfunction (LVDDF) is of importance for precise risk stratification of asymptomatic subjects. Here, we evaluated the prevalence of LVDDF and its prognostic significance in the general population using two grading approaches: the 2016 ASE/EACVI recommendations and population-derived, age-specific criteria.METHODS AND RESULTS: We randomly recruited 1407 community-dwelling participants (mean age, 51.2years; 51.1% women; 53.5% with cardiovascular risk factors). We measured left heart dimensions, strain, tricuspid regurgitation, transmitral blood flow, and mitral annular tissue velocities using conventional echocardiography and Doppler imaging. We utilized these measurements to grade of LVDDF according to the 2016 recommendations and population-derived, age-specific approach. According to the 2016 recommendations, 26 subjects (1.85%) were classified as having the advanced stage (Grade 2), whereas in 109 participants (7.75%) diastolic function was indeterminate. When applying the population-derived criteria, the prevalence of advanced LVDDF was 17.9% (n=252). During the follow-up period (8.4years), 100 participants experienced adverse cardiac events. After full adjustment, we did not observe any significant differences in the risk of events between subjects with indeterminate or any grade of LVDDF and subjects with normal diastolic function when classified according to the 2016 recommendation (P≥0.25). In contrast, the adjusted risks of adverse cardiac events (HR=1.28; P=0.0045) were significantly elevated in participants with LVDDF when classified according to the population-derived criteria.CONCLUSIONS: Our study underscored the importance of considering age- and population-derived thresholds in LVDDF grading in subjects at high cardiovascular risk which led to a better risk stratification and outcome prediction.

  View details for DOI 10.1002/ehf2.13863

  View details for PubMedID 35238176

• Heterozygous LMNA mutation-carrying iPSC lines from three cardiac laminopathy patients. Stem cell research Cho, S., Lee, C., Lai, C., Zhuge, Y., Haddad, F., Fowler, M., Sallam, K., Wu, J. C. 1800; 59: 102657

  Abstract

  LMNA-related dilated cardiomyopathy (LMNA-DCM) is caused by pathogenic variants in the LMNA gene and is characterized by left ventricular chamber enlargement, reduced systolic function, and arrhythmia. Here, we generated three human induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells (PBMCs) of three DCM patients carrying the same single heterozygous mutation, c.398 G>A, in LMNA. All lines exhibited normal iPSC morphology, expressed high levels of pluripotency markers, showed normal karyotypes, and could differentiate into the three germ layers. These patient-specific iPSC lines can serve as invaluable tools to model in vitro pathological mechanisms of LMNA-DCM.

  View details for DOI 10.1016/j.scr.2022.102657

  View details for PubMedID 34999423

• Biological and clinical correlates of the patient health questionnaire-9: exploratory cross-sectional analyses of the baseline health study. BMJ open Califf, R. M., Wong, C., Doraiswamy, P. M., Hong, D. S., Miller, D. P., Mega, J. L. 2022; 12 (1): e054741

  Abstract

  We assessed the relationship between the Patient Health Questionnaire-9 (PHQ-9) at intake and other measurements intended to assess biological factors, markers of disease and health status.We performed a cross-sectional analysis of 2365 participants from the Baseline Health Study, a prospective cohort of adults selected to represent major demographic groups in the USA. Participants underwent deep phenotyping on demographic, clinical, laboratory, functional and imaging findings.Despite extensive research on the clinical implications of the PHQ-9, data are limited on the relationship between PHQ-9 scores and other measures of health and disease; we sought to better understand this relationship.None.Cross-sectional measures of medical illnesses, gait, balance strength, activities of daily living, imaging and laboratory tests.Compared with lower PHQ-9 scores, higher scores were associated with female sex (46.9%-66.7%), younger participants (53.6-42.4 years) and compromised physical status (higher resting heart rates (65 vs 75 bpm), larger body mass index (26.5-30 kg/m2), greater waist circumference (91-96.5 cm)) and chronic conditions, including gastro-oesophageal reflux disease (13.2%-24.7%) and asthma (9.5%-20.4%) (p<0.0001). Increasing PHQ-9 score was associated with a higher frequency of comorbidities (migraines (6%-20.4%)) and active symptoms (leg cramps (6.4%-24.7%), mood change (1.2%-47.3%), lack of energy (1.2%-57%)) (p<0.0001). After adjustment for relevant demographic, socioeconomic, behavioural and medical characteristics, we found that memory change, tension, shortness of breath and indicators of musculoskeletal symptoms (backache and neck pain) are related to higher PHQ-9 scores (p<0.0001).Our study highlights how: (1) even subthreshold depressive symptoms (measured by PHQ-9) may be indicative of several individual- and population-level concerns that demand more attention; and (2) depression should be considered a comorbidity in common disease.NCT03154346.

  View details for DOI 10.1136/bmjopen-2021-054741

  View details for PubMedID 34983769

• Insulin Growth Factor Phenotypes in Heart Failure with Preserved Ejection Fraction, an INSPIRE Registry and CATHGEN Study: IGF axis in HFpEF. Journal of cardiac failure Haddad, F., Ataam, J. A., Amsallem, M., Cauwenberghs, N., Kuznetsova, T., Rosenberg-Hasson, Y., Zamanian, R. T., Karakikes, I., Horne, B. D., Muhlestein, J. B., Kwee, L., Shah, S., Maecker, H., Knight, S., Knowlton, K. 1800

  Abstract

  BACKGROUND: The insulin like growth factor (IGF) axis emerged as an important pathway in heart failure with preserved ejection (HFpEF). We aimed to identify IGF phenotypes associated with HFpEF in the context high-dimensional proteomic profiling.METHODS: From the Intermountain INSPIRE Registry, we identified 96 patients with HFpEF and matched controls. We performed targeted proteomics including IGF-1,2, IGF binding proteins (IGFBP) 1-7 and 111 other proteins (EMD Millipore and ELISA). We used partial least square discriminant analysis (PLS-DA) to identify a set of proteins associated with prevalent HFpEF, pulmonary hypertension (PH) and 5-year-all-cause mortality. K-mean clustering was used to identify IGF phenotypes.RESULTS: Patients with HFpEF had a high prevalence of systemic hypertension (95%) and coronary artery disease (74%). Using PLS-DA, we identified a set of biomarkers including IGF1,2 and IGFBP-1,2,7 that provided a strong discrimination of HFPEF, PH and mortality with an AUC of 0.91, 0.77 and 0.83, respectively. Using K mean clustering, we identified three IGF phenotypes that were independently associated with all-cause 5-year mortality after adjustment for age, NT-proBNP and kidney disease (p=0.004). Multivariable analysis validated the prognostic value of IGFBP-1 and 2 in the CATHGEN biorepository.CONCLUSION: IGF phenotypes were associated with PH and mortality in HFpEF.

  View details for DOI 10.1016/j.cardfail.2021.12.012

  View details for PubMedID 34979242

• Proteomic profiling for detection of early-stage heart failure in the community Cauwenberghs, N., Sabovcik, F., Haddad, F., Kuznetsova, T. OXFORD UNIV PRESS. 2021: 861

  View details for Web of Science ID 000720456900849

• Pulmonary Hypertension in the Context of Heart Failure with Preserved Ejection Fraction. Chest Inampudi, C., Silverman, D., Simon, M. A., Leary, P. J., Sharma, K., Houston, B. A., Vachiery, J., Haddad, F., Tedford, R. J. 2021

  Abstract

  Heart failure with preserved ejection fraction (HFpEF) is the most common form of heart failure and is frequently associated with pulmonary hypertension (PH). PH-HFpEF may be difficult to distinguish from pre-capillary forms of PH, though this distinction is crucial as therapeutic pathways are divergent for the two conditions. A comprehensive and systematic approach utilizing history, clinical exam, non-invasive and invasive evaluation with and without provocative testing may be necessary for accurate diagnosis and phenotyping. Once diagnosed, PH-HFpEF can be subdivided into isolated post-capillary pulmonary hypertension (IpcPH) and combined post- and pre-capillary pulmonary hypertension (CpcPH) based on the presence or absence of elevated pulmonary vascular resistance (PVR). CpcPH portends a worse prognosis than IpcPH. Despite its association with reduced functional capacity and quality of life, heart failure hospitalizations, and higher mortality, therapeutic options focused on pulmonary hypertension for PH-HFpEF remain limited. In this review, we aim to provide an updated overview on clinical definitions and hemodynamically characterized phenotypes of PH, pathophysiology, therapeutic strategies, and ongoing challenges in this patient population.

  View details for DOI 10.1016/j.chest.2021.08.039

  View details for PubMedID 34391755

• Temporal changes in soluble angiotensin-converting enzyme 2 associated with metabolic health, body composition, and proteome dynamics during a weight loss diet intervention: a randomized trial with implications for the COVID-19 pandemic. The American journal of clinical nutrition Cauwenberghs, N., Prunicki, M., Sabovcik, F., Perelman, D., Contrepois, K., Li, X., Snyder, M. P., Nadeau, K. C., Kuznetsova, T., Haddad, F., Gardner, C. D. 2021

  Abstract

  BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) serves protective functions in metabolic, cardiovascular, renal, and pulmonary diseases and is linked to COVID-19 pathology. The correlates of temporal changes in soluble ACE2 (sACE2) remain understudied.OBJECTIVES: We explored the associations of sACE2 with metabolic health and proteome dynamics during a weight loss diet intervention.METHODS: We analyzed 457 healthy individuals (mean±SD age: 39.8±6.6 y) with BMI 28-40kg/m2 in the DIETFITS (Diet Intervention Examining the Factors Interacting with Treatment Success) study. Biochemical markers of metabolic health and 236 proteins were measured by Olink CVDII, CVDIII, and Inflammation I arrays at baseline and at 6 mo during the dietary intervention. We determined clinical and routine biochemical correlates of the diet-induced change in sACE2 (DeltasACE2) using stepwise linear regression. We combined feature selection models and multivariable-adjusted linear regression to identify protein dynamics associated with DeltasACE2.RESULTS: sACE2 decreased on average at 6 mo during the diet intervention. Stronger decline in sACE2 during the diet intervention was independently associated with female sex, lower HOMA-IR and LDL cholesterol at baseline, and a stronger decline in HOMA-IR, triglycerides, HDL cholesterol, and fat mass. Participants with decreasing HOMA-IR (OR: 1.97; 95% CI: 1.28, 3.03) and triglycerides (OR: 2.71; 95% CI: 1.72, 4.26) had significantly higher odds for a decrease in sACE2 during the diet intervention than those without (P≤0.0073). Feature selection models linked DeltasACE2 to changes in alpha-1-microglobulin/bikunin precursor, E-selectin, hydroxyacid oxidase 1, kidney injury molecule 1, tyrosine-protein kinase Mer, placental growth factor, thrombomodulin, and TNF receptor superfamily member 10B. DeltasACE2 remained associated with these protein changes in multivariable-adjusted linear regression.CONCLUSIONS: Decrease in sACE2 during a weight loss diet intervention was associated with improvements in metabolic health, fat mass, and markers of angiotensin peptide metabolism, hepatic and vascular injury, renal function, chronic inflammation, and oxidative stress. Our findings may improve the risk stratification, prevention, and management of cardiometabolic complications.This trial was registered at clinicaltrials.gov as NCT01826591.

  View details for DOI 10.1093/ajcn/nqab243

  View details for PubMedID 34375388

• Predicting Peak VO2 In Clinical Populations With Obesity Busque, V., Monegheetti, K. J., Ashley, E. A., Wheeler, M. T., Haddad, F., Myers, J., Christle, J. W. LIPPINCOTT WILLIAMS & WILKINS. 2021: 446

  View details for Web of Science ID 000693955700606

• Respiratory Gas Kinetics After Maximal Exercise In Patients Referred For Cardiopulmonary Exercise Testing Christle, J. W., Patti, A., Blumberg, Y., Neunhaeuserer, D., Ashley, E. A., Haddad, F., Myers, J., Moneghetti, K. J. LIPPINCOTT WILLIAMS & WILKINS. 2021: 98-99

  View details for Web of Science ID 000693128400317

• Optimal Tricuspid Regurgitation Velocity to Screen for Pulmonary Hypertension in Tertiary Referral Centers. Chest Montane, B. E., Fiore, A. M., Reznicek, E. C., Jain, V., Jellis, C., Rokadia, H., Li, M., Wang, X., Dweik, R., Loh, E., Watkins, A. C., Haddad, F., Amsallem, M., Zamanian, R. T., Perez, V. J., Heresi, G. A. 2021

  Abstract

  BACKGROUND: A mean pulmonary artery pressure >20 mmHg now defines pulmonary hypertension. We hypothesize that echocardiographic thresholds need to be adjusted.RESEARCH QUESTION: Should TRV thresholds to screen for PH be revised given the new hemodynamic definition?STUDY DESIGN AND METHODS: This multicenter retrospective study included 1,608 patients that underwent both echocardiography and right heart catherization within four weeks. The discovery cohort consisted of 1,081 individuals and the validation cohort included 527. Screening criteria for pulmonary hypertension were derived using receiver operating characteristic analysis and the Youden index assuming equal cost for false positive and negative classification. A lower threshold was calculated using a predefined sensitivity: 95%.RESULTS: In the discovery cohort, echocardiographic tricuspid regurgitation velocity had a good discrimination for pulmonary hypertension, AUC 88.4 (95% CI, 85.3-91.5). A 3.4 m/s threshold provided a 78% sensitivity, 87% specificity, and 6.13 positive likelihood ratio to detect pulmonary hypertension. 2.7 m/s had a 95% sensitivity and 0.12 negative likelihood ratio to exclude pulmonary hypertension. In the validation cohort, the discovery threshold of 2.7 m/s provided a sensitivity and negative likelihood ratio of 80% and 0.34, respectively. Right cardiac size improved detection of pulmonary hypertension in the lower tricuspid regurgitation velocity groups.INTERPRETATION: Our data support a lower tricuspid regurgitation velocity around 2.7 m/s for screening pulmonary hypertension with a high sensitivity in tertiary referral centers. Right heart chamber measurements improve the diagnostic yield of echocardiography.

  View details for DOI 10.1016/j.chest.2021.06.046

  View details for PubMedID 34217680

• Right Ventricle Remodeling Metabolic Signature in Experimental Pulmonary Hypertension Models of Chronic Hypoxia and Monocrotaline Exposure. Cells Hautbergue, T., Antigny, F., Boet, A., Haddad, F., Masson, B., Lambert, M., Delaporte, A., Menager, J., Savale, L., Pavec, J. L., Fadel, E., Humbert, M., Junot, C., Fenaille, F., Colsch, B., Mercier, O. 2021; 10 (6)

  Abstract

  INTRODUCTION: Over time and despite optimal medical management of patients with pulmonary hypertension (PH), the right ventricle (RV) function deteriorates from an adaptive to maladaptive phenotype, leading to RV failure (RVF). Although RV function is well recognized as a prognostic factor of PH, no predictive factor of RVF episodes has been elucidated so far. We hypothesized that determining RV metabolic alterations could help to understand the mechanism link to the deterioration of RV function as well as help to identify new biomarkers of RV failure.METHODS: In the current study, we aimed to characterize the metabolic reprogramming associated with the RV remodeling phenotype during experimental PH induced by chronic-hypoxia-(CH) exposure or monocrotaline-(MCT) exposure in rats. Three weeks after PH initiation, we hemodynamically characterized PH (echocardiography and RV catheterization), and then we used an untargeted metabolomics approach based on liquid chromatography coupled to high-resolution mass spectrometry to analyze RV and LV tissues in addition to plasma samples from MCT-PH and CH-PH rat models.RESULTS: CH exposure induced adaptive RV phenotype as opposed to MCT exposure which induced maladaptive RV phenotype. We found that predominant alterations of arginine, pyrimidine, purine, and tryptophan metabolic pathways were detected on the heart (LV+RV) and plasma samples regardless of the PH model. Acetylspermidine, putrescine, guanidinoacetate RV biopsy levels, and cytosine, deoxycytidine, deoxyuridine, and plasmatic thymidine levels were correlated to RV function in the CH-PH model. It was less likely correlated in the MCT model. These pathways are well described to regulate cell proliferation, cell hypertrophy, and cardioprotection. These findings open novel research perspectives to find biomarkers for early detection of RV failure in PH.

  View details for DOI 10.3390/cells10061559

  View details for PubMedID 34205639

• Proteomic profiling for detection of early-stage heart failure in the community. ESC heart failure Cauwenberghs, N., Sabovcik, F., Magnus, A., Haddad, F., Kuznetsova, T. 2021

  Abstract

  AIMS: Biomarkers may provide insights into molecular mechanisms underlying heart remodelling and dysfunction. Using a targeted proteomic approach, we aimed to identify circulating biomarkers associated with early stages of heart failure.METHODS AND RESULTS: A total of 575 community-based participants (mean age, 57years; 51.7% women) underwent echocardiography and proteomic profiling (CVD II panel, Olink Proteomics). We applied partial least squares-discriminant analysis (PLS-DA) and a machine learning algorithm [eXtreme Gradient Boosting (XGBoost)] to identify key proteins associated with echocardiographic abnormalities. We used Gaussian mixture modelling for unbiased clustering to construct phenogroups based on influential proteins in PLS-DA and XGBoost. Of 87 proteins, 13 were important in PLS-DA and XGBoost modelling for detection of left ventricular remodelling, left ventricular diastolic dysfunction, and/or left atrial reservoir dysfunction: placental growth factor, kidney injury molecule-1, prostasin, angiotensin-converting enzyme-2, galectin-9, cathepsin L1, matrix metalloproteinase-7, tumour necrosis factor receptor superfamily members 10A, 10B, and 11A, interleukins 6 and 16, and alpha1-microglobulin/bikunin precursor. Based on these proteins, the clustering algorithm divided the cohort into two distinct phenogroups, with each cluster grouping individuals with a similar protein profile. Participants belonging to the second cluster (n=118) were characterized by an unfavourable cardiovascular risk profile and adverse cardiac structure and function. The adjusted risk of presenting echocardiographic abnormalities was higher in this phenogroup than in the other (P<0.0001).CONCLUSIONS: We identified proteins related to renal function, extracellular matrix remodelling, angiogenesis, and inflammation to be associated with echocardiographic signs of early-stage heart failure. Proteomic phenomapping discriminated individuals at high risk for cardiac remodelling and dysfunction.

  View details for DOI 10.1002/ehf2.13375

  View details for PubMedID 34050710

• Improving Right Ventricular Function by Increasing BMP Signaling with FK506. American journal of respiratory cell and molecular biology Boehm, M., Tian, X., Ali, M. K., Mao, Y., Ichimura, K., Zhao, M., Kuramoto, K., Dannewitz Prosseda, S., Fajardo, G., Dufva, M. J., Qin, X., Kheyfets, V. O., Bernstein, D., Reddy, S., Metzger, R. J., Zamanian, R. T., Haddad, F., Spiekerkoetter, E. 2021

  Abstract

  Right Ventricular (RV) function is the predominant determinant of survival in patients suffering from pulmonary arterial hypertension (PAH). In pre-clinical models, pharmacological activation of bone morphogenetic protein (BMP) signaling with FK506 (Tacrolimus) improved RV function by decreasing RV afterload. FK506 therapy further stabilized three end-stage PAH patients. Whether FK506 has direct effects on the pressure overloaded RV is yet unknown. We hypothesized that increasing cardiac BMP signaling with FK506 improves RV structure and function in a model of fixed RV afterload after pulmonary artery banding (PAB). Direct cardiac effects of FK506 on the microvasculature and RV fibrosis were studied after surgical PAB in wildtype and heterozygous Bmpr2 mutant mice. Right ventricular function and strain were assessed longitudinally via cardiac magnetic resonance (CMR) imaging during continuous FK506 infusion. Genetic lineage tracing of endothelial cells (ECs) was performed to assess the contribution of ECs to fibrosis. Molecular mechanistic studies were performed in human cardiac fibroblasts (hCFs) and endothelial cells. In mice, low BMP signaling in the RV exaggerated PAB-induced RV fibrosis. FK506 therapy restored cardiac BMP signaling, reduced RV fibrosis in a BMP-dependent manner independent from its immunosuppressive effect, preserved RV capillarization and improved RV function and strain over the time-course of disease. Endothelial mesenchymal transition was a rare event and did not significantly contribute to cardiac fibrosis after PAB. Mechanistically, FK506 required ALK1 in hCFs as BMPR2 co-receptor to reduce TGFbeta1-induced proliferation and collagen production. Our study demonstrates that increasing cardiac BMP signaling with FK506 improves RV structure and function independent from its previously described beneficial effects on pulmonary vascular remodeling.

  View details for DOI 10.1165/rcmb.2020-0528OC

  View details for PubMedID 33938785

• Retraction notice to ICAM-1 PROMOTES THE ABNORMAL ENDOTHELIAL CELL PHENOTYPE IN CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Arthur Ataam, J., Mercier, O., Lamrani, L., Amsallem, M., Arthur Ataam, J., Arthur Ataam, S., Guihaire, J., Lecerf, F., Capuano, V., Ghigna, M. R., Haddad, F., Fadel, E., Eddahibi, S. 2021; 40 (4): 318

  Abstract

  This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Authors. This request follows an examination by The Editors of the uncut gels provided by the authors, which led the Editors to conclude that data were compromised in the following western blot images: Figure 3C, Figure 5B and Figure 6B. Duplicated data for the beta actin images were found in Figures 5 and 6. Examination of the raw data used for the western blot quantification also revealed frequent duplicated data. The microscopy data in Figure 5A also has features compatible with compromised data although the raw data were not available to the Editors due to the regrettable death of Dr. Saadia Eddahibi. All of the remaining authors agree with the retraction and apologize to the Editors and the readers of The Journal for difficulties this issue has caused.

  View details for DOI 10.1016/j.healun.2021.01.1563

  View details for PubMedID 33810826

• CTA pulmonary artery enlargement in patients with severe aortic stenosis: Prognostic impact after TAVR. Journal of cardiovascular computed tomography Turner, V. L., Jubran, A., Kim, J. B., Maret, E., Moneghetti, K. J., Haddad, F., Amsallem, M., Codari, M., Hinostroza, V., Mastrodicasa, D., Sailer, A. M., Kobayashi, Y., Nishi, T., Yeung, A. C., Watkins, A. C., Lee, A. M., Miller, D. C., Fischbein, M. P., Fearon, W. F., Willemink, M. J., Fleischmann, D. 2021

  Abstract

  BACKGROUND: Identifying high-risk patients who will not derive substantial survival benefit from TAVR remains challenging. Pulmonary hypertension is a known predictor of poor outcome in patients undergoing TAVR and correlates strongly with pulmonary artery (PA) enlargement on CTA. We sought to evaluate whether PA enlargement, measured on pre-procedural computed tomography angiography (CTA), is associated with 1-year mortality in patients undergoing TAVR.METHODS: We retrospectively included 402 patients undergoing TAVR between July 2012 and March 2016. Clinical parameters, including Society of Thoracic Surgeons (STS) score and right ventricular systolic pressure (RVSP) estimated by transthoracic echocardiography were reviewed. PA dimensions were measured on pre-procedural CTAs. Association between PA enlargement and 1-year mortality was analyzed. Kaplan-Meier and Cox proportional hazards regression analyses were performed.RESULTS: The median follow-up time was 433 (interquartiles 339-797) days. A total of 56/402 (14%) patients died within 1 year after TAVR. Main PA area (area-MPA) was independently associated with 1-year mortality (hazard ratio per standard deviation equal to 2.04 [95%-confidence interval (CI) 1.48-2.76], p​<​0.001). Area under the curve (95%-CI) of the clinical multivariable model including STS-score and RVSP increased slightly from 0.67 (0.59-0.75) to 0.72 (0.72-0.89), p​=​0.346 by adding area-MPA. Although the AUC increased, differences were not significant (p​=​0.346). Kaplan-Meier analysis showed that mortality was significantly higher in patients with a pre-procedural non-indexed area-MPA of ≥7.40​cm2 compared to patients with a smaller area-MPA (mortality 23% vs. 9%; p​<​0.001).CONCLUSIONS: Enlargement of MPA on pre-procedural CTA is independently associated with 1-year mortality after TAVR.

  View details for DOI 10.1016/j.jcct.2021.03.004

  View details for PubMedID 33795188

• Peripheral Oxygen Extraction and Exercise Limitation in Asymptomatic Patients with Diabetes Mellitus. The American journal of cardiology Kobayashi, Y., Christle, J. W., Contrepois, K., Nishi, T., Moneghetti, K., Cauwenberghs, N., Myers, J., Kuznetsova, T., Palaniappan, L., Haddad, F. 2021

  Abstract

  Patients with diabetes mellitus (DM) frequently present reduced exercise capacity. We aimed to explore the extent to which peripheral extraction relates to exercise capacity in asymptomatic patients with DM. We prospectively enrolled 98 asymptomatic patients with type-2 DM (mean age of 59±11 years and 56% male sex), and compared with 31 age, sex and body mass index (BMI)-matched normoglycemic controls. Cardiopulmonary exercise testing (CPX) with resting echocardiography was performed. Exercise response was assessed using peak oxygen uptake (peak VO2) and ventilatory efficiency was measured using the slope of the relationship between minute ventilation and carbon dioxide production (VE/VCO2). Peripheral extraction was calculated as the ratio of VO2to cardiac output. Cardiac function was evaluated using left ventricular longitudinal strain (LVLS), E/e', and relative wall thickness (RWT). Among patients with DM, 26 patients (27%) presented reduced percent-predicted-peak VO2(<80%) and 18 (18%) presented abnormal VE/VCO2slope (>34). There was no significant difference in peak cardiac output; peripheral extraction was lower in patients with DM compared to controls. Higher peak E/e' (beta=-0.24, p=0.004) was associated with lower peak VO2along with age, sex and BMI (R2=0.53). A network correlation map revealed the connectivity of peak VO2as a central feature and cluster analysis found LVLS, E/e', RWT and peak VO2in different clusters. In conclusion, impaired peripheral extraction may contribute to reduced peak VO2in asymptomatic patients with DM. Furthermore, cluster analysis suggests that CPX and echocardiography may be complementary for defining subclinical heart failure in patients with DM.

  View details for DOI 10.1016/j.amjcard.2021.03.011

  View details for PubMedID 33757787

• Sirolimus Adverse Event Profile in a Non-Clinical Trial Cohort of Heart Transplantation Patients. Annals of transplantation Sallam, K., Bhumireddy, G. P., Evuri, V. D., Abella, J. P., Haddad, F., Valentine, H. A., Nguyen, P. K., Pham, M. X. 2021; 26: e923536

  Abstract

  BACKGROUND Sirolimus has been used increasingly in heart transplantation for its ability to reduce acute rejection, prevent the progression of cardiac allograft vasculopathy (CAV), and preserve renal function. We sought to assess the adverse reactions associated with the use of sirolimus compared to mycophenolate mofetil (MMF). MATERIAL AND METHODS We retrospectively reviewed the charts of 221 adult heart transplant patients who received either sirolimus or MMF as part of their immunosuppression from June 1, 2001 to April 1, 2005. Patients were assigned to 2 groups based upon immunosuppression use. The prevalence and types of complications were recorded in each group. RESULTS Sirolimus was received by 109 patients and 112 patients received MMF during the study period. Seventy-seven patients (71%) in the sirolimus group experienced adverse reactions compared to 45 patients (40%) in the MMF group (P<0.01). Compared to MMF, the use of sirolimus was associated with a higher prevalence of elevated triglyceride levels, lower-extremity edema, and oral ulcerations. Sirolimus was discontinued due to adverse reactions in 22% of patients, whereas no patients in the MMF group experienced adverse effects requiring drug discontinuation. CONCLUSIONS Compared to MMF, sirolimus use is associated with a higher prevalence of adverse reactions requiring drug discontinuation, but most patients were able to stay on therapy despite adverse effects.

  View details for DOI 10.12659/AOT.923536

  View details for PubMedID 33462174

• Severe Pulmonary Arterial Hypertension is Characterized by Increased Neutrophil Elastase and Relative Elafin Deficiency. Chest Sweatt, A. J., Miyagawa, K., Rhodes, C. J., Taylor, S., Del Rosario, P. A., Hsi, A., Haddad, F., Spiekerkoetter, E., Bental-Roof, M., Bland, R. D., Swietlik, E. M., Gräf, S., Wilkins, M. R., Morrell, N. W., Nicolls, M. R., Rabinovitch, M., Zamanian, R. T. 2021

  Abstract

  Preclinical evidence implicates neutrophil elastase (NE) in PAH pathogenesis, and the NE inhibitor elafin is under early therapeutic investigation.Are circulating NE and elafin levels abnormal in PAH and associated with clinical severity?. In an observational Stanford University PAH cohort (N=249), plasma NE and elafin were measured in comparison to healthy controls (N=106) then related to clinical features and relevant ancillary biomarkers. Cox regression models were fitted with cubic spline functions to associate NE and elafin with survival. To validate prognostic relationships, we analyzed two United Kingdom cohorts (N=75, N=357). Mixed effects models evaluated NE and elafin changes during disease progression. Finally, we studied effects of NE/elafin balance on pulmonary artery endothelial cells (PAECs) from PAH patients.Relative to controls, patients had increased NE (205.1 [123.6-387.3] vs. 97.6 [74.4-126.6] ng/mL, P<0.0001) and decreased elafin (32.0 [15.3-59.1] vs. 45.5 [28.1-92.8] ng/mL, P<0.0001) independent of PAH subtype, illness duration, and therapies. Higher NE associated with worse symptom severity, shorter six-minute walk distance, higher NT-proBNP, greater right ventricular dysfunction, worse hemodynamics, increased circulating neutrophils, elevated cytokine levels, and lower blood BMPR2 expression. In Stanford patients, NE>168.5 ng/mL portended increased mortality risk after adjustment for known clinical predictors (HR 2.52, CI 1.36-4.65, P=0.003) or prognostic cytokines (HR 2.63, CI 1.42-4.87, P=0.001), and NE added incremental value to established PAH risk scores. Similar prognostic thresholds were identified in validation cohorts. Longitudinal NE changes tracked with clinical trends and outcomes. PAH-PAECs exhibited increased apoptosis and attenuated angiogenesis when exposed to NE at the level observed in patients' blood. Elafin rescued PAEC homeostasis, yet the required dose exceeded levels found in patients.NE is increased and elafin deficient across PAH subtypes. NE associates with disease severity and outcomes, and this target-specific biomarker could facilitate therapeutic development of elafin.

  View details for DOI 10.1016/j.chest.2021.06.028

  View details for PubMedID 34181952

• Predicting post-operative right ventricular failure using video-based deep learning. Nature communications Shad, R., Quach, N., Fong, R., Kasinpila, P., Bowles, C., Castro, M., Guha, A., Suarez, E. E., Jovinge, S., Lee, S., Boeve, T., Amsallem, M., Tang, X., Haddad, F., Shudo, Y., Woo, Y. J., Teuteberg, J., Cunningham, J. P., Langlotz, C. P., Hiesinger, W. 2021; 12 (1): 5192

  Abstract

  Despite progressive improvements over the decades, the rich temporally resolved data in an echocardiogram remain underutilized. Human assessments reduce the complex patterns of cardiac wall motion, to a small list of measurements of heart function. All modern echocardiography artificial intelligence (AI) systems are similarly limited by design - automating measurements of the same reductionist metrics rather than utilizing the embedded wealth of data. This underutilization is most evident where clinical decision making is guided by subjective assessments of disease acuity. Predicting the likelihood of developing post-operative right ventricular failure (RV failure) in the setting of mechanical circulatory support is one such example. Here we describe a video AI system trained to predict post-operative RV failure using the full spatiotemporal density of information in pre-operative echocardiography. We achieve an AUC of 0.729, and show that this ML system significantly outperforms a team of human experts at the same task on independent evaluation.

  View details for DOI 10.1038/s41467-021-25503-9

  View details for PubMedID 34465780

• Immune biomarkers link air pollution exposure to blood pressure in adolescents. Environmental health : a global access science source Prunicki, M., Cauwenberghs, N., Ataam, J. A., Movassagh, H., Kim, J. B., Kuznetsova, T., Wu, J. C., Maecker, H., Haddad, F., Nadeau, K. 2020; 19 (1): 108

  Abstract

  BACKGROUND: Childhood exposure to air pollution contributes to cardiovascular disease in adulthood. Immune and oxidative stress disturbances might mediate the effects of air pollution on the cardiovascular system, but the underlying mechanisms are poorly understood in adolescents. Therefore, we aimed to identify immune biomarkers linking air pollution exposure and blood pressure levels in adolescents.METHODS: We randomly recruited 100 adolescents (mean age, 16years) from Fresno, California. Using central-site data, spatial-temporal modeling, and distance weighting exposures to the participant's home, we estimated average pollutant levels [particulate matter (PM), polyaromatic hydrocarbons (PAH), ozone (O3), carbon monoxide (CO) and nitrogen oxides (NOx)]. We collected blood samples and vital signs on health visits. Using proteomic platforms, we quantitated markers of inflammation, oxidative stress, coagulation, and endothelial function. Immune cellular characterization was performed via mass cytometry (CyTOF). We investigated associations between pollutant levels, cytokines, immune cell types, and blood pressure (BP) using partial least squares (PLS) and linear regression, while adjusting for important confounders.RESULTS: Using PLS, biomarkers explaining most of the variance in air pollution exposure included markers of oxidative stress (GDF-15 and myeloperoxidase), acute inflammation (C-reactive protein), hemostasis (ADAMTS, D-dimer) and immune cell types such as monocytes. Most of these biomarkers were independently associated with the air pollution levels in fully adjusted regression models. In CyTOF analyses, monocytes were enriched in participants with the highest versus the lowest PM2.5 exposure. In both PLS and linear regression, diastolic BP was independently associated with PM2.5, NO, NO2, CO and PAH456 pollution levels (P≤0.009). Moreover, monocyte levels were independently related to both air pollution and diastolic BP levels (P≤0.010). In in vitro cell assays, plasma of participants with high PM2.5 exposure induced endothelial dysfunction as evaluated by eNOS and ICAM-1 expression and tube formation.CONCLUSIONS: For the first time in adolescents, we found that ambient air pollution levels were associated with oxidative stress, acute inflammation, altered hemostasis, endothelial dysfunction, monocyte enrichment and diastolic blood pressure. Our findings provide new insights on pollution-related immunological and cardiovascular disturbances and advocate preventative measures of air pollution exposure.

  View details for DOI 10.1186/s12940-020-00662-2

  View details for PubMedID 33066786

• Biomarkers and Risk Prediction Tools for Stroke and Dementia in Patients with Atrial Fibrillation CURRENT CARDIOVASCULAR RISK REPORTS Boralkar, K. A., Haddad, F., Horne, B. D. 2020; 14 (12)

  View details for DOI 10.1007/s12170-020-00658-0

  View details for Web of Science ID 000574454900001

• Larger End-Diastolic Volume Associates With Response to Cell Therapy in Patients With Nonischemic Dilated Cardiomyopathy. Mayo Clinic proceedings Frljak, S., Poglajen, G., Zemljic, G., Cerar, A., Haddad, F., Terzic, A., Vrtovec, B. 2020; 95 (10): 2125–33

  Abstract

  OBJECTIVE: To investigate the association of left ventricular end-diastolic volume (LVEDV) and the response to cell therapy in patients with nonischemic dilated cardiomyopathy (NICM).PATIENTS AND METHODS: Five-year registry data from 133 consecutive patients with NICM who underwent CD34+ cell treatment were analyzed. All patients received granulocyte-colony stimulating factor; CD34+ cells were collected by apheresis and delivered by transendocardial injections. Patients with baseline LVEDV less than 200 mL (group A; n=72) and patients with LVEDV 200 to 370 mL (group B; n=54) were included. Patients with LVEDV greater than 370 mL were excluded (n=7). Favorable ejection fraction response was pre-defined by improvement in left ventricular ejection fraction (LVEF) greater than or equal to 5% at 1 y post-cell therapy.RESULTS: At baseline, groups A and B were comparable with regards to age (52±11 y in group A vs 53±10 y in group B; P=.95), sex (male: 79% vs 83%, respectively; P=.55), creatinine (1.07±0.28 mg/dL vs 1.03±0.21 mg/dL, respectively; P=.21), or N-terminal probrain natriuretic peptide (1454±1658 pg/mL vs 1589±1338 pg/mL, respectively; P=.80). Baseline LVEF was higher in group A (32.8±8.7%) than in group B (30.2±8.7%; P=.03). During follow-up, there were four deaths in group A (5.6%), and 2 in group B (3.7%, P=.63). At 1-year post-cell therapy, LVEDV decreased significantly in group B (-56±30 mL; P=.003), but not in group A (+12±97 mL; P=.13). On multivariate analysis, baseline LVEDV was an independent correlate of favorable response in LVEF to therapy (P=.02).CONCLUSION: Larger LVEDV was associated with more pronounced increase in LVEF after transendocardial CD34+ cell therapy in NICM patients, informing target individuals with the highest likelihood of regenerative response.TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT02445534.

  View details for DOI 10.1016/j.mayocp.2020.02.031

  View details for PubMedID 33012343

• Update on noninvasive imaging of right ventricle dysfunction in pulmonary hypertension CARDIOVASCULAR DIAGNOSIS AND THERAPY Truong, U., Meinel, K., Haddad, F., Koestenberger, M., Carlsen, J., Ivy, D., Jone, P. 2020; 10 (5): 1604–24

  Abstract

  Pulmonary hypertension (PH) is a progressive disease affecting patients across the life span. The pathophysiology primarily involves the pulmonary vasculature and right ventricle (RV), but eventually affects the left ventricular (LV) function as well. Safe, accurate imaging modalities are critical for diagnosis, serial monitoring, and tailored therapy. While cardiac catheterization remains the conventional modality for establishing diagnosis and serial monitoring, noninvasive imaging has gained considerable momentum in providing accurate assessment of the entire RV-pulmonary axis. In this state-of-the-art review, we will discuss the most recent developments in echocardiography, magnetic resonance imaging, and computed tomography in PH evaluation from pediatric to adult population.

  View details for DOI 10.21037/cdt-20-272

  View details for Web of Science ID 000582467900037

  View details for PubMedID 33224776

  View details for PubMedCentralID PMC7666960

• Subclinical Heart Dysfunction in Relation to Metabolic and Inflammatory Markers: a Community-Based Study. American journal of hypertension Cauwenberghs, N., Sabovcik, F., Eline, V., Kobayashi, Y., Haddad, F., Budts, W., Kuznetsova, T. 2020

  Abstract

  BACKGROUND: Population studies investigating the contribution of immunometabolic disturbances to heart dysfunction remain scarce. We combined high-throughput biomarker profiling, multidimensional network analyses and regression statistics to identify immunometabolic markers associated with subclinical heart dysfunction in the community.METHODS: In 1,236 individuals (mean age, 51.0 years; 51.5% women), we measured 39 metabolic and inflammatory markers and assessed echocardiographic indexes of left ventricular diastolic dysfunction (LVDD) and left atrial (LA) reservoir dysfunction. We used partial least squares (PLS) to filter the most relevant biomarkers related to the echocardiographic characteristics. Subsequently, we assessed the associations between the echocardiographic features and the biomarkers selected in PLS while accounting for clinical confounders.RESULTS: Influential biomarkers in PLS modeling of echocardiographic characteristics included blood sugar, gamma-glutamyl transferase, D-dimer, ferritin, hemoglobin, IL-4, IL-6 and serum insulin and uric acid. In stepwise regression incorporating clinical confounders, higher D-dimer was independently associated with higher E/e' ratio and LA volume index (P≤0.05 for all). In multivariable-adjusted analyses, the risk for LVDD increased with higher blood sugar and D-dimer (P≤0.048). After full adjustment, higher serum insulin and serum uric acid were independently related to worse LA reservoir strain and higher risk for LA reservoir dysfunction (P≤0.039 for all). The focused biomarker panels detected LVDD and LA reservoir dysfunction with 87% and 79% accuracy, respectively (P<0.0001).CONCLUSIONS: Biomarkers of insulin resistance, hyperuricemia and chronic low-grade inflammation were associated with impaired cardiac function. These biomarkers might help to unravel cardiac pathology and improve the detection and management of cardiac dysfunction in clinical practice.

  View details for DOI 10.1093/ajh/hpaa150

  View details for PubMedID 32918813

• Cardiopulmonary Differences Between Normal And Overweight Diabetics Christle, J. W., Kobayashi, Y., Moneghetti, K., Wheeler, M., Myers, J., Palaniappan, L., Haddad, F. LIPPINCOTT WILLIAMS & WILKINS. 2020: 131

  View details for Web of Science ID 000590026300381

• VO2/WR Slope And HR/VO2 Slope Predict Major Adverse Events In Patients With Severe Heart Failure Mueller, S., Christle, J. W., Moneghetti, K. J., Amsallem, M., Halle, M., Haddad, F., Myers, J. LIPPINCOTT WILLIAMS & WILKINS. 2020: 168

  View details for Web of Science ID 000590026300477

• Applying machine learning to detect early stages of cardiac remodelling and dysfunction. European heart journal cardiovascular Imaging Sabovcik, F., Cauwenberghs, N., Kouznetsov, D., Haddad, F., Alonso-Betanzos, A., Vens, C., Kuznetsova, T. 2020

  Abstract

  AIMS: Both left ventricular (LV) diastolic dysfunction (LVDD) and hypertrophy (LVH) as assessed by echocardiography are independent prognostic markers of future cardiovascular events in the community. However, selective screening strategies to identify individuals at risk who would benefit most from cardiac phenotyping are lacking. We, therefore, assessed the utility of several machine learning (ML) classifiers built on routinely measured clinical, biochemical, and electrocardiographic features for detecting subclinical LV abnormalities.METHODS AND RESULTS: We included 1407 participants (mean age, 51years, 51% women) randomly recruited from the general population. We used echocardiographic parameters reflecting LV diastolic function and structure to define LV abnormalities (LVDD, n=252; LVH, n=272). Next, four supervised ML algorithms (XGBoost, AdaBoost, Random Forest (RF), Support Vector Machines, and Logistic regression) were used to build classifiers based on clinical data (67 features) to categorize LVDD and LVH. We applied a nested 10-fold cross-validation set-up. XGBoost and RF classifiers exhibited a high area under the receiver operating characteristic curve with values between 86.2% and 88.1% for predicting LVDD and between 77.7% and 78.5% for predicting LVH. Age, body mass index, different components of blood pressure, history of hypertension, antihypertensive treatment, and various electrocardiographic variables were the top selected features for predicting LVDD and LVH.CONCLUSION: XGBoost and RF classifiers combining routinely measured clinical, laboratory, and electrocardiographic data predicted LVDD and LVH with high accuracy. These ML classifiers might be useful to pre-select individuals in whom further echocardiographic examination, monitoring, and preventive measures are warranted.

  View details for DOI 10.1093/ehjci/jeaa135

  View details for PubMedID 32588036

• The Project Baseline Health Study: a step towards a broader mission to map human health NPJ DIGITAL MEDICINE Arges, K., Assimes, T., Bajaj, V., Balu, S., Bashir, M. R., Beskow, L., Blanco, R., Califf, R., Campbell, P., Carin, L., Christian, V., Cousins, S., Das, M., Dockery, M., Douglas, P. S., Dunham, A., Eckstrand, J., Fleischmann, D., Ford, E., Fraulo, E., French, J., Gambhir, S. S., Ginsburg, G. S., Green, R. C., Haddad, F., Hernandez, A., Hernandez, J., Huang, E. S., Jaffe, G., King, D., Koweek, L. H., Langlotz, C., Liao, Y. J., Mahaffey, K. W., Marcom, K., Marks, W. J., Maron, D., McCabe, R., McCall, S., McCue, R., Mega, J., Miller, D., Muhlbaier, L. H., Munshi, R., Newby, L., Pak-Harvey, E., Patrick-Lake, B., Pencina, M., Peterson, E. D., Rodriguez, F., Shore, S., Shah, S., Shipes, S., Sledge, G., Spielman, S., Spitler, R., Schaack, T., Swamy, G., Willemink, M. J., Wong, C. A. 2020; 3 (1): 84

  Abstract

  The Project Baseline Health Study (PBHS) was launched to map human health through a comprehensive understanding of both the health of an individual and how it relates to the broader population. The study will contribute to the creation of a biomedical information system that accounts for the highly complex interplay of biological, behavioral, environmental, and social systems. The PBHS is a prospective, multicenter, longitudinal cohort study that aims to enroll thousands of participants with diverse backgrounds who are representative of the entire health spectrum. Enrolled participants will be evaluated serially using clinical, molecular, imaging, sensor, self-reported, behavioral, psychological, environmental, and other health-related measurements. An initial deeply phenotyped cohort will inform the development of a large, expanded virtual cohort. The PBHS will contribute to precision health and medicine by integrating state of the art testing, longitudinal monitoring and participant engagement, and by contributing to the development of an improved platform for data sharing and analysis.

  View details for DOI 10.1038/s41746-020-0290-y

  View details for Web of Science ID 000538242900001

  View details for PubMedID 32550652

  View details for PubMedCentralID PMC7275087

• PROGNOSTIC VALUE OF THE RELATIVE PULMONARY PRESSURE RATIO AND ITS TRAJECTORY IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION Bagherzadeh, S. P., Amsallem, M., Denault, A., Sweatt, A., Kudelko, K., Sung, Y., Haddad, F., Zamanian, R. ELSEVIER SCIENCE INC. 2020: 2096

  View details for Web of Science ID 000522979102081

• Total Microfluidic chip for Multiplexed diagnostics (ToMMx). Biosensors & bioelectronics Ozen, M. O., Sridhar, K., Ogut, M. G., Shanmugam, A., Avadhani, A. S., Kobayashi, Y., Wu, J. C., Haddad, F., Demirci, U. 2020; 150: 111930

  Abstract

  Microfluidic technologies offer new platforms for biosensing in various clinical and point-of-care (POC) applications. Currently, at the clinical settings, the gold standard diagnostic platforms for multiplexed sensing are multi-step, time consuming, requiring expensive and bulky instruments with a constant need of electricity which makes them unsuitable for resource-limited or POC settings. These technologies are often limited by logistics, costly assays and regular maintenance. Although there have been several attempts to miniaturize these diagnostic platforms, they stand short of batch fabrication and they are dependent on complementary components such as syringe pumps. Here, we demonstrated the development and clinical testing of a disposable, multiplexed sensing device (ToMMx), which is a portable, high-throughput and user-friendly microfluidic platform. It was built with inexpensive plastic materials and operated manually without requiring electrical power and extensive training. We validated this platform in a small cohort of 50 clinical samples from patients with cardiovascular diseases and healthy controls. The platform is rapid and gives quantifiable results with high sensitivity, as low as 5.29pg/mL, from only a small sample volume (4muL). ToMMx platform was compared side-by-side with commercial ELISA kits where the total assay time is reduced 15-fold, from 5h to 20min. This technology platform is broadly applicable to various diseases with well-known biomarkers in diagnostics and monitoring, especially with potential future impact at the POC settings.

  View details for DOI 10.1016/j.bios.2019.111930

  View details for PubMedID 31929083

• Impact of age, sex and heart rate variability on the acute cardiovascular response to isometric handgrip exercise. Journal of human hypertension Cauwenberghs, N., Cornelissen, V., Christle, J. W., Hedman, K., Myers, J., Haddad, F., Kuznetsova, T. 2020

  Abstract

  Isometric handgrip exercise (IHG) triggers acute increases in cardiac output to meet the metabolic demands of the active skeletal muscle. An abnormal cardiovascular response to IHG might reflect early stages of cardiovascular disease. In a large community-based cohort, we comprehensively assessed the clinical correlates of acute cardiovascular changes during IHG. In total, 333 randomly recruited subjects (mean age, 53±13 years, 45% women) underwent simultaneous echocardiography and finger applanation tonometry at rest and during 3min of IHG at 40% maximal handgrip force. We calculated time-domain measures of short-term heart rate variability (HRV) from finger pulse intervals. We assessed the adjusted associations of changes in blood pressure (BP) and echocardiographic indexes with clinical characteristics and HRV measures. During IHG, men presented a stronger absolute increase in heart rate, diastolic BP, left ventricular (LV) volumes and cardiac output than women, even after adjustment for covariables. In adjusted continuous and categorical analyses, age correlated positively with the increase in systolic BP and pulse pressure, but negatively with the increase in LV stroke volume and cardiac output during exercise. After full adjustment, a greater increase in systolic and diastolic BP during exercise was associated with lower absolute real variability (P≤0.026) and root mean square of successive differences (P≤0.032) in pulse intervals at rest. In a general population sample, women presented a weaker cardiovascular response to IHG than men. Older age was associated with greater rise in BP pulsatility and diminished cardiac reserve. Low HRV at rest predicted a higher BP increase during isometric exercise.

  View details for DOI 10.1038/s41371-020-0311-y

  View details for PubMedID 32042073

• Physiology of the Assisted Circulation in Cardiogenic Shock: A State-of-the-Art Perspective. The Canadian journal of cardiology Guihaire, J., Haddad, F., Hoppenfeld, M., Amsallem, M., Christle, J. W., Owyang, C., Shaikh, K., Hsu, J. L. 2020; 36 (2): 170–83

  Abstract

  Mechanical circulatory support (MCS) has made rapid progress over the last 3 decades. This was driven by the need to develop acute and chronic circulatory support as well as by the limited organ availability for heart transplantation. The growth of MCS was also driven by the use of extracorporeal membrane oxygenation (ECMO) after the worldwide H1N1 influenza outbreak of 2009. The majority of mechanical pumps (ECMO and left ventricular assist devices) are currently based on continuous flow pump design. It is interesting to note that in the current era, we have reverted from the mammalian pulsatile heart back to the continuous flow pumps seen in our simple multicellular ancestors. This review will highlight key physiological concepts of the assisted circulation from its effects on cardiac dynamic to principles of cardiopulmonary fitness. We will also examine the physiological principles of the ECMO-assisted circulation, anticoagulation, and the haemocompatibility challenges that arise when the blood is exposed to a foreign mechanical circuit. Finally, we conclude with a perspective on smart design for future development of devices used for MCS.

  View details for DOI 10.1016/j.cjca.2019.11.002

  View details for PubMedID 32036862

• Pollution-Associated Exposure Signature in Teenagers Haddad, F., Cauwenberghs, N., Movassagh, H., Maecker, H., Arthur, J., Wu, J., Nadeau, K., Prunicki, M. MOSBY-ELSEVIER. 2020: AB82

  View details for Web of Science ID 000517092700253

• Cardiogenic Shock: Reflections at the Crossroad Between Perfusion, Tissue Hypoxia, and Mitochondrial Function. The Canadian journal of cardiology O'Brien, C., Beaubien-Souligny, W., Amsallem, M., Denault, A., Haddad, F. 2020; 36 (2): 184–96

  Abstract

  Cardiogenic shock is classically defined by systemic hypotension with evidence of hypoperfusion and end organ dysfunction. In modern practice, however, these metrics often incompletely describe cardiogenic shock because patients present with more advanced cardiovascular disease and greater degrees of multiorgan dysfunction. Understanding how perfusion, congestion, and end organ dysfunction contribute to hypoxia at the cellular level are central to the diagnosis and management of cardiogenic shock. Although, in clinical practice, increased lactate level is often equated with hypoxia, several other factors might contribute to an elevated lactate level including mitochondrial dysfunction, impaired hepatic and renal clearance, as well as epinephrine use. To this end, we present the evidence underlying the value of lactate to pyruvate ratio as a potential discriminator of cellular hypoxia. We will then discuss the physiological implications of hypoxia and congestion on hepatic, intestinal, and renal physiology. Organ-specific susceptibility to hypoxia is presented in the context of their functional architecture. We discuss how the concepts of contractile reserve, fluid responsiveness, tissue oxygenation, and cardiopulmonary interactions can help personalize the management of cardiogenic shock. Finally, we highlight the limitations of using lactate for tailoring therapy in cardiogenic shock.

  View details for DOI 10.1016/j.cjca.2019.11.020

  View details for PubMedID 32036863

• Preliminary Experience Using Diastolic Right Ventricular Pressure Gradient Monitoring in Cardiac Surgery. Journal of cardiothoracic and vascular anesthesia Gronlykke, L., Couture, E. J., Haddad, F., Amsallem, M., Ravn, H. B., Raymond, M., Beaubien-Souligny, W., Demers, P., Rochon, A., Sarabi, M. E., Lamarche, Y., Desjardins, G., Denault, A. Y. 2020

  Abstract

  OBJECTIVES: Right ventricular (RV) dysfunction in cardiac surgery is associated with increased mortality and morbidity and difficult separation from cardiopulmonary bypass (DSB). The primary objective of the present study was to describe the prevalence and characteristics of patients with abnormal RV diastolic pressure gradient (PG). The secondary objective was to explore the association among abnormal diastolic PG and DSB, postoperative complications, high central venous pressure (CVP), and high RV end-diastolic pressure (RVEDP).DESIGN: Retrospective and prospective validation study.SETTING: Tertiary care cardiac institute.PARTICIPANTS: Cardiac surgical patients (n=374) from a retrospective analysis (n=259) and a prospective validation group (n=115).INTERVENTION: RV pressure waveforms were obtained using a pulmonary artery catheter with a pacing port opened at 19 cm distal to the tip of the catheter. Abnormal RV diastolic PG was defined as >4 mmHg. Both elevated RVEDP and high CVP were defined as >16 mmHg.MEASUREMENTS AND MAIN RESULTS: From the retrospective and validation cohorts, 42.5% and 48% of the patients had abnormal RV diastolic PG before cardiac surgery, respectively. Abnormal RV diastolic PG before cardiac surgery was associated with higher EuroSCORE II (odds ratio 2.29 [1.10-4.80] v 1.62 [1.10-3.04]; p = 0.041), abnormal hepatic venous flow (45% v 29%; p = 0.038), higher body mass index (28.9 [25.5-32.5] v 27.0 [24.9-30.5]; p = 0.022), pulmonary hypertension (48% v 37%; p = 0.005), and more frequent DSB (32% v 19%; p = 0.023). However, RV diastolic PG was not an independent predictor of DSB, whereas RVEDP (odds ratio 1.67 [1.09-2.55]; p = 0.018) was independently associated with DSB. In addition, RV pressure monitoring indices were superior to CVP in predicting DSB.CONCLUSION: Abnormal RV diastolic PG is common before cardiac surgery and is associated with a higher proportion of known preoperative risk factors. However, an abnormal RV diastolic PG gradient is not an independent predictor of DSB in contrast to RVEDP.

  View details for DOI 10.1053/j.jvca.2019.12.042

  View details for PubMedID 32037274

• Preoperative C-reactive protein predicts early postoperative outcomes after pulmonary endarterectomy in patients with chronic thromboembolic pulmonary hypertension. The Journal of thoracic and cardiovascular surgery Arthur Ataam, J., Amsallem, M., Guihaire, J., Haddad, F., Lamrani, L., Stephan, F., Jais, X., Humbert, M., Mercier, O., Fadel, E. 2020

  Abstract

  OBJECTIVE: To determine whether preoperative systemic inflammation (defined by C-reactive protein [CRP] levels ≥10mg/L) is associated with worse functional and hemodynamic status and poor early outcomes postendarterectomy in patients with chronic thromboembolic pulmonary hypertension (CTEPH).METHODS: This study included 159 patients who underwent pulmonary endarterectomy from 2009 to 2013 (derivation cohort) and 238 patients from 2015 to 2016 (validation cohort) with CRP data from the national CTEPH registry. The correlations between proinflammatory markers (CRP, interleukins 1 and 6, fibrinogen, and leukocytes) and hemodynamics were assessed in the derivation cohort. Pre-, perioperative characteristics, and 30-day outcomes (ie, death or lung transplant or extracorporeal membrane oxygenation need or inotropic or vasopressor need ≥3days) of patients with CRP levels≥or <10mg/L were compared.RESULTS: Median age of the derivation cohort was 63 [52-73] years with 48% female, 80% in New York Heart Association class III/IV. The validation cohort had similar demographics and disease severity. Patients with CRP ≥10mg/L had greater resistance levels and lower cardiac index than those with CRP <10mg/L in both cohorts. The primary endpoint was reached in 38% (derivation) and 42% (validation) of patients. In multivariable logistic regression analysis, CRP ≥10mg/L was associated with the primary endpoint in both the derivation cohort (odd ratio, 2.49 [1.11-5.61], independently of New York Heart class class IV and aortic clamping duration) and the validation cohort (odd ratio, 1.89 [1.09-3.61], independently of age and aortic clamping duration).CONCLUSIONS: Preoperative CRP ≥10mg/L is independently associated with adverse early outcomes postendarterectomy.

  View details for DOI 10.1016/j.jtcvs.2019.11.133

  View details for PubMedID 32007254

• Right ventricular mitochondrial respiratory function in a piglet model of chronic pulmonary hypertension JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Noly, P., Piquereau, J., Coblence, M., Ataam, J., Guihaire, J., Rucker-Martin, C., Decante, B., Haddad, F., Fadel, E., Mercier, O. 2020; 159 (1): 129–40

  View details for DOI 10.1016/j.jtcvs.2019.02.096

  View details for Web of Science ID 000507381200079

• Hemodynamic trajectories and outcomes in patients with pulmonary arterial hypertension. Pulmonary circulation Amsallem, M. n., Bagherzadeh, S. P., Boulate, D. n., Sweatt, A. J., Kudelko, K. T., Sung, Y. K., Feinstein, J. A., Fadel, E. n., Mercier, O. n., Denault, A. n., Haddad, F. n., Zamanian, R. n. 2020; 10 (4): 2045894020941343

  Abstract

  The relative pulmonary to systemic pressure ratio (mean pulmonary arterial pressure/mean arterial pressure) has been proven to be valuable in cardiac surgery. Little is known on the prognostic value of baseline and trajectory of mean pulmonary arterial pressure/mean arterial pressure in pulmonary arterial hypertension. Patients with confirmed idiopathic, familial, drug and toxins, or connective tissue disease-related pulmonary arterial hypertension and at least one complete right heart catheterization were included and prospectively followed-up for 5.9 ± 4.03 years. Correlates of the primary end point (i.e. death or lung transplant need) during follow-up were determined using Cox regression modeling. Results showed that among the 308 patients included, 187 had at least one follow-up catheterization (median time between catheterizations: 2.16 (1.16-3.19) years). In the total cohort (mean age 47.3 ± 14.9 years, 82.8% of female and 58.1% in New York Heart Association class 3 or 4), mean pulmonary arterial pressure/mean arterial pressure (1.38 (1.07-1.77)) was associated with outcome (p = 0.01). Mean pulmonary arterial pressure/mean arterial pressure was incremental to a basic model (including right atrial pressure, systolic blood pressure, New York Heart Association class 3 or 4, and connective tissue disease) for outcome prediction, while mean pulmonary arterial pressure was not. In the 187 patients with a follow-up catheterization, both delta mean pulmonary arterial pressure and delta mean pulmonary arterial pressure/mean arterial pressure were associated with outcome (1.32 (1.11-1.58) and 1.31 (1.1-1.57) respectively, p < 0.01). Mean pulmonary arterial pressure and mean pulmonary arterial pressure/mean arterial pressure were both incremental to the basic model, while worsening in mean pulmonary arterial pressure or mean pulmonary arterial pressure/mean arterial pressure did not reach significance. In conclusion, mean pulmonary arterial pressure/mean arterial pressure at baseline prognosticates long-term outcome with a significant, albeit modest, incremental value to basic variables.

  View details for DOI 10.1177/2045894020941343

  View details for PubMedID 33335708

  View details for PubMedCentralID PMC7724418

• Mechanics of right ventricular dysfunction in pulmonary arterial hypertension and heart failure with preserved ejection fraction. Cardiovascular diagnosis and therapy Bernardo, R. J., Haddad, F. n., Couture, E. J., Hansmann, G. n., de Jesus Perez, V. A., Denault, A. Y., de Man, F. S., Amsallem, M. n. 2020; 10 (5): 1580–1603

  Abstract

  Right ventricular (RV) dysfunction is the most important determinant of survival in patients with pulmonary hypertension (PH). The manifestations of RV dysfunction not only include changes in global RV systolic function but also abnormalities in the pattern of contraction and synchrony. The effects of PH on the right ventricle have been mainly studied in patients with pulmonary arterial hypertension (PAH). However, with the demographic shift towards an aging population, heart failure with preserved ejection fraction (HFpEF) has become an important etiology of PH in recent years. There are significant differences in RV mechanics, function and adaptation between patients with PAH and HFpEF (with or without PH), which are related to different patterns of remodeling and dysfunction. Due to the unique features of the RV chamber, its connection with the main pulmonary artery and the pulmonary circulation, an understanding of the mechanics of RV function and its clinical significance is mandatory for both entities. In this review, we describe the mechanics of the pressure overloaded right ventricle. We review the different mechanical components of RV dysfunction and ventricular dyssynchrony, followed by insights via analysis of pressure-volume loop, energetics and novel blood flow patterns, such as vortex imaging. We conduct an in-depth comparison of prevalence and characteristics of RV dysfunction in HFpEF and PAH, and summarize key outcome studies. Finally, we provide a perspective on needed and expected future work in the field of RV mechanics.

  View details for DOI 10.21037/cdt-20-479

  View details for PubMedID 33224775

  View details for PubMedCentralID PMC7666917

• Limitations of right ventricular annular parameters in the early postoperative period following pulmonary endarterectomy: an observational study. Interactive cardiovascular and thoracic surgery Rézaiguia-Delclaux, S. n., Haddad, F. n., Pilorge, C. n., Amsallem, M. n., Fadel, E. n., Stéphan, F. n. 2020

  Abstract

  Echocardiographic right ventricular (RV) annular parameters are probably not as reliable to evaluate the surgical success in the postoperative period after pulmonary endarterectomy (PEA), whereas RV end-diastolic/left ventricular end-diastolic area ratio (RVEDA/LVEDA ratio) could be more useful. This study examined the relationship between RV annular parameters or RVEDA/LVEDA ratio and ideal cardiac index (ICI), before and after PEA.Among 80 patients who underwent PEA, the relationships between RVEDA/LVEDA ratio (21 patients), or tricuspid annular plane systolic excursion (32 patients), or systolic tricuspid annular velocity (55 patients) and ICI were modelled.Forty-eight hours following PEA, mean pulmonary artery pressure decreased (26 ± 6 vs 46 ± 12 mmHg, P < 0.0001) and ICI improved (2.8 ± 0.8 vs 3.0 ± 0.9 l/min/m2, P = 0.02). In contrast to the moderate association between RV annular indices and ICI in the preoperative period, no significant relationship was found in the postoperative period (r = 0.54 and 0.17 for tricuspid annular plane systolic excursion and r = 0.46 and 0.16 for systolic tricuspid annular velocity, respectively). The RVEDA/LVEDA ratio significantly decreased postoperatively (0.97 ± 0.21 vs 1.19 ± 0.43, P = 0.002) and was correlated with ICI both in preoperative and postoperative periods (r = 0.57 and 0.57, respectively). There was a significant correlation between changes in RVEDA/LVEDA ratio and changes in total pulmonary resistance.Improved ICI and RVEDA/LVEDA ratio reflected the surgical success of PEA and lowering of total pulmonary resistances. In contrast to the RV/left ventricular area ratio, annular RV indices associated poorly with postoperative ICI. Recognizing this limitation is important in minimizing the overdiagnosis of RV dysfunction after PEA.

  View details for DOI 10.1093/icvts/ivaa088

  View details for PubMedID 32577738

• Molecular Choreography of Acute Exercise. Cell Contrepois, K. n., Wu, S. n., Moneghetti, K. J., Hornburg, D. n., Ahadi, S. n., Tsai, M. S., Metwally, A. A., Wei, E. n., Lee-McMullen, B. n., Quijada, J. V., Chen, S. n., Christle, J. W., Ellenberger, M. n., Balliu, B. n., Taylor, S. n., Durrant, M. G., Knowles, D. A., Choudhry, H. n., Ashland, M. n., Bahmani, A. n., Enslen, B. n., Amsallem, M. n., Kobayashi, Y. n., Avina, M. n., Perelman, D. n., Schüssler-Fiorenza Rose, S. M., Zhou, W. n., Ashley, E. A., Montgomery, S. B., Chaib, H. n., Haddad, F. n., Snyder, M. P. 2020; 181 (5): 1112–30.e16

  Abstract

  Acute physical activity leads to several changes in metabolic, cardiovascular, and immune pathways. Although studies have examined selected changes in these pathways, the system-wide molecular response to an acute bout of exercise has not been fully characterized. We performed longitudinal multi-omic profiling of plasma and peripheral blood mononuclear cells including metabolome, lipidome, immunome, proteome, and transcriptome from 36 well-characterized volunteers, before and after a controlled bout of symptom-limited exercise. Time-series analysis revealed thousands of molecular changes and an orchestrated choreography of biological processes involving energy metabolism, oxidative stress, inflammation, tissue repair, and growth factor response, as well as regulatory pathways. Most of these processes were dampened and some were reversed in insulin-resistant participants. Finally, we discovered biological pathways involved in cardiopulmonary exercise response and developed prediction models revealing potential resting blood-based biomarkers of peak oxygen consumption.

  View details for DOI 10.1016/j.cell.2020.04.043

  View details for PubMedID 32470399

• Outcomes in Patients With Cardiac Amyloidosis Undergoing Heart Transplantation. JACC. Heart failure Barrett, C. D., Alexander, K. M., Zhao, H. n., Haddad, F. n., Cheng, P. n., Liao, R. n., Wheeler, M. T., Liedtke, M. n., Schrier, S. n., Arai, S. n., Weisshaar, D. n., Witteles, R. M. 2020

  Abstract

  The purpose of this study is to report outcomes after heart transplantation in patients with cardiac amyloidosis based on a large single-center experience.Cardiac amyloidosis causes significant morbidity and mortality, often leading to restrictive cardiomyopathy, progressive heart failure, and death. Historically, heart transplantation outcomes have been worse in patients with cardiac amyloidosis compared with other heart failure populations, in part due to the systemic nature of the disease. However, several case series have suggested that transplantation outcomes may be better in the contemporary era, likely in part due to the availability of more effective light chain suppressive therapies for light chain amyloidosis.This study examined all patients seen between 2004 and 2017, either at the Stanford University Medical Center or the Kaiser Permanente Santa Clara Medical Center, who were diagnosed with cardiac amyloidosis and ultimately underwent heart transplantation. This study examined pre-transplantation characteristics and post-transplantation outcomes in this group compared with the overall transplantation population at our center.During the study period, 31 patients (13 with light chain amyloidosis and 18 with transthyretin [ATTR] amyloidosis) underwent heart transplantation. Patients with ATTR amyloidosis were older, were more likely to be male, had worse baseline renal function, and had longer waitlist times compared with both patients with light chain amyloidosis and the overall transplantation population. Post-transplantation, there were no differences in post-operative bleeding, renal failure, infection, rejection, or malignancy. There was no significant difference in mortality between patients who underwent heart transplantation for amyloid cardiomyopathy and patients who underwent heart transplantation for all other indications.In carefully selected patients with cardiac amyloidosis, heart transplantation can be an effective therapeutic option with outcomes similar to those transplanted for other causes of heart failure.

  View details for DOI 10.1016/j.jchf.2019.12.013

  View details for PubMedID 32387068

• Incremental value of diastolic stress test in identifying subclinical heart failure in patients with diabetes mellitus. European heart journal cardiovascular Imaging Nishi, T. n., Kobayashi, Y. n., Christle, J. W., Cauwenberghs, N. n., Boralkar, K. n., Moneghetti, K. n., Amsallem, M. n., Hedman, K. n., Contrepois, K. n., Myers, J. n., Mahaffey, K. W., Schnittger, I. n., Kuznetsova, T. n., Palaniappan, L. n., Haddad, F. n. 2020

  Abstract

  Resting echocardiography is a valuable method for detecting subclinical heart failure (HF) in patients with diabetes mellitus (DM). However, few studies have assessed the incremental value of diastolic stress for detecting subclinical HF in this population.Asymptomatic patients with Type 2 DM were prospectively enrolled. Subclinical HF was assessed using systolic dysfunction (left ventricular longitudinal strain <16% at rest and <19% after exercise in absolute value), abnormal cardiac morphology, or diastolic dysfunction (E/e' > 10). Metabolic equivalents (METs) were calculated using treadmill speed and grade, and functional capacity was assessed by percent-predicted METs (ppMETs). Among 161 patients studied (mean age of 59 ± 11 years and 57% male sex), subclinical HF was observed in 68% at rest and in 79% with exercise. Among characteristics, diastolic stress had the highest yield in improving detection of HF with 57% of abnormal cases after exercise and 45% at rest. Patients with revealed diastolic dysfunction during stress had significantly lower exercise capacity than patients with normal diastolic stress (7.3 ± 2.1 vs. 8.8 ± 2.5, P < 0.001 for peak METs and 91 ± 30% vs. 105 ± 30%, P = 0.04 for ppMETs). On multivariable modelling found that age (beta = -0.33), male sex (beta = 0.21), body mass index (beta = -0.49), and exercise E/e' >10 (beta = -0.17) were independently associated with peak METs (combined R2 = 0.46). A network correlation map revealed the connectivity of peak METs and diastolic properties as central features in patients with DM.Diastolic stress test improves the detection of subclinical HF in patients with diabetes mellitus.

  View details for DOI 10.1093/ehjci/jeaa070

  View details for PubMedID 32386203

• Impact of the distance from the chest wall to the heart on surface ECG voltage in athletes. BMJ open sport & exercise medicine Hedman, K., Patti, A., Moneghetti, K. J., Hsu, D., Christle, J. W., Ashley, E., Hadley, D., Haddad, F., Froelicher, V. 2020; 6 (1): e000696

  Abstract

  Objective: Available ECG criteria for detection of left ventricular (LV) hypertrophy have been reported to have limited diagnostic capability. Our goal was to describe how the distance between the chest wall and the left ventricle determined by echocardiography affected the relationship between ECG voltage and LV mass (LVM) in athletes.Methods: We retrospectively evaluated digitised ECG data from college athletes undergoing routine echocardiography as part of their preparticipation evaluation. Along with LV mass and volume, we determined the chest wall-LV distance in the parasternal short-axis and long-axis views from two-dimensional transthoracic echocardiographic images and explored the relation with ECG QRS voltages in all leads, as well as summed voltages as included in six major ECG-LVH criteria.Results: 239 athletes (43 women) were included (age 19±1years). In men, greater LV-chest wall distance was associated with higher R-wave amplitudes in leads aVL and I (R=0.20and R=0.25, both p<0.01), while in women greater distance was associated with higher R-amplitudes in V5 and V6 (R=0.42and R=0.34, both p<0.01). In women, the chest wall-LV distance was the only variable independently (and positively) associated with R V5 voltage, while LVM, height and weight contributed to the relationship in men.Conclusions: The chest wall-LV distance was weakly associated with ECG voltage in athletes. Inconsistent associations in men and women imply different intrathoracic factors affecting impedance and conductance between sexes. This may help explain the poor relationship between QRS voltage and LVM in athletes.

  View details for DOI 10.1136/bmjsem-2019-000696

  View details for PubMedID 32201618

• Cumulative Lifetime Burden of Cardiovascular Disease From Early Exposure to Air Pollution. Journal of the American Heart Association Kim, J. B., Prunicki, M. n., Haddad, F. n., Dant, C. n., Sampath, V. n., Patel, R. n., Smith, E. n., Akdis, C. n., Balmes, J. n., Snyder, M. P., Wu, J. C., Nadeau, K. C. 2020; 9 (6): e014944

  Abstract

  The disease burden associated with air pollution continues to grow. The World Health Organization (WHO) estimates ≈7 million people worldwide die yearly from exposure to polluted air, half of which-3.3 million-are attributable to cardiovascular disease (CVD), greater than from major modifiable CVD risks including smoking, hypertension, hyperlipidemia, and diabetes mellitus. This serious and growing health threat is attributed to increasing urbanization of the world's populations with consequent exposure to polluted air. Especially vulnerable are the elderly, patients with pre-existing CVD, and children. The cumulative lifetime burden in children is particularly of concern because their rapidly developing cardiopulmonary systems are more susceptible to damage and they spend more time outdoors and therefore inhale more pollutants. World Health Organization estimates that 93% of the world's children aged <15 years-1.8 billion children-breathe air that puts their health and development at risk. Here, we present growing scientific evidence, including from our own group, that chronic exposure to air pollution early in life is directly linked to development of major CVD risks, including obesity, hypertension, and metabolic disorders. In this review, we surveyed the literature for current knowledge of how pollution exposure early in life adversely impacts cardiovascular phenotypes, and lay the foundation for early intervention and other strategies that can help prevent this damage. We also discuss the need for better guidelines and additional research to validate exposure metrics and interventions that will ultimately help healthcare providers reduce the growing burden of CVD from pollution.

  View details for DOI 10.1161/JAHA.119.014944

  View details for PubMedID 32174249

• Immunologic effects of forest fire exposure show increases in IL-1β and CRP. Allergy Prunicki, M. M., Dant, C. C., Cao, S. n., Maecker, H. n., Haddad, F. n., Kim, J. B., Snyder, M. n., Wu, J. n., Nadeau, K. n. 2020

  View details for DOI 10.1111/all.14251

  View details for PubMedID 32112439

• Reply: Interpreting multiple analyses to better understand cardiac retransplantation. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Miller, R. J., Khush, K. K., Haddad, F. 2019

  View details for DOI 10.1016/j.healun.2019.12.004

  View details for PubMedID 31928919

• Novel Three-Dimensional Imaging Approach for Cryoballoon Navigation and Confirmation of Pulmonary Vein Occlusion. Pacing and clinical electrophysiology : PACE Kowalewski, C. A., Rodrigo, M., Brodt, C., Haddad, F., Wang, P. J., Narayan, S. M. 2019

  Abstract

  BACKGROUND: Cryoballoon apposition is crucial for durable pulmonary vein isolation (PVI) in atrial fibrillation, yet the balloon is difficult to visualize by conventional mapping systems, and pulmonary venography may miss small or out-of-plane leaks. We report a novel imaging system that offers real-time 3-D navigation of the cryoballoon within atrial anatomy that may circumvent these issues.METHODS AND RESULTS: A novel overlay guidance system(OGS) (Siemens Healthcare, Forchheim, Germany) registers already-acquired segmented atrial cardiac tomography (CT) with fluoroscopy, enabling real-time visualization of the cryoballoon within tomographic left atrial imaging during PVI. Phantom experiments in a patient-specific 3D printed left atrium showed feasibility for confirming PV apposition and leaks. We applied OGS prospectively to 68 PVs during PVI in 17 patients. The cryoballoon was successfully reconstructed in all cases, and its apposition was compared to concurrent PV venography. The OGS uncovered leaks undetected by venography in 9 veins (8 cases) which enabled repositioning, confirming apposition in remaining 68 veins. Concordance of OGS to venography was 83.8% (chi2 , p<0.01) CONCLUSIONS: We report a new system for real-time imaging of cryoballoon catheters to ensure PV apposition within the tomography of the left atrium. While providing high concordance with other imaging modalities for confirming balloon apposition or leak, the system also identified leaks missed by venography. Future studies should determine if this tool can provide a new reference for cryoballoon positioning. This article is protected by copyright. All rights reserved Cryoballoon ablation is increasingly used for pulmonary vein isolation (PVI), but it may be difficult to track cryoballoon position relative to the PV for complete occlusion. We describe a novel overlay guidance system (OGS) for real-time 3D visualization of the cryoballoon within atrial anatomy, by registering atrial computed tomography in 2 fluoroscopic planes. Phantom experiments with a custom 3D printed left atrium showed feasibility for visualizing balloon apposition within PVs. In 68 PVs in 17 patients, the OGS prospectively identified cryoballoon position relative to PVs, and uncovered leaks undetected by venography. Future studies should test if the OGS can serve as a new reference for cryoballoon positioning.

  View details for DOI 10.1111/pace.13858

  View details for PubMedID 31868241

• Echocardiographic Assessment of Left Ventricular Remodeling in American Style Footballers. International journal of sports medicine Moneghetti, K. J., Singh, T., Hedman, K., Christle, J. W., Kooreman, Z., Kobayashi, Y., Bouajila, S., Amsallem, M., Wheeler, M., Gerche, A. L., Ashley, E., Haddad, F. 2019

  Abstract

  Several athletic programs incorporate echocardiography during pre-participation screening of American Style Football (ASF) players with great variability in reported echocardiographic values. Pre-participation screening was performed in National Collegiate Athletic Association Division I ASF players from 2008 to 2016 at the Division of Sports Cardiology. The echocardiographic protocol focused on left ventricular (LV) mass, mass-to-volume ratio, sphericity, ejection fraction, and longitudinal Lagrangian strain. LV mass was calculated using the area-length method in end-diastole and end-systole. A total of two hundred and thirty players were included (18±1 years, 57% were Caucasian, body mass index 29±4kg/m2) after four players (2%) were excluded for pathological findings. Although there was no difference in indexed LV mass by race (Caucasian 78±11 vs. African American 81±10g/m2, p=0.089) or sphericity (Caucasian 1.81±0.13 vs. African American 1.78±0.14, p=0.130), the mass-to-volume ratio was higher in African Americans (0.91±0.09 vs. 0.83±0.08, p<0.001). No race-specific differences were noted in LV longitudinal Lagrangian strain. Player position appeared to have a limited role in defining LV remodeling. In conclusion, significant echocardiographic differences were observed in mass-to-volume ratio between African American and Caucasian players. These demographics should be considered as part of pre-participation screening.

  View details for DOI 10.1055/a-1014-2994

  View details for PubMedID 31791086

• Utility of High-Sensitivity and Conventional Troponin in Patients Undergoing Transcatheter Aortic Valve Replacement: Incremental Prognostic Value to B-type Natriuretic Peptide. Scientific reports Kobayashi, Y., Kim, J. B., Moneghetti, K. J., Fischbein, M., Lee, A., Watkins, C. A., Yeung, A. C., Liang, D., Ozen, M. O., Demirci, U., Bowen, R., Fearon, W. F., Haddad, F. 2019; 9 (1): 14936

  Abstract

  High-sensitivity Troponin (hs-Tn) has emerged as a useful marker for patients with myocardial injury or heart failure. However, few studies have compared intermediate and hs-Tn in patients undergoing transcatheter aortic valve replacement (TAVR). Moreover, there remains uncertainty of which thresholds are the most useful for discriminating ventricular dysfunction or outcome. In this study we prospectively enrolled 105 patients with severe aortic stenosis (AS) who underwent TAVR as well as blood sampling for high-sensitivity (hs-TnI) and conventional troponin I (EXL-LOCI and RXL) assessment. Patients underwent comprehensive pre-procedure echocardiography. Ventricular dysfunction was defined using left ventricular mass index (LVMI), LV global longitudinal strain (LVGLS) and LV end-diastolic pressure. The mean age was 84.0±8.7 years old and 60% were male sex with mean transaortic pressure gradient of 50.1±16.0mmHg and AVA of 0.63±0.19cm2. When using a threshold of 6ng/L, 77% had positive hs-TnI while 27% had positive hs-TnI using recommended thresholds (16ng/L for female and 34ng/L for male). Troponin levels were higher in the presence of abnormal LV phenotypes. The strongest correlate of troponin was LVMI. During median follow-up of 375 days, 21 patients (20%) died. Lower threshold of hs-TnI and EXL-TnI was more discriminatory for overall mortality (Log-rank P=0.03 for both), while higher threshold of hs-TnI (p=0.75) and RXL-TnI were not (p=0.30). Combining hs-TnI and BNP improved to predict long-term outcome (p=0.004). In conclusion, hs-TnI levels correlated with the degree of LV dysfunction phenotypes. Furthermore, applying a lower threshold for hs-TnI performed better for outcome prediction than a recommended threshold in patients undergoing TAVR. Combining hs-TnI with BNP helped better risk stratification.

  View details for DOI 10.1038/s41598-019-51371-x

  View details for PubMedID 31624275

• The 2013 ACC/AHA risk score and subclinical cardiac remodeling and dysfunction: Complementary in cardiovascular disease prediction. International journal of cardiology Cauwenberghs, N., Hedman, K., Kobayashi, Y., Vanassche, T., Haddad, F., Kuznetsova, T. 2019

  Abstract

  BACKGROUND: Echocardiography might enhance cardiovascular (CV) risk stratification beyond tools grading the risk for atherosclerotic CV diseases (ASCVD). We therefore studied the complementarity between the ASCVD risk score recommended by American cardiology societies and echocardiographic profiling in predicting adverse CV outcome in the community.METHODS: 984 community-dwelling individuals between 40 and 79 years old (51.3% women) underwent CV risk profiling and echocardiography. We estimated their 10-year ASCVD risk from baseline risk factors using the Pooled Cohort Equations. Participants were categorized as at low (<2.5%), borderline (2.5-<7.5%) or intermediate-to-high (≥7.5%) ASCVD risk. Main outcome was the incidence of CV events collected on average 7.5 years later.RESULTS: The probability for cardiac remodeling and/or dysfunction as assessed by echocardiography rose progressively with increasing 10-year ASCVD risk. During follow-up, 116 participants experienced at least one CV endpoint (15.8 events per 1000 person-years). With increasing 10-year ASCVD risk, the CV event rate increased stronger in participants with ≥1 LV abnormality at baseline. Indeed, in individuals with an intermediate-to-high ASCVD risk and ≥1 LV abnormality at baseline, the risk was significantly higher than the average population risk for a first CV event (HR: 3.00, P < 0.001). Adding the presence of ≥1 LV abnormality to a ASCVD risk score-based model yielded significant improvement in C-statistics (P = 0.024), integrated discrimination (P = 0.0085) and net reclassification (P < 0.001) for adverse CV events.CONCLUSIONS: Echocardiographic profiling enhanced CV risk stratification in individuals at intermediate-to-high ASCVD risk. Echocardiographic screening might supplement traditional ASCVD risk grading for CV disease prediction.

  View details for DOI 10.1016/j.ijcard.2019.09.061

  View details for PubMedID 31623873

• Limitations of Electrocardiography for Detecting Left Ventricular Hypertrophy or Concentric Remodeling in Athletes. The American journal of medicine Hedman, K., Moneghetti, K. J., Hsu, D., Christle, J. W., Patti, A., Ashley, E., Hadley, D., Haddad, F., Froelicher, V. 2019

  Abstract

  BACKGROUND: Electrocardiography (ECG) is used to screen for left ventricular hypertrophy (LVH), but common ECG-LVH criteria have been found less effective in athletes. The purpose of this study was to comprehensively evaluate the value of ECG for identifying athletes with left ventricular hypertrophy and/or a concentric cardiac phenotype.METHODS: A retrospective analysis of 196 male division 1 college athletes routinely screened with ECG and echocardiography within The Stanford Athletic Cardiovascular Screening Program was performed. Left-ventricular mass and volume were determined using echocardiography. Left ventricular hypertrophy was defined as left ventricular mass >102 g/m2; a concentric cardiac phenotype as left ventricular mass/volume (M/V) ≥1.05 g/mL. Twelve-lead ECGs including high-resolution time intervals and QRS voltages were obtained. 37 previously published ECG-LVH criteria were applied, of which the majority have never been evaluated in athletes. C-statistics, including area under the receiver operating curve (AUC), and likelihood ratios were calculated.RESULTS: ECG lead voltages were poorly associated with left ventricular mass (r=0.18-0.30) and M/V (r=0.15-0.25). The proportion of athletes with ECG-LVH was 0-74% across criteria, with sensitivity and specificity ranging between 0-91% and 27-99.5%, respectively. The average AUC of the criteria in identifying the 11 athletes with left ventricular hypertrophy was 0.57 (95% CI 0.56-0.59), while the average AUC for identifying the eight athletes with a concentric phenotype was 0.59 (95% CI 0.56-0.62).CONCLUSION: The diagnostic capacity of all ECG-LVH criteria were inadequate and therefore not clinically useful in screening for left ventricular hypertrophy or a concentric phenotype in athletes. This is probably due to the weak association between left ventricular mass and ECG voltage.

  View details for DOI 10.1016/j.amjmed.2019.06.028

  View details for PubMedID 31738876

• Commentary: Postoperative right ventricular dysfunction-Integrating right heart profiles beyond long-axis function. The Journal of thoracic and cardiovascular surgery Denault, A., Haddad, F., Lamarche, Y., Bouabdallaoui, N., Deschamps, A., Desjardins, G. 2019

  View details for DOI 10.1016/j.jtcvs.2019.05.064

  View details for PubMedID 31301900

• Athletic Remodeling in Female College Athletes: The "Morganroth Hypothesis" Revisited CLINICAL JOURNAL OF SPORT MEDICINE Kooreman, Z., Giraldeau, G., Finocchiaro, G., Kobayashi, Y., Wheeler, M., Perez, M., Moneghetti, K., Oxborough, D., George, K. P., Myers, J., Ashley, E., Haddad, F. 2019; 29 (3): 224–31

  View details for DOI 10.1097/JSM.0000000000000501

  View details for Web of Science ID 000480736100009

• The Impact of Prescribed Fire versus Wildfire on the Immune and Cardiovascular Systems of Children. Allergy Prunicki, M., Kelsey, R., Lee, J., Zhou, X., Smith, E., Haddad, F., Wu, J., Nadeau, K. 2019

  View details for PubMedID 31002401

• Discovery of Distinct Immune Phenotypes Using Machine Learning in Pulmonary Arterial Hypertension CIRCULATION RESEARCH Sweatt, A. J., Hedlin, H. K., Balasubramanian, V., Hsi, A., Blum, L. K., Robinson, W. H., Haddad, F., Hickey, P. M., Condliffe, R., Lawrie, A., Nicolls, M. R., Rabinovitch, M., Khatri, P., Zamanian, R. T. 2019; 124 (6): 904–19

  View details for DOI 10.1161/CIRCRESAHA.118.313911

  View details for Web of Science ID 000469341600015

• COMPARISON OF UNITED STATES AND EUROPEAN CRITERIA FOR HYPERTENSION IN A LARGE COHORT OF COMPETITIVE ATHLETES EXAMINED AS PART OF PRE-PARTICIPATION EVALUATION Hedman, K., Moneghetti, K., Christle, J. W., Bagherzadeh, S. P., Haddad, F., Ashley, E. A., Froelicher, V. ELSEVIER SCIENCE INC. 2019: 446

  View details for Web of Science ID 000460565900446

• THE EFFECTS OF CD34+CELL THERAPY ON FUNCTIONAL MITRAL REGURGITATION IN PATIENTS WITH NON-ISCHEMIC DILATED CARDIOMYOPATHY Frljak, S., Zemljic, G., Poglajen, G., Cerar, A., Jaklic, M., Haddad, F., Vrtovec, B. ELSEVIER SCIENCE INC. 2019: 1010

  View details for Web of Science ID 000460565901023

• INDEPENDENT PROGNOSTIC VALUES OF CLINICAL RISK SCORES, RIGHT VENTRICULAR SYSTOLIC PRESSURE, AND N-TERMINAL PRO-B-TYPE PEPTIDE IN HEART FAILURE WITH PRESERVED EJECTION FRACTION: INSIGHTS FROM SUPERVISED AND UNSUPERVISED MODELS Tremblay-Gravel, M., Kobayashi, Y., Boralkar, K., Li, X., Bouajila, S., Nishi, T., Amsallem, M., Moneghetti, K., Selej, M., Ozen, M., Demirci, U., Ashley, E. A., Wheeler, M., Knowlton, K., Kouznetsova, T., Haddad, F. ELSEVIER SCIENCE INC. 2019: 718

  View details for Web of Science ID 000460565900718

• RESTING BLOOD PRESSURE IN 2881 ATHLETES AGED 9-35 YEARS OF AGE AND THE RELATION TO SEX, AGE, BODY SIZE, AND AFRO-AMERICAN DESCENT Bagherzadeh, S. P., Hedman, K., Christle, J. W., Moneghetti, K., Ashley, E. A., Haddad, F., Froelicher, V. ELSEVIER SCIENCE INC. 2019: 447

  View details for Web of Science ID 000460565900447

• REPLY: Increasingly Recognized Role of Right Ventricle Assessment in Cardiac Amyloidosis JACC-HEART FAILURE Amsallem, M., Witteles, R., Haddad, F. 2019; 7 (3): 279–80

  View details for DOI 10.1016/j.jchf.2018.12.010

  View details for Web of Science ID 000460037600017

  View details for PubMedID 30819389

• Time based versus strain based myocardial performance indices in hypertrophic cardiomyopathy, the merging role of left atrial strain EUROPEAN HEART JOURNAL-CARDIOVASCULAR IMAGING Kobayashi, Y., Moneghetti, K. J., Bouajila, S., Stolfo, D., Finocchiaro, G., Kuznetsova, T., Liang, D., Schnittger, I., Ashley, E., Wheeler, M., Haddad, F. 2019; 20 (3): 334–42

  View details for DOI 10.1093/ehjci/jey097

  View details for Web of Science ID 000481422400015

• STRONG-D: Strength training regimen for normal weight diabetics: Rationale and design. Contemporary clinical trials Faroqi, L., Bonde, S., Goni, D. T., Wong, C. W., Wong, M., Walai, K., Araya, S., Azamey, S., Schreiner, G., Bandy, M., Raghuram, S. S., Mittal, A., Mukherji, A., Wangdak, T., Talamoa, R., Vera, K., Nacif-Coelho, C., Cde, L. G., Christensen, M., Johannsen, N., Haddad, F., Moharir, M., Palaniappan, L. 2019

  Abstract

  BACKGROUND: Currently, there is a lack of data on effective lifestyle recommendations for normal-weight diabetics (NWD), who can represent up to 1 in 5 individuals with Type II Diabetes Mellitus (T2DM). NWD is especially prevalent in Asian populations and the elderly. Specific exercise treatment recommendations are needed for patients with normal-weight diabetes (NWD), as those in this category face higher mortality rates than overweight and obese diabetics. Standard T2DM treatment recommends aerobic training; however, performing aerobic training alone may not be appropriate for NWD and strength training may be a more effective treatment recommendation.OBJECTIVE: While it is known that strength and aerobic training are beneficial in obese diabetics, there is currently insufficient evidence to recommend this regimen in NWD. The Strength Training Regimen for Normal Weight Diabetics (STRONG-D) study aims to determine the best exercise regimen for NWD and address the current lack of appropriate physical activity recommendations for this population. The primary goal of this study is to determine whether strength training aids glycemic control better than aerobic training in NWD.STUDY DESIGN: STRONG-D is a three-arm randomized controlled trial designed to compare the clinical effectiveness of structured strength training only, aerobic training only, and combination (strength + aerobic) training sessions, modeled after the intervention in the Health Benefits of Aerobic and Resistance Training in T2DM patients (HART-D) study. Potential participants meeting eligibility criteria of HbA1c values of 6.5% to 13.0% and BMI of 18.5 kg/m2 to 25 kg/m2 will be enrolled. After randomization, participants will begin a 9-month exercise intervention. The primary outcomes will be HbA1c levels. The secondary endpoints will include physical fitness, body composition measured by Dual X-Ray Absorptiometry (DXA) scans, and leg strength and endurance measured by Biodex testing. Initial follow-up visits will occur at 3 months, 6 months, and 9 months. To determine the long-term effects of the exercise intervention, passive follow-up will continue via electronic health records (EHR) until a 24-month follow-up visit. A total of 282 participants will be randomized into the three study arms determine the clinically significant differences between strength-only, aerobic-only and combination regimens.

  View details for PubMedID 30625372

• Temporal changes in left ventricular longitudinal strain in general population: Clinical correlates and impact on cardiac remodeling. Echocardiography (Mount Kisco, N.Y.) Kuznetsova, T., Nijs, E., Cauwenberghs, N., Knez, J., Thijs, L., Haddad, F., Yang, W., Kerkhof, P. L., Voigt, J., Staessen, J. A. 2019

  Abstract

  BACKGROUND: Recent studies in patients and general population have reported the role of left ventricular (LV) longitudinal strain (LS) as an independent predictor of outcome. However, there are few data on changes in LS over time. We therefore investigated in a general population clinical correlates of temporal changes in LS. We also explored the potential correlation between temporal changes in LV volumes and LS.METHODS AND RESULTS: We measured LV end-systolic (ESV) and end-diastolic (EDV) volumes by conventional echocardiography and LS by 2D speckle tracking in 627 participants (mean age 50.6years, 51.4% women; 41.3% hypertensives) at baseline and after 4.7years. For statistical analysis, we used the absolute values of LS. In stepwise regression, the magnitude of the decrease in all LV LS indexes over time was greater in men than in women (P<0.0001). Higher baseline mean arterial pressure (MAP), a larger longitudinal increase in MAP, and stopping diuretic treatment during follow-up were related to larger decreases in LS indexes. In multivariable-adjusted analysis, we observed an inverse correlation between baseline ESV and LV LS (P≤0.0017). Similarly, lower baseline LS and a larger decrease in LS over time were correlated with a lesser longitudinal decrease in ESV (P≤0.0004).CONCLUSIONS: A significant decrease in LS over time was associated with male sex, higher baseline MAP, ∆MAP, and alteration in antihypertensive treatment. We suggested an interaction between a longitudinal decrease in LV deformation and adverse cardiac remodeling, while underscoring the importance of deformation analysis based on LS assessment in patients at risk.

  View details for PubMedID 30609050

• Athletic Remodeling in Female College Athletes: The "Morganroth Hypothesis" Revisited. Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine Kooreman, Z. n., Giraldeau, G. n., Finocchiaro, G. n., Kobayashi, Y. n., Wheeler, M. n., Perez, M. n., Moneghetti, K. n., Oxborough, D. n., George, K. P., Myers, J. n., Ashley, E. n., Haddad, F. n. 2019; 29 (3): 224–31

  Abstract

  There is limited data regarding ventricular remodeling in college female athletes, especially when appropriate scaling of cardiac dimensions to lean body mass (LBM) is considered. Moreover, it is not well established whether cardiac remodeling in female athletes is a balanced process with proportional increase in left ventricular (LV) mass and volume or the right and LV size.During the preparticipation competitive screening, 72 female college athletes volunteered to undergo dual energy x-ray absorptiometry scan for quantification of LBM and comprehensive 2D echocardiography including assessment of longitudinal myocardial strain. The athletes were divided in 2 groups according to the intensity of the dynamic and static components of their sport categories, ie, a higher intensity dynamic and resistive group (n = 37 participating in rowing, water polo and lacrosse) and a lower intensity group (n = 35, participating in short distance running, sailing, synchronized swimming, and softball). In addition, we recruited a group of 31 age-matched nonathlete controls.The mean age of the study population was 18.7 ± 1.0 years. When scaled to body surface area, the higher intensity group had 17.1 ± 3.6% (P < 0.001) greater LV mass when compared with the lower intensity group and 21.7 ± 4.0% (P < 0.001) greater LV mass than the control group. The differences persisted after scaling to LBM with 14.2 ± 3.2% (P < 0.001) greater LV mass in the higher intensity group. By contrast, there was no difference in any of the relative remodeling indices including the LV mass to volume ratio, right to LV area ratio, or left atrial to LV volume ratio (P > 0.50 for all). In addition, no significant difference was noted among the 3 groups in LV ejection fraction (P = 0.22), LV global longitudinal strain (P = 0.55), LV systolic strain rate (P = 0.62), or right ventricular global longitudinal strain (P = 0.61).Female collegiate athletes participating in higher intensity dynamic and resistive sports have higher indexed LV mass even when scaled to LBM. The remodeling process does however appear to be a balanced process not only at the intraventricular level but also at the interventricular and atrioventricular levels.

  View details for PubMedID 31033616

• Incremental Value of Aortomitral Continuity Calcification for Risk Assessment after Transcatheter Aortic Valve Replacement. Radiology. Cardiothoracic imaging Willemink, M. J., Maret, E. n., Moneghetti, K. J., Kim, J. B., Haddad, F. n., Kobayashi, Y. n., Nishi, T. n., Nieman, K. n., Cauwenberghs, N. n., Kuznetsova, T. n., Higashigaito, K. n., Sailer, A. M., Yeung, A. C., Lee, A. M., Miller, D. C., Fischbein, M. n., Fearon, W. F., Fleischmann, D. n. 2019; 1 (5): e190067

  Abstract

  To investigate the association of aortomitral continuity calcification (AMCC) with all-cause mortality, postprocedural paravalvular leak (PVL), and prolonged hospital stay in patients undergoing transcatheter aortic valve replacement (TAVR).The authors retrospectively evaluated 329 patients who underwent TAVR between March 2013 and March 2016. AMCC, aortic valve calcification (AVC), and coronary artery calcification (CAC) were quantified by using preprocedural CT. Pre-procedural Society of Thoracic Surgeons (STS) score was recorded. Associations between baseline AMCC, AVC, and CAC and 1-year mortality, PVL, and hospital stay longer than 7 days were analyzed.The median follow-up was 415 days (interquartiles, 344-727 days). After 1 year, 46 of the 329 patients (14%) died and 52 (16%) were hospitalized for more than 7 days. Of the 326 patients who underwent postprocedural echocardiography, 147 (45%) had postprocedural PVL. The CAC score (hazard ratio: 1.11 per 500 points) and AMCC mass (hazard ratio: 1.13 per 500 mg) were associated with 1-year mortality. AVC mass (odds ratio: 1.93 per 100 mg) was associated with postprocedural PVL. Only the STS score was associated with prolonged hospital stay (odds ratio: 1.19 per point).AMCC is associated with mortality within 1 year after TAVR and substantially improves individual risk classification when added to a model consisting of STS score and AVC mass only.Supplemental material is available for this article.© RSNA, 2019See also the commentary by Brown and Leipsic in this issue.

  View details for DOI 10.1148/ryct.2019190067

  View details for PubMedID 33778530

  View details for PubMedCentralID PMC7977784

• Echocardiographic evaluations of right ventriculo-arterial coupling in experimental and clinical pulmonary hypertension. Physiological reports Boulate, D. n., Amsallem, M. n., Kuznetsova, T. n., Zamanian, R. T., Fadel, E. n., Mercier, O. n., Haddad, F. n. 2019; 7 (24): e14322

  Abstract

  Tricuspid annular systolic excursion (TAPSE) or velocities (s') and right ventricular (RV) end-systolic dimensions are predictors of outcome in patients with pulmonary hypertension (PH). We explored the value of combining peak s' and RV end-systolic area index (RVESAi) as a surrogate of RV-pulmonary artery (RV-PA) coupling in a large animal of precapillary PH as well as clinically.The first experimental group included four control and four piglets with thromboembolic disease. RV-PA coupling was assessed by ventricular to arterial elastance ratio (Ees/Ea) at baseline, after esmolol and dobutamine administration. Echocardiographic metrics included s', TAPSE, fractional area change (RVFAC), and RVESAi. The findings were validated in six piglets with severe PH. Clinical cohorts were stable outpatients (n = 141) and acutely decompensated pulmonary arterial hypertension (n = 48).In the first experimental group, the best linear correlates of Ees/Ea were s' (R2  = .51, p < .001) and RVESAi (R2  = .50, p < .001), while RVFAC (R2  = .17, p = .01) and TAPSE showed weaker association (R2  = .21, p = .39). The ratio s'/RVESAi showed nominally but not significantly (higher) association with Ees/Ea (R2  = .58, p < .01). The association between changes in s'/RVESAi and Ees/Ea was strong (R2  = .56, p < .001). In more severe PH, Ees/Ea and changes in Ees/Ea correlated significantly with s'/RVESAi and changes in s'/RVESAi (R2  = .69; p < .001 and R2  = .64, p < .001, respectively). In the two clinical cohorts, the s'/RVESAi did not emerge as a stronger predictor of outcome than RVESAi.RV s'/RVESAi index represents a reasonable bedside-usable surrogate of RV-PA coupling and of its acute variations in PH. Its incremental prognostic value over end-systolic dimension alone remains to be proven.

  View details for DOI 10.14814/phy2.14322

  View details for PubMedID 31876125

• Value of Neutrophil to Lymphocyte Ratio and Its Trajectory in Patients Hospitalized With Acute Heart Failure and Preserved Ejection Fraction. The American journal of cardiology Boralkar, K. A., Kobayashi, Y. n., Amsallem, M. n., Ataam, J. A., Moneghetti, K. J., Cauwenberghs, N. n., Horne, B. D., Knowlton, K. U., Maecker, H. n., Kuznetsova, T. n., Heidenreich, P. A., Haddad, F. n. 2019

  Abstract

  The neutrophil to lymphocyte ratio (NLR) has been proposed as a simple and routinely obtained marker of inflammation. This study sought to determine whether the NLR on admission as well as NLR trajectory would be complementary to the Get with the Guidelines Heart Failure (GWTG-HF) risk score in patients hospitalized with acute heart failure with preserved ejection fraction (HFpEF).Using the Stanford Translational Research Database, we identified 443 patients between January 2002 and December 2013 hospitalized with acute HFpEF and with complete data of NLR both on admission and at discharge. The primary endpoint was all-cause mortality. Mean age was 77 ± 16 years, 58% were female, with a high prevalence of diabetes mellitus (35.4%), coronary artery disease (58.2%), systemic hypertension (96.6%) and history of atrial fibrillation (57.5%). Over a median follow-up of 2.2 years, 121 (27.3%) patients died. The median NLR on admission was 6.5 (IQR 3.6 - 11.1); a majority of patients decreased their NLR during the course of hospitalization. On multivariable Cox modeling, both NLR on admission (HR 1.18 95% CI (1.00 - .38), p = 0.04) and absolute NLR trajectory (HR 1.26 95% CI (1.10 - 1.45), p = 0.001) were shown to be incremental to GWTG-HF risk score (p < 0.05) for outcome prediction. Adding the NLR or absolute NLR trajectory to the GWTG-HF risk score significantly improved the area under the operator-receiver curve and the reclassification up to 3 years after admission.This simple, readily available marker of inflammation may be useful when stratifying the risk of patients hospitalized with HFpEF.

  View details for DOI 10.1016/j.amjcard.2019.10.020

  View details for PubMedID 31753313

• A Changing Landscape of Mortality for Systemic Light Chain Amyloidosis. JACC. Heart failure Barrett, C. D., Dobos, K. n., Liedtke, M. n., Tuzovic, M. n., Haddad, F. n., Kobayashi, Y. n., Lafayette, R. n., Fowler, M. B., Arai, S. n., Schrier, S. n., Witteles, R. M. 2019

  Abstract

  The purpose of this study was to address the overall trends in mortality since the adoption of modern therapies for treatment of systemic amyloidosis, and to reconsider the prognostic significance of individual components of the current staging system.Systemic light chain (AL) amyloidosis involves deposition of immunoglobulin light chains in organs throughout the body and is known to have the highest mortality when significant cardiac involvement is present. Survival has historically been poor but may be improving as systemic therapies continue to advance. This study assesses whether recent advancements in light chain directed therapy have led to improved survival in patients with systemic AL amyloidosis.We reviewed all cases of patients who were evaluated for a new diagnosis of AL amyloidosis at the Stanford Amyloid Center between 2009 and 2016. Patients' stage at diagnosis was determined according to the most commonly used staging system. Clinical data, overall survival from diagnosis, and the independent influence of each component of the staging system were analyzed.At total of 194 patients were identified with a new diagnosis of systemic AL amyloidosis. Median overall survival was 59 months and 6 months for stage 3 and 4 patients, respectively. Median overall survival was not reached in stage 1 and 2 groups, as survival was >50% by the end of the study. Mean overall survival was 118 months, 76 months, 64 months, and 27 months in Stages 1, 2, 3, and 4 patients, respectively. Although N-terminal pro-B-type natriuretic peptide and troponin I concentrations had large effects on prognosis, differences in serum free light chains (dFLC) on initial staging laboratory results ≥18 mg/dl, part of the current staging system, did not contribute significantly to prognosis for values ≥5 mg/dl.Survival for patients with systemic AL amyloidosis has improved for patients at all stages of disease in the present era of rapid advancements in light chain-reducing therapies. Cardiac biomarkers at diagnosis, but not baseline dFLC ≥18 mg/dl, continue to provide important prognostic information.

  View details for DOI 10.1016/j.jchf.2019.07.007

  View details for PubMedID 31606365

• Workload-indexed blood pressure response is superior to peak systolic blood pressure in predicting all-cause mortality. European journal of preventive cardiology Hedman, K. n., Cauwenberghs, N. n., Christle, J. W., Kuznetsova, T. n., Haddad, F. n., Myers, J. n. 2019: 2047487319877268

  Abstract

  The association between peak systolic blood pressure (SBP) during exercise testing and outcome remains controversial, possibly due to the confounding effect of external workload (metabolic equivalents of task (METs)) on peak SBP as well as on survival. Indexing the increase in SBP to the increase in workload (SBP/MET-slope) could provide a more clinically relevant measure of the SBP response to exercise. We aimed to characterize the SBP/MET-slope in a large cohort referred for clinical exercise testing and to determine its relation to all-cause mortality.Survival status for male Veterans who underwent a maximal treadmill exercise test between the years 1987 and 2007 were retrieved in 2018. We defined a subgroup of non-smoking 10-year survivors with fewer risk factors as a lower-risk reference group. Survival analyses for all-cause mortality were performed using Kaplan-Meier curves and Cox proportional hazard ratios (HRs (95% confidence interval)) adjusted for baseline age, test year, cardiovascular risk factors, medications and comorbidities. A total of 7542 subjects were followed over 18.4 (interquartile range 16.3) years. In lower-risk subjects (n = 709), the median (95th percentile) of the SBP/MET-slope was 4.9 (10.0) mmHg/MET. Lower peak SBP (<210 mmHg) and higher SBP/MET-slope (>10 mmHg/MET) were both associated with 20% higher mortality (adjusted HRs 1.20 (1.08-1.32) and 1.20 (1.10-1.31), respectively). In subjects with high fitness, a SBP/MET-slope > 6.2 mmHg/MET was associated with a 27% higher risk of mortality (adjusted HR 1.27 (1.12-1.45)).In contrast to peak SBP, having a higher SBP/MET-slope was associated with increased risk of mortality. This simple, novel metric can be considered in clinical exercise testing reports.

  View details for DOI 10.1177/2047487319877268

  View details for PubMedID 31564136

• Assessment of Left Ventricular Diastolic Function by Transesophageal Echocardiography Before Cardiopulmonary Bypass: Clinical Implications of a Restrictive Profile. Journal of cardiothoracic and vascular anesthesia Beaubien-Souligny, W. n., Brand, F. Z., Lenoir, M. n., Amsallem, M. n., Haddad, F. n., Denault, A. Y. 2019; 33 (9): 2394–2401

  Abstract

  Left ventricular (LV) diastolic function can be assessed by transesophageal echocardiography before cardiopulmonary bypass in the setting of cardiac surgery. The objective of this study was to determine whether the assessment of LV diastolic dysfunction (LVDD) improves mortality risk prediction.Retrospective single-center cohort study.Single tertiary cardiac surgery center.Data from patients undergoing cardiac surgery using cardiopulmonary bypass (CPB) and for which an evaluation for LVDD was performed before CPB between February 1999 and November 2015.Cases were reviewed retrospectively from a transesophageal echocardiography hemodynamic database. LV diastolic function was graded as normal, impaired relaxation (grade 1), pseudo-normalization (grade 2), or restrictive (grade 3) determined by mitral inflow waves, tissue Doppler imaging of the mitral annulus, and pulmonary venous flow. The main outcome was in-hospital mortality.A total of 760 patients were included, 144 (18.9%) patients with normal diastolic function, 331 (43.6%) patients with grade 1 LVDD, 218 (28.7%) patients with grade 2 LVDD, and 67 (8.8%) patients with grade 3 LVDD. In-hospital mortality occurred in 31 patients (4.1%). The presence of grade 3 LVDD was associated with an increased likelihood of in-hospital mortality (odds ratio [OR]: 19.39, confidence interval [CI]: 2.37-158.48, p = 0.006). In contrast, LV systolic dysfunction was not independently associated with increased mortality. When added to the Parsonnet score, the addition of diastolic function resulted in a net reclassification improvement of in-hospital mortality (NRI: 0.419 CI: 0.049-0.759, p = 0.02), and in integrated discrimination improvement (IDI: 0.0179 CI: 0.0049-0.031, p = 0.007). Difficult separation from CPB was observed more frequently in patients with grade 3 LVDD (62.9% v 36.1%, p = 0.01).In contrast to LV systolic dysfunction, restrictive LVDD is associated with an increased risk of in-hospital mortality in cardiac surgical patients. Further studies should explore how this information may be used by the attending anesthesiologist to tailor perioperative management.

  View details for DOI 10.1053/j.jvca.2019.05.014

  View details for PubMedID 31235379

• ICAM-1 promotes the abnormal endothelial cell phenotype in chronic thromboembolic pulmonary hypertension. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Arthur Ataam, J. n., Mercier, O. n., Lamrani, L. n., Amsallem, M. n., Arthur Ataam, J. n., Arthur Ataam, S. n., Guihaire, J. n., Lecerf, F. n., Capuano, V. n., Ghigna, M. R., Haddad, F. n., Fadel, E. n., Eddahibi, S. n. 2019

  Abstract

  Pulmonary endothelial cells play a key role in the pathogenesis of Chronic Thromboembolic Pulmonary Hypertension (CTEPH). Increased synthesis and/or the release of intercellular adhesion molecule-1 (ICAM-1) by pulmonary endothelial cells of patients with CTEPH has been recently reported, suggesting a potential role for ICAM-1 in CTEPH.We studied pulmonary endarterectomy specimens from 172 patients with CTEPH and pulmonary artery specimens from 97 controls undergoing lobectomy for low-stage cancer without metastasis.ICAM-1 was overexpressed in vitro in isolated and cultured endothelial cells from endarterectomy specimens. Endothelial cell growth and apoptosis resistance were significantly higher in CTEPH specimens than in the controls (p < 0.001). Both abnormalities were abolished by pharmacological inhibition of ICAM-1 synthesis or activity. The overexpression of ICAM-1 contributed to the acquisition and maintenance of abnormal EC growth and apoptosis resistance via the phosphorylation of SRC, p38 and ERK1/2 and the overproduction of survivin. Regarding the ICAM-1 E469K polymorphism, the KE heterozygote genotype was significantly more frequent in CTEPH than in the controls, but it was not associated with disease severity among patients with CTEPH.ICAM-1 contributes to maintaining the abnormal endothelial cell phenotype in CTEPH.

  View details for DOI 10.1016/j.healun.2019.06.010

  View details for PubMedID 31324443

• Approaching Higher Dimension Imaging Data Using Cluster-Based Hierarchical Modeling in Patients with Heart Failure Preserved Ejection Fraction. Scientific reports Kobayashi, Y. n., Tremblay-Gravel, M. n., Boralkar, K. A., Li, X. n., Nishi, T. n., Amsallem, M. n., Moneghetti, K. J., Bouajila, S. n., Selej, M. n., Ozen, M. O., Demirci, U. n., Ashley, E. n., Wheeler, M. n., Knowlton, K. U., Kouznetsova, T. n., Haddad, F. n. 2019; 9 (1): 10431

  Abstract

  Heart failure with preserved ejection fraction (HFpEF) is a major cause of morbidity and mortality, accounting for the majority of heart failure (HF) hospitalization. To identify the most complementary predictors of mortality among clinical, laboratory and echocardiographic data, we used cluster based hierarchical modeling. Using Stanford Translational Research Database, we identified patients hospitalized with HFpEF between 2005 and 2016 in whom echocardiogram and NT-proBNP were both available at the time of admission. Comprehensive echocardiographic assessment including left ventricular longitudinal strain (LVLS), right ventricular function and right ventricular systolic pressure (RVSP) was performed. The outcome was defined as all-cause mortality. Among patients identified, 186 patients with complete echocardiographic assessment were included in the analysis. The cohort included 58% female, with a mean age of 78.7 ± 13.5 years, LVLS of -13.3 ± 2.5%, an estimated RVSP of 38 ± 13 mmHg. Unsupervised cluster analyses identified six clusters including ventricular systolic-function cluster, diastolic-hemodynamic cluster, end-organ function cluster, vital-sign cluster, complete blood count and sodium clusters. Using a stepwise hierarchical selection from each cluster, we identified NT-proBNP (standard hazard ratio [95%CI] = 1.56 [1.17-2.08]) and RVSP (1.37 [1.09-1.78]) as independent correlates of outcome. When adding these parameters to the well validated Get with the Guideline Heart Failure risk score, the Chi-square was significantly improved (p = 0.01). In conclusion, NT-proBNP and RVSP were independently predictive in HFpEF among clinical, imaging, and biomarker parameters. Cluster-based hierarchical modeling may help identify the complementally predictive parameters in small cohorts with higher dimensional clinical data.

  View details for DOI 10.1038/s41598-019-46873-7

  View details for PubMedID 31320698

• Improving risk stratification in heart failure with preserved ejection fraction by combining two validated risk scores. Open heart Boralkar, K. A., Kobayashi, Y., Moneghetti, K. J., Pargaonkar, V. S., Tuzovic, M., Krishnan, G., Wheeler, M. T., Banerjee, D., Kuznetsova, T., Horne, B. D., Knowlton, K. U., Heidenreich, P. A., Haddad, F. 2019; 6 (1): e000961

  Abstract

  Introduction: The Intermountain Risk Score (IMRS) was developed and validated to predict short-term and long-term mortality in hospitalised patients using demographics and commonly available laboratory data. In this study, we sought to determine whether the IMRS also predicts all-cause mortality in patients hospitalised with heart failure with preserved ejection fraction (HFpEF) and whether it is complementary to the Get with the Guidelines Heart Failure (GWTG-HF) risk score or N-terminal pro-B-type natriuretic peptide (NT-proBNP).Methods and results: We used the Stanford Translational Research Integrated Database Environment to identify 3847 adult patients with a diagnosis of HFpEF between January 1998 and December 2016. Of these, 580 were hospitalised with a primary diagnosis of acute HFpEF. Mean age was 76±16 years, the majority being female (58%), with a high prevalence of diabetes mellitus (36%) and a history of coronary artery disease (60%). Over a median follow-up of 2.0 years, 140 (24%) patients died. On multivariable analysis, the IMRS and GWTG-HF risk score were independently associated with all-cause mortality (standardised HRs IMRS (1.55 (95% CI 1.27 to 1.93)); GWTG-HF (1.60 (95% CI 1.27 to 2.01))). Combining the two scores, improved the net reclassification over GWTG-HF alone by 36.2%. In patients with available NT-proBNP (n=341), NT-proBNP improved the net reclassification of each score by 46.2% (IMRS) and 36.3% (GWTG-HF).Conclusion: IMRS and GWTG-HF risk scores, along with NT-proBNP, play a complementary role in predicting outcome in patients hospitalised with HFpEF.

  View details for DOI 10.1136/openhrt-2018-000961

  View details for PubMedID 31217994

• Transplant Outcomes in Destination Therapy Left Ventricular Assist Device Patients. ASAIO journal (American Society for Artificial Internal Organs : 1992) Miller, R. J., Moayedi, Y. n., Sharma, A. n., Haddad, F. n., Hiesinger, W. n., Banerjee, D. n. 2019

  Abstract

  Left ventricular assist devices (LVAD) can be implanted as either a bridge to transplantation (BTT) or destination therapy (DT). This definition is fluid, as some DT patients undergo transplantation. This study compared posttransplant outcomes between BTT and DT LVAD patients. We performed a retrospective analysis of LVAD patients who underwent cardiac transplantation from 2010 to 2016. Outcomes including mortality, rejection, infection, and overall readmission were assessed with univariable Cox analyses. This cohort included 92 LVAD patients underwent transplantation: 57 BTT, mean age 52 years, and 79% male. The DT group had a longer LVAD support time (median support 406 versus 161 days, p < 0.001) with no significant difference in 1-year survival (BTT 86% and DT 92%, p = 0.52) or survival time (HR 0.89, 95% confidence interval [CI] 0.33-2.41, p = 0.82). Rates of nonfatal adverse events were also similar between BTT and DT patients. In our cohort, DT patients had similar long-term survival and rates of adverse events as compared with BTT, despite a longer time to transplant. This study suggests that transplant outcomes are acceptable for patients initially labeled DT and that a longer duration of LVAD support may not adversely affect posttransplant outcomes.

  View details for DOI 10.1097/MAT.0000000000001016

  View details for PubMedID 31192848

• EXPRESS: Myocardial Bridge - An Unrecognized Cause of Chest Pain in Pulmonary Arterial Hypertension. Pulmonary circulation Rajmohan, D. n., Sung, Y. K., Kudelko, K. n., Perez, V. i., Haddad, F. n., Tremmel, J. n., Schnittger, I. n., Zamanian, R. T., Spiekerkoetter, E. F. 2019: 2045894019860738

  View details for DOI 10.1177/2045894019860738

  View details for PubMedID 31187693

• A longitudinal big data approach for precision health. Nature medicine Schüssler-Fiorenza Rose, S. M., Contrepois, K. n., Moneghetti, K. J., Zhou, W. n., Mishra, T. n., Mataraso, S. n., Dagan-Rosenfeld, O. n., Ganz, A. B., Dunn, J. n., Hornburg, D. n., Rego, S. n., Perelman, D. n., Ahadi, S. n., Sailani, M. R., Zhou, Y. n., Leopold, S. R., Chen, J. n., Ashland, M. n., Christle, J. W., Avina, M. n., Limcaoco, P. n., Ruiz, C. n., Tan, M. n., Butte, A. J., Weinstock, G. M., Slavich, G. M., Sodergren, E. n., McLaughlin, T. L., Haddad, F. n., Snyder, M. P. 2019; 25 (5): 792–804

  Abstract

  Precision health relies on the ability to assess disease risk at an individual level, detect early preclinical conditions and initiate preventive strategies. Recent technological advances in omics and wearable monitoring enable deep molecular and physiological profiling and may provide important tools for precision health. We explored the ability of deep longitudinal profiling to make health-related discoveries, identify clinically relevant molecular pathways and affect behavior in a prospective longitudinal cohort (n = 109) enriched for risk of type 2 diabetes mellitus. The cohort underwent integrative personalized omics profiling from samples collected quarterly for up to 8 years (median, 2.8 years) using clinical measures and emerging technologies including genome, immunome, transcriptome, proteome, metabolome, microbiome and wearable monitoring. We discovered more than 67 clinically actionable health discoveries and identified multiple molecular pathways associated with metabolic, cardiovascular and oncologic pathophysiology. We developed prediction models for insulin resistance by using omics measurements, illustrating their potential to replace burdensome tests. Finally, study participation led the majority of participants to implement diet and exercise changes. Altogether, we conclude that deep longitudinal profiling can lead to actionable health discoveries and provide relevant information for precision health.

  View details for PubMedID 31068711

• Cytokines profile of reverse cardiac remodeling following transcatheter aortic valve replacement. International journal of cardiology Kim, J. B., Kobayashi, Y., Kuznetsova, T., Moneghetti, K. J., Brenner, D. A., O'Malley, R., Dao, C., Wu, J. C., Fischbein, M., Craig Miller, D., Yeung, A. C., Liang, D., Haddad, F., Fearon, W. F. 2018; 270: 83–88

  Abstract

  OBJECTIVE: Previous studies have suggested that cytokines and growth factors may predict ventricular recovery following aortic valve replacement (AVR). The primary objective of this study was to identify cytokines that predict ventricular recovery following transcatheter AVR (TAVR).METHODS: We prospectively enrolled 121 consecutive patients who underwent TAVR. Standard echocardiographic assessment at baseline, 1-month and 1-year after TAVR included left ventricular (LV) mass index (LVMI) and global longitudinal strain (GLS). Blood samples were obtained at the time of the procedure to measure cytokines using a 63-plex Luminex platform. Partial least squares-discriminant analysis was performed to identify cytokines associated with ventricular remodeling and function at baseline as well as 1 year after TAVR.RESULTS: The mean age was 84 ± 9 years, with a majority of male subjects (59%), a mean LVMI of 120.4 ± 45.1 g/m2 and LVGLS of -13.0 ± 3.2%. On average, LV mass decreased by 8.1% and GLS improved by 20.3% at 1 year following TAVR. Among cytokines assayed, elevated hepatocyte growth factor (HGF) emerged as a common factor significantly associated with worse baseline LVMI and GLS as well as reduced ventricular recovery (p < 0.005). Other factors associated with ventricular recovery included a select group of vascular growth factors, inflammatory mediators and tumor necrosis factors, including VEGF-D, ICAM-1, TNFbeta, and IL1beta.CONCLUSION: We identified a network of cytokines, including HGF, that are significantly correlated with baseline LVMI and GLS, and ventricular recovery following TAVR.

  View details for PubMedID 30219541

• Effects of acute increases in right ventricular preload and afterload on pulmonary artery pulse pressure in a chronic thromboembolic hypertension model Boulate, D., Chemla, D., Loisel, F., Decante, B., Herve, P., Haddad, F., Fadel, E., Mercier, O. EUROPEAN RESPIRATORY SOC JOURNALS LTD. 2018

  View details for DOI 10.1183/13993003.congress-2018.PA3074

  View details for Web of Science ID 000455567104106

• Evaluating the clinical implementation of structured exercise: A randomized controlled trial among non-insulin dependent type II diabetics. Contemporary clinical trials Dpm, L. F., Wong, M., Bonde, S., Wong, C. W., Walai, K., West, W., Goni, D. T., Araya, S., Azamey, S., Nacif-Coelho, C., Raghuram, S. S., Vera, K., Mittal, A., Cde, L. G., Christensen, M., Johannsen, N., Haddad, F., Moharir, M., Palaniappan, L. 2018

  Abstract

  BACKGROUND: The American Diabetes Association (ADA) currently recommends 150 min of moderate-intensity aerobic exercise per week and resistance exercise at least twice per week in individuals with type 2 diabetes (T2DM) to improve overall health.1 However, approximately 38% of patients with T2DM do not exercise at recommended levels and 31% do not exercise at all.2 The efficacy of structured exercise interventions has been proven effective in reducing glycosylated hemoglobin A1c (HbA1c) levels in patients, but practical approaches are needed to translate these findings into the clinical setting.3-7 OBJECTIVE: The Initiate and Maintain Physical Activity in Clinics (IMPACT) Study aims to compare structured group exercise within the clinic to usual care in T2DM patients. The main purpose of the study is to determine the optimal and feasible level and weekly frequency of structured contact in a clinical setting needed to initiate and maintain physical activity recommendations long-term.STUDY DESIGN: IMPACT is a longitudinal, randomized-controlled study designed to track study participants over 30 months. Once study participants have met eligibility and enrollment criteria, they are randomized and enrolled into one of three arms: 1* per week exercise, 3* per week exercise, or the usual care control group. After randomization, participants begin Phase 1: Initiate lasting 6 months. Over the course of Phase 1, participants in the exercise groups will attend instructor led group training at a Stanford approved physical fitness facility. At the end of 6 months, participants enter Phase 2: Maintain lasting 24 months. Over the course of Phase 2, participants in all three arms will attend periodic follow-up visits for clinical measurements and survey administration for their final two years of participation. These findings will enable the clinical implementation of a structured exercise regimen designed to specifically address the aerobic and resistance training recommendations for patients with T2DM.

  View details for PubMedID 30205182

• Time based versus strain based myocardial performance indices in hypertrophic cardiomyopathy, the merging role of left atrial strain. European heart journal cardiovascular Imaging Kobayashi, Y., Moneghetti, K. J., Bouajila, S., Stolfo, D., Finocchiaro, G., Kuznetsova, T., Liang, D., Schnittger, I., Ashley, E., Wheeler, M., Haddad, F. 2018

  Abstract

  Aims: The myocardial performance index (MPI) is a time-based index of global myocardial performance. In this study, we sought to compare the prognostic value of the MPI with other strain and remodelling indices in hypertrophic cardiomyopathy (HCM).Methods and results: We enrolled 126 patients with HCM and 50 age- and sex-matched controls. Along with traditional echocardiographic assessment, MPI, left ventricular global longitudinal strain (LVGLS), E/e' ratio, and total left atrial (LA) global strain (LAS) were also measured. Time-based MPI was calculated from flow or tissue-based pulse wave Doppler (PWD and TDI) as the (isovolumic-relaxation and contraction time)/systolic-time. We used hierarchical clustering and network analysis to better visualize the relationship between parameters. The primary endpoint was the composite of all-cause death, heart transplantation, left ventricular assist device implantation, and clinical worsening. Left ventricular outflow tract (LVOT) obstruction was present in 56% of patients. Compared with controls, patients with HCM had worse LVGLS (-14.0±3.4% vs. -19.6±1.5%), higher E/e' (12.9±7.2 vs. 6.1±1.5), LA volume index (LAVI) (36.4±13.8ml/m2 vs. 25.6±6.7ml/m2), and MPI (0.55±0.17 vs. 0.40±0.11 for PWD and 0.59±0.22 vs. 0.46±0.09 for TDI) (all P<0.001). During a median follow-up of 55months, 47 endpoints occurred. PWD or TDI-based MPI was not associated with outcome, while LAVI, LAS, LVGLS, and E/e' were (all P<0.01). On multivariable analysis, LVOT obstruction (P<0.001), LAS (P<0.001), and E/e' (P=0.02) were retained as independent associates. They were in different clusters suggesting complemental relationship between them.Conclusion: Time-based index is less predictive of outcome than strain or tissue Doppler indices. LAS may be a promising prognostic marker in HCM.

  View details for PubMedID 30060097

• Applying current normative data to prognosis in heart failure: The Fitness Registry and the Importance of Exercise National Database (FRIEND) INTERNATIONAL JOURNAL OF CARDIOLOGY Moneghetti, K. J., Hock, J., Kaminsky, L., Arena, R., Lui, G. K., Haddad, F., Wheeler, M., Froelicher, V., Ashley, E., Myers, J., Christle, J. W. 2018; 263: 75–79

  Abstract

  Percent of predicted peak VO2 (ppVO2) is considered a standard measure for establishing disease severity, however, there are known limitations to traditional normative values. This study sought to compare ppVO2 from the newly derived "Fitness Registry and the Importance of Exercise: a National Database" (FRIEND) registry equation to conventional prediction equations in a clinical cohort of patients undergoing cardiopulmonary exercise testing (CPX).We selected 1094 patients referred for evaluation of heart failure (HF) symptoms who underwent CPX. ppVO2 was calculated using the FRIEND, Wasserman/Hansen and Jones equations. Participants were followed for a median of 4.5 years [Interquartile range 3.5-6.0] for the composite endpoint of death, advanced HF therapy, or acute decompensated HF requiring hospital admission. Mean age was 48 ± 15 years and 62% were female. The FRIEND registry equation predicted the lowest ppVO2 (measured/predicted; 71 ± 31%), compared to the Wasserman/Hansen (74 ± 29%) and Jones equations (83 ± 33%) (p < 0.001). All expressions of peak VO2 were significant as univariate predictors of outcome with no significant differences between equations on pairwise analysis of receiver operating characteristic curves. When compared at a similar threshold of ppVO2 the event rate was significantly lower in the FRIEND registry equation versus the currently used Wasserman and Jones equations.The use of the newly derived FRIEND registry equation predicts HF outcomes; however, it appears to predict a higher predicted VO2; the clinical implication being a lower threshold of percent predicted peak VO2 should be considered when risk stratifying patients with HF.

  View details for PubMedID 29525067

• Determining the Pathogenicity of a Genomic Variant of Uncertain Significance Using CRISPR/Cas9 and Human-Induced Pluripotent Stem Cells. Circulation Ma, N., Zhang, J., Itzhaki, I., Zhang, S. L., Chen, H., Haddad, F., Kitani, T., Wilson, K. D., Tian, L., Shrestha, R., Wu, H., Lam, C. K., Sayed, N., Wu, J. C. 2018

  Abstract

  Background -The progression toward low-cost and rapid next-generation sequencing has uncovered a multitude of variants of uncertain significance (VUS) in both patients and asymptomatic "healthy" individuals. A VUS is a rare or novel variant for which disease pathogenicity has not been conclusively demonstrated or excluded, and thus cannot be definitively annotated. VUS, therefore, pose critical clinical interpretation and risk-assessment challenges, and new methods are urgently needed to better characterize their pathogenicity. Methods -To address this challenge and showcase the uncertainty surrounding genomic variant interpretation, we recruited a "healthy" asymptomatic individual, lacking cardiac-disease clinical history, carrying a hypertrophic cardiomyopathy (HCM)-associated genetic variant (NM_000258.2:c.170C>A, NP_000249.1:p.Ala57Asp) in the sarcomeric gene MYL3, reported by the ClinVar database to be "likely pathogenic." Humaninduced pluripotent stem cells (iPSCs) were derived from the heterozygous VUSMYL3(170C>A) carrier, and their genome was edited using CRISPR/Cas9 to generate 4 isogenic iPSC lines: (1) corrected "healthy" control; (2) homozygous VUSMYL3(170C>A); (3) heterozygous frameshift mutation MYL3(170C>A/fs); and (4) known heterozygous MYL3 pathogenic mutation (NM_000258.2:c.170C>G), at the same nucleotide position as VUSMYL3(170C>A), lines. Extensive assays including measurements of gene expression, sarcomere structure, cell size, contractility, action potentials, and calcium handling were performed on the isogenic iPSC-derived cardiomyocytes (iPSC-CMs). Results -The heterozygous VUSMYL3(170C>A)-iPSC-CMs did not show an HCM phenotype at the gene expression, morphology, or functional levels. Furthermore, genome-edited homozygous VUSMYL3(170C>A)- and frameshift mutation MYL3(170C>A/fs)-iPSC-CMs lines were also asymptomatic, supporting a benign assessment for this particular MYL3 variant. Further assessment of the pathogenic nature of a genome-edited isogenic line carrying a known pathogenic MYL3 mutation, MYL3(170C>G), and a carrier-specific iPSC-CMs line, carrying a MYBPC3(961G>A) HCM variant, demonstrated the ability of this combined platform to provide both pathogenic and benign assessments. Conclusions -Our study illustrates the ability of clustered regularly interspaced short palindromic repeats/Cas9 genome-editing of carrier-specific iPSCs to elucidate both benign and pathogenic HCM functional phenotypes in a carrierspecific manner in a dish. As such, this platform represents a promising VUS riskassessment tool that can be used for assessing HCM-associated VUS specifically, and VUS in general, and thus significantly contribute to the arsenal of precision medicine tools available in this emerging field.

  View details for PubMedID 29914921

• Effects of Repetitive Transendocardial CD34+ Cell Transplantation in Patients with Non-Ischemic Dilated Cardiomyopathy. Circulation research Vrtovec, B., Poglajen, G., Sever, M., Zemljic, G., Frljak, S., Cerar, A., Cukjati, M., Jaklic, M., Cernelc, P., Haddad, F., Wu, J. C. 2018

  Abstract

  Rationale: Preclinical data in heart failure models suggest that repetitive stem cell therapy may be superior to single-dose cell administration. Objective: We investigated whether repetitive administration of CD34+ cells is superior to single dose administration in patients with non-ischemic dilated cardiomyopathy (DCM). Methods and Results: Of 66 patients with DCM, NYHA functional class III, and left ventricular ejection fraction (LVEF)< 40% enrolled in the study, 60 were randomly allocated to repetitive cell therapy (Group A, N=30), or single cell therapy (Group B, N=30). Patients received granulocyte-colony stimulating factor (G-CSF) for 5 days and 80 million CD34+ cells were collected by apheresis and injected transendocardially. In Group A, cell therapy was repeated at 6 months. All patients were followed for 1 year, and the primary end-point was the difference in change in LVEF between the groups. At baseline, the groups did not differ in age, sex, LVEF, NT-proBNP, or 6-minute walk test distance. When directly comparing groups A and B at 1 year, there was no significant difference in change in LVEF (from 32.2±9.3% to 41.2±6.5% in Group A and from 30.0±7.0% to 37.9±5.3% in Group B, P=0.40). From baseline to 6 months, both groups improved in LVEF (+6.9±3.3% in Group A, P=0.001 and +7.1±3.5% in Group B, P=0.001), NT-proBNP (-578±211 pg/ml, P=0.02 and -633±305 pg/ml, P=0.01) and 6MWT (+87±21 m, P=0.03 and +92±25 m, P=0.02). In contrast, we observed no significant changes between 6 months and 1 year (LVEF: +2.1±2.3% in Group A, P=0.19 and +0.8±3.1% in Group B, P=0.56; NT-proBNP: -215±125 pg/ml, P=0.26 and -33±205 pg/ml, P=0.77; 6MWT: +27±11 m, P=0.2 and +12±18 m, P=0.42). Conclusions: In patients with DCM, repetitive CD34+ cell administration does not appear to be associated with superior improvements in LVEF, NT-proBNP, or 6MWT when compared to single dose cell therapy. Clinical Trial: NCT02248532.

  View details for PubMedID 29880546

• Impact of the initiation of balloon pulmonary angioplasty program on referral of patients with chronic thromboembolic pulmonary hypertension to surgery. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Amsallem, M., Guihaire, J., Arthur Ataam, J., Lamrani, L., Boulate, D., Mussot, S., Fabre, D., Taniguchi, Y., Haddad, F., Sitbon, O., Jais, X., Humbert, M., Simonneau, G., Mercier, O., Brenot, P., Fadel, E. 2018

  Abstract

  BACKGROUND: Balloon pulmonary angioplasty (BPA) is a technique proposed for inoperable patients with chronic thromboembolic pulmonary hypertension (CTEPH). In this study we aimed to determine whether initiation of the BPA program has modified the characteristics and outcome of patients undergoing pulmonary endarterectomy (PEA), and compared the characteristics of patients undergoing one or the other procedure.METHODS: This prospective registry study included all patients with CTEPH who underwent PEA in the French National Reference Center before (2012 to 2013) and after (2015 to 2016) BPA program initiation (February 2014). Pre-operative clinical and hemodynamics profiles, peri-operative (Jamieson classification, surgery duration, need of assistance) characteristics of both groups, and all-cause mortality were compared using the t-test or chi-square test. Characteristics of patients subjected to surgery or BPA since February 2014 were also compared.RESULTS: The total number of patients referred to the CTEPH team increased in the BPA era (n = 291vs n = 484). The pre-operative characteristics of patients from the pre-BPA era (n = 240) were similar to those from the BPA era (n = 246). Despite more Jamieson Type 3 cases (29%) in the second period, 30- and 90-day mortality remained stable (both p > 0.30). Patients subjected to BPA (n = 177) were older than those subjected to PEA (n = 364) (64 ± 14vs 60 ± 14years, respectively), and had higher rates of splenectomy (10% vs 1%) or implantable port (9% vs 3%), lower total pulmonary resistance, better cardiac index, and better renal function (all p < 0.01).CONCLUSIONS: This study shows the influence of the initiation of the BPA program on the profile of patients with CTEPH undergoing PEA.

  View details for PubMedID 30037729

• Right Ventricular Structure and Function in the Veteran Ultramarathon Runner: Is There Evidence for Chronic Maladaptation? JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY Rothwell, O., George, K., Somauroo, J., Lord, R., Stembridge, M., Shave, R., Hoffman, M. D., Wilson, M., Ashley, E., Haddad, F., Eijsvogels, T. H., Oxborough, D. 2018; 31 (5): 598-+

  Abstract

  It has been proposed that chronic exposure to prolonged strenuous exercise may result in maladaptation of the right ventricle (RV). The aim of this study was to establish RV structure and function, including septal insertion points, using conventional echocardiography and myocardial strain (ε) imaging in a veteran population of ultramarathon runners (UR) and age- and sex-matched controls.A retrospective study design provided 40 UR (>35 years old; mean ± SD training experience, 18 ± 12 years) and 24 sedentary controls who had previously undergone conventional two-dimensional, tissue Doppler and speckle-tracking echocardiography to measure RV size and function. Peak RV ε and strain rate (SR) were assessed from the base, mid, and apical lateral wall. SR were assessed during systole (SRs'), early diastole (SRe') and late diastole (SRa'). Regional assessment of RV insertion points was made at the basal inferoseptum and apical septum using left ventricular (LV) longitudinal ε and at the anteroseptum and inferoseptum using LV circumferential and radial ε.All structural indices of RV size were significantly larger in UR. RV regional and global peak ε were not different between groups, whereas basal RV SR was significantly lower in UR. UR had significantly higher peak LV circumferential ε (anteroseptum, -26% ± 8% vs -21% ± 6%; inferoseptum, -25% ± 6% vs -16% ± 9%) and higher peak LV longitudinal ε (apical septum, -28% ± 7% vs -22% ± 4%) compared with controls. There was regional heterogeneity in UR that was not observed in controls with significantly lower longitudinal ε at the basal inferoseptal insertion point when compared with the global ε (-19% ± 2% vs -22% ± 4%).Myocardial ε imaging highlights no overt maladaptation in this cohort of veteran UR, although lower insertion point ε, compared with global ε, in UR may warrant further investigation.

  View details for PubMedID 29305036

• Large Q and S waves in lead III on the electrocardiogram distinguish patients with hypertrophic cardiomyopathy from athletes. Heart (British Cardiac Society) Chen, A. S., Bent, R. E., Wheeler, M., Knowles, J. W., Haddad, F., Froelicher, V., Ashley, E., Perez, M. V. 2018

  Abstract

  OBJECTIVE: To identify electrocardiographic findings, especially deep Q and S waves in lead III, that differentiate athletes from patients with hypertrophic cardiomyopathy (HCM).METHODS: Digital ECGs of athletes and patients with HCM followed at the Stanford Center for Inherited Cardiovascular Disease were studied retrospectively. All patients with HCM had an echocardiogram performed. A multivariable logistic regression model was used to calculate ORs for various demographic and ECG characteristics. Linear regression was used to correlate ECG characteristics with echocardiogram findings.RESULTS: We studied 1124 athletes and 240 patients with HCM. The average Q+Swave amplitude in lead III (IIIQ+S) was significantly higher in patients with HCM compared with athletes (0.71±0.69mV vs 0.21±0.17mV, p<0.001). In patients with HCM, IIIQ+S directly correlated with interventricular septal (IVS) thickness on echocardiography (rho=0.45, p<0.001). In a multivariable analysis adjusted for demographic and ECG characteristics, higher IIIQ+S values remained independently associated with HCM compared with athletes (OR=4.2 per 0.5mV, p<0.001). In subgroup analyses of young patients, African-American subjects and subjects without left axis deviation (LAD), IIIQ+S remained associated with HCM. The addition of IIIQ+S>1.0 mV as an abnormal finding to the International Criteria for athletic ECG interpretation improved sensitivity from 64.2% to 70.4%, with a minimal decrease in specificity.CONCLUSION: Large Q and S waves in lead III distinguished athletes from patients with HCM, independent of axis and well-known ECG markers associated with HCM. The correlation between IVS thickness in patients with HCM and IIIQ+S suggests a partial explanation for this association.

  View details for PubMedID 29680808

• Relation of Insulin Resistance to Longitudinal Changes in Left Ventricular Structure and Function in a General Population JOURNAL OF THE AMERICAN HEART ASSOCIATION Cauwenberghs, N., Knez, J., Thijs, L., Haddad, F., Vanassche, T., Yang, W., Wei, F., Staessen, J. A., Kuznetsova, T. 2018; 7 (7)

  Abstract

  Population data on the longitudinal changes of left ventricular (LV) structure and function in relation to insulin resistance are sparse. Therefore, we assessed in a general population whether hyperinsulinemia predicts longitudinal changes in LV and arterial characteristics.In 627 participants (mean age 50.7 years, 51.4% women), we assessed echocardiographic indexes of LV structure and function and carotid-femoral pulse wave velocity by applanation tonometry at baseline and after 4.7 years. We regressed longitudinal changes in these indexes on baseline insulin and its change during follow-up, and reported standardized effect sizes as a percentage of the SD of LV changes associated with a doubling of insulin. After adjustment, higher baseline insulin predicted a greater temporal increase in LV mass index (effect size: +15.1%) and E/e' ratio (+22.1%), and a greater decrease in e' peak and longitudinal strain (-11.2% to -17.1%). A greater increase in insulin during follow-up related to a greater increase in LV mass index (+10.7%) and decline in ejection fraction and longitudinal strain (-11.4% to -15.7%). Participants who became or remained insulin resistant during follow-up experienced worse changes in longitudinal strain, E/e', and LV mass index as compared with participants who did not develop or had improved insulin resistance over time (P≤0.033). Moreover, multivariable-adjusted increase in pulse wave velocity was higher in participants with diabetes mellitus than in participants without diabetes mellitus (+1.46 m/s versus +0.71 m/s; P=0.039).Hyperinsulinemia at baseline and during follow-up predicted worsening of LV function and remodeling over time. Our findings underline the importance of management of insulin resistance.

  View details for DOI 10.1161/JAHA.117.008315

  View details for Web of Science ID 000430009000011

  View details for PubMedID 29574459

  View details for PubMedCentralID PMC5907600

• THE COMPLEMENTARY VALUE OF THE GET WITH THE GUIDELINES: HEART FAILURE RISK SCORE AND LABORATORY MARKERS AT DISCHARGE IN PREDICTING MORTALITY IN PATIENTS HOSPITALIZED WITH HEART FAILURE WITH PRESERVED EJECTION FRACTION Boralkar, K., Kobayashi, Y., Pargaonkar, V., Moneghetti, K., Tuzovic, M., Krishnan, G., Amsallem, M., Kouznetsova, T., Horne, B., Knowlton, K., Heidenreich, P., Haddad, F. ELSEVIER SCIENCE INC. 2018: 839

  View details for DOI 10.1016/S0735-1097(18)31380-9

  View details for Web of Science ID 000429659702089

• RIGHT HEART MALADAPTIVE PHENOTYPES AND PREDICTION OF RIGHT HEART FAILURE FOLLOWING CONTINUOUS-FLOW LEFT VENTRICULAR ASSIST DEVICE IMPLANTATION Aymami, M., Haddad, F., Amsallem, M., Wheeler, M., Moneghetti, K., Adams, J., Verhoye, J., Sallam, K., Woo, Y., Ha, R., Banerjee, D. ELSEVIER SCIENCE INC. 2018: 652

  View details for DOI 10.1016/S0735-1097(18)31193-8

  View details for Web of Science ID 000429659701502

• RIGHT VENTRICULAR LOAD ADAPTABILITY IN PATIENTS UNDERGOING CONTINUOUS-FLOW LEFT VENTRICULAR ASSIST DEVICE IMPLANTATION Amsallem, M., Aymami, M., Hiesinger, W., Zeigler, S., Moneghetti, K., Marques, M., Wheeler, M., Teuteberg, J., Ha, R., Banerjee, D., Haddad, F. ELSEVIER SCIENCE INC. 2018: 1624

  View details for DOI 10.1016/S0735-1097(18)32165-X

  View details for Web of Science ID 000429659703274

• SUBCLINICAL LEFT VENTRICULAR DYSFUNCTION IN WOMEN WITH ANGINA IN THE ABSENCE OF OBSTRUCTIVE CORONARY ARTERY DISEASE: A COMPREHENSIVE INVASIVE AND ECHOCARDIOGRAPHIC STUDY Bouajila, S., Pargaonkar, V., Kobayashi, Y., Kobayashi, Y., Haddad, F., Tremmel, J. ELSEVIER SCIENCE INC. 2018: 132

  View details for DOI 10.1016/S0735-1097(18)30673-9

  View details for Web of Science ID 000429659700133

• INTEGRATING CORRELATION BASED NETWORKS INTO RISK PROGNOSTICATION OF CARDIOMYOPATHY Moneghetti, K., Kim, J., Kobayashi, Y., Boralkar, K., Wheeler, M., Ashley, E., Haddad, F. ELSEVIER SCIENCE INC. 2018: 837

  View details for DOI 10.1016/S0735-1097(18)31378-0

  View details for Web of Science ID 000429659702087

• IMMUNE PROFILE OF HEALTHY CARDIOVASCULAR AGING: INSIGHTS FROM A POPULATION-BASED STUDY AND NETWORK MODELING Bouajila, S., Moneghetti, K., Kobayashi, Y., Gomari, F. A., Abbasi, F., Davis, M. M., Wu, J. C., Kuznetsova, T., Sayed, N., Haddad, F. ELSEVIER SCIENCE INC. 2018: 1657

  View details for Web of Science ID 000429659703307

• THE PROGNOSTIC VALUE OF COMPUTED TOMOGRAPHY FRAILTY MEASURES FOR PROLONGED HOSPITAL STAY AFTER TAVR IN 429 PATIENTS Maret, E., Willemink, M., Moneghetti, K., Kim, J., Haddad, F., Kobayashi, Y., Miller, C., Yeung, A., Fishbein, M., Fearon, W., Fleischmann, D. ELSEVIER SCIENCE INC. 2018: 1414

  View details for DOI 10.1016/S0735-1097(18)31955-7

  View details for Web of Science ID 000429659703064

• PREDICTING MORTALITY WITH AORTOMITRAL CALCIFICATIONS IN 317 TAVR PATIENTS Willemink, M., Maret, E., Moneghetti, K., Kim, J., Haddad, F., Kobayashi, Y., Higashigaito, K., Yeung, A., Lee, A., Miller, D., Fischbein, M., Fearon, W., Fleischmann, D. ELSEVIER SCIENCE INC. 2018: 1591

  View details for DOI 10.1016/S0735-1097(18)32132-6

  View details for Web of Science ID 000429659703241

• Stem cell therapy targeting the right ventricle in pulmonary arterial hypertension: is it a potential avenue of therapy? PULMONARY CIRCULATION Loisel, F., Provost, B., Haddad, F., Guihaire, J., Amsallem, M., Vrtovec, B., Fadel, E., Uzan, G., Mercier, O. 2018; 8 (2): 2045893218755979

  Abstract

  Pulmonary arterial hypertension (PAH) is an incurable disease characterized by an increase in pulmonary arterial pressure due to pathological changes to the pulmonary vascular bed. As a result, the right ventricle (RV) is subject to an increased afterload and undergoes multiple changes, including a decrease in capillary density. All of these dysfunctions lead to RV failure. A number of studies have shown that RV function is one of the main prognostic factors for PAH patients. Many stem cell therapies targeting the left ventricle are currently undergoing development. The promising results observed in animal models have led to clinical trials that have shown an improvement of cardiac function. In contrast to left heart disease, stem cell therapy applied to the RV has remained poorly studied, even though it too may provide a therapeutic benefit. In this review, we discuss stem cell therapy as a treatment for RV failure in PAH. We provide an overview of the results of preclinical and clinical studies for RV cell therapies. Although a large number of studies have targeted the pulmonary circulation rather than the RV directly, there are nonetheless encouraging results in the literature that indicate that cell therapies may have a direct beneficial effect on RV function. This cell therapy strategy may therefore hold great promise and warrants further studies in PAH patients.

  View details for PubMedID 29480154

  View details for PubMedCentralID PMC5844533

• Circulating Biomarkers to Identify Responders in Cardiac Cell therapy (vol 7, 4419, 2017) SCIENTIFIC REPORTS Jokerst, J. V., Cauwenberghs, N., Kuznetsova, T., Haddad, F., Sweeney, T., Hou, J., Rosenberg-Hasson, Y., Zhao, E., Schutt, R., Bolli, R., Traverse, J. H., Pepine, C. J., Henry, T. D., Schulman, I. H., Moye, L., Taylor, D. A., Yang, P. C. 2018; 8: 4257

  Abstract

  A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

  View details for PubMedID 29511207

• Value of Circulating Cytokine Profiling During Submaximal Exercise Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Scientific reports Moneghetti, K. J., Skhiri, M. n., Contrepois, K. n., Kobayashi, Y. n., Maecker, H. n., Davis, M. n., Snyder, M. n., Haddad, F. n., Montoya, J. G. 2018; 8 (1): 2779

  Abstract

  Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS) is a heterogeneous syndrome in which patients often experience severe fatigue and malaise following exertion. Immune and cardiovascular dysfunction have been postulated to play a role in the pathophysiology. We therefore, examined whether cytokine profiling or cardiovascular testing following exercise would differentiate patients with ME/CFS. Twenty-four ME/CFS patients were matched to 24 sedentary controls and underwent cardiovascular and circulating immune profiling. Cardiovascular analysis included echocardiography, cardiopulmonary exercise and endothelial function testing. Cytokine and growth factor profiles were analyzed using a 51-plex Luminex bead kit at baseline and 18 hours following exercise. Cardiac structure and exercise capacity were similar between groups. Sparse partial least square discriminant analyses of cytokine profiles 18 hours post exercise offered the most reliable discrimination between ME/CFS and controls (κ = 0.62(0.34,0.84)). The most discriminatory cytokines post exercise were CD40L, platelet activator inhibitor, interleukin 1-β, interferon-α and CXCL1. In conclusion, cytokine profiling following exercise may help differentiate patients with ME/CFS from sedentary controls.

  View details for PubMedID 29426834

• Pilot studies demonstrate the potential benefits of antiinflammatory therapy in human lymphedema. JCI insight Rockson, S. G., Tian, W. n., Jiang, X. n., Kuznetsova, T. n., Haddad, F. n., Zampell, J. n., Mehrara, B. n., Sampson, J. P., Roche, L. n., Kim, J. n., Nicolls, M. R. 2018; 3 (20)

  Abstract

  Lymphedema is a common condition affecting millions around the world that still lacks approved medical therapy. Because ketoprofen, an NSAID, has been therapeutic in experimental lymphedema, we evaluated its efficacy in humans.We first performed an exploratory open-label trial. Patients with either primary or secondary lymphedema received ketoprofen 75 mg by mouth 3 times daily for 4 months. Subjects were evaluated for changes in histopathology, with skin thickness, limb volume, and tissue bioimpedance changes serving as secondary endpoints. Based on our encouraging findings, we next conducted a placebo-controlled trial, with the primary outcome defined as a change in skin thickness, as measured by skin calipers. Secondary endpoints for this second study included histopathology, limb volume, bioimpedance, and systemic inflammatory mediators.We enrolled 21 lymphedema patients in the open-label trial, from November 2010 to July 2011. Histopathology and skin thickness were significantly improved at 4 months compared with baseline. In the follow-up, double-blind, placebo-controlled trial, we enrolled 34 patients from August 2011 to October 2015, with 16 ketoprofen recipients and 18 placebo-treated subjects. No serious adverse events occurred. The ketoprofen recipients demonstrated reduced skin thickness, as well as improved composite measures of histopathology and decreased plasma granulocyte CSF (G-CSF) expression.These 2 exploratory studies together support the utility of targeted antiinflammatory therapy with ketoprofen in patients with lymphedema. Our results highlight the promise of such approaches to help restore a failing lymphatic circulation.ClinicalTrials.gov NCT02257970.

  View details for PubMedID 30333315

• EXPRESS: Non-invasive Right Ventricular Load Adaptability Indices in Patients with Scleroderma-Associated Pulmonary Arterial Hypertension. Pulmonary circulation French, S., Amsallem, M., Ouazani, N., Li, S., Kudelko, K., Zamanian, R., Haddad, F., Chung, L. 2018: 2045894018788268

  View details for PubMedID 29938590

• Current Knowledge and Recent Advances of Right Ventricular Molecular Biology and Metabolism from Congenital Heart Disease to Chronic Pulmonary Hypertension BIOMED RESEARCH INTERNATIONAL Guimaron, S., Guihaire, J., Amsallem, M., Haddad, F., Fadel, E., Mercier, O. 2018: 1981568

  Abstract

  Studies about pulmonary hypertension and congenital heart diseases have introduced the concept of right ventricular remodeling leading these pathologies to a similar outcome: right ventricular failure. However right ventricular remodeling is also a physiological process that enables the normal fetal right ventricle to adapt at birth and gain its adult phenotype. The healthy mature right ventricle is exposed to low pulmonary vascular resistances and is compliant. However, in the setting of chronic pressure overload, as in pulmonary hypertension, or volume overload, as in congenital heart diseases, the right ventricle reverts back to a fetal phenotype to sustain its function. Mechanisms include angiogenic changes and concomitant increased metabolic activity to maintain energy production. Eventually, the remodeled right ventricle cannot resist the increased afterload, leading to right ventricular failure. After comparing the fetal and adult healthy right ventricles, we sought to review the main metabolic and cellular changes occurring in the setting of PH and CHD. Their association with RV function and potential impact on clinical practice will also be discussed.

  View details for PubMedID 29581963

  View details for PubMedCentralID PMC5822779

• Exercise testing in heart failure: a contemporary discussion in an era of novel diagnostic techniques and biomarkers. Current opinion in cardiology Moneghetti, K. J., Christle, J. W., Myers, J. n., Haddad, F. n. 2018; 33 (2): 217–24

  Abstract

  The purpose of this review is to highlight recent advances in the field of exercise testing for patients with heart failure.The importance of assessment of cardiorespiratory fitness (CRF) and exercise testing in heart failure is highlighted in the consensus recommendation of the American Heart Association. Contemporary studies have validated the independent and incremental strength of CRF metrics in patients with heart failure and coronary artery disease. The use of respiratory gas analysis and imaging or hemodynamics during physical exercise is feasible and results in high prognostic utility across the continuum of heart failure. Understanding how CRF metrics complement existing and novel biomarkers and risk scores is an emerging subject of scientific inquiry.In the current era of personalized medicine, integrating CRF, imaging and circulating biomarkers will allow us to further develop individualized strategies for improving outcome in patients with heart failure.

  View details for PubMedID 29227300

• Athletic Remodeling in Female College Athletes, the "Morganroth Hypothesis" Revisited. Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine Kooreman, Z. n., Giraldeau, G. n., Finocchiaro, G. n., Kobayashi, Y. n., Wheeler, M. n., Perez, M. n., Moneghetti, K. n., Oxborough, D. n., George, K. P., Myers, J. n., Ashley, E. n., Haddad, F. n. 2018

  Abstract

  There is limited data regarding ventricular remodeling in college female athletes, especially when appropriate scaling of cardiac dimensions to lean body mass (LBM) is considered. Moreover, it is not well established whether cardiac remodeling in female athletes is a balanced process with proportional increase in left ventricular (LV) mass and volume or the right and LV size.During the preparticipation competitive screening, 72 female college athletes volunteered to undergo dual energy x-ray absorptiometry scan for quantification of LBM and comprehensive 2D echocardiography including assessment of longitudinal myocardial strain. The athletes were divided in 2 groups according to the intensity of the dynamic and static components of their sport categories, ie, a higher intensity dynamic and resistive group (n = 37 participating in rowing, water polo and lacrosse) and a lower intensity group (n = 35, participating in short distance running, sailing, synchronized swimming, and softball). In addition, we recruited a group of 31 age-matched nonathlete controls.The mean age of the study population was 18.7 ± 1.0 years. When scaled to body surface area, the higher intensity group had 17.1 ± 3.6% (P < 0.001) greater LV mass when compared with the lower intensity group and 21.7 ± 4.0% (P < 0.001) greater LV mass than the control group. The differences persisted after scaling to LBM with 14.2 ± 3.2% (P < 0.001) greater LV mass in the higher intensity group. By contrast, there was no difference in any of the relative remodeling indices including the LV mass to volume ratio, right to LV area ratio, or left atrial to LV volume ratio (P > 0.50 for all). In addition, no significant difference was noted among the 3 groups in LV ejection fraction (P = 0.22), LV global longitudinal strain (P = 0.55), LV systolic strain rate (P = 0.62), or right ventricular global longitudinal strain (P = 0.61).Female collegiate athletes participating in higher intensity dynamic and resistive sports have higher indexed LV mass even when scaled to LBM. The remodeling process does however appear to be a balanced process not only at the intraventricular level but also at the interventricular and atrioventricular levels.

  View details for PubMedID 29369833

• The importance of capillary density-stroke work mismatch for right ventricular adaptation to chronic pressure overload. The Journal of thoracic and cardiovascular surgery Noly, P. E., Haddad, F., Arthur-Ataam, J., Langer, N., Dorfmüller, P., Loisel, F., Guihaire, J., Decante, B., Lamrani, L., Fadel, E., Mercier, O. 2017; 154 (6): 2070-2079

  Abstract

  Mechanisms of right ventricular (RV) adaptation to chronic pressure overload are not well understood. We hypothesized that a lower capillary density (CD) to stroke work ratio would be associated with more fibrosis and RV maladaptive remodeling.We induced RV chronic pressure overload over a 20-week period in 2 piglet models of pulmonary hypertension; that is, a shunt model (n = 5) and a chronic thromboembolic pulmonary hypertension model (n = 5). We assessed hemodynamic parameters and RV remodeling as well as RV CD, fibrosis, and angiogenic factors expression.Although RV was similarly hypertrophied in both models, maladapted RV remodeling with impaired systolic function was only seen in chronic thromboembolic pulmonary hypertension group members who had lower CD (484 ± 99 vs 1213 ± 74 cap/mm2; P < .01), lower CD to stroke work ratio (0.29 ± 0.07 vs 0.82 ± 0.16; P = .02), higher myocardial fibrosis (15.4% ± 3.8% vs 8.0% ± 2.5%; P < .01), as well as a higher angiogenic and fibrosis factors expression.The RV adaptive response to chronic pressure overload differs between 2 different piglet models of PH. Mismatch between angiogenesis and workload (CD to stroke work ratio) was associated with greater degree of myocardial fibrosis and RV dysfunction and could be a promising index of RV maladaptation. Further studies are needed to understand the underlying mechanisms.

  View details for DOI 10.1016/j.jtcvs.2017.05.102

  View details for PubMedID 28712579

• Full Circle on Pulmonary Flow Dynamics in Pulmonary Arterial Hypertension. JACC. Cardiovascular imaging Haddad, F., Amsallem, M. 2017; 10 (10 Pt B): 1278-1280

  View details for DOI 10.1016/j.jcmg.2016.12.022

  View details for PubMedID 29025578

• Randomised placebo-controlled safety and tolerability trial of FK506 (tacrolimus) for pulmonary arterial hypertension EUROPEAN RESPIRATORY JOURNAL Spiekerkoetter, E., Sung, Y. K., Sudheendra, D., Scott, V., Del Rosario, P., Bill, M., Haddad, F., Long-Boyle, J., Hedlin, H., Zamanian, R. T. 2017; 50 (3)

  Abstract

  Pulmonary arterial hypertension (PAH) is a devastating disease characterised by occlusive pulmonary vasculopathy. Activation of bone morphogenetic protein receptor 2 (BMPR2) signalling by FK506 (tacrolimus) reverses occlusive vasculopathy in rodent PAH models. Here, we determined the safety and tolerability of low-level FK506 therapy in stable PAH patients.We performed a randomised, double-blind, placebo-controlled, 16-week, single-centre, phase IIa trial in PAH patients with New York Heart Association functional class II/III symptoms using three FK506 target levels (<2, 2-3 and 3-5 ng·mL-1). 23 patients were randomised and 20 patients completed the trial.FK506 was generally well tolerated, with nausea/diarrhoea being the most commonly reported adverse event and no observation of line infections in patients on intravenous prostacyclin therapy. PAH patients had significantly lower BMPR2 expression in peripheral blood mononuclear cells versus healthy controls (n=13; p=0.005), which improved after FK506 treatment. While we observed that some patients responded with a pronounced increase in BMPR2 expression as well as improvement in 6-min walk distance, and serological and echocardiographic parameters of heart failure, these changes were not significant.Low-level FK506 is well tolerated and increases BMPR2 in subsets of PAH patients. These results support the study of FK506 in a phase IIb efficacy trial.

  View details for PubMedID 28893866

• Report from the Annual Conference of the British Society of Echocardiography, November 2016, Queen Elizabeth II Conference Centre, London. Echo research and practice Steeds, R. P., Cowie, M. R., Rana, B. S., Chambers, J. B., Ray, S., Srinivasan, J., Schwarz, K., Neil, C. J., Scally, C., Horowitz, J. D., Frenneaux, M. P., Pislaru, C., Dawson, D. K., Rothwell, O. J., George, K., Somauroo, J. D., Lord, R., Stembridge, M., Shave, R., Hoffman, M., Ashley, E. A., Haddad, F., Eijsvogels, T. M., Oxborough, D., Hampson, R., Kinsey, C. D., Gurunathan, S., Vamvakidou, A., Karogiannis, N., Senior, R., Ahmadvazir, S., Shah, B. N., Zacharias, K., Bowen, D., Robinson, S., Ihekwaba, U., Parker, K., Boyd, J., Densem, C. G., Atkinson, C., Hinton, J., Gaisie, E. B., Rakhit, D. J., Yue, A. M., Roberts, P. R., Thomas, D., Phen, P., Sibley, J., Fergey, S., Russhard, P. 2017; 4 (3): M1

  View details for DOI 10.1530/ERP-17-0046

  View details for PubMedID 30390608

• Load Adaptability in Patients With Pulmonary Arterial Hypertension. The American journal of cardiology Amsallem, M., Boulate, D., Aymami, M., Guihaire, J., Selej, M., Huo, J., Denault, A. Y., McConnell, M. V., Schnittger, I., Fadel, E., Mercier, O., Zamanian, R. T., Haddad, F. 2017; 120 (5): 874-882

  Abstract

  Right ventricular (RV) adaptation to pressure overload is a major prognostic factor in patients with pulmonary arterial hypertension (PAH). The objectives were first to define the relation between RV adaptation and load using allometric modeling, then to compare the prognostic value of different indices of load adaptability in PAH. Both a derivation (n = 85) and a validation cohort (n = 200) were included. Load adaptability was assessed using 3 approaches: (1) surrogates of ventriculo-arterial coupling (e.g., RV area change/end-systolic area), (2) simple ratio of function and load (e.g., tricuspid annular plane systolic excursion/right ventricular systolic pressure), and (3) indices assessing the proportionality of adaptation using allometric pressure-function or size modeling. Proportional hazard modeling was used to compare the hazard ratio for the outcome of death or lung transplantation. The mean age of the derivation cohort was 44 ± 11 years, with 80% female and 74% in New York Heart Association class III or IV. Mean pulmonary vascular resistance index (PVRI) was 24 ± 11 with a wide distribution (1.6 to 57.5 WU/m2). Allometric relations were observed between PVRI and RV fractional area change (R2 = 0.53, p < 0.001) and RV end-systolic area indexed to body surface area right ventricular end-systolic area index (RVESAI) (R2 = 0.29, p < 0.001), allowing the derivation of simple ratiometric load-specific indices of RV adaptation. In right heart parameters, RVESAI was the strongest predictor of outcomes (hazard ratio per SD = 1.93, 95% confidence interval 1.37 to 2.75, p < 0.001). Although RVESAI/PVRI0.35 provided small incremental discrimination on multivariate modeling, none of the load-adaptability indices provided stronger discrimination of outcome than simple RV adaptation metrics in either the derivation or the validation cohort. In conclusion, allometric modeling enables quantification of the proportionality of RV load adaptation but offers small incremental prognostic value to RV end-systolic dimension in PAH.

  View details for DOI 10.1016/j.amjcard.2017.05.053

  View details for PubMedID 28705377

• Incremental value of right heart metrics and exercise performance to well-validated risk scores in dilated cardiomyopathy. European heart journal cardiovascular Imaging Moneghetti, K. J., Giraldeau, G., Wheeler, M. T., Kobayashi, Y., Vrtovec, B., Boulate, D., Kuznetsova, T., Schnittger, I., Wu, J. C., Myers, J., Ashley, E., Haddad, F. 2017

  Abstract

  Risk stratification in heart failure (HF) relies on several established clinical risk scores, however, myocardial deformation, right heart metrics, and exercise performance have not usually been considered. This study sought to assess the incremental value of advanced echocardiographic and cardiopulmonary exercise testing (CPX) parameters to validated risk scores in HF.The Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) and Metabolic Exercise Test Data Combined with Cardiac and Kidney Indexes (MECKI) scores were applied to 208 ambulatory patients with dilated cardiomyopathy (DCM) who completed echocardiography in conjunction with CPX as part of the Stanford Exercise Testing registry. Patients were followed for the composite end point of death, heart transplant, left ventricular device implantation, and hospitalization for acute HF. Mean age, left ventricular ejection fraction (LVEF), and left ventricular global longitudinal strain (LVGLS) were 47 ± 13 years, 33 ± 13%, and -10.6 ± 4.4%, respectively, while right ventricular free-wall longitudinal strain was -18.8 ± 5.5%. Partial correlation mapping identified strong correlations between LVEF, LVGLS, and LV systolic strain rate, with a moderate correlation between these metrics and peak VO2. Over a median follow up of 5.3 years, the composite end point occurred in 60 patients. Cox proportional hazards identified MAGGIC score [hazard ratio (HR) (2.04 [1.39-3.01], P < 0.01], peak VO2 HR (0.52 [0.28-0.97], P = 0.04), and right atrial volume indexed (RAVI) HR (1.31 [1.07-1.61], P < 0.01) as independent correlates of outcome. RAVI remained an independent correlate when combined with the MECKI score (2.21 [1.59-3.07]), P < 0.01, RAVI, 1.33 [1.06-1.67], P = 0.01).Our study demonstrates that RAVI is complementary to well-validated HF risk scores and highlights the importance of exercise performance in DCM.

  View details for DOI 10.1093/ehjci/jex187

  View details for PubMedID 28977353

• Circulating Biomarkers to Identify Responders in Cardiac Cell therapy SCIENTIFIC REPORTS Jokerst, J. V., Cauwenberghs, N., Kuznetsova, T., Haddad, F., Sweeney, T., Hou, J., Rosenberg-Hasson, Y., Zhao, E., Schutt, R., Bolli, R., Traverse, J. H., Pepine, C. J., Henry, T. D., Schulman, I. H., Moye, L., Taylor, D. A., Yang, P. C. 2017; 7: 4419

  Abstract

  Bone marrow mononuclear cell (BM-MNC) therapy in ST-elevation acute myocardial infarction (STEMI) has no biological inclusion criteria. Here, we analyzed 63 biomarkers and cytokines in baseline plasma samples from 77 STEMI patients treated with BM-MNCs in the TIME and Late-TIME trials as well as 61 STEMI patients treated with placebo. Response to cell therapy was defined by changes in left ventricular ejection fraction, systolic/diastolic volumes, and wall motion indexes. We investigated the clinical value of circulating proteins in outcome prediction using significance testing, partial least squares discriminant analysis, and receiver operating characteristic (ROC) analysis. Responders had higher biomarker levels (76-94% elevated) than non-responders. Several biomarkers had values that differed significantly (P < 0.05) between responders and non-responders including stem cell factor, platelet-derived growth factor, and interleukin-15. We then used these lead candidates for ROC analysis and found multiple biomarkers with values areas under the curve >0.70 including interleukin 15. These biomarkers were not involved in the placebo-treated subjects suggesting that they may have predictive power. We conclude that plasma profiling after STEMI may help identify patients with a greater likelihood of response to cell-based treatment. Prospective trials are needed to assess the predictive value of the circulating biomarkers.

  View details for PubMedID 28667255

• Right Heart End-Systolic Remodeling Index Strongly Predicts Outcomes in Pulmonary Arterial Hypertension: Comparison With Validated Models. Circulation. Cardiovascular imaging Amsallem, M., Sweatt, A. J., Aymami, M. C., Kuznetsova, T., Selej, M., Lu, H., Mercier, O., Fadel, E., Schnittger, I., McConnell, M. V., Rabinovitch, M., Zamanian, R. T., Haddad, F. 2017; 10 (6)

  Abstract

  Right ventricular (RV) end-systolic dimensions provide information on both size and function. We investigated whether an internally scaled index of end-systolic dimension is incremental to well-validated prognostic scores in pulmonary arterial hypertension.From 2005 to 2014, 228 patients with pulmonary arterial hypertension were prospectively enrolled. RV end-systolic remodeling index (RVESRI) was defined by lateral length divided by septal height. The incremental values of RV free wall longitudinal strain and RVESRI to risk scores were determined. Mean age was 49±14 years, 78% were female, 33% had connective tissue disease, 52% were in New York Heart Association class ≥III, and mean pulmonary vascular resistance was 11.2±6.4 WU. RVESRI and right atrial area were strongly connected to the other right heart metrics. Three zones of adaptation (adapted, maladapted, and severely maladapted) were identified based on the RVESRI to RV systolic pressure relationship. During a mean follow-up of 3.9±2.4 years, the primary end point of death, transplant, or admission for heart failure was reached in 88 patients. RVESRI was incremental to risk prediction scores in pulmonary arterial hypertension, including the Registry to Evaluate Early and Long-Term PAH Disease Management score, the Pulmonary Hypertension Connection equation, and the Mayo Clinic model. Using multivariable analysis, New York Heart Association class III/IV, RVESRI, and log NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) were retained (χ(2), 62.2; P<0.0001). Changes in RVESRI at 1 year (n=203) were predictive of outcome; patients initiated on prostanoid therapy showed the greatest improvement in RVESRI. Among right heart metrics, RVESRI demonstrated the best test-retest characteristics.RVESRI is a simple reproducible prognostic marker in patients with pulmonary arterial hypertension.

  View details for DOI 10.1161/CIRCIMAGING.116.005771

  View details for PubMedID 28592589

• Cell Transplantation on Diastolic Parameters in Patients with Nonischemic Dilated Cardiomyopathy. Stem cells translational medicine Bervar, M., Kozelj, M., Poglajen, G., Sever, M., Zemljic, G., Frljak, S., Cukjati, M., Cernelc, P., Haddad, F., Vrtovec, B. 2017; 6 (6): 1515-1521

  Abstract

  We sought to evaluate the physiological background and the effects of CD34(+) cell transplantation on diastolic parameters in nonischemic dilated cardiomyopathy patients (DCM). We enrolled 38 DCM patients with NYHA class III and LVEF < 40% who underwent transendocardial CD34(+) cell transplantation. Peripheral blood CD34(+) cells were mobilized by G-CSF, collected via apheresis, and injected transendocardially in the areas of myocardial hibernation. Patients were followed for 1 year. At baseline, estimated filling pressures were significantly elevated (E/e' ≥ 15) in 18 patients (Group A), and moderately elevated (E/e '< 15) in 20 patients (Group B). The groups did not differ in age (54 ± 9 years vs. 52 ± 10 years; p = .62), gender (male: 85% vs. 78%; p = .57), or LVEF (31 ± 7% vs. 34 ± 6%; p = .37). When compared to Group B patients in Group A had more segments with myocardial scar (4.9 ± 2.7 vs. 2.7 ± 2.9; p = .03), myocardial hibernation (2.2 ± 1.6 vs. 0.9 ± 1.1; p = .02), and longer average local relaxation time on electroanatomical mapping (378 ± 41 ms vs. 333 ± 34 ms, p = .01). During follow-up there was an improvement in diastolic parameters in Group A (E/e': from 24.3 ± 12.1 to 16.3 ± 8.0; p = .005), but not in Group B (E/e': from 10.2 ± 3.7 to 13.2 ± 9.1; p = .19). Accordingly, in Group A, we found an increase in 6-minute walk distance (from 463 ± 83 m to 546 ± 91 m; p = .03), and a decrease in NT-proBNP (from 2140 ± 1743 pg/ml to 863 ± 836 pg/ml; p = .02). In nonischemic DCM, diastolic dysfunction appears to correlate with areas of myocardial scar and hibernation. Transendocardial CD34(+) cell transplantation may improve diastolic parameters in this patient cohort. Stem Cells Translational Medicine 2017;6:1515-1521.

  View details for DOI 10.1002/sctm.16-0331

  View details for PubMedID 28296283

• Dynamic changes in aortic impedance after transcatheter aortic valve replacement and its impact on exploratory outcome. international journal of cardiovascular imaging Kobayashi, Y., Kim, J. B., Moneghetti, K. J., Kobayashi, Y., Zhang, R., Brenner, D. A., O'Malley, R., Schnittger, I., Fischbein, M., Miller, D. C., Yeung, A. C., Liang, D., Haddad, F., Fearon, W. F. 2017

  Abstract

  Valvulo-arterial impedance (Zva) has been shown to predict worse outcome in medically managed aortic stenosis (AS) patients. We aimed to investigate the association between Zva and left ventricular (LV) adaptation and to explore the predictive value of Zva for cardiac functional recovery and outcome after transcatheter aortic valve replacement (TAVR). We prospectively enrolled 128 patients with AS who underwent TAVR. Zva was calculated as: (systolic blood pressure + mean transaortic gradient)/stroke volume index). Echocardiographic assessment occurred at baseline, 1-month and 1-year after TAVR. The primary endpoints were to investigate associations between Zva and global longitudinal strain (GLS) at baseline as well as GLS change after TAVR. The secondary was to compare all-cause mortality after TAVR between patients with pre-defined Zva (=5 mmHg m(2)/ml), stroke volume index (=35 ml/m(2)), and GLS (=-15%) cutoffs. The mean GLS was reduced (-13.0 ± 3.2%). The mean Zva was 5.2 ± 1.6 mmHg*m(2)/ml with 55% of values ≥5.0 mmHg*m(2)/ml, considered to be abnormally high. Higher Zva correlated with worse GLS (r = -0.33, p < 0.001). After TAVR, Zva decreased significantly (5.1 ± 1.6 vs. 4.5 ± 1.6 mmHg*m(2)/ml, p = 0.001). A reduction of Zva at 1-month was associated with GLS improvement at 1-month (r = -0.31, p = 0.001) and at 1-year (r = -0.36 and p = 0.001). By Kaplan-Meier analysis, patients with higher Zva at baseline had higher mortality (Log-rank p = 0.046), while stroke volume index and GLS did not differentiate outcome (Log-rank p = 0.09 and 0.25, respectively). As a conclusion, Zva is correlated with GLS in AS as well as GLS improvement after TAVR. Furthermore, a high baseline Zva may have an additional impact to traditional parameters on predicting worse mortality after TAVR.

  View details for DOI 10.1007/s10554-017-1155-6

  View details for PubMedID 28516313

• Left atrial function and phenotypes in asymmetric hypertrophic cardiomyopathy. Echocardiography (Mount Kisco, N.Y.) Kobayashi, Y., Wheeler, M., Finocchiaro, G., Ariyama, M., Kobayashi, Y., Perez, M. V., Liang, D., Kuznetsova, T., Schnittger, I., Ashley, E., Haddad, F. 2017

  Abstract

  Few studies have analyzed changes in left atrial (LA) function associated with different phenotypes of asymmetric hypertrophic cardiomyopathy (HCM). We sought to demonstrate the association of impairments in LA function with disease phenotype in patients with obstructive and nonobstructive HCM.From Stanford Cardiomyopathy Registry, we randomly selected 50 age-/sex-matched healthy controls, 35 patients with nonobstructive HCM (HCM 1), 35 patients with obstructive HCM (HCM 2), and 35 patients with obstructive HCM requiring septal reduction therapy (HCM 3). Echocardiography was performed to evaluate left ventricular (LV) strain as well as LA function including LA emptying fraction and LA strain.The mean age was 51±14 years and 57% were male. LA volume index differed among all four predefined groups (25.6±6.7 mL/m(2) in controls, 32.2±13.3 mL/m(2) in HCM 1, 42.0±12.9 mL/m(2) in HCM 2, 52.4±15.2 mL/m(2) for HCM 3, and P<.05 all between groups). All measurement of LA function was impaired in patients with HCM than controls. Total and passive LA function was further impaired in HCM 2 or 3 compared with HCM 1, while active LA function was not different among the three groups. Among LV strains, only septal longitudinal strain differed among all groups (-18.5±1.9% in controls, -14.5±1.9% in HCM 1, -13.3±1.8% in HCM 2, -11.6±2.3% in HCM 3, and P<.05 all between groups).LA function was impaired in patients with HCM even in minimally symptomatic nonobstructive phenotype. Total and passive LA function was further impaired in patients with obstructive HCM.

  View details for DOI 10.1111/echo.13533

  View details for PubMedID 28370331

• Left Atrium Maximal Axial Cross-Sectional Area is a Specific Computed Tomographic Imaging Biomarker of World Health Organization Group 2 Pulmonary Hypertension. Journal of thoracic imaging Jivraj, K., Bedayat, A., Sung, Y. K., Zamanian, R. T., Haddad, F., Leung, A. N., Rosenberg, J., Guo, H. H. 2017; 32 (2): 121-126

  Abstract

  Left heart disease is associated with left atrial enlargement and is a common cause of pulmonary hypertension (PH). We investigated the relationship between left atrium maximal axial cross-sectional area (LA-MACSA), as measured on chest computed tomography (CT), and PH due to left heart disease (World Health Organization group 2) in patients with right heart catheterization-proven PH.A total of 165 patients with PH who had undergone right heart catheterization with pulmonary artery pressure and pulmonary capillary wedge pressure (PCWP) measurements and nongated chest CTs were included. LA-MACSA, LA anterior-posterior, and LA transverse measurements were independently obtained using the hand-drawn region-of-interest and distance measurement tools on standard PACS by 2 blinded cardiothoracic radiologists. Nonparametric statistical analyses and receiver operating characteristic curve were performed.Forty-three patients had group 2 PH (PCWP>15 mm Hg), and 122 had nongroup 2 PH (PCWP≤15 mm Hg). Median LA-MACSA was significantly different between the group 2 PH and nongroup 2 PH patients (2312 vs. 1762 mm, P<0.001). Interobserver concordance correlation for LA-MACSA was high at 0.91 (P<0.001). At a threshold of 2400 mm, LA-MACSA demonstrated 93% specificity for classifying group 2 PH (area under the curve, 0.73; P<0.001).LA-MACSA is a readily obtainable and reproducible measurement of left atrial enlargement on CT and can distinguish between group 2 and nongroup 2 PH with high specificity.

  View details for DOI 10.1097/RTI.0000000000000252

  View details for PubMedID 28009778

• Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states NATURE MEDICINE Furman, D., Chang, J., Lartigue, L., Bolen, C. R., Haddad, F., Gaudilliere, B., Ganio, E. A., Fragiadakis, G. K., Spitzer, M. H., Douchet, I., Daburon, S., Moreau, J., Nolan, G. P., Blanco, P., Dechanet-Merville, J., Dekker, C. L., Jojic, V., Kuo, C. J., Davis, M. M., Faustin, B. 2017; 23 (2): 174-184

  Abstract

  Low-grade, chronic inflammation has been associated with many diseases of aging, but the mechanisms responsible for producing this inflammation remain unclear. Inflammasomes can drive chronic inflammation in the context of an infectious disease or cellular stress, and they trigger the maturation of interleukin-1β (IL-1β). Here we find that the expression of specific inflammasome gene modules stratifies older individuals into two extremes: those with constitutive expression of IL-1β, nucleotide metabolism dysfunction, elevated oxidative stress, high rates of hypertension and arterial stiffness; and those without constitutive expression of IL-1β, who lack these characteristics. Adenine and N(4)-acetylcytidine, nucleotide-derived metabolites that are detectable in the blood of the former group, prime and activate the NLRC4 inflammasome, induce the production of IL-1β, activate platelets and neutrophils and elevate blood pressure in mice. In individuals over 85 years of age, the elevated expression of inflammasome gene modules was associated with all-cause mortality. Thus, targeting inflammasome components may ameliorate chronic inflammation and various other age-associated conditions.

  View details for DOI 10.1038/nm.4267

  View details for Web of Science ID 000393729000009

  View details for PubMedID 28092664

• Electroanatomic Properties of the Myocardium Predict Response to CD34+Cell Therapy in Patients With Ischemic and Nonischemic Heart Failure JOURNAL OF CARDIAC FAILURE Zemljic, G., Poglajen, G., Sever, M., Cukjati, M., Frljak, S., Androcec, V., Cernelc, P., Haddad, F., Vrtovec, B. 2017; 23 (2): 153-160

  Abstract

  We investigated a correlation between electromechanical properties of the myocardium and response to CD34+ cell therapy in patients with chronic heart failure.We enrolled 40 patients with ischemic cardiomyopathy (ICM) and 40 with nonischemic dilated cardiomyopathy (DCM). All patients were in New York Heart Association functional class III and had a left ventricular ejection fraction (LVEF) <40%. CD34+ cells were mobilized by granulocyte colony-stimulating factor and collected via apheresis. Electroanatomic mapping was performed to define areas of myocardial scar and hibernation, and CD34+ cells were injected transendocardially in the hibernating areas. Patient were followed for 6 months; responders were defined as patients with LVEF increase of >5%. At baseline, the groups did not differ in sex, LVEF, creatinine, N-terminal pro-B-type natriuretic peptide or electroanatomic parameters (scar area: 53 ± 18% in ICM vs 55 ± 23% in DCM [P = .83]; hibernating area: 23 ± 13% vs 22 ± 12% [P = .56]). At 6 months we found similar rates of responders in both groups (60% in ICM vs 65% in DCM [P = .95]). When compared with nonresponders, responders had less myocardial scar (47 ± 17% vs 58 ± 15% [P = .003]).In patients with chronic heart failure due to ICM and DCM we observed similar electroanatomic properties of the myocardium. In both groups, lower myocardial scar burden was associated with better clinical response to CD34+ cell therapy.

  View details for DOI 10.1016/j.cardfail.2016.08.002

  View details for Web of Science ID 000393535300010

  View details for PubMedID 27523610

• Investigating the value of right heart echocardiographic metrics for detection of pulmonary hypertension in patients with advanced lung disease. The international journal of cardiovascular imaging Amsallem, M., Boulate, D., Kooreman, Z., Zamanian, R. T., Fadel, G., Schnittger, I., Fadel, E., McConnell, M. V., Dhillon, G., Mercier, O., Haddad, F. 2017

  Abstract

  This study determined whether novel right heart echocardiography metrics help to detect pulmonary hypertension (PH) in patients with advanced lung disease (ALD). We reviewed echocardiography and catheterization data of 192 patients from the Stanford ALD registry and echocardiograms of 50 healthy controls. Accuracy of echocardiographic right heart metrics to detect PH was assessed using logistic regression and area under the ROC curves (AUC) analysis. Patients were divided into a derivation (n = 92) and validation cohort (n = 100). Experimental validation was assessed in a piglet model of mild PH followed longitudinally. Tricuspid regurgitation (TR) was not interpretable in 52% of patients. In the derivation cohort, right atrial maximal volume index (RAVI), ventricular end-systolic area index (RVESAI), free-wall longitudinal strain and tricuspid annular plane systolic excursion (TAPSE) differentiated patients with and without PH; 20% of patients without PH had moderate to severe RV enlargement by RVESAI. On multivariate analysis, RAVI and TAPSE were independently associated with PH (AUC = 0.77, p < 0.001), which was confirmed in the validation cohort (0.78, p < 0.001). Presence of right heart metrics abnormalities did not improve detection of PH in patients with interpretable TR (p > 0.05) and provided moderate detection value in patients without TR. Only two patients with more severe PH (mean pulmonary pressure 35 and 36 mmHg) were missed. The animal model confirmed that right heart enlargement discriminated best pigs with PH from shams. This study highlights the frequency of right heart enlargement and dysfunction in ALD irrespectively from presence of PH, therefore limiting their use for detection of PH.

  View details for DOI 10.1007/s10554-017-1069-3

  View details for PubMedID 28120156

• Contractile reserve and cardiopulmonary exercise parameters in patients with dilated cardiomyopathy, the two dimensions of exercise testing. Echocardiography (Mount Kisco, N.Y.) Moneghetti, K. J., Kobayashi, Y. n., Christle, J. W., Ariyama, M. n., Vrtovec, B. n., Kouznetsova, T. n., Wilson, A. n., Ashley, E. n., Wheeler, M. T., Myers, J. n., Haddad, F. n. 2017

  Abstract

  Left ventricular (LV) contractile reserve assessed using imaging and cardiopulmonary exercise testing (CPX) has been shown to predict outcome in patients with dilated cardiomyopathy (DCM). Few clinical studies have, however, analyzed the relationship between them.A cohort of 75 ambulatory patients with DCM underwent stress treadmill echocardiography with CPX. LV contractile reserve was calculated as absolute change (ΔLVEF=LVEFpeak -LVEFrest ) and percent change (%LVEF=[(LVEFpeak -LVEFrest )/LVEFpeak) ]×100) in LVEF, circumferential and longitudinal strain (LS). Exercise capacity was measured as peak oxygen uptake (peak VO2 ) and ventilatory efficiency as the slope of minute ventilation to CO2 production (VE/VCO2 slope). Values of contractile reserve were compared to matched controls. We also explored which metric of ventricular response (absolute or percent change) was less dependent on baseline LV function.Patients with DCM had a mean age, rest and peak LVEF of 44±10 years, 42±10% and 50±12%, respectively. Among parameters of contractile reserve, peak cardiac output was the strongest parameter associated with peak VO2 (r=.63, P<.001). Along with age, sex, and BMI, it explained more than 70% of the variance in peak VO2 . In contrast, LVEF and LS were only weakly related to peak VO2 . With regard to ventilatory efficiency, the strongest parameter that emerged was right atrial volume index (r=.36, P<.001). Percent change in LVEF was more independent of baseline function than absolute change.Echocardiographic contractile reserve and CPX provide complementary information. Percent change in contractile reserve was most independent of baseline function, therefore may be preferred when analyzing the ventricular response to exercise.

  View details for PubMedID 28681553

• Autoantibody profiling on a plasmonic nano-gold chip for the early detection of hypertensive heart disease. Proceedings of the National Academy of Sciences of the United States of America Li, X. n., Kuznetsova, T. n., Cauwenberghs, N. n., Wheeler, M. n., Maecker, H. n., Wu, J. C., Haddad, F. n., Dai, H. n. 2017; 114 (27): 7089–94

  Abstract

  The role of autoimmunity in cardiovascular (CV) diseases has been increasingly recognized. Autoimmunity is most commonly examined by the levels of circulating autoantibodies in clinical practices. Measurement of autoantibodies remains, however, challenging because of the deficiency of reproducible, sensitive, and standardized assays. The lack of multiplexed assays also limits the potential to identify a CV-specific autoantibody profile. To overcome these challenges, we developed a nanotechnology-based plasmonic gold chip for autoantibody profiling. This approach allowed simultaneous detection of 10 CV autoantibodies targeting the structural myocardial proteins, the neurohormonal regulatory proteins, the vascular proteins, and the proteins associated with apoptosis and coagulation. Autoantibodies were measured in four groups of participants across the continuum of hypertensive heart diseases. We observed higher levels of all 10 CV autoantibodies in hypertensive subjects (n= 77) compared with healthy participants (n= 30), and the autoantibodies investigated were related to each other, forming a highly linked network. In addition, we established that autoantibodies to troponin I, annexin-A5, and beta 1-adrenegic receptor best discriminated hypertensive subjects with adverse left ventricular (LV) remodeling or dysfunction (n= 49) from hypertensive subjects with normal LV structure and function (n= 28). By further linking these three significant CV autoantibodies to the innate and growth factors, we revealed a positive but weak association between autoantibodies to troponin I and proinflammatory cytokine IL-18. Overall, we demonstrated that this platform can be used to evaluate autoantibody profiles in hypertensive subjects at risk for heart failure.

  View details for PubMedID 28630342

• Value of Strain Imaging and Maximal Oxygen Consumption in Patients With Hypertrophic Cardiomyopathy. The American journal of cardiology Moneghetti, K. J., Stolfo, D. n., Christle, J. W., Kobayashi, Y. n., Finocchiaro, G. n., Sinagra, G. n., Myers, J. n., Ashley, E. A., Haddad, F. n., Wheeler, M. T. 2017; 120 (7): 1203–8

  Abstract

  Longitudinal strain (LS) has been shown to be predictive of outcome in hypertrophic cardiomyopathy (HC). Percent predicted peak oxygen uptake (ppVO2), among other cardiopulmonary exercise testing (CPX) metrics, is a strong predictor of prognosis in HC. However, there has been limited investigation into the combination of LS and CPX metrics. This study sought to determine how LS and parameters of exercise performance contribute to prognosis in HC. One hundred and thirty-one consecutive patients with HC who underwent CPX and stress echocardiography were included. Global, septal, and lateral LS were assessed at rest and stress. Eighty matched individuals were used as controls. Patients were followed for the composite end point of death and worsening heart failure. All absolute LS components were lower in patients with HC than in controls (global 14.3 ± 4.0% vs 18.8 ± 2.2%, p <0.001; septal 11.9 ± 4.9% vs 17.9 ± 2.7%, p <0.001; lateral 16.0 ± 4.7% vs 19.4 ± 3.1%, p = 0.001). Global strain reserve was also reduced in patients with HC (13 ± 5% vs 19 ± 8%, p = 0.002). Over a median follow-up of 56 months (interquartile range 14 to 69), the composite end point occurred in 53 patients. Global LS was predictive of outcome on univariate analysis (0.55 [0.41 to 0.74], p <0.001). When combined with CPX metrics, lateral LS was the only strain variable predictive of outcome along with indexed left atrial volume (LAVI) and ppVO2. The worst outcomes were observed for patients with lateral LS <16.1%, LAVI >52 ml/m2, and ppVO2 <80%. The combination of lateral LS, LAVI, and ppVO2 presents a simple model for outcome prediction.

  View details for PubMedID 28802509

• GDF-15 (Growth Differentiation Factor 15) Is Associated With Lack of Ventricular Recovery and Mortality After Transcatheter Aortic Valve Replacement. Circulation. Cardiovascular interventions Kim, J. B., Kobayashi, Y. n., Moneghetti, K. J., Brenner, D. A., O'Malley, R. n., Schnittger, I. n., Wu, J. C., Murtagh, G. n., Beshiri, A. n., Fischbein, M. n., Miller, D. C., Liang, D. n., Yeung, A. C., Haddad, F. n., Fearon, W. F. 2017; 10 (12)

  Abstract

  Recent data suggest that circulating biomarkers may predict outcome in patients undergoing transcatheter aortic valve replacement (TAVR). We examined the association between inflammatory, myocardial, and renal biomarkers and their role in ventricular recovery and outcome after TAVR.A total of 112 subjects undergoing TAVR were included in the prospective registry. Plasma levels of B-type natriuretic peptide, hs-TnI (high-sensitivity troponin I), CRP (C-reactive protein), GDF-15 (growth differentiation factor 15), GAL-3 (galectin-3), and Cys-C (cystatin-C) were assessed before TAVR and in 100 sex-matched healthy controls. Among echocardiographic parameters, we measured global longitudinal strain, indexed left ventricular mass, and indexed left atrial volume. The TAVR group included 59% male, with an average age of 84 years, and 1-year mortality of 18%. Among biomarkers, we found GDF-15 and CRP to be strongly associated with all-cause mortality (P<0.001). Inclusion of GDF-15 and CRP to the Society of Thoracic Surgeons score significantly improved C index (0.65-0.79; P<0.05) and provided a category-free net reclassification improvement of 106% at 2 years (P=0.01). Among survivors, functional recovery in global longitudinal strain (>15% improvement) and indexed left ventricular mass (>20% decrease) at 1 year occurred in 48% and 22%, respectively. On multivariate logistic regression, lower baseline GDF-15 was associated with improved global longitudinal strain at 1 year (hazard ratio=0.29; P<0.001). Furthermore, improvement in global longitudinal strain at 1 month correlated with lower overall mortality (hazard ratio=0.45; P=0.03).Elevated GDF-15 correlates with lack of reverse remodeling and increased mortality after TAVR and improves risk prediction of mortality when added to the Society of Thoracic Surgeons score.

  View details for PubMedID 29222133

• Functional Cardiac Recovery and Hematologic Response to Chemotherapy in Patients With Light-Chain Amyloidosis (from the Stanford University Amyloidosis Registry). The American journal of cardiology Tuzovic, M. n., Kobayashi, Y. n., Wheeler, M. n., Barrett, C. n., Liedtke, M. n., Lafayette, R. n., Schrier, S. n., Haddad, F. n., Witteles, R. n. 2017; 120 (8): 1381–86

  Abstract

  Cardiac involvement is common in patients with light-chain (AL) amyloidosis and portends a poor prognosis, although little is known about the changes in cardiac mechanics after chemotherapy. We sought to explore the relation between amyloidosis staging and baseline cardiac mechanics and to investigate short-term changes in cardiac mechanics after chemotherapy. We identified 41 consecutive patients from the Stanford Amyloid Center who had echocardiograms and free light-chain values before and after chemotherapy, along with 40 age- and gender-matched controls. Echocardiographic assessment included left ventricular global longitudinal strain, E/e' ratio, and left atrial (LA) stiffness. Hematologic response to chemotherapy was defined as ≥50% reduction in the difference between the involved and the uninvolved free light chain (dFLC). The mean age was 66.9 ± 8.4 years and 66% were men. Before chemotherapy, global longitudinal strain, E/e' ratio, and LA stiffness were impaired in patients with amyloidosis compared with controls, and the severity of impairment worsened with advanced staging. After chemotherapy, hematologic response was observed in 30 (73%) patients. There was a significant association between the change in dFLC and cardiac function (E/e' ratio: r = -0.43, p = 0.01; LA stiffness: r = -0.35, p = 0.05). There was no significant improvement in cardiac mechanics in patients without a hematologic response to chemotherapy. In conclusion, amyloidosis stage correlated with noninvasive measurements of cardiac mechanics, and improvement in dFLC correlated with cardiac improvement on short-term follow-up echocardiography.

  View details for PubMedID 28844519

• Incremental Value of Deformation Imaging and Hemodynamics Following Heart Transplantation: Insights From Graft Function Profiling. JACC. Heart failure Kobayashi, Y. n., Sudini, N. L., Rhee, J. W., Aymami, M. n., Moneghetti, K. J., Bouajila, S. n., Kobayashi, Y. n., Kim, J. B., Schnittger, I. n., Teuteberg, J. J., Khush, K. K., Fearon, W. F., Haddad, F. n. 2017; 5 (12): 930–39

  Abstract

  This study investigated to define graft dysfunction and to determine its incremental association with long-term outcome after heart transplantation (HT).Although graft failure is an established cause of late mortality after HT, few studies have analyzed the prognostic value of graft dysfunction at 1- and 5-year follow-up of HT.Patients who underwent HT and completed their first annual evaluation with right heart catheterization and echocardiography at Stanford University between January 1999 and December 2011 were included in the study. Hierarchical clustering was used to identify modules to capture independent features of graft dysfunction at 1 year. The primary endpoint for analysis consisted of the composite of cardiovascular mortality, re-transplantation, or heart failure hospitalization within 5 years of HT. The study further explored whether changes in graft dysfunction between 1 and 5 years were associated with 10-year all-cause mortality.A total of 215 HT recipients were included in the study. Using hierarchical clustering, 3 functional modules were identified; among them, left ventricular global longitudinal strain (LVGLS), stroke volume index, and right atrial pressure (RAP) or pulmonary capillary wedge pressure (PCWP) captured key features of graft function. Graft dysfunction based on pre defined LVGLS in absolute value <14%, stroke volume index <35 ml/m2, RAP >10 mm Hg, or PCWP >15 mm Hg were present in 41%, 36%, and 27%, respectively. The primary endpoint at 5 years occurred in 52 patients (24%), whereas 10-year all-cause mortality occurred in 30 (27%) of 110 patients alive at 5 years. On multivariate analysis, RAP (standardized hazard ratio: 1.63), LVGLS (standardized hazard ratio: 1.39), and a history of hemodynamically compromising rejection within 1 year (hazard ratio: 2.18) were independent predictors of 5-year outcome. RAP at 5 years, as well as change in RAP from 1 to 5 years, was predictive of 10-year all-cause mortality.RAP and LVGLS at the first annual evaluation provide complementary prognostic information in predicting 5-year outcome after HT.

  View details for PubMedID 29191301

• Load Adaptability in Patients With Pulmonary Arterial Hypertension. Am J Cardiol Amsallem, M., et al 2017: 874–82

  Abstract

  Right ventricular (RV) adaptation to pressure overload is a major prognostic factor in patients with pulmonary arterial hypertension (PAH). The objectives were first to define the relation between RV adaptation and load using allometric modeling, then to compare the prognostic value of different indices of load adaptability in PAH. Both a derivation (n = 85) and a validation cohort (n = 200) were included. Load adaptability was assessed using 3 approaches: (1) surrogates of ventriculo-arterial coupling (e.g., RV area change/end-systolic area), (2) simple ratio of function and load (e.g., tricuspid annular plane systolic excursion/right ventricular systolic pressure), and (3) indices assessing the proportionality of adaptation using allometric pressure-function or size modeling. Proportional hazard modeling was used to compare the hazard ratio for the outcome of death or lung transplantation. The mean age of the derivation cohort was 44 ± 11 years, with 80% female and 74% in New York Heart Association class III or IV. Mean pulmonary vascular resistance index (PVRI) was 24 ± 11 with a wide distribution (1.6 to 57.5 WU/m2). Allometric relations were observed between PVRI and RV fractional area change (R2 = 0.53, p < 0.001) and RV end-systolic area indexed to body surface area right ventricular end-systolic area index (RVESAI) (R2 = 0.29, p < 0.001), allowing the derivation of simple ratiometric load-specific indices of RV adaptation. In right heart parameters, RVESAI was the strongest predictor of outcomes (hazard ratio per SD = 1.93, 95% confidence interval 1.37 to 2.75, p < 0.001). Although RVESAI/PVRI0.35 provided small incremental discrimination on multivariate modeling, none of the load-adaptability indices provided stronger discrimination of outcome than simple RV adaptation metrics in either the derivation or the validation cohort. In conclusion, allometric modeling enables quantification of the proportionality of RV load adaptation but offers small incremental prognostic value to RV end-systolic dimension in PAH.

  View details for DOI 10.1016/j.amjcard.2017.05.053

• Myocardial bridging is associated with exercise-induced ventricular arrhythmia and increases in QT dispersion. Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc Nishikii-Tachibana, M. n., Pargaonkar, V. S., Schnittger, I. n., Haddad, F. n., Rogers, I. S., Tremmel, J. A., Wang, P. J. 2017

  Abstract

  A myocardial bridge (MB) has been associated with ventricular arrhythmia and sudden death during exercise. QT dispersion (QTd) is a measure of abnormal repolarization and may predict ventricular arrhythmia. We investigated the frequency of ventricular arrhythmias during exercise and the QTd at rest and after exercise, in patients with an MB compared to a normal cohort.We studied the rest and stress ECG tracings of patients with an MB suspected by focal septal buckling on exercise echocardiography (EE) (Echo-MB group, N = 510), those with an MB confirmed by another examination (MB group, N = 110), and healthy controls (Control group, N = 198).The frequency of exercise-induced premature ventricular contractions (PVCs) was significantly higher in the Echo-MB and MB groups compared with the Control group (both p < .001). In all, 25 patients (4.9%) in the Echo-MB group, seven patients (6.4%) in the MB group and no patients in the Control group had exercise-induced non-sustained ventricular tachycardia (NSVT). There was no difference in the baseline QTd between the groups. In the Echo-MB and MB groups, QTd postexercise increased significantly when compared with baseline (both p < .001). Patients with NSVT had a higher frequency of male gender and an even greater increase in QTd with exercise compared with the non-NSVT group.There is an increased frequency of exercise-induced PVCs and NSVT in patients with MBs. Exercise significantly increases QTd in MB patients, with an even greater increase in QTd in MB patients with NSVT. Exercise in MB patients results in ventricular arrhythmias and abnormalities in repolarization.

  View details for PubMedID 28921787

• Upregulation of HERV-K is Linked to Immunity and Inflammation in Pulmonary Arterial Hypertension. Circulation Saito, T. n., Miyagawa, K. n., Chen, S. Y., Tamosiuniene, R. n., Wang, L. n., Sharp, O. n., Samayoa, E. n., Harada, D. n., Moonen, J. A., Cao, A. n., Chen, P. I., Hennigs, J. K., Gu, M. n., Li, C. G., Leib, R. D., Li, D. n., Adams, C. M., Del Rosario, P. A., Bill, M. A., Haddad, F. n., Montoya, J. G., Robinson, W. n., Fantl, W. J., Nolan, G. P., Zamanian, R. T., Nicolls, M. R., Chiu, C. Y., Ariza, M. E., Rabinovitch, M. n. 2017

  Abstract

  Background -Immune dysregulation has been linked to occlusive vascular remodeling in pulmonary arterial hypertension (PAH) that is hereditary, idiopathic or associated with other conditions. Circulating autoantibodies, lung perivascular lymphoid tissue and elevated cytokines have been related to PAH pathogenesis but without clear understanding of how these abnormalities are initiated, perpetuated and connected in the progression of disease. We therefore set out to identify specific target antigens in PAH lung immune complexes as a starting point toward resolving these issues to better inform future application of immunomodulatory therapies. Methods -Lung immune complexes were isolated and PAH target antigens were identified by liquid chromatography tandem mass spectrometry (LCMS), confirmed by ELISA, and localized by confocal microscopy. One PAH antigen linked to immunity and inflammation was pursued and a link to PAH pathophysiology was investigated by next generation sequencing, functional studies in cultured monocytes and endothelial cells (EC) and hemodynamic and lung studies in a rat. Results -SAM domain and HD1 domain-containing protein (SAMHD1), an innate immune factor that suppresses HIV replication was identified and confirmed as highly expressed in immune complexes from 16 hereditary and idiopathic PAH vs. 12 control lungs. Elevated SAMHD1 was localized to endothelial cells (EC), perivascular dendritic cells and macrophages and SAMHD1 antibodies were prevalent in tertiary lymphoid tissue. An unbiased screen using metagenomic sequencing related SAMHD1 to increased expression of human endogenous retrovirus K (HERV-K) in PAH vs. control lungs (n=4 each). HERV-K envelope and deoxyuridine triphosphate nucleotidohydrolase (dUTPase) mRNAs were elevated in PAH vs. control lungs (n=10) and proteins were localized to macrophages. HERV-K dUTPase induced SAMHD1 and pro-inflammatory cytokines (e.g., IL6, IL1β and TNFα) in circulating monocytes and pulmonary arterial (PA) EC, and activated B cells. Vulnerability of PAEC to apoptosis was increased by HERV-K dUTPase in an IL6 independent manner. Furthermore, three weekly injections of HERV-K dUTPase induced hemodynamic and vascular changes of pulmonary hypertension in rats (n=8), and elevated IL6. Conclusions -Our study reveals that upregulation of the endogenous retrovirus HERV-K could both initiate and sustain activation of the immune system and cause vascular changes associated with PAH.

  View details for PubMedID 28935667

• Incremental value of right heart metrics and exercise performance to well-validated risk scores in dilated cardiomyopathy European Heart Journal - Cardiovascular Imaging Moneghetti , K. J., Giraldeau, G., Wheeler, M. T., Kobayashi , Y., Vrtovec, B., Boulate, D., Kuznetsova, T., Schnittger, I., Wu, J. C., Myers, J., Ashely, E., Haddad , F. 2017

  View details for DOI 10.1093/ehjci/jex187

• Exploratory insights from the right-sided electrocardiogram following prolonged endurance exercise. European journal of sport science Lord, R., George, K., Somauroo, J., Jain, N., Reese, K., Hoffman, M. D., Haddad, F., Ashley, E., Jones, H., Oxborough, D. 2016; 16 (8): 1014-1022

  Abstract

  Prolonged strenuous exercise has a profound effect on cardiac function. The right heart may be more susceptible to this imposition; yet, right-sided chest leads have not been utilised in this setting.Thirty highly trained athletes at the 2014 Western States 100-mile Endurance Run from Squaw Valley to Auburn, California (body mass 68 ± 12 kg, age 45 ± 10 years, 57 ± 15 miles per week) were recruited for the study. Pre- and post-race, a right-sided 12-lead ECG was obtained and data were extracted for P, R and S waves, J point, ST segment and T wave amplitude. Data were compared using Students T-test and statistical significance set as P < .05.There was a significant increase in P wave amplitude (29%) and QTc interval (4%) pre- to post-race from standard 12-lead ECG. From the right-sided12-lead ECG, a 23% (P = .01) and 38% (P = .03) increase in J point amplitude in V1R and V2R and a 22% (P = .05) increase in ST segment integral in V2R and V3R were evident. T wave inversion was evident in leads V2R-V6R in 50-90% of athletes, respectively. Close examination revealed marked heterogeneity in individual ECGs.Completion of a 100-mile ultra-marathon resulted in significant changes in the right-sided ECG alongside more marked responses in specific individuals. P wave, ST segment and T wave changes post-race are indicative of acute exercise-induced right heart electrical adaptation.

  View details for DOI 10.1080/17461391.2016.1165292

  View details for PubMedID 27027796

• A multicentre randomized-controlled trial of inhaled milrinone in high-risk cardiac surgical patients CANADIAN JOURNAL OF ANESTHESIA-JOURNAL CANADIEN D ANESTHESIE Denault, A. Y., Bussieres, J. S., Arellano, R., Finegan, B., Gavra, P., Haddad, F., Nguyen, A. Q., Varin, F., Fortier, A., Levesque, S., Shi, Y., Elmi-Sarabi, M., Tardif, J., Perrault, L. P., Lambert, J. 2016; 63 (10): 1140-1153

  Abstract

  Inhaled milrinone (iMil) has been used for the treatment of pulmonary hypertension (PH) but its efficacy, safety, and prophylactic effects in facilitating separation from cardiopulmonary bypass (CPB) and preventing right ventricular (RV) dysfunction have not yet been evaluated in a clinical trial. The purpose of this study was to investigate if iMil administered before CPB would be superior to placebo in facilitating separation from CPB.High-risk cardiac surgical patients with PH were randomized to receive iMil or placebo after the induction of anesthesia and before CPB. Hemodynamic parameters and RV function were evaluated by means of pulmonary artery catheterization and transesophageal echocardiography. The groups were compared for the primary outcome of the level of difficulty in weaning from CPB. Among the secondary outcomes examined were the reduction in the severity of PH, the incidence of RV failure, and mortality.Of the 124 patients randomized, the mean (standard deviation [SD]) EuroSCORE II was 8.0 (2.6), and the baseline mean (SD) systolic pulmonary artery pressure (SPAP) was 53 (9) mmHg. The use of iMil was associated with increases in cardiac output (P = 0.03) and a reduction in SPAP (P = 0.04) with no systemic hypotension. Nevertheless, there was no difference in the combined incidence of difficult or complex separation from CPB between the iMil and control groups (30% vs 28%, respectively; absolute difference, 2%; 95% confidence interval [CI], -14 to 18; P = 0.78). There was also no difference in RV failure between the iMil and control groups (15% vs 14%, respectively; difference, 1%; 95% CI, -13 to 12; P = 0.94). Mortality was increased in patients with RV failure vs those without (22% vs 2%, respectively; P < 0.001).In high-risk cardiac surgery patients with PH, the prophylactic use of iMil was associated with favourable hemodynamic effects that did not translate into improvement of clinically relevant endpoints. This trial was registered at ClinicalTrials.gov; identifier: NCT00819377.

  View details for DOI 10.1007/s12630-016-0709-8

  View details for Web of Science ID 000383592000004

  View details for PubMedID 27470232

• Challenging the complementarity of different metrics of left atrial function: insight from a cardiomyopathy-based study. European heart journal cardiovascular Imaging Kobayashi, Y., Moneghetti, K. J., Boralkar, K., Amsallem, M., Tuzovic, M., Liang, D., Yang, P. C., Narayan, S., Kuznetsova, T., Wu, J. C., Schnittger, I., Haddad, F. 2016

  Abstract

  Left ventricular (LV) strain provides incremental values to LV ejection fraction (LVEF) in predicting outcome. We sought to investigate if similar relationship is observed between left atrial (LA) emptying fraction and LA strain.In this study, we selected 50 healthy subjects, 50 patients with dilated, 50 hypertrophic, and 50 infiltrative (light-chain (AL) amyloidosis) cardiomyopathy (CMP). Echocardiographic measures included LVEF and LA emptying fraction as well as LV and LA longitudinal strain (LVLS and LALS). After regression analysis, comparison of least square means of LA strain among aetiologies was performed. Intraclass correlation coefficient (ICC) and coefficient of variation (COV) were used in the assessment of variability and reproducibility of LV and LA metrics. The mean LVLS and all LA metrics were impaired in patients with all CMP compared with healthy subjects. In contrast to the moderate relationship between LVEF and LVLS (r = -0.51, P < 0.001), there was a strong linear relationship between LA emptying fraction and LA strain (r = 0.87, P < 0.001). In multiple regression analysis, total LA strain was associated with LVLS (β = -0.48, P < 0.001), lateral E/e' (β = -0.24, P < 0.001), age (β = -0.21, P < 0.001), and heart rate (β = -0.14, P = 0.02). The least square mean of LA strain adjusted for the parameters was not different among aetiologies (ANOVA P = 0.82). The ICC (>0.77) and COV (<13) were acceptable.In contrast to LV measures, there is a strong linear relationship between volumetric and longitudinal deformation indices of left atrium irrespective of CMP aetiology. Either LA emptying fraction or LA strain could be used as an important parameter in predictive models.

  View details for PubMedID 27638850

• [OP.4B.04] LONGITUDINAL CHANGES IN LEFT VENTRICULAR STRUCTURE AND DIASTOLIC FUNCTION IN RELATION TO ARTERIAL PROPERTIES IN A GENERAL POPULATION. Journal of hypertension Cauwenberghs, N., Knez, J., D'hooge, J., Thijs, L., Yang, W. Y., Haddad, F., Staessen, J. A., Kuznetsova, T. 2016; 34: e44-5

  Abstract

  Serial imaging studies are needed to clarify the relation of change in left ventricular (LV) structure and function with arterial stiffness. In this longitudinal population study, we assessed in continuous and categorical analyses to what extent arterial properties predict alterations in echocardiographic indexes reflecting LV structure and function.In 607 participants (50.7% women; mean age, 50.7 years), using conventional echocardiography and tissue Doppler imaging, we measured LV dimensions, transmitral blood flow and mitral annular tissue Doppler velocities at baseline and after 4.7 years. Using applanation tonometry, we assessed augmentation pressure (AP), central pulse pressure (cPP) and carotid-femoral pulse wave velocity (PWV) at baseline. Standardized effect size was expressed as percent of changes in standard deviation (SD) of δ echocardiographic indexes associated with 1-SD increase in baseline arterial indexes.The clinical correlates of δLV indexes included baseline LV index, age, sex, body mass index, mean blood pressure, pulse rate and changes over time in these co-variables. After full adjustment, longitudinal increase in LV septal (standardized effect size: +14.6%; P = 0.0017) and posterior wall (+13.3%; P = 0.0015) thickness was significantly associated with higher PWV at baseline, whereas LV internal diameter (-12.2%; P = 0.014) decreased with PWV. Consequently, a greater increase in relative wall thickness was associated with baseline PWV (+17.2%; P < 0.0001). We observed similar longitudinal increase in LV wall thickness in relation to higher baseline PWV in men and women. In adjusted logistic analysis, higher baseline PWV was associated with a 156% increase in the odds of developing LV concentric remodeling during follow-up as compared to participants who improved LV geometry (P = 0.0088). Furthermore, in women, a higher baseline cPP predicted a greater increase in LV mass (+18.1%, P = 0.018) and E/e' ratio (+25.8%, P = 0.0064).The key finding of this study is that longitudinal increase in LV relative wall thickness was associated with higher baseline PWV, measure of arterial stiffness. Moreover, in women, a higher cPP predicted worsening of LV diastolic function. Our study demonstrated the importance of arterial properties as a mediator of LV concentric remodeling in men and women, and diastolic dysfunction in women.

  View details for DOI 10.1097/01.hjh.0000491450.97368.ae

  View details for PubMedID 27508699

• Right heart imaging in patients with heart failure: a tale of two ventricles. Current opinion in cardiology Amsallem, M., Kuznetsova, T., Hanneman, K., Denault, A., Haddad, F. 2016; 31 (5): 469-482

  Abstract

  The purpose is to describe the recent advances made in imaging of the right heart, including deformation imaging, tissue, and flow characterization by MRI, and molecular imaging.Recent developments have been made in the field of deformation imaging of the right heart, which may improve risk stratification of patients with heart failure and pulmonary hypertension. In addition, more attention has been given to load adaptability metrics of the right heart; these simplified indices, however, still face challenges from a conceptual point of view. The emergence of novel MRI sequences, such as native T1 mapping, allows better detection and quantification of myocardial fibrosis and could allow better prediction of postsurgical recovery of the right heart. Other advances in MRI include four-dimensional flow imaging, which may be particularly useful in congenital heart disease or for the detection of early stages of pulmonary vascular disease.The review will place the recent developments in right heart imaging in the context of clinical care and research.

  View details for DOI 10.1097/HCO.0000000000000315

  View details for PubMedID 27467173

• Alterations in Cardiac Mechanics Following Ultra-Endurance Exercise: Insights from Left and Right Ventricular Area-Deformation Loops. Journal of the American Society of Echocardiography Lord, R., George, K., Somauroo, J., Stembridge, M., Jain, N., Hoffman, M. D., Shave, R., Haddad, F., Ashley, E., Jones, H., Oxborough, D. 2016; 29 (9): 879-887 e1

  Abstract

  The aim of this study was to use novel area-deformation (ε) loops to interrogate the interaction between the right ventricular (RV) and left ventricular (LV) mechanics following a 100-mile endurance run.Fifteen participants (mean body mass, 70.1 ± 8.8 kg; mean age, 40 ± 8 years) were recruited for the study. Echocardiography was performed before the race, after the race, and 6 hours into recovery. RV and LV area and longitudinal ε were assessed using standard and speckle-tracking echocardiography. Following cubic spline interpolation, these variables were obtained across the same cardiac cycle and used to derive area-ε loops.The RV area-ε loop demonstrated a rightward shift after the race, with increased RV area (from 26.0 to 27.1 cm(2)) and reduced peak RV ε (from -28.6% to -25.8%). The recovery RV area-ε loop was similar to the postrace loop. A leftward shift was observed in the LV area-ε loop after the race, secondary to reduced LV area (from 35.8 to 32.5 cm(2)) and reduced peak ε (from -18.3% to -16.6%). In recovery, LV ε values returned toward baseline.A 100-mile ultramarathon resulted in a rightward shift in the RV area-ε loop as a result of RV dilatation. There was a concomitant leftward shift in the LV area-ε loop as a result of underfilling of the left ventricle. At 6 hours after exercise, there was a partial recovery of the left ventricle, while RV function remained depressed. It appears that changes in RV function do not have a serial impact on the left ventricle during recovery from ultra-endurance activity.

  View details for DOI 10.1016/j.echo.2016.05.004

  View details for PubMedID 27373587

• Heart rate-guided, but not dose-guided titration of beta blockers stabilizes ventricular repolarization in patients with chronic heart failure JOURNAL OF ELECTROCARDIOLOGY Fister, M., Mikuz, U., Starc, V., Vrtovec, B., Haddad, F. 2016; 49 (4): 579-586

  Abstract

  We compared the effects of heart rate-guided and dose-guided beta-blocker titration strategies on QT variability in patients with chronic heart failure (CHF).In a prospective study we recorded 5-minute resting high-resolution ECGs (HRECG) in 100 patients with CHF and measured heart rate (HR) and ventricular repolarization by QT variability index (QTVI). In a subgroup of patients not reaching target HR (<70bpm) we uptitrated beta blockers and repeated HRECG measurements 3months thereafter.Target HR was present in 46 patients (group A), and in 54 patients HR was above target (group B). The groups did not differ in age, gender, NYHA class, NT pro-BNP, creatinine, or beta blocker dose. Patients in group A displayed significantly lower QTVI than patients in group B (-1.25±0.55 vs. -1.52±0.42, P=0.013). When uptitrating beta-blockers we found a decrease in HR (from 91±15bpm to 71±15bpm, P<0.001), NTpro BNP levels (from 4474±3878pg/ml to 3042±2566pg/ml, P=0.024), and NYHA class (from 3.0±0.8 to 2.5±0.7, P=0.006). With beta-blocker uptitration QTVI decreased in 10 of 24 patients (42%). In these patients HR decreased more than in the remaining cohort (-25±20bpm vs. -15±17bpm, P=0.017). On multivariate analysis, the presence of target HR was a predictor of QTVI decrease (P=0.017), but beta-blocker dose was not.In patients with CHF treated by beta-blockers, changes in QT variability appear to occur in parallel with changes of heart rate. This suggests that heart rate-guided titration of beta-blockers may be associated with decreased risk of sudden cardiac death.

  View details for DOI 10.1016/j.jelectrocard.2016.01.002

  View details for Web of Science ID 000378981900018

  View details for PubMedID 26875428

• Additive Prognostic Value of Left Ventricular Systolic Dysfunction in a Population-Based Cohort CIRCULATION-CARDIOVASCULAR IMAGING Kuznetsova, T., Cauwenberghs, N., Knez, J., Yang, W., Herbots, L., D'hooge, J., Haddad, F., Thijs, L., Voigt, J., Staessen, J. A. 2016; 9 (7)

  Abstract

  Techniques of 2-dimensional speckle tracking enable the measurement of myocardial deformation (strain) during systole. Recent clinical studies explored the prognostic role of left ventricular global longitudinal strain (GLS). However, there are few data on the association between cardiovascular outcome and GLS in the community. Therefore, we hypothesized that GLS contains additive prognostic information over and beyond traditional cardiovascular risk factors in a large, population-based cohort.We measured GLS by 2-dimensional speckle tracking in the apical 4-chamber view in 791 participants (mean age 50.9 years). We calculated multivariable adjusted hazard ratios for midwall, endocardial, and epicardial GLS, while accounting for family cluster and cardiovascular risk factors. Median follow-up was 7.9 years (5th to 95th percentile, 3.7-9.6). In continuous analysis, with adjustments applied for covariables, midwall, endocardial, and epicardial GLS were significant predictors of fatal and nonfatal cardiovascular (n=96; P<0.0001) and cardiac events (n=68; P≤0.001). In the sex-specific low quartile of midwall GLS (<18.8% in women and <17.4% in men), the risk was significantly higher than the average population risk for cardiovascular (128%, P<0.0001) and cardiac (94%, P=0.0007) events. We also noticed that the risk for cardiovascular events increased with increasing number of left ventricular abnormalities, such as low GLS, diastolic dysfunction, and hypertrophy (log-rank P<0.0001).Low GLS measured by 2-dimensional speckle tracking predicts future cardiovascular events independent of conventional risk factors. Left ventricular midwall strain represents a simple echocardiographic measure, which might be used for assessing cardiovascular risk in a population-based cohort.

  View details for DOI 10.1161/CIRCIMAGING.116.004661

  View details for Web of Science ID 000380608900007

  View details for PubMedID 27329778

• Extracorporeal Life Support After Pulmonary Endarterectomy as a Bridge to Recovery or Transplantation: Lessons From 31 Consecutive Patients ANNALS OF THORACIC SURGERY Boulate, D., Mercier, O., Mussot, S., Fabre, D., Stephan, F., Haddad, F., Jais, X., Dartevelle, P., Fadel, E. 2016; 102 (1): 260-268

  Abstract

  Extracorporeal life support (ECLS) can be used to sustain patients having cardiorespiratory failure after pulmonary endarterectomy (PEA). We aimed to assess outcomes and to identify factors associated with short-term survival among patients who required ECLS after PEA.We reviewed the charts of consecutive patients who required ECLS after PEA between 2005 and 2013 at our institution. Patients with failed PEA were scheduled for heart-lung transplantation, and patients with potentially reversible hemodynamic or respiratory failure were given appropriate supportive care until recovery.Of the 829 patients who underwent PEA, 31 (3.7%) required postoperative ECLS. Of these, 23 continued to receive support, and 8 were listed for heart-lung transplantation during ECLS. Overall inhospital survival was 48.4% (15 of 31). Of patients listed for transplantation, 2 died while on support; 4 of the 6 patients undergoing transplantation lived to hospital discharge. Of the 23 supportive care patients, 11 (47.8%) were alive at hospital discharge. The factors associated with survival were younger age (p = 0.02), larger post-PEA decrease in mean pulmonary artery pressure (p = 0.020), lower post-PEA total pulmonary resistance (p = 0.008), and pure respiratory failure related to reperfusion edema or airway bleeding (p = 0.003).Extracorporeal life support may be useful to support patients with complications after PEA either to recovery or to salvage transplantation.

  View details for DOI 10.1016/j.athoracsur.2016.01.103

  View details for Web of Science ID 000378634400063

  View details for PubMedID 27112656

• Impact and pitfalls of scaling of left ventricular and atrial structure in population-based studies JOURNAL OF HYPERTENSION Kuznetsova, T., Haddad, F., Tikhonoff, V., Kloch-Badelek, M., Ryabikov, A., Knez, J., Malyutina, S., Stolarz-Skrzypek, K., Thijs, L., Schnittger, I., Wu, J. C., Casiglia, E., Narkiewicz, K., Kawecka-Jaszcz, K., Staessen, J. A. 2016; 34 (6): 1186-1194

  Abstract

  Several allometric methods for indexing cardiac structures to body size have been proposed but the optimal way for normalization of cardiac structures is still controversial. We aimed to estimate the allometric exponents that best describe the relationships between cardiac dimensions and body size, propose normative values, and analyze how the different scaling metrics influence the prevalence of left ventricular hypertrophy (LVH) and chambers enlargement as well as predictive models for cardiovascular outcome in the community.We measured left ventricular end-diastolic dimension, end-diastolic volume, left ventricular mass, and left atrial volume in randomly recruited population cohorts (n = 1509; 52.8% women; mean age, 47.8 years).In a healthy subgroup (n = 656), the allometric exponents that described the relationships between left ventricular end-diastolic dimension and body size were 1, 0.5, and 0.33 for body height, body surface area (BSA), and estimated lean body mass, respectively. With regard to left ventricular end-diastolic volume, left ventricular mass, and left atrial volume the allometric exponents for body height were 2.9, 2.7, and 2.0, respectively; for BSA, they ranged from 1.7 to 1.8; for estimated lean body mass all exponents were around 1. These exponents were used to appropriately scale the cardiac dimensions to body size and derived sex-specific cut-off limits for different indexed cardiac dimensions. The hazard ratios of cardiovascular outcome were highest for LVH defined by left ventricular mass/height.Our study resulted in a proposal for thresholds for various indexed cardiac dimensions. Left ventricular mass indexed to height was sensitive in detection of LVH associated with obesity and slightly better predicted outcome.

  View details for DOI 10.1097/HJH.0000000000000922

  View details for Web of Science ID 000375146000024

  View details for PubMedID 27035735

• Impact of Septal Reduction on Left Atrial Size and Diastole in Hypertrophic Cardiomyopathy ECHOCARDIOGRAPHY-A JOURNAL OF CARDIOVASCULAR ULTRASOUND AND ALLIED TECHNIQUES Finocchiaro, G., Haddad, F., Kobayashi, Y., Lee, D., Pavlovic, A., Schnittger, I., Sinagra, G., Magavern, E., Myers, J., Froelicher, V., Knowles, J. W., Ashley, E. 2016; 33 (5): 686-694

  Abstract

  Both myectomy and alcohol septal ablation (ASA) can substantially reduce left ventricular (LV) outflow obstruction, relieve symptoms, and improve outcomes in hypertrophic cardiomyopathy (HCM). It is unclear whether septal reduction decreases left atrial (LA) size and improves diastolic function. The aim of this study was to analyze the consequences of septal reduction on LA size and diastolic function in a cohort of patients with HCM.Forty patients (mean age: 50 ± 14, male sex 64%) with HCM who underwent septal reduction (myectomy or alcohol septal ablation) were studied. Retrospective analyses of echocardiograms preprocedure, postprocedure, and at 1 year of follow-up were performed.Thirty-one patients had septal myectomy and 9 ASA. The degree of reduction in rest peak LV outflow tract gradient was significant (57 ± 32 vs. 23 ± 20 mmHg at 1 year, P < 0.001). Maximal interventricular septal thickness decreased from 22 ± 6 mm preprocedure to 19 ± 4 mm postprocedure (P < 0.001); moderate-to-severe mitral regurgitation (MR) was initially present in 34% of the sample and only 2% after the procedure. Average LA volume index (LAVI) decreased from 63 ± 20 to 55 ± 20 mL/m(2) at the 1-year follow-up (P < 0.001). We did not observe a significant improvement in diastolic function at Doppler (E/A 1.2 ± 0.4 vs. 1.1 ± 0.5, P = 0.07; E' 7.6 ± 3.6 vs. 6.9 ± 3.0, P = 0.4) pre- and postprocedure, respectively). At 1 year, only 5% of the patients were severely symptomatic (NYHA III). On multivariate analysis, a significant change in the LVOT gradient during stress (Δ gradient ≥30 mmHg) was the only variable independently associated with LAVI reverse remodeling >10 mL/m(2) [OR = 6.4 (CI 95% 1.12-36.44), P = 0.04].Septal reduction is effective in the relief of LV obstruction and symptoms in patients with HCM. The hemodynamic changes result in a significant LA reverse remodeling, but not in an improvement of diastolic function in these patients.

  View details for DOI 10.1111/echo.13158

  View details for PubMedID 26926154

• Efficacy of CD34(+) Stem Cell Therapy in Nonischemic Dilated Cardiomyopathy Is Absent in Patients With Diabetes but Preserved in Patients With Insulin Resistance STEM CELLS TRANSLATIONAL MEDICINE Vrtovec, B., Sever, M., Jensterle, M., Poglajen, G., Janez, A., Kravos, N., Zemljic, G., Cukjati, M., Cernelc, P., Haddad, F., Wu, J. C., Jorde, U. P. 2016; 5 (5): 632-638

  Abstract

  : We evaluated the association of diabetes and insulin resistance with the response to cell therapy in patients with nonischemic dilated cardiomyopathy (DCM). A total of 45 outpatients with DCM received granulocyte colony-stimulating factor for 5 days. CD34(+) cells were then collected by apheresis and injected transendocardially. Twelve patients had diabetes mellitus (DM group), 17 had insulin resistance (IR group), and 16 displayed normal glucose metabolism (no-IR group). After stimulation, we found higher numbers of CD34(+) cells in the IR group (94 ± 73 × 10(6) cells per liter) than in the no-IR group (54 ± 35 × 10(6) cells per liter) or DM group (31 ± 20 × 10(6) cells per liter; p = .005). Similarly, apheresis yielded the highest numbers of CD34(+) cells in the IR group (IR group, 216 ± 110 × 10(6) cells; no-IR group, 127 ± 82 × 10(6) cells; DM group, 77 ± 83 × 10(6) cells; p = .002). Six months after cell therapy, we found an increase in left ventricular ejection fraction in the IR group (+5.6% ± 6.9%) and the no-IR group (+4.4% ± 7.2%) but not in the DM group (-0.9% ± 5.4%; p = .035). The N-terminal pro-brain natriuretic peptide levels decreased in the IR and no-IR groups, but not in the DM group (-606 ± 850 pg/ml; -698 ± 1,105 pg/ml; and +238 ± 963 pg/ml, respectively; p = .034). Transendocardial CD34(+) cell therapy appears to be ineffective in DCM patients with diabetes. IR was associated with improved CD34(+) stem cell mobilization and a preserved clinical response to cell therapy.The present study is the first clinical study directly evaluating the effects of altered glucose metabolism on the efficacy of CD34(+) stem cell therapy in patients with nonischemic dilated cardiomyopathy. The results offer critical insights into the physiology of stem cell mobilization in heart failure and possibly an explanation for the often conflicting results obtained with stem cell therapy for heart failure. These results demonstrate that patients with dilated cardiomyopathy and diabetes do not benefit from autologous CD34(+) cell therapy. This finding could serve as a useful tool when selecting heart failure patients for future clinical studies in the field of stem cell therapy.

  View details for DOI 10.5966/sctm.2015-0172

  View details for Web of Science ID 000375176200013

  View details for PubMedID 27025690

  View details for PubMedCentralID PMC4835245

• De Novo and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects. PLoS genetics Priest, J. R., Osoegawa, K., Mohammed, N., Nanda, V., Kundu, R., Schultz, K., Lammer, E. J., Girirajan, S., Scheetz, T., Waggott, D., Haddad, F., Reddy, S., Bernstein, D., Burns, T., Steimle, J. D., Yang, X. H., Moskowitz, I. P., Hurles, M., Lifton, R. P., Nickerson, D., Bamshad, M., Eichler, E. E., Mital, S., Sheffield, V., Quertermous, T., Gelb, B. D., Portman, M., Ashley, E. A. 2016; 12 (4)

  Abstract

  Congenital heart disease (CHD) has a complex genetic etiology, and recent studies suggest that high penetrance de novo mutations may account for only a small fraction of disease. In a multi-institutional cohort surveyed by exome sequencing, combining analysis of 987 individuals (discovery cohort of 59 affected trios and 59 control trios, and a replication cohort of 100 affected singletons and 533 unaffected singletons) we observe variation at novel and known loci related to a specific cardiac malformation the atrioventricular septal defect (AVSD). In a primary analysis, by combining developmental coexpression networks with inheritance modeling, we identify a de novo mutation in the DNA binding domain of NR1D2 (p.R175W). We show that p.R175W changes the transcriptional activity of Nr1d2 using an in vitro transactivation model in HUVEC cells. Finally, we demonstrate previously unrecognized cardiovascular malformations in the Nr1d2tm1-Dgen knockout mouse. In secondary analyses we map genetic variation to protein-interaction networks suggesting a role for two collagen genes in AVSD, which we corroborate by burden testing in a second replication cohort of 100 AVSDs and 533 controls (p = 8.37e-08). Finally, we apply a rare-disease inheritance model to identify variation in genes previously associated with CHD (ZFPM2, NSD1, NOTCH1, VCAN, and MYH6), cardiac malformations in mouse models (ADAM17, CHRD, IFT140, PTPRJ, RYR1 and ATE1), and hypomorphic alleles of genes causing syndromic CHD (EHMT1, SRCAP, BBS2, NOTCH2, and KMT2D) in 14 of 59 trios, greatly exceeding variation in control trios without CHD (p = 9.60e-06). In total, 32% of trios carried at least one putatively disease-associated variant across 19 loci,suggesting that inherited and de novo variation across a heterogeneous group of loci may contribute to disease risk.

  View details for DOI 10.1371/journal.pgen.1005963

  View details for PubMedID 27058611

• Doppler indexes of left ventricular systolic and diastolic function in relation to the arterial stiffness in a general population JOURNAL OF HYPERTENSION Cauwenberghs, N., Knez, J., Tikhonoff, V., D'hooge, J., Kloch-Badelek, M., Thijs, L., Stolarz-Skrzypek, K., Haddad, F., Wojciechowska, W., Swierblewska, E., Casiglia, E., Kawecka-Jaszcz, K., Narkiewicz, K., Staessen, J. A., Kuznetsova, T. 2016; 34 (4): 762-771

  Abstract

  Late-systolic loading of the left ventricular (LV) is determined by arterial wave reflections and central vascular stiffening. We, therefore, investigated the relationship between various Doppler indexes reflecting LV systolic and diastolic function and arterial stiffness in the framework of a large population study of randomly recruited study participants.In 1233 study participants (51.7% women; mean age, 48 years; 41.5% hypertensive), using conventional and tissue Doppler imaging, we measured: the transmitral early (E) and late (A) diastolic velocities; tissue Doppler imaging systolic and early (e') and late diastolic mitral annular velocities; and end-systolic longitudinal and radial strain. Using applanation tonometry, we assessed central pulse pressure (cPP), augmentation pressure and carotid-femoral pulse wave velocity.After full adjustment, transmitral E and A peaks increased with augmentation pressure and cPP (P less than 0.0001) and e' was positively associated with cPP (P = 0.013). The E/e' ratio increased significantly with augmentation pressure (P less than 0.0001), cPP (P less than 0.0001) and pulse wave velocity (P = 0.048). Although accounting for covariables, all arterial indexes were on average significantly higher in the diastolic dysfunction group with elevated filling pressure (n = 171) when compared to participants with normal diastolic function (n = 961; P ≤ 0.0004) or with impaired relaxation (n = 101; P ≤ 0.008). Longitudinal strain decreased independently with mean arterial pressure (P = 0.03). The correlation between radial strain and the arterial indexes shifted from positive at middle age (50-60 years) to negative at older (P less than 0.0001 for interaction).Our study underscored the importance of arterial characteristics as a mediator of LV systolic and diastolic dysfunction. We demonstrated an age-dependent relationship between radial strain and indexes of arterial stiffness.

  View details for DOI 10.1097/HJH.0000000000000854

  View details for Web of Science ID 000371856900024

  View details for PubMedID 26828786

• Comparison of left ventricular manual versus automated derived longitudinal strain: implications for clinical practice and research INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING Kobayashi, Y., Ariyama, M., Kobayashi, Y., Giraldeau, G., Fleischman, D., Kozelj, M., Vrtovec, B., Ashley, E., Kuznetsova, T., Schnittger, I., Liang, D., Haddad, F. 2016; 32 (3): 429-437

  Abstract

  Systolic global longitudinal strain (GLS) is emerging as a useful metric of ventricular function in heart failure and usually assessed using post-processing software. The purpose of this study was to investigate whether longitudinal strain (LS) derived using manual-tracings of ventricular lengths (manual-LS) can be reliable and time efficient when compared to LS obtained by post-processing software (software-LS). Apical 4-chamber view images were retrospectively examined in 50 healthy controls, 100 patients with dilated cardiomyopathy (DCM), and 100 with hypertrophic cardiomyopathy (HCM). We measured endocardial and mid-wall manual-LS and software-LS, using peak of average regional curve [software-LS(a)] and global ventricular lengths [software-LS(l)] according to definition of Lagragian strain. We compared manual-LS and software-LS by using Bland-Altman plot and coefficient of variation (COV). In addition, test-retest was also performed for further assessment of variability in measurements. While manual-LS was obtained in all subjects, software-LS could be obtained in 238 subjects (95 %). The time spent for obtaining manual-LS was significantly shorter than for the software-LS (94 ± 39 s vs. 141 ± 79 s, P < 0.001). Overall, manual-LS had an excellent correlation with both software-LS (a) (R(2) = 0.93, P < 0.001) and software-LS(l) (R(2) = 0.84, P < 0.001). The bias (95 %CI) between endocardial manual-LS and software-LS(a) was 0.4 % [-2.8, 3.6 %] in absolute and 3.5 % [-17.0, 24.0 %] in relative difference while it was 0.4 % [-2.5, 3.3 %] and 3.4 % [-16.2, 23.1 %], respectively with software-LS(l). Mid-wall manual-LS and mid-wall software-LS(a) also had good agreement [a bias (95 % CI) for absolute value of 0.1 % [-2.1, 2.5 %] in HCM, and 0.2 % [-2.2, 2.6 %] in controls]. The COV for manual and software derived LS were below 6 %. Test-retest showed good variability for both methods (COVs were 5.8 and 4.7 for endocardial and mid-wall manual-LS, and 4.6 and 4.9 for endocardial and mid-wall software-LS(a), respectively. Manual-LS appears to be as reproducible as software-LS; this may be of value especially when global strain is the metric of interest.

  View details for DOI 10.1007/s10554-015-0804-x

  View details for Web of Science ID 000370166100008

  View details for PubMedID 26578468

• Regional right ventricular dysfunction in acute pulmonary embolism: relationship with clot burden and biomarker profile INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING Tuzovic, M., Adigopula, S., Amsallem, M., Kobayashi, Y., Kadoch, M., Boulate, D., Krishnan, G., Liang, D., Schnittger, I., Fleischmann, D., McConnell, M. V., Haddad, F. 2016; 32 (3): 389-398

  Abstract

  Regional right ventricular (RV) dysfunction (RRVD) is an echocardiographic feature in acute pulmonary embolism (PE), primarily reported in patients with moderate-to-severe RV dysfunction. This study investigated the clinical importance of RRVD by assessing its relationship with clot burden and biomarkers. We identified consecutive patients admitted to the emergency department between 1999 and 2014 who underwent computed tomographic angiography, echocardiography, and biomarker testing (troponin and NT-proBNP) for suspected acute PE. RRVD was defined as normal excursion of the apex contrasting with hypokinesis of the mid-free wall segment. RV assessment included measurements of ventricular dimensions, fractional area change, free-wall longitudinal strain and tricuspid annular plane systolic excursion. Clot burden was assessed using the modified Miller score. Of 82 patients identified, 51 had acute PE (mean age 66 ± 17 years, 43 % male). No patient had RV myocardial infarction. RRVD was present in 41 % of PEs and absent in all patients without PE. Among patients with PE, 86 % of patients with RRVD had central or multi-lobar PE. Patients with RRVD had higher prevalence of moderate-to-severe RV dilation (81 vs. 30 %, p < 0.01) and dysfunction (86 vs. 23 %, p < 0.01). There was a strong trend for higher troponin level in PE patients with RRVD (38 vs. 13 % in PE patients without RRVD, p = 0.08), while there was no significant difference for NT-proBNP (67 vs. 73 %, p = 0.88). RRVD showed good concordance between readers (87 %). RRVD is associated with an increased clot burden in acute PE and is more prevalent among patients with moderate-to-severe RV enlargement and dysfunction.

  View details for DOI 10.1007/s10554-015-0780-1

  View details for PubMedID 26428674

• Pearls and pitfalls in managing right heart failure in cardiac surgery CURRENT OPINION IN ANESTHESIOLOGY Haddad, F., Elmi-Sarabi, M., Fadel, E., Mercier, O., Denault, A. Y. 2016; 29 (1): 68-79

  Abstract

  To review the recent insights in the evaluation and management of perioperative (RHF).Recent studies highlight the potential role of myocardial deformation imaging in the evaluation of patients at risk of postoperative RHF. There is also a growing interest to study the value of load-adaptation indices of the right heart in the setting of pulmonary hypertension or left ventricular assist device implantation. Finally, the field of temporary extracorporeal life support devices for RHF is rapidly evolving and new strategies are emerging.An integrated approach for assessing the cardiopulmonary axis combining imaging, hemodynamic and tissue perfusion monitoring is emerging, as particularly helpful in the field. Several developments in the field of temporary right heart support including the pumpless interventional lung assist membrane ventilator are offering new opportunities to support the right-heart pulmonary circulation. Future multicenter studies are needed to develop more effective preventive and therapeutic strategies for RHF.

  View details for DOI 10.1097/ACO.0000000000000284

  View details for Web of Science ID 000369423600011

  View details for PubMedID 26658183

• Addressing the Controversy of Estimating Pulmonary Arterial Pressure by Echocardiography JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY Amsallem, M., Sternbach, J. M., Adigopula, S., Kobayashi, Y., Vu, T. A., Zamanian, R., Liang, D., Dhillon, G., Schnittger, I., McConnell, M. V., Haddad, F. 2016; 29 (2): 93-102

  Abstract

  There is currently controversy over whether echocardiography provides reliable estimations of pulmonary pressures. The objective of this study was to determine the factors influencing the accuracy and reliability of estimating right ventricular systolic pressure (RVSP) using echocardiography in patients with advanced lung disease or pulmonary arterial hypertension.Between January 2001 and December 2012, 667 patients with advanced lung disease or pulmonary arterial hypertension underwent right heart catheterization and transthoracic echocardiography. Of those, 307 had both studies within 5 days of each other. The correlation and bias in estimating RVSP according to tricuspid regurgitation (TR) signal quality and reader expertise were retrospectively determined. Reasons for under- and overestimation were analyzed. The diagnostic performance of estimated RVSP, relative right ventricular size, eccentricity index, and tricuspid annular plane systolic excursion was compared for classifying patients with pulmonary hypertension (mean pulmonary artery pressure ≥ 25 mm Hg).Invasive mean and systolic pulmonary artery pressures were strongly correlated (R(2) = 0.95, P < .001), with mean pulmonary artery pressure = 0.60 × systolic pulmonary artery pressure + 2.1 mm Hg. Among patients undergoing right heart catheterization and transthoracic echocardiography within 5 days, level 3 readers considered only 61% of TR signals interpretable, compared with 72% in clinical reports. Overestimation in the clinical report was related mainly to not assigning peak TR velocity at the modal frequency and underestimation to overreading of uninterpretable signals. When the TR signal was interpretable, the areas under the curve for classifying pulmonary hypertension were 0.97 for RVSP and 0.98 for RVSP and eccentricity index (P > .05). When TR signals were uninterpretable, eccentricity index and right ventricular size were independently associated with pulmonary hypertension (area under the curve, 0.77).Echocardiography reliably estimates RVSP when attention is given to simple quality metrics.

  View details for DOI 10.1016/j.echo.2015.11.001

  View details for Web of Science ID 000369168700003

• Addressing the Controversy of Estimating Pulmonary Arterial Pressure by Echocardiography. Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography Amsallem, M., Sternbach, J. M., Adigopula, S., Kobayashi, Y., Vu, T. A., Zamanian, R., Liang, D., Dhillon, G., Schnittger, I., McConnell, M. V., Haddad, F. 2015

  Abstract

  There is currently controversy over whether echocardiography provides reliable estimations of pulmonary pressures. The objective of this study was to determine the factors influencing the accuracy and reliability of estimating right ventricular systolic pressure (RVSP) using echocardiography in patients with advanced lung disease or pulmonary arterial hypertension.Between January 2001 and December 2012, 667 patients with advanced lung disease or pulmonary arterial hypertension underwent right heart catheterization and transthoracic echocardiography. Of those, 307 had both studies within 5 days of each other. The correlation and bias in estimating RVSP according to tricuspid regurgitation (TR) signal quality and reader expertise were retrospectively determined. Reasons for under- and overestimation were analyzed. The diagnostic performance of estimated RVSP, relative right ventricular size, eccentricity index, and tricuspid annular plane systolic excursion was compared for classifying patients with pulmonary hypertension (mean pulmonary artery pressure ≥ 25 mm Hg).Invasive mean and systolic pulmonary artery pressures were strongly correlated (R(2) = 0.95, P < .001), with mean pulmonary artery pressure = 0.60 × systolic pulmonary artery pressure + 2.1 mm Hg. Among patients undergoing right heart catheterization and transthoracic echocardiography within 5 days, level 3 readers considered only 61% of TR signals interpretable, compared with 72% in clinical reports. Overestimation in the clinical report was related mainly to not assigning peak TR velocity at the modal frequency and underestimation to overreading of uninterpretable signals. When the TR signal was interpretable, the areas under the curve for classifying pulmonary hypertension were 0.97 for RVSP and 0.98 for RVSP and eccentricity index (P > .05). When TR signals were uninterpretable, eccentricity index and right ventricular size were independently associated with pulmonary hypertension (area under the curve, 0.77).Echocardiography reliably estimates RVSP when attention is given to simple quality metrics.

  View details for DOI 10.1016/j.echo.2015.11.001

  View details for PubMedID 26691401

• Heart-lung vs. double-lung transplantation for idiopathic pulmonary arterial hypertension. Clinical transplantation Hill, C., Maxwell, B., Boulate, D., Haddad, F., Ha, R., Afshar, K., Weill, D., Dhillon, G. S. 2015; 29 (12): 1067-1075

  Abstract

  Patients with idiopathic pulmonary arterial hypertension (IPAH) have improved survival after heart-lung transplantation (HLT) and double-lung transplantation (DLT). However, the optimal procedure for patients with IPAH undergoing transplantation remains unclear. We hypothesized that critically-ill IPAH patients, defined by admission to the intensive care units (ICU), would demonstrate improved survival with HLT versus DLT. All adult IPAH patients (>18 years) in the Scientific Registry of Transplant Recipients (SRTR) database, who underwent either HLT or DLT between 1987 and 2012, were included. Baseline characteristics, survival, and adjusted survival were compared between the HLT and DLT groups. Similar analyses were performed for the sub-groups as defined by the recipients' hospitalization status. 928 IPAH patients (667 DLT, 261 HLT) were included in this analysis. The HLT recipients were younger, more likely to be admitted to the ICU, and have had their transplant in previous eras. Overall the adjusted survivals after HLT or DLT were similar. The recipients who were hospitalized in the ICU, DLT was associated with worse outcomes (HR 1.827; 95% CI 1.018-3.279). In IPAH patients, the overall survival after HLT or DLT is comparable. HLT may provide improved outcomes in critically-ill IPAH patients admitted to the ICU at time of transplantation. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/ctr.12628

  View details for PubMedID 26358537

• Cytokines profile in hypertensive patients with left ventricular remodeling and dysfunction JOURNAL OF THE AMERICAN SOCIETY OF HYPERTENSION Kuznetsova, T., Haddad, F., Knez, J., Rosenberg-Hasson, Y., Sung, J., Cauwenberghs, N., Thijs, L., Karakikes, I., Maecker, H., Mahaffey, K. W., Wu, J. C., Staessen, J. A. 2015; 9 (12): 975-984

  Abstract

  There is strong evidence that inflammatory mediators play a key role in the progression to heart failure in patients with systemic hypertension (HTN). The present study aimed to identify a set of cytokines that are associated with early left ventricular (LV) remodeling and dysfunction as captured by echocardiography in patients with HTN in a cross-sectional case-control study nested within the FLEMish study on ENvironment, Genes and Health Outcome. We identified three groups of participants from the cohort: normotensive subjects (normotension; n = 30), HTN with normal LV structure and function (HTN [LV-]; n = 30), and HTN with evidence of adverse LV remodeling (HTN [LV+]; n = 50). We measured cytokines using a 63-plex Luminex platform. Using partial least squares-discriminant analysis, we constructed three latent variables from the measured cytokines that explained 35%-45% of the variance between groups. We identified five common cytokines (interleukin 18, monokine induced by gamma interferon, hepatocyte growth factor, epithelial neutrophil-activating peptide 78, and vascular endothelial growth factor D) with a stable signal which had a major impact on the construction of the latent variables. Among these cytokines, after adjustment for confounders, interleukin 18 remained significantly different between HTN participants with and without LV involvement (P = .02). Moreover, granulocyte-macrophage colony-stimulating factor and leptin showed a consistent upward trend in all HTN patients compared with normotensive subjects. In conclusion, in HTN patients with LV remodeling or/and dysfunction, we identified a set of cytokines strongly associated with LV maladaptation. We also found a distinct profile of inflammatory biomarkers that characterize HTN.

  View details for DOI 10.1016/j.jash.2015.10.003

  View details for Web of Science ID 000367214500014

  View details for PubMedID 26565110

• Heart-lung vs. double-lung transplantation for idiopathic pulmonary arterial hypertension CLINICAL TRANSPLANTATION Hill, C., Maxwell, B., Boulate, D., Haddad, F., Ha, R., Afshar, K., Weill, D., Dhillon, G. S. 2015; 29 (12): 1067-1075

  Abstract

  Patients with idiopathic pulmonary arterial hypertension (IPAH) have improved survival after heart-lung transplantation (HLT) and double-lung transplantation (DLT). However, the optimal procedure for patients with IPAH undergoing transplantation remains unclear. We hypothesized that critically-ill IPAH patients, defined by admission to the intensive care units (ICU), would demonstrate improved survival with HLT versus DLT. All adult IPAH patients (>18 years) in the Scientific Registry of Transplant Recipients (SRTR) database, who underwent either HLT or DLT between 1987 and 2012, were included. Baseline characteristics, survival, and adjusted survival were compared between the HLT and DLT groups. Similar analyses were performed for the sub-groups as defined by the recipients' hospitalization status. 928 IPAH patients (667 DLT, 261 HLT) were included in this analysis. The HLT recipients were younger, more likely to be admitted to the ICU, and have had their transplant in previous eras. Overall the adjusted survivals after HLT or DLT were similar. The recipients who were hospitalized in the ICU, DLT was associated with worse outcomes (HR 1.827; 95% CI 1.018-3.279). In IPAH patients, the overall survival after HLT or DLT is comparable. HLT may provide improved outcomes in critically-ill IPAH patients admitted to the ICU at time of transplantation. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/ctr.12628

  View details for Web of Science ID 000367825400004

• Cytokines profile in hypertensive patients with left ventricular remodeling and dysfunction. Journal of the American Society of Hypertension Kuznetsova, T., Haddad, F., Knez, J., Rosenberg-Hasson, Y., Sung, J., Cauwenberghs, N., Thijs, L., Karakikes, I., Maecker, H., Mahaffey, K. W., Wu, J. C., Staessen, J. A. 2015; 9 (12): 975-984 e3

  Abstract

  There is strong evidence that inflammatory mediators play a key role in the progression to heart failure in patients with systemic hypertension (HTN). The present study aimed to identify a set of cytokines that are associated with early left ventricular (LV) remodeling and dysfunction as captured by echocardiography in patients with HTN in a cross-sectional case-control study nested within the FLEMish study on ENvironment, Genes and Health Outcome. We identified three groups of participants from the cohort: normotensive subjects (normotension; n = 30), HTN with normal LV structure and function (HTN [LV-]; n = 30), and HTN with evidence of adverse LV remodeling (HTN [LV+]; n = 50). We measured cytokines using a 63-plex Luminex platform. Using partial least squares-discriminant analysis, we constructed three latent variables from the measured cytokines that explained 35%-45% of the variance between groups. We identified five common cytokines (interleukin 18, monokine induced by gamma interferon, hepatocyte growth factor, epithelial neutrophil-activating peptide 78, and vascular endothelial growth factor D) with a stable signal which had a major impact on the construction of the latent variables. Among these cytokines, after adjustment for confounders, interleukin 18 remained significantly different between HTN participants with and without LV involvement (P = .02). Moreover, granulocyte-macrophage colony-stimulating factor and leptin showed a consistent upward trend in all HTN patients compared with normotensive subjects. In conclusion, in HTN patients with LV remodeling or/and dysfunction, we identified a set of cytokines strongly associated with LV maladaptation. We also found a distinct profile of inflammatory biomarkers that characterize HTN.

  View details for DOI 10.1016/j.jash.2015.10.003

  View details for PubMedID 26565110

• Gender Differences in Ventricular Remodeling and Function in College Athletes, Insights from Lean Body Mass Scaling and Deformation Imaging AMERICAN JOURNAL OF CARDIOLOGY Giraldeau, G., Kobayashi, Y., Finocchiaro, G., Wheeler, M., Perez, M., Kuznetsova, T., Lord, R., George, K. P., Oxborough, D., Schnittger, T., Froelicher, V., Liang, D., Ashley, E., Haddad, F. 2015; 116 (10): 1610-1616

  Abstract

  Several studies suggest gender differences in ventricular dimensions in athletes. Few studies have, however, made comparisons of data indexed for lean body mass (LBM) using allometry. Ninety Caucasian college athletes (mixed sports) who were matched for age, ethnicity, and sport total cardiovascular demands underwent dual-energy x-ray absorptiometry scan for quantification of LBM. Athletes underwent comprehensive assessment of left and right ventricular and atrial structure and function using 2-dimensional echocardiography and deformation imaging using the TomTec analysis system. The mean age of the study population was 18.9 ± 1.9 years. Female athletes (n = 45) had a greater fat free percentage (19.4 ± 3.7%) compared to male athletes (11.5 ± 3.7%). When scaled to body surface area, male had on average 19 ± 3% (p <0.001) greater left ventricular (LV) mass; in contrast, when scaled to LBM, there was no significant difference in indexed LV mass -1.4 ± 3.0% (p = 0.63). Similarly, when allometrically scaled to LBM, there was no significant gender-based difference in LV or left atrial volumes. Although female athletes had mildly higher LV ejection fraction and LV global longitudinal strain in absolute value, systolic strain rate and allometrically indexed stroke volume were not different between genders (1.5 ± 3.6% [p = 0.63] and 0.0 ± 3.7% [p = 0.93], respectively). There were no differences in any of the functional atrial indexes including strain or strain rate parameters. In conclusion, gender-related differences in ventricular dimensions or function (stroke volume) appear less marked, if not absent, when indexing using LBM allometrically.

  View details for DOI 10.1016/j.amjcard.2015.08.026

  View details for PubMedID 26456207

• Exercise Strain Echocardiography in Patients With a Hemodynamically Significant Myocardial Bridge Assessed by Physiological Study. Journal of the American Heart Association Kobayashi, Y., Tremmel, J. A., Kobayashi, Y., Amsallem, M., Tanaka, S., Yamada, R., Rogers, I. S., Haddad, F., Schnittger, I. 2015; 4 (11)

  Abstract

  Although a myocardial bridge (MB) is often regarded as a benign coronary variant, recent studies have associated MB with focal myocardial ischemia. The physiological consequences of MB on ventricular function during stress have not been well established.We enrolled 58 patients with MB of the left anterior descending artery, diagnosed by intravascular ultrasound. Patients underwent invasive physiological evaluation of the MB by diastolic fractional flow reserve during dobutamine challenge and exercise echocardiography. Septal and lateral longitudinal strain (LS) were assessed at rest and immediately after exercise and compared with strain of matched controls. Absolute and relative changes in strain were also calculated. The mean age was 42.5±16.0 years. Fifty-five patients had a diastolic fractional flow reserve ≤0.76. At rest, there was no significant difference between the 2 groups in septal LS (19.0±1.8% for patients with MB versus 19.2±1.5% for control, P=0.53) and lateral LS (20.1±2.0% versus 20.0±1.6%, P=0.83). With stress, compared with controls, patients with MB had a lower peak septal LS (18.9±2.6% versus 21.7±1.6%, P<0.001) and lower absolute (-0.1±2.1% versus 2.5±1.3%, P<0.001) and relative change (-0.6±11.2% versus 13.1±7.8%, P<0.001) in septal LS, whereas there was no significant difference in lateral LS. In multivariate analysis, diastolic fractional flow reserve and length were independent determinants of lower changes in septal LS.Patients with a hemodynamically significant MB, determined by invasive diastolic fractional flow reserve, have significantly lower change in septal LS on exercise echocardiography, suggesting that septal LS may be useful for noninvasively assessing the hemodynamic significance of an MB.

  View details for DOI 10.1161/JAHA.115.002496

  View details for PubMedID 26581225

• Exercise Strain Echocardiography in Patients With a Hemodynamically Significant Myocardial Bridge Assessed by Physiological Study JOURNAL OF THE AMERICAN HEART ASSOCIATION Kobayashi, Y., Tremmel, J. A., Kobayashi, Y., Amsallem, M., Tanaka, S., Yamada, R., Rogers, I. S., Haddad, F., Schnittger, I. 2015; 4 (11)

  Abstract

  Although a myocardial bridge (MB) is often regarded as a benign coronary variant, recent studies have associated MB with focal myocardial ischemia. The physiological consequences of MB on ventricular function during stress have not been well established.We enrolled 58 patients with MB of the left anterior descending artery, diagnosed by intravascular ultrasound. Patients underwent invasive physiological evaluation of the MB by diastolic fractional flow reserve during dobutamine challenge and exercise echocardiography. Septal and lateral longitudinal strain (LS) were assessed at rest and immediately after exercise and compared with strain of matched controls. Absolute and relative changes in strain were also calculated. The mean age was 42.5±16.0 years. Fifty-five patients had a diastolic fractional flow reserve ≤0.76. At rest, there was no significant difference between the 2 groups in septal LS (19.0±1.8% for patients with MB versus 19.2±1.5% for control, P=0.53) and lateral LS (20.1±2.0% versus 20.0±1.6%, P=0.83). With stress, compared with controls, patients with MB had a lower peak septal LS (18.9±2.6% versus 21.7±1.6%, P<0.001) and lower absolute (-0.1±2.1% versus 2.5±1.3%, P<0.001) and relative change (-0.6±11.2% versus 13.1±7.8%, P<0.001) in septal LS, whereas there was no significant difference in lateral LS. In multivariate analysis, diastolic fractional flow reserve and length were independent determinants of lower changes in septal LS.Patients with a hemodynamically significant MB, determined by invasive diastolic fractional flow reserve, have significantly lower change in septal LS on exercise echocardiography, suggesting that septal LS may be useful for noninvasively assessing the hemodynamic significance of an MB.

  View details for DOI 10.1161/JAHA.115.002496

  View details for Web of Science ID 000366615600020

  View details for PubMedID 26581225

• Increased red cell distribution width is associated with poor stem cell mobilization in patients with advanced chronic heart failure BIOMARKERS Poglajen, G., Sever, M., Cernelc, P., Haddad, F., Vrtovec, B. 2015; 20 (6-7): 365-370

  View details for DOI 10.3109/1354750X.2015.1094137

  View details for PubMedID 26472500

• Prognostic utility of right atrial emptying fractions in pulmonary arterial hypertension. Pulmonary circulation Brunner, N. W., Haddad, F., Kobayashi, Y., Hsi, A., Swiston, J. R., Gin, K. G., Zamanian, R. T. 2015; 5 (3): 473-480

  Abstract

  Although left atrial function has been extensively studied in patients with heart failure, the determinants and clinical correlates of impaired right atrial (RA) function have been poorly studied. We investigated measures of RA function in pulmonary arterial hypertension (PAH). We identified all treatment-naive patients with World Health Organization category 1 PAH seen at our center during 2000-2011 who had right heart catheterization and 6-minute walk test (6MWT) within 1 month of initial echocardiographic examination. Atrial size was measured using the monoplane area-length method, and atrial function was quantified using total, passive, and active RA emptying fractions (RAEFs). We compared measures of RAEF with known prognostic clinical, echocardiographic, and hemodynamic parameters. For the subset of patients with follow-up echocardiographic examination/6MWT within 6-18 months, we investigated the change in RAEF. In an exploratory analysis, we investigated the association between RAEF and mortality. Our population consisted of 39 patients with treatment-naive (incident) PAH, 30 of whom had follow-up testing. The mean total, passive, and active RAEFs were 24.4% ± 15.1%, 8.5% ± 6.9%, and 17.6% ± 13.9%, respectively. Total and active RAEFs correlated with tricuspid annular plane systolic excursion (P = 0.004 and P = 0.005) and cardiac output (P = 0.02 and P = 0.01). The change in active RAEF correlated with change in 6-minute walk distance (P = 0.02). In our Cox regression analysis, low active and total RAEF were associated with mortality, with hazard ratios of 5.6 (95% confidence interval [CI], 1.2-26.2; P = 0.03) and 4.2 (95% CI, 1.1-15.5; P = 0.03), respectively. Passive RAEF was poorly reproducible and not associated with outcome. Measures of RAEF appear to have prognostic importance in PAH and warrant further study.

  View details for DOI 10.1086/682218

  View details for PubMedID 26401248

• Right Ventricular Depression After Cardiopulmonary Bypass for Valvular Surgery JOURNAL OF CARDIOTHORACIC AND VASCULAR ANESTHESIA Denault, A. Y., Couture, P., Beaulieu, Y., Haddad, F., Deschamps, A., Nozza, A., Page, P., Tardif, J., Lambert, J. 2015; 29 (4): 836-844

  View details for DOI 10.1053/j.jvca.2015.01.011

  View details for Web of Science ID 000359825600003

• Right Ventricular Depression After Cardiopulmonary Bypass for Valvular Surgery. Journal of cardiothoracic and vascular anesthesia Denault, A. Y., Couture, P., Beaulieu, Y., Haddad, F., Deschamps, A., Nozza, A., Pagé, P., Tardif, J. C., Lambert, J. 2015; 29 (4): 836-44

  Abstract

  To assess if right ventricular (RV) dysfunction is associated with increased mortality after cardiac surgery.Post-hoc analysis of a single-center double-blind randomized controlled trial.University hospital.A total of 120 patients undergoing simple or complex valvular surgery.Patients were randomized to receive intravenous amiodarone or placebo intraoperatively. As secondary analysis, patients were divided into those requiring or not requiring postoperative inotropic agents.After cardiopulmonary bypass (CPB), there were significant increases in heart rate, cardiac index, systolic and mean arterial pressures, central venous pressure and pulmonary capillary wedge pressure with reduction in systemic vascular resistance (p<0.05). Right ventricular end-systolic area became larger in those without inotropes and tricuspid annular plane systolic excursion was reduced in all patients; mitral annular systolic velocities were higher in patients receiving inotropes. Both right- and left-sided Doppler signals were altered significantly after CPB, which may be attributed to increased filling pressure. Inotropic agents were required in 56 patients after CPB (47%). The use of inotropic agents was associated with increased left and right atrial velocities (p<0.05). There were no differences in postoperative complications between groups; however, the number of deaths at 6 years was increased in patients who received inotropes after CPB (p = 0.0247).The increases in right-sided dimensions after CPB are associated with reduction in RV function and increased biventricular filling pressure, suggesting worsening biventricular function and interventricular dependence. Inotropic medications were associated with unaltered RV dimensions and increased biatrial activity.

  View details for DOI 10.1053/j.jvca.2015.01.011

  View details for PubMedID 25976606

• Acute intraoperative effect of intravenous amiodarone on right ventricular function in patients undergoing valvular surgery. European heart journal. Acute cardiovascular care Denault, A. Y., Beaulieu, Y., Couture, P., Haddad, F., Shi, Y., Pagé, P., Levesque, S., Tardif, J., Lambert, J. 2015; 4 (4): 316-325

  Abstract

  Amiodarone is commonly used in the acute care setting. However the acute hemodynamic and echocardiographic effect of intravenous amiodarone administered intraoperatively on right ventricular (RV) systolic and diastolic function using transesophageal echocardiography (TEE) has not been described.The study design was a randomized controlled trial in elective cardiac surgical patients undergoing valvular surgery. Patients received an intravenous loading dose of 300 mg of either amiodarone or placebo in the operating room, followed by an infusion of 15 mg/kg for two days. Hemodynamic profiles, echocardiographic measurement of RV and left ventricular (LV) dimensions, Doppler interrogation of tricuspid and mitral valve, hepatic and pulmonary venous flow combined with tissue Doppler imaging of the tricuspid and mitral valve annulus were obtained before and after bolus.Although more patients in the placebo group had chronic obstructive lung disease (14 vs 6, p=0.05) and diabetes (14 vs 5; p=0.0244), there was no difference in terms of baseline hemodynamic, 2D and Doppler variables. After bolus, a significant increase in pulmonary artery pressure, central venous pressure and pulmonary vascular resistance index (p<0.05) was observed in the amiodarone group with reduction in systolic to diastolic (S/D) ratio of the hepatic (p=0.0247) and pulmonary venous (p=0.0052) velocity.Acute administration of amiodarone is associated with alteration in RV diastolic properties and has minimal negative inotropic effect on RV systolic function in cardiac surgical patients with valvular disease.

  View details for DOI 10.1177/2048872614549102

  View details for PubMedID 25178692

• Immunologic Network and Response to Intramyocardial CD34(+) Stem Cell Therapy in Patients With Dilated Cardiomyopathy JOURNAL OF CARDIAC FAILURE Haddad, F., Sever, M., Poglajen, G., Lezaic, L., Yang, P., Maecker, H., Davis, M., Kuznetsova, T., Wu, J. C., Vrtovec, B. 2015; 21 (7): 572-582

  Abstract

  Although stem cell therapy (SCT) is emerging as a potential treatment for patients with dilated cardiomyopathy (DCM), clinical response remains variable. Our objective was to determine whether baseline differences in circulating immunologic and nonimmunologic biomarkers may help to identify patients more likely to respond to intramyocardial injection of CD34(+)-based SCT.We enrolled from January 3, 2011 to March 5, 2012 37 patients with longstanding DCM (left ventricular ejection fraction [LVEF] <40%, New York Heart Association functional class III) who underwent peripheral CD34(+) stem cell mobilization with granulocyte colony-stimulating factor (G-CSF) and collection by means of apheresis. CD34(+) cells were labeled with (99m)Tc-hexamethylpropyleneamine oxime to allow assessment of stem cell retention at 18 hours. Response to SCT was predefined as an increase in LVEF of ≥5% at 3 months. The majority (84%) of patients were male with an overall mean LVEF of 27 ± 7% and a median N-terminal pro-B-type natriuretic peptide (NT-proBNP) level of 2,774 pg/mL. Nineteen patients (51%) were responders to SCT. There was no significant difference between responders and nonresponders regarding to age, sex, baseline LVEF, NT-proBNP levels, or 6-minute walking distance. With the use of a partial least squares (PLS) predictive model, we identified 9 baseline factors that were associated with both stem cell response and stem cell retention (mechanistic validation). Among the baseline factors positively associated with both clinical response and stem cell retention were G-CSF, SDF-1, LIF, MCP-1, and MCP-3. Among baseline factors negatively associated with both clinical response and retention were IL-12p70, FASL, ICAM-1, and GGT. A decrease in G-CSF at 3-month follow-up was also observed in responders compared with nonresponders (P = .02).If further validated, baseline immunologic and nonimmunologic biomarkers may help to identify patients with DCM who are more likely to respond to CD34(+)-based SCT.

  View details for DOI 10.1016/j.cardfail.2015.03.011

  View details for Web of Science ID 000358105900007

  View details for PubMedID 25863169

• Systematic Comparison of Digital Electrocardiograms From Healthy Athletes and Patients With Hypertrophic Cardiomyopathy. Journal of the American College of Cardiology Bent, R. E., Wheeler, M. T., Hadley, D., Knowles, J. W., Pavlovic, A., Finocchiaro, G., Haddad, F., Salisbury, H., Race, S., Shmargad, Y., Matheson, G. O., Kumar, N., Saini, D., Froelicher, V., Ashley, E., Perez, M. V. 2015; 65 (22): 2462-2463

  View details for DOI 10.1016/j.jacc.2015.03.559

  View details for PubMedID 26046742

• Right Heart Score for Predicting Outcome in Idiopathic, Familial, or Drug- and Toxin-Associated Pulmonary Arterial Hypertension. JACC. Cardiovascular imaging Haddad, F., Spruijt, O. A., Denault, A. Y., Mercier, O., Brunner, N., Furman, D., Fadel, E., Bogaard, H. J., Schnittger, I., Vrtovec, B., Wu, J. C., de Jesus Perez, V., Vonk-Noordegraaf, A., Zamanian, R. T. 2015; 8 (6): 627-638

  Abstract

  This study sought to determine whether a simple score combining indexes of right ventricular (RV) function and right atrial (RA) size would offer good discrimination of outcome in patients with pulmonary arterial hypertension (PAH).Identifying a simple score of outcome could simplify risk stratification of patients with PAH and potentially lead to improved tailored monitoring or therapy.We recruited patients from both Stanford University (derivation cohort) and VU University Medical Center (validation cohort). The composite endpoint for the study was death or lung transplantation. A Cox proportional hazard with bootstrap CI adjustment model was used to determine independent correlates of death or transplantation. A predictive score was developed using the beta coefficients of the multivariable models.For the derivation cohort (n = 95), the majority of patients were female (79%), average age was 43 ± 11 years, mean pulmonary arterial pressure was 54 ± 14 mm Hg, and pulmonary vascular resistance index was 25 ± 12 Wood units m(2). Over an average follow-up of 5 years, the composite endpoint occurred in 34 patients, including 26 deaths and 8 patients requiring lung transplant. On multivariable analysis, RV systolic dysfunction grade (hazard ratio [HR]: 3.4 per grade; 95% confidence interval [CI]: 2.0 to 7.8; p < 0.001), severe RA enlargement (HR: 3.0; 95% CI: 1.3 to 8.1; p = 0.009), and systemic blood pressure <110 mm Hg (HR: 3.3; 95% CI: 1.5 to 9.4; p < 0.001) were independently associated with outcome. A right heart (RH) score constructed on the basis of these 3 parameters compared favorably with the National Institutes of Health survival equation (0.88; 95% CI: 0.79 to 0.94 vs. 0.60; 95% CI: 0.49 to 0.71; p < 0.001) but was not statistically different than the REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management) score c-statistic of 0.80 (95% CI: 0.69 to 0.88) with p = 0.097. In the validation cohort (n = 87), the RH score remained the strongest independent correlate of outcome.In patients with prevalent PAH, a simple RH score may offer good discrimination of long-term outcome.

  View details for DOI 10.1016/j.jcmg.2014.12.029

  View details for PubMedID 25981508

• 8A.02: THE ASSOCIATION OF LEFT VENTRICULAR AND ATRIAL STRUCTURE WITH BODY COMPOSITION: IMPACT AND PITFALLS OF SCALING IN POPULATION BASED STUDIES. Journal of hypertension Kuznetsova, T., Haddad, F., Thijs, L., Tikhonoff, V., Kloch-Badelek, M., Sakiewicz, W., Ryabikov, A., Knez, J., Malyutina, S., Stolarz-Skrzypek, K., Casiglia, E., Narkiewicz, K., Kawecka-Jaszcz, K., Staessen, J. A. 2015; 33

  Abstract

  Several allometric methods for indexing cardiac structures to body size have been proposed but the optimal way for normalization of cardiac structures is still controversial. We aimed to estimate the allometric exponents that best describe the relationships between cardiac dimensions and body size and propose normative values. We also explored how different scaling metrics influence the associations of left heart size with cardiovascular risk factors and outcome in the general population.We measured left ventricular end-diastolic dimension (LVEDD), end-diastolic volume (LVEDV), left ventricular mass (LVM) and left atrial volume (LAV) in randomly recruited population cohorts (n = 1509; 52.8% women; mean age, 47.8 years). After determining optimal scaling metrics in a healthy reference population (n = 656) and proposing normative values, we analyzed how the different scaling metrics influence predictive models for left ventricular hypertrophy (LVH) and left atrial enlargement (LAE) as well as cardiovascular outcome.The allometric exponents that described the relationships between LVEDD and body size were 1, 0.5 and 0.33 for body height (BH), body surface area (BSA) and estimated lean body mass (eLBM), respectively. With regards to LVEDV, LVM and LAV the allometric exponents for BH were 2.9, 2.7 and 2.0, respectively; for BSA they ranged from 1.7 to 1.8; for eLBM all exponents were around 1. These exponents were used to appropriately scale the cardiac dimensions to body size and derived sex-specific cut-off limits for different indexed cardiac dimensions. Indexation of LVM to height2.7 better detected LVH in overweight and obese subjects. The hazard ratios of cardiovascular outcome were highest for LVH defined by LVM/height2.7.Our current study resulted in a proposal for thresholds for various indexed cardiac dimensions. LVM indexed to height has the advantage of being more sensitive in detection of LVH associated with obesity and slightly better for prediction of outcome.

  View details for DOI 10.1097/01.hjh.0000467631.86257.8b

  View details for PubMedID 26102661

• Right Heart Score for Predicting Outcome in Idiopathic, Familial, or Drug- and Toxin-Associated Pulmonary Arterial Hypertension JACC-CARDIOVASCULAR IMAGING Haddad, F., Spruijt, O. A., Denault, A. Y., Mercier, O., Brunner, N., Furman, D., Fadel, E., Bogaard, H. J., Schnittger, I., Vrtovec, B., Wu, J. C., Perez, V. D., Vonk-Noordegraaf, A., Zamanian, R. T. 2015; 8 (6): 627-638

  View details for DOI 10.1016/j.jcmg.2014.12.029

  View details for Web of Science ID 000356560600001

  View details for PubMedID 25981508

• Cardiopulmonary responses and prognosis in hypertrophic cardiomyopathy: a potential role for comprehensive noninvasive hemodynamic assessment. JACC. Heart failure Finocchiaro, G., Haddad, F., Knowles, J. W., Caleshu, C., Pavlovic, A., Homburger, J., Shmargad, Y., Sinagra, G., Magavern, E., Wong, M., Perez, M., Schnittger, I., Myers, J., Froelicher, V., Ashley, E. A. 2015; 3 (5): 408-418

  Abstract

  This study sought to discover the key determinants of exercise capacity, maximal oxygen consumption (oxygen uptake [Vo2]), and ventilatory efficiency (ventilation/carbon dioxide output [VE/Vco2] slope) and assess the prognostic potential of metabolic exercise testing in hypertrophic cardiomyopathy (HCM).The intrinsic mechanisms leading to reduced functional tolerance in HCM are unclear.The study sample included 156 HCM patients consecutively enrolled from January 1, 2007 to January 1, 2012 with a complete clinical assessment, including rest and stress echocardiography and cardiopulmonary exercise test (CPET) with impedance cardiography. Patients were also followed for the composite outcome of cardiac-related death, heart transplant, and functional deterioration leading to septal reduction therapy (myectomy or septal alcohol ablation).Abnormalities in CPET responses were frequent, with 39% (n = 61) of the sample showing a reduced exercise tolerance (Vo2 max <80% of predicted) and 19% (n = 30) characterized by impaired ventilatory efficiency (VE/Vco2 slope >34). The variables most strongly associated with exercise capacity (expressed in metabolic equivalents), were peak cardiac index (r = 0.51, p < 0.001), age (r = -0.25, p < 0.01), male sex (r = 0.24, p = 0.02), and indexed right ventricular end-diastolic area (r = 0.31, p = 0.002), resulting in an R(2) of 0.51, p < 0.001. Peak cardiac index was the main predictor of peak Vo2 (r = 0.61, p < 0.001). The variables most strongly related to VE/VCO2 slope were E/E' (r = 0.23, p = 0.021) and indexed left atrial volume index (LAVI) (r = 0.34, p = 0.005) (model R(2) = 0.15). The composite endpoint occurred in 21 (13%) patients. In an exploratory analysis, 3 variables were independently associated with the composite outcome (mean follow-up 27 ± 11 months): peak Vo2 <80% of predicted (hazard ratio: 4.11; 95% confidence interval [CI]: 1.46 to 11.59; p = 0.008), VE/Vco2 slope >34 (hazard ratio: 3.14; 95% CI: 1.26 to 7.87; p = 0.014), and LAVI >40 ml/m(2) (hazard ratio: 3.32; 95% CI: 1.08 to 10.16; p = 0.036).In HCM, peak cardiac index is the main determinant of exercise capacity, but it is not significantly related to ventilatory efficiency. Peak Vo2, ventilatory inefficiency, and LAVI are associated with an increased risk of major events in the short-term follow-up.

  View details for DOI 10.1016/j.jchf.2014.11.011

  View details for PubMedID 25863972

• 3A. Personal History: Have You Ever Had Excessive Shortness of Breath or Fatigue with Exercise beyond What Is Expected for Your Level of Fitness? CURRENT SPORTS MEDICINE REPORTS Haddad, F., Finocchiaro, G., Myers, J. 2015; 14 (3): 257-259

  View details for Web of Science ID 000354551400028

  View details for PubMedID 25968867

• Prevalence and Prognostic Role of Right Ventricular Involvement in Stress-Induced Cardiomyopathy JOURNAL OF CARDIAC FAILURE Finocchiaro, G., Kobayashi, Y., Magavern, E., Zhou, J. Q., Ashley, E., Sinagra, G., Schnittger, I., Knowles, J. W., Fearon, W. F., Haddad, F., Tremmel, J. A. 2015; 21 (5): 419-425

  Abstract

  Stress-induced cardiomyopathy (SCM) is a reversible cardiomyopathy observed in patients without significant coronary disease. The aim of this study was to assess the incidence and clinical significance of right ventricular (RV) involvement in SCM.We retrospectively analyzed echocardiograms from 40 consecutive patients who presented with SCM at Stanford University Medical Center from September 2000 to November 2010. The primary end point was overall mortality. RV involvement was observed in 20 patients (50%; global RV hypokinesia in 15 patients and focal RV apical akinesia in 5 patients). The independent correlates of RV involvement were older age (odds ratio [OR] 1.09, 95% confidence interval [CI] 1.02-1.7two, P = .01) and LVEF (per 10% decrease: OR 3.60, CI 1.77-7.32; P = .02). At a mean follow-up of 44 ± 32 months, 12 patients (30%) died (in-hospital death in 3 patients). At multivariate analysis, the presence of an RV fractional area change <35% emerged as an independent predictor of death (OR 3.6, CI 1.06-12.41; P = .04).RV involvement is a common finding in SCM, and may present as either global or focal RV apical involvement. Both older age and lower LVEF are associated with a higher risk of RV involvement, which appears to be a major predictor of death.

  View details for DOI 10.1016/j.cardfail.2015.02.001

  View details for PubMedID 25704104

• Noninvasive imaging in the assessment of the cardiopulmonary vascular unit. Circulation Vonk Noordegraaf, A., Haddad, F., Bogaard, H. J., Hassoun, P. M. 2015; 131 (10): 899-913

  View details for DOI 10.1161/CIRCULATIONAHA.114.006972

  View details for PubMedID 25753343

• Right ventricular reserve in a piglet model of chronic pulmonary hypertension EUROPEAN RESPIRATORY JOURNAL Guihaire, J., Haddad, F., Noly, P., Boulate, D., Decante, B., Dartevelle, P., Humbert, M., Verhoye, J., Mercier, O., Fadel, E. 2015; 45 (3): 709-717

  Abstract

  Right ventricular (RV) response to exercise or pharmacological stress is not well documented in pulmonary hypertension (PH). We investigated the relationship between RV reserve and ventricular-arterial coupling. Surgical ligation of the left pulmonary artery was performed in 13 Large White piglets (PH group), thereafter weekly embolisations of the right lower lobe were performed for 5 weeks. A control group of six piglets underwent sham procedures. Right heart catheterisation and echocardiography were performed at week 6. Pressure-volume loops were recorded before and after dobutamine infusion. Induction of experimental PH resulted in a higher mean ± sd pulmonary artery pressure (34 ± 9 versus 14 ± 2 mmHg; p<0.01) and in a lower ventricular-arterial coupling efficiency (0.66 ± 0.18 versus 1.24 ± 0.17; p<0.01) compared with controls at 6 weeks. Dobutamine-induced relative changes in RV stroke volume index (SVI) and end-systolic elastance were lower in the PH group (mean ± SD 47 ± 5% versus 20 ± 5%, p<0.01, and 81 ± 37% versus 32 ± 14%, p<0.01, respectively). Change in SVI was strongly associated with resting ventricular-arterial coupling (R(2)=0.74; p<0.01). RV reserve was associated with ventricular-arterial coupling in a porcine model of chronic pressure overload.

  View details for DOI 10.1183/09031936.00081314

  View details for Web of Science ID 000350701200020

  View details for PubMedID 25504996

• Intracoronary Transplantation of CD34(+) Cells Is Associated With Improved Myocardial Perfusion in Patients With Nonischemic Dilated Cardiomyopathy. Journal of cardiac failure Lezaic, L., Socan, A., Poglajen, G., Peitl, P. K., Sever, M., Cukjati, M., Cernelc, P., Wu, J. C., Haddad, F., Vrtovec, B. 2015; 21 (2): 145-152

  Abstract

  We investigated the effects of intracoronary transplantation of CD34(+) cells on myocardial perfusion in patients with nonischemic dilated cardiomyopathy (DCM).We enrolled 21 patients with DCM (left ventricular ejection fraction [LVEF] <40%, New York Heart Association functional class III) who underwent peripheral stem cell mobilization with granulocyte-colony stimulating factor (G-CSF). CD34(+) cells were collected by means of apheresis. Patients underwent myocardial perfusion imaging, and CD34(+) cells were injected in the coronary artery supplying viable segments with reduced myocardial perfusion and regional dysfunction. Myocardial perfusion imaging was repeated 6 months later. Clinical response to stem cell therapy was predefined as a change in LVEF >5%. The majority of patients were men (81%) with an overall mean age 53 ± 9 years, LVEF 25 ± 5%, and 6-minute walking distance 354 ± 71 m. Myocardial perfusion defects at rest were observed in 86% of patients and were more common in the left anterior descending territory (50%). At 6 months' follow-up, there was a significant improvement in rest myocardial perfusion scores (6.3 ± 5.8 vs 3.1 ± 4.3; P < .001), LVEF (25 ± 7% vs 29 ± 8%; P = .005), and 6-minute walking distance (354 ± 71 m vs 404 ± 91 m; P < .001). Responders to stem cell therapy had lower summed rest perfusion score at both baseline (3.2 ± 3.0 vs 9.1 ± 6.3; P = .015) and follow-up (1.0 ± 1.5 vs 5.0 ± 5.1; P = .028).CD34(+) cell transplantation may lead to improved myocardial perfusion in patients with nonischemic DCM. Patients with less severe myocardial perfusion defects at baseline may have an increased likelihood to respond to intracoronary CD34(+) cell transplantation.

  View details for DOI 10.1016/j.cardfail.2014.11.005

  View details for PubMedID 25459687

• The right ventricle following ultra-endurance exercise: insights from novel echocardiography and 12-lead electrocardiography EUROPEAN JOURNAL OF APPLIED PHYSIOLOGY Lord, R., Somauroo, J., Stembridge, M., Jain, N., Hoffman, M. D., George, K., Jones, H., Shave, R., Haddad, F., Ashley, E., Oxborough, D. 2015; 115 (1): 71-80

  Abstract

  There is contradictory evidence related to the impact of ultra-marathon running on right ventricular (RV) structure and function. Consequently, the aims of this study were to: (1) comprehensively assess RV structure and function before and immediately following a 100-mile ultra-marathon in highly trained runners, (2) determine the nature of RV recovery 6 h post-race, and (3) document 12-lead electrocardiogram (ECG) changes post-exercise.Echocardiography and 12-lead ECG were assessed in 15 competitors in a repeated measures design before and immediately after completion of the 2013 Western States Endurance Race. A subset of nine was reassessed 6 h into recovery. Standard echocardiography was used to determine RV size, function and wall stress. Myocardial speckle tracking (MST) provided peak, time to peak and temporal indices for RV longitudinal strain and strain rates (ε and SR).RV size was increased post-race (inflow tract 14 %, outflow tract 11 %, P = 0.004 and 0.002). RV wall stress was elevated by 11 % post-race. Peak RV ε was reduced by 10 % (P = 0.007) and significantly delayed post-race (P = 0.008). Most changes in RV function persisted at the 6-h assessment. Post-race there was an increase in the prevalence of right-sided ECG changes.Completion of a 100-mile ultra-marathon resulted in acute changes in RV structure and function that persisted 6 h into recovery and are consistent with sustained exposure to an elevated RV wall stress. These findings were supported by right-sided changes to the 12-lead ECG.

  View details for DOI 10.1007/s00421-014-2995-6

  View details for Web of Science ID 000347293500004

  View details for PubMedID 25204280

• The Presence of Electromechanical Mismatch In Nonischemic Dilated Cardiomyopathy Is Associated With Ventricular Repolarization Instability JOURNAL OF CARDIAC FAILURE Mikuz, U., Poglajen, G., Fister, M., Starc, V., Wu, J. C., Hsia, H., Haddad, F., Vrtovec, B. 2014; 20 (12): 891-898

  Abstract

  We analyzed electromechanical mismatch (EMM) and its relationship to ventricular repolarization in patients with non-ischemic dilated cardiomyopathy (DCM).In 39 DCM patients with LVEF<40% and NHYA class ≥III, electroanatomical mapping was used to quantify areas of EMM. High resolution ECG was used to measure heart rate variability (HRV) and QT variability (QTVI). EMM was present in 22 patients (56%, Group 1), whereas 17 patients presented no mismatched segments (44%, Group 2). The groups did not differ in age (56±10 years in Group 1 vs. 57±7 years in Group 2, P=0.82), sex (male: 82% vs. 94%, P=0.40), LVEF (27±8% vs. 25±6%, P=0.18), or NT-proBNP (2350 pg/ml vs. 2831 pg/ml, P=0.32). Although heart rate and HRV were similar in both groups (rate: 80±20 bpm in Group 1 vs. 74±19 bpm in Group 2, P=0.47; SDNN: 106±79 vs. 88±115, P=0.61), we found significantly higher QTVI values in patients from Group 1 (-1.15±0.46 vs. -1.62±0.51 in Group 2, P=0.005). In patients with ICDs, ventricular arrhythmias recorded within 1 year prior enrollment were more frequent in Group 1 than Group 2 (58% vs. 13%, P=0.02).EMM is present in majority of patients with DCM and is associated with ventricular repolarization instability.clinicaltrials.gov: NCT01350310.

  View details for DOI 10.1016/j.cardfail.2014.10.002

  View details for Web of Science ID 000346229300004

  View details for PubMedID 25305502

• Brief report: an open-label study of the neurosteroid pregnenolone in adults with autism spectrum disorder. Journal of autism and developmental disorders Fung, L. K., Libove, R. A., Phillips, J., Haddad, F., Hardan, A. Y. 2014; 44 (11): 2971-2977

  Abstract

  The objective of this study was to assess the tolerability and efficacy of pregnenolone in reducing irritability in adults with autism spectrum disorder (ASD). This was a pilot, open-label, 12-week trial that included twelve subjects with a mean age of 22.5 ± 5.8 years. Two participants dropped out of the study due to reasons unrelated to adverse effects. Pregnenolone yielded a statistically significant improvement in the primary measure, Aberrant Behavior Checklist (ABC)-Irritability [from 17.4 ± 7.4 at baseline to 11.2 ± 7.0 at 12 weeks (p = 0.028)]. Secondary measures were not statistically significant with the exception of ABC-lethargy (p = 0.046) and total Short Sensory Profile score (p = 0.009). No significant vital sign changes occurred during this study. Pregnenolone was not associated with any severe side effects. Single episodes of tiredness, diarrhea and depressive affect that could be related to pregnenolone were reported. Overall, pregnenolone was modestly effective and well-tolerated in individuals with ASD.

  View details for DOI 10.1007/s10803-014-2144-4

  View details for PubMedID 24849255

• RV dysfunction after lung transplantation: a new prognostic marker or mainly a correlate of lung allograft function? JACC. Cardiovascular imaging Haddad, F., Fadel, E. 2014; 7 (11): 1095-7

  View details for DOI 10.1016/j.jcmg.2014.08.004

  View details for PubMedID 25459590

• Biventricular VAD versus LVAD for right heart failure. Annals of cardiothoracic surgery Boulate, D., Marques, M. A., Ha, R., Banerjee, D., Haddad, F. 2014; 3 (6): 585-588

  View details for DOI 10.3978/j.issn.2225-319X.2014.08.08

  View details for PubMedID 25512899

  View details for PubMedCentralID PMC4250556

• Brief Report: An Open-Label Study of the Neurosteroid Pregnenolone in Adults with Autism Spectrum Disorder JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Fung, L. K., Libove, R. A., Phillips, J., Haddad, F., Hardan, A. Y. 2014; 44 (11): 2971-2977

  Abstract

  The objective of this study was to assess the tolerability and efficacy of pregnenolone in reducing irritability in adults with autism spectrum disorder (ASD). This was a pilot, open-label, 12-week trial that included twelve subjects with a mean age of 22.5 ± 5.8 years. Two participants dropped out of the study due to reasons unrelated to adverse effects. Pregnenolone yielded a statistically significant improvement in the primary measure, Aberrant Behavior Checklist (ABC)-Irritability [from 17.4 ± 7.4 at baseline to 11.2 ± 7.0 at 12 weeks (p = 0.028)]. Secondary measures were not statistically significant with the exception of ABC-lethargy (p = 0.046) and total Short Sensory Profile score (p = 0.009). No significant vital sign changes occurred during this study. Pregnenolone was not associated with any severe side effects. Single episodes of tiredness, diarrhea and depressive affect that could be related to pregnenolone were reported. Overall, pregnenolone was modestly effective and well-tolerated in individuals with ASD.

  View details for DOI 10.1007/s10803-014-2144-4

  View details for Web of Science ID 000343724000027

• The effects of levosimendan on renal function early after heart transplantation: results from a pilot randomized trial CLINICAL TRANSPLANTATION Knezevic, I., Poglajen, G., Hrovat, E., Oman, A., Pintar, T., Wu, J. C., Vrtovec, B., Haddad, F. 2014; 28 (10): 1105-1111

  Abstract

  We evaluated the effects of a levosimendan (LS)-based strategy compared with standard inotropic therapy on renal function in heart transplantation.Using a randomized study design, 94 patients were assigned to LS-based therapy or standard inotropic support. At the time of transplantation, the groups did not differ in age, gender, heart failure etiology, hemodynamic profile, LVEF, or comorbidities. While there were no differences in serum creatinine (sCr) or eGFR between groups at baseline, patients in the LS group had a greater increase in their relative eGFR (62% vs. 12%, p = 0.002) and a lower incidence of acute kidney injury (AKI) (28% vs. 6%, p = 0.01) during the first post-transplant week. On logistic regression analysis, correlates of AKI were randomization to LS therapy (OR = 0.21 [0.09-0.62], p = 0.01), baseline renal dysfunction (OR = 3.9 [1.1-13.6], p = 0.032), and diabetes mellitus (OR = 4.2 [1.1-16.5], p = 0.038). However, LS was associated with a greater need for additional norepinephrine therapy (40 [85%] vs. 15 [31%], p < 0.001) and a trend toward longer intensive care unit stay (9.5 ± 9.0 d vs. 7.0 ± 6.0 d, p = 0.13).In patients undergoing heart transplantation, levosimendan-based strategy may be associated with better renal function when compared to standard therapy.

  View details for DOI 10.1111/ctr.12424

  View details for Web of Science ID 000344186200007

  View details for PubMedID 25053182

• [Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology]. Türk Kardiyoloji Dernegi arsivi : Türk Kardiyoloji Derneginin yayin organidir Vonk-Noordegraaf, A., Haddad, F., Chin, K. M., Forfia, P. R., Kawut, S. M., Lumens, J., Naeije, R., Newman, J., Oudiz, R. J., Provencher, S., Torbicki, A., Voelkel, N. F., Hassoun, P. M. 2014; 42: 29-44

  Abstract

  Survival in patients with pulmonary arterial hypertension (PAH) is closely related to right ventricular (RV) function. Although pulmonary load is an important determinant of RV systolic function in PAH, there remains a significant variability in RV adaptation to pulmonary hypertension. In this report, the authors discuss the emerging concepts of right heart pathobiology in PAH. More specifically, the discussion focuses on the following questions. 1) How is right heart failure syndrome best defined? 2) What are the uderlying molecular mechanisms of the failing right ventricle in PAH? 3) How are RV contractility and function and their prognostic implications best assessed? 4) What is the role of targeted RV therapy? Throughout the report, the authors highlight differences between right and left heart failure and outline key areas of future investigation. (J Am Coll Cardiol 2013;62:D22-33) a 2013 by the American College of Cardiology Foundation).

  View details for PubMedID 25697032

• Effects of Transendocardial CD34(+) Cell Transplantation in Patients With Ischemic Cardiomyopathy CIRCULATION-CARDIOVASCULAR INTERVENTIONS Poglajen, G., Sever, M., Cukjati, M., Cernelc, P., Knezevic, I., Zemljic, G., Haddad, F., Wu, J. C., Vrtovec, B. 2014; 7 (4): 552-559

  Abstract

  We investigated the effects of transendocardial CD34(+) cell transplantation in patients with ischemic cardiomyopathy.In a prospective crossover study, we enrolled 33 patients with ischemic cardiomyopathy with New York Heart Association class III and left ventricular ejection fraction <40%. In phase 1, patients were treated with medical therapy for 6 months. Thereafter, all patients underwent transendocardial CD34(+) cell transplantation. Peripheral blood CD34(+) cells were mobilized by granulocyte colony stimulating factor, collected via apheresis, and injected transendocardially in the areas of hibernating myocardium. Patients were followed up for 6 months after the procedure (phase 2). Two patients died during phase 1 and none during phase 2. The remaining 31 patients were 85% men, aged 57±6 years. In phase 1, we found no change in left ventricular ejection fraction (from 25.2±6.2% to 27.1±6.6%; P=0.23), N-terminal pro B-type natriuretic peptide (from 3322±3411 to 3672±5165 pg/mL; P=0.75) or 6-minute walk distance (from 373±68 to 411±116 m; P=0.17). In contrast, in phase 2 there was an improvement in left ventricular ejection fraction (from 27.1±6.6% to 34.9±10.9%; P=0.001), increase in 6-minute walk distance (from 411±116 to 496±113 m; P=0.001), and a decrease in N-terminal pro B-type natriuretic peptide (from 3672±5165 to 1488±1847 pg/mL; P=0.04). The average number of injected CD34(+) cells was 90.6±7.5×10(6). Higher doses of CD34(+) cells and a more diffuse distribution of transendocardial cell injections were associated with better clinical response.Transendocardial CD34(+) cell transplantation may be associated with improved left ventricular function, decreased N-terminal pro B-type natriuretic peptide levels, and better exercise capacity in patients with ischemic cardiomyopathy. These effects seem to be particularly pronounced in patients receiving diffusely distributed cell injections and high-dose cell therapy.http://www.clinicaltrials.gov. Unique identifier: NCT01350310.

  View details for DOI 10.1161/CIRCINTERVENTIONS.114.001436

  View details for Web of Science ID 000341205500019

  View details for PubMedID 25097199

• Pulmonary hypertension in patients with advanced heart failure is associated with increased levels of interleukin-6 BIOMARKERS Dolenc, J., Sebestjen, M., Vrtovec, B., Kozelj, M., Haddad, F. 2014; 19 (5): 385-390

  Abstract

  Inflammatory, endothelial and neurohormonal biomarkers are involved in heart failure (HF) and pulmonary hypertension (PH) pathogenesis.To study these biomarkers in PH due to advanced HF.Thirty adults with HF were included. Interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), high-sensitivity C-reactive protein (hsCRP), endothelin-1 and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) were measured in peripheral vein and pulmonary artery during right heart catheterisation.IL-6, TNF-α, hsCRP and NT-proBNP correlated with pulmonary pressures independent of ventricular function, HF etiology and vascular bed. IL-6 was independent predictor of systolic pulmonary artery pressure (sPAP).Inflammatory biomarkers correlate to PH severity. IL-6 predicts sPAP in advanced HF.

  View details for DOI 10.3109/1354750X.2014.918654

  View details for Web of Science ID 000340430100005

  View details for PubMedID 24831174

• Septal curvature is marker of hemodynamic, anatomical, and electromechanical ventricular interdependence in patients with pulmonary arterial hypertension. Echocardiography (Mount Kisco, N.Y.) Haddad, F., Guihaire, J., Skhiri, M., Denault, A. Y., Mercier, O., Al-Halabi, S., Vrtovec, B., Fadel, E., Zamanian, R. T., Schnittger, I. 2014; 31 (6): 699-707

  Abstract

  The objective of this study was to determine the factors independently associated with septal curvature in patients with pulmonary arterial hypertension (PAH).Eighty-five consecutive patients with PAH who had an echocardiogram and a right heart catheterization within 24 hours of each others were included in the study. Septal curvature was assessed at the mid-papillary level using the eccentricity index (EI). Marked early systolic septal anterior motion was defined as a change in EI > 0.2 between end-diastole and early systole. Inter-ventricular mechanical delay was calculated as the percent time difference between right ventricular (RV) to left ventricular (LV) end-ejection time normalized for the RR interval.Average age was 45 ± 11 years and the majority of patients were women (75%). Mean right atrial pressure was 11 ± 7 mmHg, mean PAP was 52 ± 13 mmHg, relative RV area 1.8 ± 0.9, and RV fractional area change 24 ± 8%. End-diastolic EI was 1.6 ± 0.4 and systolic EI was 2.5 ± 0.8. On multivariate analysis relative pulmonary pressure, relative RV area, and inter-ventricular mechanical delay were independently associated with systolic EI (R(2)  = 0.72, P < 0.001). Independent determinants of diastolic EI included relative RV area and mean PAP (R(2)  = 0.69, P < 0.001). A systolic EI >1.08 differentiated patients with PAH from healthy controls with an AUC = 0.99. Patients with early systolic septal anterior motion (44% of subjects) had lower exercise capacity, more extensive ventricular remodeling, and worst ventricular function.Septal curvature is a useful marker of structural, hemodynamic, and electromechanical ventricular interdependence in PAH.

  View details for DOI 10.1111/echo.12468

  View details for PubMedID 24372843

• Impact of insulin resistance on ventricular function in pulmonary arterial hypertension. journal of heart and lung transplantation Brunner, N. W., Skhiri, M., Fortenko, O., Hsi, A., Haddad, F., Khazeni, N., Zamanian, R. T. 2014; 33 (7): 721-726

  Abstract

  Insulin resistance (IR) is an independent prognostic marker in pulmonary arterial hypertension (PAH), although the mechanism by which it engenders risk is unknown. We prospectively investigated the clinical, laboratory, hemodynamic, and echocardiographic characteristics of insulin-sensitive (IS) and IR patients with PAH.This was a prospective cohort study including well-phenotyped patients with PAH proven at cardiac catheterization. Patients were classified as IS or IR on the basis of the well-validated triglyceride/high-density lipoprotein-cholesterol ratio. Clinical, laboratory, and hemodynamic characteristics were compared between cohorts. Distance walked on the 6-minute walk test (6MWT) and echocardiograms were compared between IS and IR for the sub-set of patients that had these tests within 1 month of cardiac catheterization.Of the 111 PAH patients enrolled, 59 were IS, 25 were IR, and 27 were classified as indeterminate. Mean age was 45.8 ± 15.0 years. IR was associated with worse New York Heart Association class (p = 0.02). There were no differences in hemodynamics, biomarkers, 6MWT distance, or parameters of right ventricular function (i.e., tricuspid annular plane systolic excursion, myocardial performance index, and fractional area change) between groups. Despite similar systemic vascular resistance, parameters of left ventricular diastolic function were more favorable for IS vs IR, including mitral inflow E wave velocity (82 ± 17 vs 64 ± 19 msec, p = 0.02), E/A ratio (1.2 ± 0.4 vs 0.8 ± 0.2, p = 0.01), and lateral mitral valve E' velocity (13.9 ± 3.5 vs 10.4 ± 2.2 msec, p = 0.01).IR is associated with worse functional class and diastology compared with IS in PAH, although other prognostic parameters are similar.

  View details for DOI 10.1016/j.healun.2014.02.016

  View details for PubMedID 24819985

• Dichloroacetate prevents restenosis in preclinical animal models of vessel injury. Nature Deuse, T., Hua, X., Wang, D., Maegdefessel, L., Heeren, J., Scheja, L., Bolaños, J. P., Rakovic, A., Spin, J. M., Stubbendorff, M., Ikeno, F., Länger, F., Zeller, T., Schulte-Uentrop, L., Stoehr, A., Itagaki, R., Haddad, F., Eschenhagen, T., Blankenberg, S., Kiefmann, R., Reichenspurner, H., Velden, J., Klein, C., Yeung, A., Robbins, R. C., Tsao, P. S., Schrepfer, S. 2014; 509 (7502): 641-644

  Abstract

  Despite the introduction of antiproliferative drug-eluting stents, coronary heart disease remains the leading cause of death in the United States. In-stent restenosis and bypass graft failure are characterized by excessive smooth muscle cell (SMC) proliferation and concomitant myointima formation with luminal obliteration. Here we show that during the development of myointimal hyperplasia in human arteries, SMCs show hyperpolarization of their mitochondrial membrane potential (ΔΨm) and acquire a temporary state with a high proliferative rate and resistance to apoptosis. Pyruvate dehydrogenase kinase isoform 2 (PDK2) was identified as a key regulatory protein, and its activation proved necessary for relevant myointima formation. Pharmacologic PDK2 blockade with dichloroacetate or lentiviral PDK2 knockdown prevented ΔΨm hyperpolarization, facilitated apoptosis and reduced myointima formation in injured human mammary and coronary arteries, rat aortas, rabbit iliac arteries and swine (pig) coronary arteries. In contrast to several commonly used antiproliferative drugs, dichloroacetate did not prevent vessel re-endothelialization. Targeting myointimal ΔΨm and alleviating apoptosis resistance is a novel strategy for the prevention of proliferative vascular diseases.

  View details for DOI 10.1038/nature13232

  View details for PubMedID 24747400

• Dichloroacetate prevents restenosis in preclinical animal models of vessel injury. Nature Deuse, T., Hua, X., Wang, D., Maegdefessel, L., Heeren, J., Scheja, L., Bolaños, J. P., Rakovic, A., Spin, J. M., Stubbendorff, M., Ikeno, F., Länger, F., Zeller, T., Schulte-Uentrop, L., Stoehr, A., Itagaki, R., Haddad, F., Eschenhagen, T., Blankenberg, S., Kiefmann, R., Reichenspurner, H., Velden, J., Klein, C., Yeung, A., Robbins, R. C., Tsao, P. S., Schrepfer, S. 2014; 509 (7502): 641-644

  Abstract

  Despite the introduction of antiproliferative drug-eluting stents, coronary heart disease remains the leading cause of death in the United States. In-stent restenosis and bypass graft failure are characterized by excessive smooth muscle cell (SMC) proliferation and concomitant myointima formation with luminal obliteration. Here we show that during the development of myointimal hyperplasia in human arteries, SMCs show hyperpolarization of their mitochondrial membrane potential (ΔΨm) and acquire a temporary state with a high proliferative rate and resistance to apoptosis. Pyruvate dehydrogenase kinase isoform 2 (PDK2) was identified as a key regulatory protein, and its activation proved necessary for relevant myointima formation. Pharmacologic PDK2 blockade with dichloroacetate or lentiviral PDK2 knockdown prevented ΔΨm hyperpolarization, facilitated apoptosis and reduced myointima formation in injured human mammary and coronary arteries, rat aortas, rabbit iliac arteries and swine (pig) coronary arteries. In contrast to several commonly used antiproliferative drugs, dichloroacetate did not prevent vessel re-endothelialization. Targeting myointimal ΔΨm and alleviating apoptosis resistance is a novel strategy for the prevention of proliferative vascular diseases.

  View details for DOI 10.1038/nature13232

  View details for PubMedID 24747400

• Relationship between Echocardiographic and Magnetic Resonance Derived Measures of Right Ventricular Size and Function in Patients with Pulmonary Hypertension. Journal of the American Society of Echocardiography Shiran, H., Zamanian, R. T., McConnell, M. V., Liang, D. H., Dash, R., Heidary, S., Sudini, N. L., Wu, J. C., Haddad, F., Yang, P. C. 2014; 27 (4): 405-412

  Abstract

  Transthoracic echocardiographic (TTE) imaging is the mainstay of clinical practice for evaluating right ventricular (RV) size and function, but its accuracy in patients with pulmonary hypertension has not been well validated.Magnetic resonance imaging (MRI) and TTE images were retrospectively reviewed in 40 consecutive patients with pulmonary hypertension. RV and left ventricular volumes and ejection fractions were calculated using MRI. TTE areas and indices of RV ejection fraction (RVEF) were compared.The average age was 42 ± 12 years, with a majority of women (85%). There was a wide range of mean pulmonary arterial pressures (27-81 mm Hg) and RV end-diastolic volumes (111-576 mL), RVEFs (8%-67 %), and left ventricular ejection fractions (26%-72%) by MRI. There was a strong association between TTE and MRI-derived parameters: RV end-diastolic area (by TTE imaging) and RV end-diastolic volume (by MRI), R(2) = 0.78 (P < .001); RV fractional area change by TTE imaging and RVEF by MRI, R(2) = 0.76 (P < .001); and tricuspid annular plane systolic excursion by TTE imaging and RVEF by MRI, R(2) = 0.64 (P < .001). By receiver operating characteristic curve analysis, an RV fractional area change < 25% provided excellent discrimination of moderate systolic dysfunction (RVEF < 35%), with an area under the curve of 0.97 (P < .001). An RV end-diastolic area index of 18 cm(2)/m(2) provided excellent discrimination for moderate RV enlargement (area under the curve, 0.89; P < .001).Echocardiographic estimates of RV volume (by RV end-diastolic area) and function (by RV fractional area change and tricuspid annular plane systolic excursion) offer good approximations of RV size and function in patients with pulmonary hypertension and allow the accurate discrimination of normal from abnormal.

  View details for DOI 10.1016/j.echo.2013.12.011

  View details for PubMedID 24444659

• Latent obstruction and left atrial size are predictors of clinical deterioration leading to septal reduction in hypertrophic cardiomyopathy. Journal of cardiac failure Finocchiaro, G., Haddad, F., Pavlovic, A., Sinagra, G., Schnittger, I., Knowles, J. W., Perez, M., Magavern, E., Myers, J., Ashley, E. 2014; 20 (4): 236-243

  Abstract

  Exercise echocardiography is a reliable tool to assess left ventricular (LV) dynamic obstruction in hypertrophic cardiomyopathy (HCM). The aim of this study was to determine the role of exercise echocardiography in the evaluation of latent obstruction and in predicting clinical deterioration in HCM patients.We considered 283 HCM patients studied with exercise echocardiography. The end point was clinical deterioration leading to septal reduction (myectomy or alcohol septal ablation). LV latent obstruction was present at enrollment in 67 patients (24%). During a mean follow-up of 42 ± 31 months, 42 patients had clinical deterioration leading to septal reduction therapy: in 12/67 (22%) patients with a latent obstruction at enrollment, in 28/84 (33%) patients with obstruction at rest, and in 2/132 (1.5%) with obstruction neither at rest or during stress. Multivariate analysis identified the following variables as independently associated with the end point: LV gradient >30 mm Hg at rest (hazard ratio [HR] 2.56, 95% CI 1.27-5.14; P = .009), LV gradient >30 mm Hg during stress (HR 4.96, 95% CI 1.81-13.61; P = .002), and indexed left atrial volume (LAVi ) >40 mL/m(2) (HR 2.86, 95% CI 1.47-5.55; P = .002). In patients with a latent obstruction, the strongest independent predictor of outcome was LAVi >40 mL/m(2) (HR 3.75, 95% CI 1.12-12.51; P = .032).Assessment of LV gradient during stress with exercise echocardiography is an important tool for the evaluation of latent obstruction in HCM and may have a role in risk stratification of these patients.

  View details for DOI 10.1016/j.cardfail.2014.01.014

  View details for PubMedID 24486928

• Unexplained double-chambered left ventricle associated with contracting right ventricular aneurysm and right atrial enlargement. Echocardiography (Mount Kisco, N.Y.) Finocchiaro, G., Murphy, D., Pavlovic, A., Haddad, F., Shiran, H., Sinagra, G., Ashley, E. A., Knowles, J. W. 2014; 31 (3): E80-4

  Abstract

  In this article, we describe a double-chambered left ventricle (LV) associated with a functional right ventricular (RV) aneurysm and right atrial (RA) enlargement in an asymptomatic 24-year-old woman with a family history of sudden cardiac death. We will discuss the differential diagnosis, genetic testing and possible prognostic implications.

  View details for DOI 10.1111/echo.12467

  View details for PubMedID 24299065

• Perioperative pharmacological management of pulmonary hypertensive crisis during congenital heart surgery PULMONARY CIRCULATION Brunner, N., Perez, V. A., Richter, A., Haddad, F., Denault, A., Rojas, V., Yuan, K., Orcholski, M., Liao, X. 2014; 4 (1): 10-24

  Abstract

  Pulmonary hypertensive crisis is an important cause of morbidity and mortality in patients with pulmonary arterial hypertension secondary to congenital heart disease (PAH-CHD) who require cardiac surgery. At present, prevention and management of perioperative pulmonary hypertensive crisis is aimed at optimizing cardiopulmonary interactions by targeting prostacyclin, endothelin, and nitric oxide signaling pathways within the pulmonary circulation with various pharmacological agents. This review is aimed at familiarizing the practitioner with the current pharmacological treatment for dealing with perioperative pulmonary hypertensive crisis in PAH-CHD patients. Given the life-threatening complications associated with pulmonary hypertensive crisis, proper perioperative planning can help anticipate cardiopulmonary complications and optimize surgical outcomes in this patient population.

  View details for DOI 10.1086/674885

  View details for Web of Science ID 000209982100003

  View details for PubMedCentralID PMC4070760

• Perioperative pharmacological management of pulmonary hypertensive crisis during congenital heart surgery. Pulmonary circulation Brunner, N., de Jesus Perez, V. A., Richter, A., Haddad, F., Denault, A., Rojas, V., Yuan, K., Orcholski, M., Liao, X. 2014; 4 (1): 10-24

  Abstract

  Pulmonary hypertensive crisis is an important cause of morbidity and mortality in patients with pulmonary arterial hypertension secondary to congenital heart disease (PAH-CHD) who require cardiac surgery. At present, prevention and management of perioperative pulmonary hypertensive crisis is aimed at optimizing cardiopulmonary interactions by targeting prostacyclin, endothelin, and nitric oxide signaling pathways within the pulmonary circulation with various pharmacological agents. This review is aimed at familiarizing the practitioner with the current pharmacological treatment for dealing with perioperative pulmonary hypertensive crisis in PAH-CHD patients. Given the life-threatening complications associated with pulmonary hypertensive crisis, proper perioperative planning can help anticipate cardiopulmonary complications and optimize surgical outcomes in this patient population.

  View details for DOI 10.1086/674885

  View details for PubMedID 25006417

• Unexplained double-chambered left ventricle associated with contracting right ventricular aneurysm and right atrial enlargement. Echocardiography (Mount Kisco, N.Y.) Finocchiaro, G., Murphy, D., Pavlovic, A., Haddad, F., Shiran, H., Sinagra, G., Ashley, E. A., Knowles, J. W. 2014; 31 (3): E80-4

  View details for DOI 10.1111/echo.12467

  View details for PubMedID 24299065

• Right ventricular plasticity in a porcine model of chronic pressure overload. journal of heart and lung transplantation Guihaire, J., Haddad, F., Boulate, D., Capderou, A., Decante, B., Flécher, E., Eddahibi, S., Dorfmüller, P., Hervé, P., Humbert, M., Verhoye, J., Dartevelle, P., Mercier, O., Fadel, E. 2014; 33 (2): 194-202

  Abstract

  Ventricular-arterial coupling is a measure of the relationship between ventricular contractility and afterload. We sought to determine the relationship between ventricular-arterial coupling and right ventricular (RV) remodeling in a novel porcine model of progressive pulmonary hypertension (PH).Chronic PH was induced in pigs by ligation of the left pulmonary artery (PA) followed by 5 weekly injections of cyanoacrylate to progressively obstruct the right lower lobe arteries (PH group, n = 10). At 6 weeks, 5 PH animals underwent reperfusion of the left lung through conduit anastomosis to decrease RV afterload, whereas 5 other animals received no treatment. Five sham-operated piglets were used as controls. RV function was assessed using echocardiography and conductance catheterization. RV gene expression of beta-myosin heavy chain (β-MHC) and B-type natriuretic peptide (BNP) were quantified by polymerase chain reaction.At 6 weeks, compared with controls, the PH group had higher mean PA pressure (32 ± 6 vs 14 ± 2 mm Hg, p < 0.01). The increase in RV elastance was insufficient to compensate for the increase in pulmonary arterial elastance in the PH group and altered ventricular-arterial coupling occurred (0.65 ± 0.16 vs 1.28 ± 0.14, p < 0.01). The degree of ventricular-arterial uncoupling was related to RV enlargement and systolic dysfunction. Ventricular-arterial uncoupling and increased RV mass index were associated with up-regulation of β-MHC and BNP expression.Ventricular-arterial coupling is closely associated with ventricular remodeling and systolic function as well as contractile and BNP gene expression. Dynamic changes in myosin expression may determine RV work efficiency in PH.

  View details for DOI 10.1016/j.healun.2013.10.026

  View details for PubMedID 24290166

• Prevalence and clinical correlates of right ventricular dysfunction in patients with hypertrophic cardiomyopathy. American journal of cardiology Finocchiaro, G., Knowles, J. W., Pavlovic, A., Perez, M., Magavern, E., Sinagra, G., Haddad, F., Ashley, E. A. 2014; 113 (2): 361-367

  Abstract

  Hypertrophic cardiomyopathy (HC) is a disease that mainly affects the left ventricle (LV), however recent studies have suggested that it can also be associated with right ventricular (RV) dysfunction. The objective of this study was to determine the prevalence of RV dysfunction in patients with HC and its relation with LV function and outcome. A total of 324 consecutive patients with HC who received care at Stanford Hospital from 1999 to 2012 were included in the study. A group of 99 prospectively recruited age- and gender-matched healthy volunteers were used as controls. RV function was quantified using the RV fractional area change, tricuspid annular plane systolic excursion (TAPSE), and RV myocardial performance index (RVMPI). Compared with the controls, the patients with HC had a higher RVMPI (0.51 ± 0.18 vs 0.25 ± 0.06, p <0.001) and lower TAPSE (20 ± 3 vs 24 ± 4, p <0.001). RV dysfunction based on an RVMPI >0.4 and TAPSE <16 mm was found in 71% and 11% of the HC and control groups, respectively. Worst LV function and greater pulmonary pressures were independent correlates of RV dysfunction. At an average follow-up of 3.7 ± 2.3 years, 17 patients had died and 4 had undergone heart transplantation. LV ejection fraction <50% and TAPSE <16 mm were independent correlates of outcome (hazard ratio 3.98, 95% confidence interval 1.22 to 13.04, p = 0.02; and hazard ratio 3.66, 95% confidence interval 1.38 to 9.69, p = 0.009, respectively). In conclusion, RV dysfunction based on the RVMPI is common in patients with HC and more frequently observed in patients with LV dysfunction and pulmonary hypertension. RV dysfunction based on the TAPSE was independently associated with an increased likelihood of death or transplantation.

  View details for DOI 10.1016/j.amjcard.2013.09.045

  View details for PubMedID 24230980

• How does morphology impact on diastolic function in hypertrophic cardiomyopathy? A single centre experience. BMJ open Finocchiaro, G., Haddad, F., Pavlovic, A., Magavern, E., Sinagra, G., Knowles, J. W., Myers, J., Ashley, E. A. 2014; 4 (6)

  Abstract

  It is unclear if morphology impacts on diastole in hypertrophic cardiomyopathy (HCM). We sought to determine the relationship between various parameters of diastolic function and morphology in a large HCM cohort.Tertiary referral centre from Stanford, California, USA.383 patients with HCM and normal systolic function between 1999 and 2011. A group of 100 prospectively recruited age-matched and sex-matched healthy participants were used as controls.Echocardiograms were assessed by two blinded board-certified cardiologists. HCM morphology was classified as described in the literature (reverse, sigmoid, symmetric, apical and undefined).Reverse curvature morphology was most commonly observed (218 (57%). Lateral mitral annular E'<12 cm/s was present in 86% of reverse, 88% of sigmoid, 79% of symmetric, 86% of apical and 81% of undefined morphology, p=0.65. E/E' was similarly elevated (E/E': 12.3±7.9 in reverse curvature, 12.1±6.1 in sigmoid, 12.7±9.5 in symmetric, 9.4±4.0 in apical, 12.7±7.9 in undefined morphology, p=0.71) and indexed left atrial volume (LAVi)>40 mL/m(2) was present in 47% in reverse curvature, 33% in sigmoid, 32% in symmetric, 37% in apical and 32% in undefined, p=0.09. Each morphology showed altered parameters of diastolic function when compared with the control population. Left ventricular (LV) obstruction was independently associated with all three diastolic parameters considered, in particular with LAVi>40 mL/m(2) (OR 2.04 (95% CI 1.23 to 3.39), p=0.005), E/E'>15 (OR 4.66 (95% CI 2.51 to 8.64), p<0.001) and E'<8 (OR 2.55 (95% CI 1.42 to 4.53), p=0.001). Other correlates of diastolic dysfunction were age, LV wall thickness and moderate-to-severe mitral regurgitation.In HCM, diastolic dysfunction is present to similar degrees independently from the morphological pattern. The main correlates of diastolic dysfunction are LV obstruction, age, degree of hypertrophy and degree of mitral regurgitation.

  View details for DOI 10.1136/bmjopen-2014-004814

  View details for PubMedID 24928584

  View details for PubMedCentralID PMC4067898

• How does morphology impact on diastolic function in hypertrophic cardiomyopathy? A single centre experience. BMJ open Finocchiaro, G., Haddad, F., Pavlovic, A., Magavern, E., Sinagra, G., Knowles, J. W., Myers, J., Ashley, E. A. 2014; 4 (6)

  View details for DOI 10.1136/bmjopen-2014-004814

  View details for PubMedID 24928584

• Cardiac metastases and tumor embolization: A rare sequelae of primary undifferentiated liver sarcoma. International journal of surgery case reports Dua, M. M., Cloyd, J. M., Haddad, F., Beygui, R. E., Norton, J. A., Visser, B. C. 2014; 5 (12): 927-931

  Abstract

  Primary hepatic sarcomas are uncommon malignant neoplasms; prognostic features, natural history, and optimal management of these tumors are not well characterized.This report describes the management of a 51-year-old patient that underwent a right trisectionectomy for a large hepatic mass found to be a liver sarcoma on pathology. He subsequently developed tumor emboli to his lungs and was discovered to have cardiac intracavitary metastases from his primary tumor. The patient underwent cardiopulmonary bypass and resection of the right-sided heart metastases to prevent further pulmonary sequela of tumor embolization.The lack of distinguishing symptoms or imaging characteristics that clearly define hepatic sarcomas makes it challenging to achieve a diagnosis prior to pathologic examination. Metastatic spread is frequently to the lung or pleura, but very rarely seen within the heart. Failure to recognize cardiac metastatic disease will ultimately lead to progressive tumor embolization and cardiac failure if left untreated.The most effective therapy for primary liver sarcomas is surgery; radical resection should be performed if possible given the aggressive nature of these tumors to progress and metastasize.

  View details for DOI 10.1016/j.ijscr.2014.10.004

  View details for PubMedID 25460438

• Right Heart Adaptation to Pulmonary Arterial Hypertension Physiology and Pathobiology JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Vonk-Noordegraaf, A., Haddad, F., Chin, K. M., Forfia, P. R., Kawut, S. M., Lumens, J., Naeije, R., Newman, J., Oudiz, R. J., Provencher, S., Torbicki, A., Voelkel, N. F., Hassoun, P. M. 2013; 62 (25): D22-D33

  Abstract

  Survival in patients with pulmonary arterial hypertension (PAH) is closely related to right ventricular (RV) function. Although pulmonary load is an important determinant of RV systolic function in PAH, there remains a significant variability in RV adaptation to pulmonary hypertension. In this report, the authors discuss the emerging concepts of right heart pathobiology in PAH. More specifically, the discussion focuses on the following questions. 1) How is right heart failure syndrome best defined? 2) What are the underlying molecular mechanisms of the failing right ventricle in PAH? 3) How are RV contractility and function and their prognostic implications best assessed? 4) What is the role of targeted RV therapy? Throughout the report, the authors highlight differences between right and left heart failure and outline key areas of future investigation.

  View details for DOI 10.1016/j.jacc.2013.10.027

  View details for Web of Science ID 000329459400004

  View details for PubMedID 24355638

• Non-invasive indices of right ventricular function are markers of ventriculararterial coupling rather than ventricular contractility: insights from a porcine model of chronic pressure overload EUROPEAN HEART JOURNAL-CARDIOVASCULAR IMAGING Guihaire, J., Haddad, F., Boulate, D., Decante, B., Denault, A. Y., Wu, J., Herve, P., Humbert, M., Dartevelle, P., Verhoye, J., Mercier, O., Fadel, E. 2013; 14 (12): 1140-1149

  Abstract

  To investigate the physiological correlates of indices of RV function in a model of chronic pressure overload.Chronic pulmonary hypertension (PH) was induced in piglets by ligation of the left pulmonary artery (PA) followed by weekly embolization of right lower lobe arteries for 5 weeks (the PH group, n = 11). These animals were compared with sham-operated animals (controls, n = 6). At 6 weeks, a subgroup of five PH pigs underwent surgical reperfusion of the left lung and four others were followed until 12 weeks without treatment. Right ventricular function was assessed using echocardiography and conductance catheter measurements. At 6 weeks, mean PA pressure was higher in PH group compared with controls (35 ± 9 vs. 14 ± 2 mmHg, P < 0.01). Although RV elastance (Ees) increased at 6 weeks in the PH group (0.55 ± 0.09 vs. 0.38 ± 0.05 mmHg/mL, P < 0.001), ventricular-arterial coupling measured by the ratio of Ees on PA elastance (Ea) was decreased (0.68 ± 0.17 vs. 1.18 ± 0.18, P < 0.001). There was a strong direct relationship between Ees/Ea and indices of RV function, while relationship between Ees and indices of RV function was moderate. Changes in indices of RV function with time and after left lung reperfusion were associated with changes in Ees/Ea.Usual indices of RV function are associated with ventricular-arterial coupling rather than with ventricular contractility in a model of chronic pressure overload.

  View details for DOI 10.1093/ehjci/jet092

  View details for Web of Science ID 000326966100004

  View details for PubMedID 23677917

• CD34(+) Stem Cell Therapy in Nonischemic Dilated Cardiomyopathy Patients. Clinical pharmacology & therapeutics Vrtovec, B., Poglajen, G., Sever, M., Lezaic, L., Socan, A., Haddad, F., Wu, J. C. 2013; 94 (4): 452-458

  Abstract

  Recent trends indicate that patients with nonischemic dilated cardiomyopathy represent the largest subpopulation of heart failure patients with a significant need for alternative treatment modalities. Similar to patients with ischemic cardiomyopathy, patients with nonischemic dilated cardiomyopathy have been found to have myocardial regions with flow abnormalities, which may represent targets for neoangiogenic therapies. CD34(+) stem cells might contribute to the formation of new blood vessels from existing vascular structures in ischemic tissues by the direct incorporation of injected cells into the newly developing vasculature or by the production and secretion of angiogenic cytokines. This review summarizes the long-term clinical effects and potential underlying mechanisms of CD34(+) cell therapy in patients with nonischemic dilated cardiomyopathy.Clinical Pharmacology & Therapeutics (2013); 94 4, 452-458. doi:10.1038/clpt.2013.134.

  View details for DOI 10.1038/clpt.2013.134

  View details for PubMedID 23903668

• Imaging cardiac stem cell transplantation using radionuclide labeling techniques: clinical applications and future directions. Methodist DeBakey cardiovascular journal Lezaic, L., Haddad, F., Vrtovec, B., Wu, J. C. 2013; 9 (4): 218-222

  Abstract

  Stem cell therapy is emerging as a potential new therapy for patients with advanced heart failure. In recent years, advances in molecular imaging have allowed monitoring of stem cell homing and survival. In this review article, we will discuss the clinical application and future directions of stem cell imaging in advanced heart failure.

  View details for PubMedID 24298314

  View details for PubMedCentralID PMC3846077

• Comparison of transendocardial and intracoronary CD34+ cell transplantation in patients with nonischemic dilated cardiomyopathy. Circulation Vrtovec, B., Poglajen, G., Lezaic, L., Sever, M., Socan, A., Domanovic, D., Cernelc, P., Torre-Amione, G., Haddad, F., Wu, J. C. 2013; 128 (11): S42-9

  Abstract

  In an open-label blinded study, we compared intracoronary and transendocardial CD34(+) cell transplantation in patients with nonischemic dilated cardiomyopathy.Of the 40 patients with dilated cardiomyopathy, 20 were randomized to receive intracoronary injection and 20 received transendocardial CD34(+) cell delivery. In both groups, CD34(+) cells were mobilized by filgrastim, collected via apheresis, and labeled with technetium-99m radioisotope for single-photon emission computed tomographic imaging. In the intracoronary group, cells were injected intracoronarily in the artery supplying segments of greater perfusion defect on myocardial perfusion scintigraphy. In the transendocardial group, electroanatomic mapping was used to identify viable but dysfunctional myocardium, and transendocardial cell injections were performed. Nuclear single-photon emission computed tomographic imaging for quantification of myocardial retention was performed 18 hours thereafter. At baseline, groups did not differ in age, sex, left ventricular ejection fraction, or N-terminal pro-brain natriuretic peptide levels. The number of CD34(+) cells was also comparable (105 ± 31 × 10(6) in the transendocardial group versus 103 ± 27 × 10(6) in the intracoronary group, P=0.62). At 18 hours after procedure, myocardial retention was higher in the transendocardial group (19.2 ± 4.8%) than in the intracoronary group (4.4 ± 1.2%, P<0.01). At 6 months, left ventricular ejection fraction improved more in the transendocardial group (+8.1 ± 4.3%) than in the intracoronary group (+4.2 ± 2.3%, P=0.03). The same pattern was observed for the 6-minute walk test distance (+125 ± 33 m in the transendocardial group versus +86 ± 13 m in the intracoronary group, P=0.03) and N-terminal pro-brain natriuretic peptide (-628 ± 211 versus -315 ± 133 pg/mL, P=0.04).In patients with dilated cardiomyopathy, transendocardial CD34(+) cell transplantation is associated with higher myocardial retention rates and greater improvement in ventricular function, N-terminal pro-brain natriuretic peptide, and exercise capacity compared with intracoronary route.http://www.clinicaltrials.gov. Unique identifier: NCT01350310.

  View details for DOI 10.1161/CIRCULATIONAHA.112.000230

  View details for PubMedID 24030420

• Race differences in ventricular remodeling and function among college football players. American journal of cardiology Haddad, F., Peter, S., Hulme, O., Liang, D., Schnittger, I., Puryear, J., Gomari, F. A., Finocchiaro, G., Myers, J., Froelicher, V., Garza, D., Ashley, E. A. 2013; 112 (1): 128-134

  Abstract

  Athletic training is associated with increases in ventricular mass and volume. Recent studies have shown that left ventricular mass increases proportionally in white athletes with a mass/volume ratio approaching unity. The objective of this study was to compare the proportionality in ventricular remodeling and ventricular function in black versus white National Collegiate Athletic Association Division I football players. From 2008 to 2011, football players at Stanford University underwent cardiovascular screening with a 12-point history and physical examination, electrocardiography, and focused echocardiography. Compared with white players, black players had on average higher left ventricular mass indexes (77 ± 11 vs 71 ± 11 g/m(2), p = 0.009), higher mass/volume ratios (1.18 ± 0.16 vs 1.06 ± 0.09 g/ml, p <0.001), and higher QRS vector magnitudes (3.2 ± 0.7 vs 2.7 ± 0.8, p = 0.002). Black race had an odds ratio of 14 (95% confidence interval 5 to 42, p <0.001) for a mass/volume ratio >1.2. Mass/volume ratio was inversely related to early diastolic tissue Doppler velocity e' (r = -0.50, p <0.001) but not to QRS vector magnitude (r = 0.065, p = 0.034). With regard to systolic indexes, there was no significant difference in the left ventricular ejection fraction, velocity of circumferential shortening, and isovolumic acceleration. In conclusion, black college football players exhibit more concentric ventricular remodeling, lower early diastolic annular velocities, and increased ventricular voltage compared with white players. Ventricular mass increases proportionally to volume in white players but not in black players.

  View details for DOI 10.1016/j.amjcard.2013.02.065

  View details for PubMedID 23602691

• Granulocyte colony-stimulating factor therapy is associated with a reduced incidence of acute rejection episodes or allograft vasculopathy in heart transplant recipients. Transplantation proceedings Vrtovec, B., Haddad, F., Pham, M., Deuse, T., Fearon, W. F., Schrepfer, S., Leon, S., Vu, T., Valantine, H., Hunt, S. A. 2013; 45 (6): 2406-2409

  Abstract

  We evaluated the potential effects of granulocyte colony-simulating factor (G- CSF) on the incidence of rejection and allograft vasculopathy in heart transplant recipients.Of 247 patients undergoing heart transplantation from 2000 to 2007, 52 (21%) developed leukopenia (white blood cell [WBC] <2.5 × 10(9)cells/L) in the absence of active infection, rejection, or malignancy. In 24 (46%) patients a clinical decision was made to treat the leukopenia with G-CSF (G-CSF group), and 28 (54%) Patients received no G-CSF (non-GCSF group). Patients followed up for 1 year after the period of leukopenia were assessed for allograft vasculopathy and acute rejection incidence.At baseline, the G-CSF group and the non-GCSF group did not differ in age, gender, race, heart failure etiology, creatinine, left ventricular ejection fraction (LVEF) or immunosupressive regimen. During 1-year follow-up there were no deaths in the G-CSF group, and 1 death in the non-GCSF group (P = .34). The incidence of rejection or progressive allograft vasculopathy was lower in the G-CSF group when compared with the non-GCSF group (2 [8%] vs 15 [53%]; P < .01). Multivariate analysis identified both prior rejection episodes and G-CSF therapy as factors associated with the combined end-point of rejection or progressive allograft vasculopathy (odds ratio [OR] = 7.89 [1.67-37.2] and OR = 0.09 [0.02-0.52], respectively).G-CSF therapy appears to be associated with a decreased incidence of acute rejection episodes or allograft vasculopathy in heart transplant recipients, suggesting a potential immunomodulatory effect of G-CSF.

  View details for DOI 10.1016/j.transproceed.2013.01.106

  View details for PubMedID 23953556

• Clinical and Echocardiographic Presentation of Rejection Episodes Following Heart Transplantation 33rd Annual Meeting and Scientific Sessions of the International-Society-for-Heart-and-Lung-Transplantation Sudini, N. L., Huo, J., Pan, S., Montoya, J., Leon, S., Vu, T., Beygui, R. E., Vrtovec, B., Wu, J. C., Pham, M., KUSH, K., Berry, G., Hunt, S., Haddad, F. ELSEVIER SCIENCE INC. 2013: S254–S254

  View details for Web of Science ID 000316712100696

• Relation of B-Type Natriuretic Peptide Level in Heart Failure to Sudden Cardiac Death in Patients With and Without QT Interval Prolongation AMERICAN JOURNAL OF CARDIOLOGY Vrtovec, B., Knezevic, I., Poglajen, G., Sebestjen, M., Olcrajsek, R., Haddad, F. 2013; 111 (6): 886-890

  Abstract

  Increased levels of B-type natriuretic peptide (BNP) are associated with prolongation of the action potential in ventricular myocardium. We investigated the relation of a BNP increase, QT interval, and sudden cardiac death (SCD) in the presence of heart failure (HF). We enrolled 398 patients with HF, New York Heart Association class III or IV, and left ventricular ejection fraction <40%. At baseline and after 3 months, we measured BNP and the QT interval. A BNP increase was defined as a change in BNP of ≥+10%. The QTc interval was calculated using the Bazett formula. QTc interval prolongation was defined as a change in QTc of ≥+10%. The patients were followed up for 1 year. During a 3-month period, BNP increased significantly in 53% of the patients (group 1) and did not in 47% (group 2). During the same period, the QTc interval was more prolonged in group 1 (+44 ± 12 ms) than in group 2 (+7 ± 6 ms; p = 0.01). During 1 year of follow-up, 20 patients died suddenly (SCD), 16 from pump failure. Although the SCD rates did not differ between the 2 groups (5.7% in group 1 vs 4.2% in group 2, p = 0.53), they were significantly greater in the patients in group 1 with QTc interval prolongation ≥+10% (13.8%, p <0.001). The Kaplan-Meier-derived SCD-free survival rates were 2.9 times greater in patients without QTc interval prolongation than in those with prolonged QTc (p <0.001). QTc interval prolongation was an independent correlate of SCD (p = 0.006), but BNP increase was not (p = 0.32). In conclusion, a BNP increase in patients with HF was associated with an increased risk of SCD only in patients with QTc interval prolongation.

  View details for DOI 10.1016/j.amjcard.2012.11.041

  View details for Web of Science ID 000316537700019

• RIGHT ATRIAL EMPTYING FRACTIONS ARE ASSOCIATED WITH SURVIVAL IN PULMONARY ARTERIAL HYPERTENSION 62nd Annual Scientific Session of the American-College-of-Cardiology Brunner, N. W., Haddad, F., Swiston, J. R., Gin, K., Tsang, T. S., Zamanian, R. T. ELSEVIER SCIENCE INC. 2013: E896–E896

  View details for Web of Science ID 000316555201001

• IMPROVEMENT IN RIGHT ATRIAL FUNCTION IS ASSOCIATED WITH IMPROVED FUNCTIONAL CAPACITY IN PULMONARY ARTERIAL HYPERTENSION 62nd Annual Scientific Session of the American-College-of-Cardiology Brunner, N. W., Haddad, F., Swiston, J. R., Gin, K., Tsang, T. S., Zamanian, R. T. ELSEVIER SCIENCE INC. 2013: E1246–E1246

  View details for Web of Science ID 000316555201351

• ST-Elevation Myocardial Infarction Following Heart Transplantation as an Unusual Presentation of Coronary Allograft Vasculopathy: A Case Report TRANSPLANTATION PROCEEDINGS Peter, S., HULME, O., Deuse, T., Vrtovec, B., Fearon, W. F., Hunt, S., Haddad, F. 2013; 45 (2): 787-791

  Abstract

  The presentation, mechanisms, and incidence of ST elevation myocardial infarction (STEMI) in heart transplant recipients have been characterized only to a limited degree in the current literature. Herein, we present a unique case of STEMI years after heart transplantation with a focus on the salient features of its diagnosis and interventions. We also provide a review of the epidemiology of this phenomenon.A 33-year-old woman who was status post cardiac transplantation for dilated cardiomyopathy presented to the clinic with mild nonspecific fatigue and concern after having noticed relative bradycardia compared with her posttransplantation baseline heart rate. Electrocardiogram (ECG) showed junctional rhythm and inferior ST elevations, likely reflecting nodal ischemia. Troponins were grossly positive and echocardiogram showed marked right ventricular dysfunction.Successful percutaneous coronary intervention (PCI) with aspiration thrombectomy and drug-eluting stent placement was emergently performed. The heart's rhythm soon returned to sinus tachycardia. Right ventricular wall-motion abnormalities resolved. The patient suffered no clinical sequelae of her STEMI.This case illustrated that "classic" symptoms of STEMI may not occur at all in the setting of heart transplantation. To our knowledge, this is the first case of posttransplantation STEMI presenting as asymptomatic bradycardia, and highlights the importance of maintaining high clinical suspicion for ischemia in transplant recipients with subtle changes. In reviewing the epidemiology of this case, we locate and bundle different types of studies that have directly or indirectly looked at STEMI in heart transplantation. For a variety of putative pathophysiological reasons, STEMI is indeed a rare manifestation of the common transplant phenomenon of coronary artery vasculopathy (CAV).

  View details for DOI 10.1016/j.transproceed.2012.08.021

  View details for PubMedID 23498821

• Perioperative right ventricular dysfunction CURRENT OPINION IN ANESTHESIOLOGY Denault, A. Y., Haddad, F., Jacobsohn, E., Deschamps, A. 2013; 26 (1): 71-81

  Abstract

  To evaluate new information on the importance of right ventricular function, diagnosis and management in cardiac surgical patients.There is growing evidence that right ventricular function is a key determinant in survival in cardiac surgery, particularly in patients with pulmonary hypertension. The diagnosis of this condition is helped by the use of specific hemodynamic parameters and echocardiography. In that regard, international consensus guidelines on the echocardiographic assessment of right ventricular function have been recently published. New monitoring modalities in cardiac surgery such as regional near-infrared spectroscopy can also assist management. Management of right ventricular failure will be influenced by the presence or absence of myocardial ischemia and left ventricular dysfunction. The differential diagnosis and management will be facilitated using a systematic approach.The use of right ventricular pressure monitoring and the publications of guidelines for the echocardiographic assessment of right ventricular anatomy and function allow the early identification of right ventricular failure. The treatment success will be associated by optimization of the hemodynamic, echocardiographic and near-infrared spectroscopy parameters.

  View details for DOI 10.1097/ACO.0b013e32835b8be2

  View details for Web of Science ID 000312953900012

  View details for PubMedID 23235519

• Right-ventricular failure following left ventricle assist device implantation CURRENT OPINION IN CARDIOLOGY Patlolla, B., Beygui, R., Haddad, F. 2013; 28 (2): 223-233

  Abstract

  To review recent insights on right-ventricular failure (RVF) following left-ventricular assist device (LVAD) implantation.Even with the availability of new generation continuous mechanical assist devices, RVF after implantation of LVAD is still associated with high morbidity and mortality. Recent studies have tried to better define the risk of RVF using combined clinical scores and measures of right-ventricular function or strain. Small exploratory studies have also investigated the role of pulmonary vasodilators and phosphodiesterase inhibitors in selected patients receiving LVAD implantation.Measure of right-ventricular function could improve the risk stratification of RVF following LVAD implantation. Future multicenter studies are needed to validate right-ventricular risk scores and to develop evidence-guided preventive and therapeutic strategies.

  View details for DOI 10.1097/HCO.0b013e32835dd12c

  View details for Web of Science ID 000314811800018

  View details for PubMedID 23337895

• Stem cell therapy in patients with heart failure. Methodist DeBakey cardiovascular journal Vrtovec, B., Poglajen, G., Haddad, F. 2013; 9 (1): 6-10

  Abstract

  Heart failure results from injury to the myocardium from a variety of causes, including ischemic and nonischemic etiologies. Severe heart failure carries a 50% 5-year mortality rate and is responsible for more than one-third of cardiovascular deaths in the United States.1 Heart failure progression is accompanied by activation of neurohormonal and cytokine systems as well as a series of adaptive changes within the myocardium, collectively referred to as left ventricular remodelling. The unfavorable alterations may be categorized broadly into changes that occur in the cardiac myocytes and changes that occur in the volume and composition of the extracellular matrix.2 Since remodelling in heart failure is progressive and eventually becomes detrimental, the majority of treatment strategies are aimed at stopping or reversing this process. Although medical management, cardiac resychronization therapy, and long-term or destination mechanical circulatory support have been successful in this regard, a considerable number of patients still progress to end-stage heart failure with limited therapeutic options. For these patients, stem cell therapies are being investigated as a safe treatment strategy for decreasing cardiac remodelling on top of conventional medical and device treatment.

  View details for PubMedID 23518819

• Comparison of Aortic Root Diameter to Left Ventricular Outflow Diameter Versus Body Surface Area in Patients With Marfan Syndrome AMERICAN JOURNAL OF CARDIOLOGY Shiran, H., Haddad, F., Miller, D. C., Liang, D. 2012; 110 (10): 1518-1522

  Abstract

  Aortic root dilation is important in the diagnosis of familial aortic syndromes, such as Marfan syndrome, and an important risk factor for aortic complications, such as dissection or rupture. Transthoracic echocardiography reliably measures the absolute aortic root size; however, the degree of abnormality of the measurement requires correction for the expected normal aortic root size for each patient. The expected normal size is currently predicted according to the body surface area (BSA) and age. However, the correlation between root size and BSA is imperfect, particularly for older patients. A potential exists to improve the diagnosis and treatment of patients with aortic disease, with an improved estimation of normal aortic root size. A reference size derived from within the cardiovascular system has been hypothesized to provide a more direct correlation with the aortic root size. Images from the Stanford echocardiography database were reviewed, and measurements of the aortic root and internal dimensions were performed in a control cohort (n = 150). The measurements were repeated in adult patients with Marfan syndrome (n = 70) on serial echocardiograms (145 total studies reviewed). Of the 150 control patients, excellent correlation was found between the aortic root and left ventricular outflow tract diameters, r(2) = 0.67, and r(2) = 0.34 with BSA (p <0.0001, for both). More importantly, using the left ventricular outflow tract to predict the normal aortic root size, instead of the BSA and age, improved the diagnostic accuracy of aortic root measurements for diagnosing Marfan syndrome. In conclusion, an internal cardiovascular reference, the left ventricular outflow tract diameter, can improve the diagnosis of aortic disease and might provide a better reference for the degree of abnormality.

  View details for DOI 10.1016/j.amjcard.2012.06.062

  View details for Web of Science ID 000311523900021

  View details for PubMedID 22858189

• Clinical and Functional Correlates of Early Microvascular Dysfunction After Heart Transplantation CIRCULATION-HEART FAILURE Haddad, F., Khazanie, P., Deuse, T., Weisshaar, D., Zhou, J., Nam, C. W., Vu, T. A., Gomari, F. A., Skhiri, M., Simos, A., Schnittger, I., Vrotvec, B., Hunt, S. A., Fearon, W. F. 2012; 5 (6): 759-768

  Abstract

  Microvascular dysfunction is emerging as a strong predictor of outcome in heart transplant recipients. At this time, the determinants and consequences of early microvascular dysfunction are not well established. The objective of the study was to determine the risk factors and functional correlates associated with early microvascular dysfunction in heart transplant recipients.Sixty-three heart transplant recipients who had coronary physiology assessment, right heart catheterization, and echocardiography performed at the time of their first annual evaluation were included in the study. Microvascular dysfunction was assessed using the recently described index of microcirculatory resistance. The presence of microvascular dysfunction, predefined by an index of microcirculatory resistance >20, was observed in 46% of patients at 1 year. A history of acute rejection and undersized donor hearts were associated with microvascular dysfunction at 1 year, with odds ratio of 4.0 (1.3-12.8) and 3.6 (1.2-11.1), respectively. Patients with microvascular dysfunction had lower cardiac index (3.1±0.7 versus 3.5±0.7 L/min per m(2); P=0.02) and mild graft dysfunction measured by echocardiography-derived left and right myocardial performance indices ([0.54±0.09 versus 0.43±0.09; P<0.01] and [0.47±0.14 versus 0.32±0.05; P<0.01], respectively). Microvascular dysfunction was also associated with a higher likelihood of death, graft failure, or allograft vasculopathy at 5 years after transplant (hazard ratio, 2.52 [95% CI, 1.04-5.91]).A history of acute rejection during the first year and smaller donor hearts were identified as risk factors for early microvascular dysfunction. Microvascular dysfunction assessed using index of microcirculatory resistances at 1 year was also associated with worse graft function and possibly worse clinical outcomes.

  View details for DOI 10.1161/CIRCHEARTFAILURE.111.962787

  View details for PubMedID 22933526

• Pulmonary Hypertension A Stage for Ventricular Interdependence? JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Hsia, H. H., Haddad, F. 2012; 59 (24): 2203-2205

  View details for DOI 10.1016/j.jacc.2011.12.049

  View details for Web of Science ID 000304932500011

  View details for PubMedID 22676941

• The Intersection of Genes and Environment Development of Pulmonary Arterial Hypertension in a Patient With Hereditary Hemorrhagic Telangiectasia and Stimulant Exposure CHEST Ayala, E., Kudelko, K. T., Haddad, F., Zamanian, R. T., Perez, V. d. 2012; 141 (6): 1598-1600

  Abstract

  Pulmonary arterial hypertension (PAH) is a rare complication of hereditary hemorrhagic telangiectasia (HHT). The triggers that promote the development of PAH in HHT remain poorly understood. We present the case of a 45-year-old woman with decompensated right-sided heart failure secondary to newly diagnosed PAH. The clinical diagnosis of HHT was confirmed on the basis of recurrent spontaneous epistaxis, multiple typical mucocutaneous telangiectasia, and the presence of pulmonary arteriovenous malformation. There was also a suggestive family history. The patient was discovered to have active and extensive stimulant abuse in addition to HHT. We concluded that there may be a temporal relationship between exposure to stimulants and development of PAH in a host with underlying gene mutation. This case highlights the paradigm of PAH development after environmental exposure in a genetically susceptible host.

  View details for DOI 10.1378/chest.11-1402

  View details for Web of Science ID 000305039300054

  View details for PubMedID 22670022

  View details for PubMedCentralID PMC3367481

• Diagnosis and management of pulmonary hypertension associated with left ventricular diastolic dysfunction. Pulmonary circulation Perez, V. A., Haddad, F., Zamanian, R. T. 2012; 2 (2): 163-169

  Abstract

  Pulmonary hypertension (PH) is commonly seen in patients who present with left ventricular diastolic dysfunction (LVDD) and is considered a marker of poor prognosis. While PH in this setting is thought to result from pulmonary venous congestion, there is a subset of patients in which pulmonary pressures fail to improve with appropriate management of diastolic heart failure and go on to develop a clinical picture similar to that of patients with pulmonary arterial hypertension (PAH). Despite the utility of Doppler echocardiography and exercise testing in the initial evaluation of patients with suspected PH-LVDD, the diagnosis can only be confirmed using right heart catheterization. Management of PH-LVDD centers on both optimizing fluid management and afterload reduction to reducing left ventricular diastolic pressures and also increase pulmonary venous return. To date, there is no clear evidence that addition of PH-specific drugs can improve clinical outcomes, and their use should only be considered in the setting of clinical trials. In conclusion, PH-LVDD remains a challenging clinical entity that complicates the management of left ventricular dysfunction and significantly contributes to its morbidity and mortality. Determination of the optimal diagnostic and treatment strategies for this form of PH should be the goal of future studies.

  View details for DOI 10.4103/2045-8932.97598

  View details for PubMedID 22837857

• Cardiac Paraganglioma: Diagnostic and Surgical Challenges JOURNAL OF CARDIAC SURGERY Huo, J. L., Choi, J. C., DeLuna, A., Lee, D., Fleischmann, D., Berry, G. J., Deuse, T., Haddad, F. 2012; 27 (2): 178-182

  Abstract

  Primary cardiac paragangliomas are rare extra-adrenal tumors. Though they account for less than 1% of all primary cardiac tumors, they are considerable sources of morbidity and mortality. In this case review, we discuss the challenges associated with the diagnosis and management of cardiac paragangliomas.

  View details for DOI 10.1111/j.1540-8191.2011.01378.x

  View details for Web of Science ID 000302172800009

  View details for PubMedID 22273468

• Endothelial progenitor cells in cardiovascular disease and chronic inflammation: from biomarker to therapeutic agent BIOMARKERS IN MEDICINE Grisar, J. C., Haddad, F., Gomari, F. A., Wu, J. C. 2011; 5 (6): 731-744

  Abstract

  The discovery of endothelial progenitor cells in the 1990s challenged the paradigm of angiogenesis by showing that cells derived from hematopoietic stem cells are capable of forming new blood vessels even in the absence of a pre-existing vessel network, a process termed vasculogenesis. Since then, the majority of studies in the field have found a strong association between circulating endothelial progenitor cells and cardiovascular risk. Several studies have also reported that inflammation influences the mobilization and differentiation of endothelial progenitor cells. In this review, we discuss the emerging role of endothelial progenitor cells as biomarkers of cardiovascular disease as well as the interplay between inflammation and endothelial progenitor cell biology. We will also review the challenges in the field of endothelial progenitor cell-based therapy.

  View details for DOI 10.2217/BMM.11.92

  View details for Web of Science ID 000298488200005

  View details for PubMedID 22103609

  View details for PubMedCentralID PMC3285378

• Quantitative Comparison of Microcirculatory Dysfunction in Patients With Stress Cardiomyopathy and ST-Segment Elevation Myocardial Infarction JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Kim, H., Tremmel, J. A., Nam, C., Zhou, J., Haddad, F., Vagelos, R. H., Lee, D. P., Yeung, A. C., Fearon, W. F. 2011; 58 (23): 2430-2431

  View details for DOI 10.1016/j.jacc.2011.08.046

  View details for Web of Science ID 000297319700016

  View details for PubMedID 22115653

• Characteristics and Outcome After Hospitalization for Acute Right Heart Failure in Patients With Pulmonary Arterial Hypertension CIRCULATION-HEART FAILURE Haddad, F., Peterson, T., Fuh, E., Kudelko, K. T., Perez, V. D., Skhiri, M., Vagelos, R., Schnittger, I., Denault, A. Y., Rosenthal, D. N., Doyle, R. L., Zamanian, R. T. 2011; 4 (6): 692-699

  Abstract

  Although much is known about the risk factors for poor outcome in patients hospitalized with acute heart failure and left ventricular dysfunction, much less is known about the syndrome of acute heart failure primarily affecting the right ventricle (acute right heart failure).By using Stanford Hospital's pulmonary hypertension database, we identified consecutive acute right heart failure hospitalizations in patients with PAH. We used longitudinal regression analysis with the generalized estimating equations method to identify factors associated with an increased likelihood of 90-day mortality or urgent transplantation. From June 1999 to September 2009, 119 patients with PAH were hospitalized for acute right heart failure (207 episodes). Death or urgent transplantation occurred in 34 patients by 90 days of admission. Multivariable analysis identified a higher respiratory rate on admission (>20 breaths per minute; OR, 3.4; 95% CI, 1.5-7.8), renal dysfunction on admission (glomerular filtration rate <45 mL/min per 1.73 m2; OR, 2.7; 95% CI, 1.2-6.3), hyponatremia (serum sodium ≤136 mEq/L; OR, 3.6; 95% CI, 1.7-7.9), and tricuspid regurgitation severity (OR, 2.5 per grade; 95% CI, 1.2-5.5) as independent factors associated with an increased likelihood of death or urgent transplantation.These results highlight the high mortality after hospitalizations for acute right heart failure in patients with PAH. Factors identifiable within hours of hospitalization may help predict the likelihood of death or the need for urgent transplantation in patients with PAH.

  View details for DOI 10.1161/CIRCHEARTFAILURE.110.949933

  View details for PubMedID 21908586

• Pulmonary Hypertension Associated With Left Heart Disease: Characteristics, Emerging Concepts, and Treatment Strategies PROGRESS IN CARDIOVASCULAR DISEASES Haddad, F., Kudelko, K., Mercier, O., Vrtovec, B., Zamanian, R. T., Perez, V. D. 2011; 54 (2): 154-167

  Abstract

  Left heart disease (LHD) represents the most common causes of pulmonary hypertension (PH). Whether caused by systolic or diastolic dysfunction or valvular heart disease, a hallmark of PH associated with LHD is elevated left atrial pressure. In all cases, the increase in left atrial pressure causes a passive increase in pulmonary pressure. In some patients, a superimposed active component caused by pulmonary arterial vasoconstriction and vascular remodeling may lead to a further increase in pulmonary arterial pressure. When present, PH is associated with a worse prognosis in patients with LHD. In addition to local abnormalities in nitric oxide and endothelin production, gene modifiers such as serotonin polymorphisms may be associated with the pathogenesis of PH in LHD. Optimizing heart failure regimens and corrective valve surgery represent the cornerstone of the treatment of PH in LHD. Recent studies suggest that sildenafil, a phosphodiesterase-5 inhibitor, is a promising agent in the treatment of PH in LHD. Unloading the left ventricle with circulatory support may also reverse severe PH in patients with end-stage heart failure allowing candidacy to heart transplantation.

  View details for DOI 10.1016/j.pcad.2011.06.003

  View details for Web of Science ID 000294880400009

  View details for PubMedID 21875514

• Incidence, Correlates, and Consequences of Acute Kidney Injury in Patients With Pulmonary Arterial Hypertension Hospitalized With Acute Right-Side Heart Failure JOURNAL OF CARDIAC FAILURE Haddad, F., Fuh, E., Peterson, T., Skhiri, M., Kudelko, K. T., Perez, V. D., Winkelmayer, W. C., Doyle, R. L., Chertow, G. M., Zamanian, R. T. 2011; 17 (7): 533-539

  Abstract

  Though much is known about the prognostic influence of acute kidney injury (AKI) in left-side heart failure, much less is known about AKI in patients with pulmonary arterial hypertension (PAH).We identified consecutive patients with PAH who were hospitalized at Stanford Hospital for acute right-side heart failure. AKI was diagnosed according to the criteria of the Acute Kidney Injury Network. From June 1999 to June 2009, 105 patients with PAH were hospitalized for acute right-side heart failure (184 hospitalizations). AKI occurred in 43 hospitalizations (23%) in 34 patients (32%). The odds of developing AKI were higher among patients with chronic kidney disease (odds ratio [OR] 3.9, 95% confidence interval [CI] 1.8-8.5), high central venous pressure (OR 1.8, 95% CI 1.1-2.4, per 5 mm Hg), and tachycardia on admission (OR 4.3, 95% CI 2.1-8.8). AKI was strongly associated with 30-day mortality after acute right-side heart failure hospitalization (OR 5.3, 95% CI 2.2-13.2).AKI is relatively common in patients with PAH and associated with a short-term risk of death.

  View details for DOI 10.1016/j.cardfail.2011.03.003

  View details for PubMedID 21703524

• Effects of Intracoronary Stem Cell Transplantation in Patients With Dilated Cardiomyopathy JOURNAL OF CARDIAC FAILURE Vrtovec, B., Poglajen, G., Sever, M., Lezaic, L., Domanovic, D., Cernelc, P., Haddad, F., Torre-Amione, G. 2011; 17 (4): 272-281

  Abstract

  We investigated clinical effects of intracoronary transplantation of CD34+ cells in patients with dilated cardiomyopathy (DCM).Of 55 patients with DCM, 28 were randomized to CD34+ transplantation (SC group), and 27 patients did not receive stem cell therapy (controls). In the SC group, peripheral blood CD34+ cells were mobilized by granulocyte-colony stimulating factor and collected via apheresis. Patients underwent myocardial scintigraphy and CD34+ cells were injected in the coronary artery supplying the segments with reduced viability.At baseline, the 2 groups did not differ in age, gender, left ventricular ejection fraction (LVEF), or NT-proBNP levels. At 1 year, stem cell therapy was associated with an increase in LVEF (from 25.5 ± 7.5% to 30.1 ± 6.7%; P = .03), an increase in 6-minute walk distance (from 359 ± 104 m to 485 ± 127 m; P = .001), and a decrease in NT-proBNP (from 2069 ± 1996 pg/mL to 1037 ± 950 pg/mL; P = .01). The secondary endpoint of 1-year mortality or heart transplantation was lower in patients receiving SC therapy (2/28, 7%) than in controls (8/27, 30%) (P = .03), and SC therapy was the only independent predictor of outcome on multivariable analysis (P = .04).Intracoronary stem cell transplantation could lead to improved ventricular remodeling, better exercise tolerance and potentially improved survival in patients with DCM.

  View details for DOI 10.1016/j.cardfail.2010.11.007

  View details for Web of Science ID 000289318500002

  View details for PubMedID 21440864

• Stress-induced cardiomyopathy associated with a transfusion reaction: A case of potential crosstalk between the histaminic and adrenergic systems EXPERIMENTAL & CLINICAL CARDIOLOGY Zhou, J. Q., Choe, E., Ang, L., Schnittger, I., Rockson, S. G., Tremmel, J. A., Haddad, F. 2011; 16 (1): 30-32

  Abstract

  The adrenergic and histaminergic systems have been reported to have analogous effects on the heart. A case of transient ventricular dysfunction with echocardiographic findings characteristic of stress-induced cardiomyopathy (also known as takotsubo cardiomyopathy) in a patient who had an urticarial transfusion reaction is described. The effect of histamine on ventricular function and its interaction with the adrenergic system are discussed.

  View details for Web of Science ID 000300518800008

  View details for PubMedID 21523205

  View details for PubMedCentralID PMC3076164

• The concept of ventricular reserve in heart failure and pulmonary hypertension: an old metric that brings us one step closer in our quest for prediction CURRENT OPINION IN CARDIOLOGY Haddad, F., Vrtovec, B., Ashley, E. A., Deschamps, A., Haddad, H., Denault, A. Y. 2011; 26 (2): 123-131

  Abstract

  Ventricular reserve is emerging a strong predictor of outcome in heart failure and cardiovascular disease. Ventricular reserve is the term used to describe the extent of increase or change in ventricular function that occurs during exercise or pharmacological stress (typically with dobutamine).The interest in ventricular reserve lies in its ability to assess viability in coronary artery disease, to predict clinical outcome and response to therapy in patients with heart failure and to screen patients for early cardiovascular disease.In this paper, we will review the emerging role of ventricular reserve in heart failure and pulmonary hypertension. We will also explore the mechanisms involved in the pathophysiology of impaired ventricular reserve and discuss future directions of research in the field.

  View details for DOI 10.1097/HCO.0b013e3283437485

  View details for Web of Science ID 000287189400008

  View details for PubMedID 21297465

• Cardiac myosin heavy chain gene regulation by thyroid hormone involves altered histone modifications AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Haddad, F., Jiang, W., Bodell, P. W., Qin, A. X., Baldwin, K. M. 2010; 299 (6): H1968-H1980

  Abstract

  The antithetical regulation of cardiac α- and β-myosin heavy chain (MHC) genes by thyroid hormone (T(3)) is not well understood but appears to involve thyroid hormone interaction with its nuclear receptor and MHC promoters as well as cis-acting noncoding regulatory RNA (ncRNA). Both of these phenomena involve epigenetic regulations. This study investigated the extent that altered thyroid state induces histone modifications in the chromatin associated with the cardiac MHC genes. We hypothesized that specific epigenetic events could be identified and linked to cardiac MHC gene switching in response to a hypothyroid or hyperthyroid state. A hypothyroid state was induced in rats by propylthiouracil treatment (PTU), whereas a hyperthyroid (T(3)) was induced by T(3) treatment. The left ventricle was analyzed after 7 days for MHC pre-mRNA expression, and the chromatin was assessed for enrichment in specific histone modifications using chromatin immunoprecipitation quantitative PCR assays. At both the α-MHC promoter and the intergenic region, the enrichment in acetyl histone H3 at K9/14 (H3K9/14ac) and trimethyl histone H3 at K4 (H3K4me3) changed in a similar fashion. They were both decreased with PTU treatment but did not change under T(3), except at a location situated 5' to the antisense intergenic transcription start site. These same marks varied differently on the β-MHC promoter. For example, H3K4me3 enrichment correlated with the β-promoter activity in PTU and T(3) groups, whereas H3K9/14ac was repressed in the T(3) group but did not change under PTU. Histone H3K9me was enriched in chromatin of both the intergenic and α-MHC promoters in the PTU group, whereas histone H4K20me1 was enriched in chromatin of β-MHC promoter in the normal control and T(3) groups. Collectively, these findings provide evidence that specific epigenetic phenomena modulate MHC gene expression in altered thyroid states.

  View details for DOI 10.1152/ajpheart.00644.2010

  View details for Web of Science ID 000284936600027

  View details for PubMedID 20833952

• Right ventricular failure: a novel era of targeted therapy. Current heart failure reports Banerjee, D., Haddad, F., Zamanian, R. T., Nagendran, J. 2010; 7 (4): 202-211

  Abstract

  There now is strong evidence to recognize the pivotal role of the right ventricle (RV) in heart disease and to establish it as a unique and separate entity than the left ventricle (LV). Here, we summarize the differences between the two ventricles, the diagnosis of RV failure, and the management of acute and chronic RV failure. We review the indices derived by echocardiography used to measure RV function, and novel biomarkers that may play a role diagnosing and prognosticating in RV-specific disease. There are new novel therapies that specifically target the RV in disease. For example, phosphodiesterase type 5 inhibitors improve contractility of the hypertrophied RV while sparing the normal LV in pulmonary arterial hypertension. The metabolism of the hypertrophied RV is another area for therapeutic exploitation by metabolic modulation. We also suggest future potential molecular targets that may be unique to the RV because they are upregulated in RV hypertrophy greater than in LV hypertrophy.

  View details for DOI 10.1007/s11897-010-0031-7

  View details for PubMedID 20890792

• Improved Screening for Aortic Root Dilation by Transthoracic Echocardiography Shiran, H., Haddad, F., Liang, D. LIPPINCOTT WILLIAMS & WILKINS. 2010

  View details for Web of Science ID 000208231602191

• Epoprostenol-associated pneumonitis: diagnostic use of a T-cell proliferation assay. journal of heart and lung transplantation Kudelko, K. T., Nadeau, K., Leung, A. N., Liu, J., Haddad, F., Zamanian, R. T., de Jesus Perez, V. 2010; 29 (9): 1071-1075

  Abstract

  We describe a case of severe drug-induced interstitial pneumonitis in a woman with idiopathic pulmonary arterial hypertension receiving epoprostenol confirmed by a drug T-cell proliferation assay. Proliferation assays were completed in our patient and in a healthy control. Isolated T cells were incubated with CD3-depleted peripheral blood mononuclear cells and then stimulated to proliferate with (3)H-thymidine in the presence of epoprostenol, other prostanoid analogs, and controls. A significant (p < 0.001) T-cell proliferation response occurred in our patient in the presence of epoprostenol alone. There was a trend towards an increased T-cell response to treprostinil but this was statistically insignificant. There was no significant T-cell response to the diluent alone, normal saline, iloprost, or alprostadil. There was no significant proliferation to any drug in the healthy control. Hence, a drug T-cell proliferation assay confirmed that epoprostenol can rarely incite a profound inflammatory response in the pulmonary interstitium.

  View details for DOI 10.1016/j.healun.2010.04.023

  View details for PubMedID 20627625

  View details for PubMedCentralID PMC2926193

• Epoprostenol-associated pneumonitis: Diagnostic use of a T-cell proliferation assay JOURNAL OF HEART AND LUNG TRANSPLANTATION Kudelko, K. T., Nadeau, K., Leung, A. N., Liu, J., Haddad, F., Zamanian, R. T., Perez, V. D. 2010; 29 (9): 1071-1075

  Abstract

  We describe a case of severe drug-induced interstitial pneumonitis in a woman with idiopathic pulmonary arterial hypertension receiving epoprostenol confirmed by a drug T-cell proliferation assay. Proliferation assays were completed in our patient and in a healthy control. Isolated T cells were incubated with CD3-depleted peripheral blood mononuclear cells and then stimulated to proliferate with (3)H-thymidine in the presence of epoprostenol, other prostanoid analogs, and controls. A significant (p < 0.001) T-cell proliferation response occurred in our patient in the presence of epoprostenol alone. There was a trend towards an increased T-cell response to treprostinil but this was statistically insignificant. There was no significant T-cell response to the diluent alone, normal saline, iloprost, or alprostadil. There was no significant proliferation to any drug in the healthy control. Hence, a drug T-cell proliferation assay confirmed that epoprostenol can rarely incite a profound inflammatory response in the pulmonary interstitium.

  View details for DOI 10.1016/j.healun.2010.04.023

  View details for Web of Science ID 000281494800016

  View details for PubMedCentralID PMC2926193

• Review of Heart-Lung Transplantation at Stanford ANNALS OF THORACIC SURGERY Deuse, T., Sista, R., Weill, D., Tyan, D., Haddad, F., Dhillon, G., Robbins, R. C., Reitz, B. A. 2010; 90 (1): 329-337

  Abstract

  Long-term survival after heart-lung transplantation was first achieved in 1981 at Stanford and a total of 217 heart-lung transplantations had been performed by June 2008. This review summarizes Stanford's cumulative experience with heart-lung transplantation, demonstrates the progress that has been made, and discusses past and persistent problems. Diagnostic tools and treatment options for infectious diseases and rejection have changed and patient survival markedly improved over the almost three decades. Eight patients lived longer than 20 years. Further options to treat infections and strategies to control bronchiolitis obliterans syndrome, the main causes of early and long-term mortality, respectively, are required to achieve routine long-term survival.

  View details for DOI 10.1016/j.athoracsur.2010.01.023

  View details for PubMedID 20609821

• Evidence-Based Management of Right Heart Failure: a Systematic Review of an Empiric Field REVISTA ESPANOLA DE CARDIOLOGIA Skhiri, M., Hunt, S. A., Denault, A. Y., Haddad, F. 2010; 63 (4): 451-471

  Abstract

  In recent years, several studies have shown that right ventricular function is an important predictor of survival in patients with congenital heart disease, pulmonary hypertension or left heart failure. Our understanding of right heart failure has improved considerably over the last two decades. In this review article, our objective was to provide a critical summary of the evidence underlying the management of right heart failure. A systematic review of the literature was performed using PubMed and the latest issue of the Cochrane Central Register of Controlled Trials to identify studies conducted between January 1975 and January 2010. The literature search encompassed observational studies, randomized controlled trials and meta-analyses. The evidence underlying the use of beta-blockade, angiotensin-converting enzyme inhibitors, inhaled nitric oxide, hydralazine, warfarin, and resynchronization therapy in right heart failure was systematically reviewed. Emerging new therapies, such as metabolic modulators, and the pearls and pitfalls of managing right heart failure are also discussed in the article.

  View details for Web of Science ID 000276217300011

  View details for PubMedID 20334811

• [Tratamiento basado en la evidencia de la insuficiencia cardiaca derecha: una revisión sistemática de un campo empírico]. Revista española de cardiología (English ed.) Skhiri, M., Hunt, S. A., Denault, A. Y., Haddad, F. 2010; 63 (4): 451-471

  Abstract

  In recent years, several studies have shown that right ventricular function is an important predictor of survival in patients with congenital heart disease, pulmonary hypertension or left heart failure. Our understanding of right heart failure has improved considerably over the last two decades. In this review article, our objective was to provide a critical summary of the evidence underlying the management of right heart failure. A systematic review of the literature was performed using PubMed and the latest issue of the Cochrane Central Register of Controlled Trials to identify studies conducted between January 1975 and January 2010. The literature search encompassed observational studies, randomized controlled trials and meta-analyses. The evidence underlying the use of beta-blockade, angiotensinconverting enzyme inhibitors, inhaled nitric oxide, hydralazine, warfarin, and resynchronization therapy in right heart failure was systematically reviewed. Emerging new therapies, such as metabolic modulators, and the perils and pitfalls of managing right heart failure are also discussed in the article.

  View details for DOI 10.1016/S1885-5857(10)70094-3

  View details for PubMedID 24776472

• Risk Factors Predictive of Right Ventricular Failure After Left Ventricular Assist Device Implantation AMERICAN JOURNAL OF CARDIOLOGY Drakos, S. G., Janicki, L., Horne, B. D., Kfoury, A. G., Reid, B. B., Clayson, S., Horton, K., Haddad, F., Li, D. Y., Renlund, D. G., Fisher, P. W. 2010; 105 (7): 1030-1035

  Abstract

  Right ventricular failure (RVF) after left ventricular assist device (LVAD) implantation appears to be associated with increased mortality. However, the determination of which patients are at greater risk of developing postoperative RVF remains controversial and relatively unknown. We sought to determine the preoperative risk factors for the development of RVF after LVAD implantation. The data were obtained for 175 consecutive patients who had received an LVAD. RVF was defined by the need for inhaled nitric oxide for >/=48 hours or intravenous inotropes for >14 days and/or right ventricular assist device implantation. An RVF risk score was developed from the beta coefficients of the independent variables from a multivariate logistic regression model predicting RVF. Destination therapy (DT) was identified as the indication for LVAD implantation in 42% of our patients. RVF after LVAD occurred in 44% of patients (n = 77). The mortality rates for patients with RVF were significantly greater at 30, 180, and 365 days after implantation compared to patients with no RVF. By multivariate logistic regression analysis, 3 preoperative factors were significantly associated with RVF after LVAD implantation: (1) a preoperative need for intra-aortic balloon counterpulsation, (2) increased pulmonary vascular resistance, and (3) DT. The developed RVF risk score effectively stratified the risk of RV failure and death after LVAD implantation. In conclusion, given the progressively growing need for DT, the developed RVF risk score, derived from a population with a large percentage of DT patients, might lead to improved patient selection and help stratify patients who could potentially benefit from early right ventricular assist device implantation.

  View details for DOI 10.1016/j.amjcard.2009.11.026

  View details for Web of Science ID 000276576200023

  View details for PubMedID 20346326

• Changing trends in infectious disease in heart transplantation JOURNAL OF HEART AND LUNG TRANSPLANTATION Haddad, F., Deuse, T., Pham, M., Khazanie, P., Rosso, F., Luikart, H., Valantine, H., Leon, S., Vu, T. A., Hunt, S. A., Oyer, P., Montoya, J. G. 2010; 29 (3): 306-315

  Abstract

  During the past 25 years, advances in immunosuppression and the use of selective anti-microbial prophylaxis have progressively reduced the risk of infection after heart transplantation. This study presents a historical perspective of the changing trends of infectious disease after heart transplantation.Infectious complications in 4 representative eras of immunosuppression and anti-microbial prophylaxis were analyzed: (1) 38 in the pre-cyclosporine era (1978-1980), (2) 72 in the early cyclosporine era (1982-1984), where maintenance immunosuppression included high-dose cyclosporine and corticosteroid therapy; (3) 395 in the cyclosporine era (1988-1997), where maintenance immunosuppression included cyclosporine, azathioprine, and lower corticosteroid doses; and (4) 167 in the more recent era (2002-2005), where maintenance immunosuppression included cyclosporine and mycophenolate mofetil.The overall incidence of infections decreased in the 4 cohorts from 3.35 episodes/patient to 2.03, 1.35, and 0.60 in the more recent cohorts (p < 0.001). Gram-positive bacteria are emerging as the predominant cause of bacterial infections (28.6%, 31.4%, 51.0%, 67.6%, p = 0.001). Cytomegalovirus infections have significantly decreased in incidence and occur later after transplantation (88 +/- 77 days, pre-cyclosporine era; 304 +/- 238 days, recent cohort; p < 0.001). Fungal infections also decreased, from an incidence of 0.29/patient in the pre-cyclosporine era to 0.08 in the most recent era. A major decrease in Pneumocystis jiroveci and Nocardia infections has also occurred.The overall incidence and mortality associated with infections continues to decrease in heart transplantation and coincides with advances in immunosuppression, the use of selective anti-microbial prophylaxis, and more effective treatment regimens.

  View details for DOI 10.1016/j.healun.2009.08.018

  View details for PubMedID 19853478

• New insights for the diagnosis and management of right ventricular failure, from molecular imaging to targeted right ventricular therapy CURRENT OPINION IN CARDIOLOGY Haddad, F., Ashley, E., Michelakis, E. D. 2010; 25 (2): 131-140

  Abstract

  Despite the recognition of a critical role of the right ventricle (RV) in many aspects of cardiovascular medicine, there has been surprisingly little interest in right ventricular-targeted imaging and therapeutic approaches. Compared with the left ventricle, the RV has a different embryologic origin, undergoes a dramatic change during the transition from the fetal to the adult circulation and normally operates in a low resistance or impedance arterial system. Here, we review new insights on the pathophysiology, assessment and management of right ventricular failure.Our understanding of the mechanisms underlying right ventricular failure has improved. As in the left ventricle, decrease in alpha-myosin heavy chain and a switch towards glycolysis from fatty acid oxidation is observed in the stressed RV, but the key question remains unanswered: why is the RV so much more vulnerable to failure upon afterload increase compared with the left ventricle? In assessing the RV, it is becoming increasingly important to consider the RV and pulmonary artery as a unit. New therapies that could specifically target the RV, such as metabolic modulators and phosphodiesterase type 5 inhibitors, are now being considered.A better understanding of the molecular mechanisms of right ventricular failure will lead to the development of new strategies for the diagnosis and management of right ventricular failure. Right ventricular-targeted therapies are needed in a number of diseases in which only the RV fails.

  View details for DOI 10.1097/HCO.0b013e328335febd

  View details for Web of Science ID 000274797100010

  View details for PubMedID 20130456

• Calcineurin plays a modulatory role in loading-induced regulation of type I myosin heavy chain gene expression in slow skeletal muscle AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Pandorf, C. E., Jiang, W. H., Qin, A. X., Bodell, P. W., Baldwin, K. M., Haddad, F. 2009; 297 (4): R1037-R1048

  Abstract

  The role of calcineurin (Cn) in skeletal muscle fiber-type expression has been a subject of great interest because of reports indicating that it controls the slow muscle phenotype. To delineate the role of Cn in phenotype remodeling, particularly its role in driving expression of the type I myosin heavy chain (MHC) gene, we used a novel strategy whereby a profound transition from fast to slow fiber type is induced and examined in the absence and presence of cyclosporin A (CsA), a Cn inhibitor. To induce the fast-to-slow transition, we first subjected rats to 7 days of hindlimb suspension (HS) + thyroid hormone [triiodothyronine (T(3))] to suppress nearly all expression of type I MHC mRNA in the soleus muscle. HS + T(3) was then withdrawn, and rats resumed normal ambulation and thyroid state, during which vehicle or CsA (30 mg x kg(-1) x day(-1)) was administered for 7 or 14 days. The findings demonstrate that, despite significant inhibition of Cn, pre-mRNA, mRNA, and protein abundance of type I MHC increased markedly during reloading relative to HS + T(3) (P < 0.05). Type I MHC expression was, however, attenuated by CsA compared with vehicle treatment. In addition, type IIa and IIx MHC pre-mRNA, mRNA, and relative protein levels were increased in Cn-treated compared with vehicle-treated rats. These findings indicate that Cn has a modulatory role in MHC transcription, rather than a role as a primary regulator of slow MHC gene expression.

  View details for DOI 10.1152/ajpregu.00349.2009

  View details for Web of Science ID 000270184100014

  View details for PubMedID 19657098

• A Novel Non-Invasive Method of Estimating Pulmonary Vascular Resistance in Patients With Pulmonary Arterial Hypertension JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY Haddad, F., Zamanian, R., Beraud, A., Schnittger, I., Feinstein, J., Peterson, T., Yang, P., Doyle, R., Rosenthal, D. 2009; 22 (5): 523-529

  Abstract

  The assessment of pulmonary vascular resistance (PVR) plays an important role in the diagnosis and management of pulmonary arterial hypertension (PAH). The main objective of this study was to determine whether the noninvasive index of systolic pulmonary arterial pressure (SPAP) to heart rate (HR) times the right ventricular outflow tract time-velocity integral (TVI(RVOT)) (SPAP/[HR x TVI(RVOT)]) provides clinically useful estimations of PVR in PAH.Doppler echocardiography and right-heart catheterization were performed in 51 consecutive patients with established PAH. The ratio of SPAP/(HR x TVI(RVOT)) was then correlated with invasive indexed PVR (PVRI) using regression and Bland-Altman analysis. Using receiver operating characteristic curve analysis, a cutoff value for the Doppler equation was generated to identify patients with PVRI > or = 15 Wood units (WU)/m2.The mean pulmonary arterial pressure was 52 +/- 15 mm Hg, the mean cardiac index was 2.2 +/- 0.6 L/min/m2, and the mean PVRI was 20.5 +/- 9.6 WU/m2. The ratio of SPAP/(HR x TVI(RVOT)) correlated very well with invasive PVRI measurements (r = 0.860; 95% confidence interval, 0.759-0.920). A cutoff value of 0.076 provided well-balanced sensitivity (86%) and specificity (82%) to determine PVRI > 15 WU/m2. A cutoff value of 0.057 increased sensitivity to 97% and decreased specificity to 65%.The novel index of SPAP/(HR x TVI(RVOT)) provides useful estimations of PVRI in patients with PAH.

  View details for DOI 10.1016/j.echo.2009.01.021

  View details for PubMedID 19307098

• The Efficacy of Implantable Cardioverter-Defibrillators in Heart Transplant Recipients Results From a Multicenter Registry CIRCULATION-HEART FAILURE Tsai, V. W., Cooper, J., Garan, H., Natale, A., Ptaszek, L. M., Ellinor, P. T., Hickey, K., Downey, R., Zei, P., Hsia, H., Wang, P., Hunt, S., Haddad, F., Al-Ahmad, A. 2009; 2 (3): 197-201

  Abstract

  Sudden cardiac death among orthotopic heart transplant recipients is an important mechanism of death after cardiac transplantation. The role for implantable cardioverter-defibrillators (ICDs) in this population is not well established. This study sought to determine whether ICDs are effective in preventing sudden cardiac death in high-risk heart transplant recipients.We retrospectively analyzed the records of all orthotopic heart transplant patients who had ICD implantation between January 1995 and December 2005 at 5 heart transplant centers. Thirty-six patients were considered high risk for sudden cardiac death. The mean age at orthotopic heart transplant was 44+/-14 years, the majority being male (n=29). The mean age at ICD implantation was 52+/-14 years, whereas the average time from orthotopic heart transplant to ICD implant was 8 years +/-6 years. The main indications for ICD implantation were severe allograft vasculopathy (n=12), unexplained syncope (n=9), history of cardiac arrest (n=8), and severe left ventricular dysfunction (n=7). Twenty-two shocks were delivered to 10 patients (28%), of whom 8 (80%) received 12 appropriate shocks for either rapid ventricular tachycardia or ventricular fibrillation. The shocks were effective in terminating the ventricular arrhythmias in all cases. Three (8%) patients received 10 inappropriate shocks. Underlying allograft vasculopathy was present in 100% (8 of 8) of patients who received appropriate ICD therapy.Use of ICDs after heart transplantation may be appropriate in selected high-risk patients. Further studies are needed to establish an appropriate prevention strategy in this population.

  View details for DOI 10.1161/CIRCHEARTFAILURE.108.814525

  View details for Web of Science ID 000269161600007

  View details for PubMedID 19808340

• Angina Associated With Left Main Coronary Artery Compression in Pulmonary Hypertension JOURNAL OF HEART AND LUNG TRANSPLANTATION Perez, V. A., Haddad, F., Vagelos, R. H., Fearon, W., Feinstein, J., Zamanian, R. T. 2009; 28 (5): 527-530

  Abstract

  Chest pain is a common complaint in patients with pulmonary arterial hypertension (PAH). Left main coronary artery (LMCA) compression by an enlarged pulmonary artery trunk (PAT) has been associated with angina, but appropriate diagnostic and treatment approaches remain poorly defined. We present two cases of angina caused by LMCA compression from an enlarged pulmonary artery, one of which also presented with new, severe left ventricular systolic dysfunction attributed to myocardial ischemia. Diagnosis of LMCA stenosis was made via coronary angiography followed by computed tomography-gated coronary angiography (CT-CA), which confirmed pulmonary artery enlargement as the source of extrinsic compression. Restoring LMCA patency with percutaneous intervention and/or aggressive treatment of pulmonary hypertension led to significant improvement in angina, cardiac function and quality of life. Given the negative impact on cardiac function, prompt diagnosis and treatment of extrinsic LMCA compression should be considered a priority.

  View details for DOI 10.1016/j.healun.2008.12.008

  View details for PubMedID 19416787

• Right Ventricular Dysfunction Predicts Poor Outcome Following Hemodynamically Compromising Rejection JOURNAL OF HEART AND LUNG TRANSPLANTATION Haddad, F., Fisher, P., Pham, M., Berry, G., Weisshaar, D., Kuppahally, S., Vrtovec, B., Deuse, T., Virani, S., Fearon, W., Valantine, H., Hunt, S. 2009; 28 (4): 312-319

  Abstract

  Hemodynamically compromising rejection (HCR) is a major cause of mortality and morbidity after heart transplantation. Right ventricular (RV) function is a strong predictor of outcome in patients with heart failure and myocarditis. The objective of the current study is to determine whether RV dysfunction predicts event-free survival in patients with HCR.Medical records of 548 heart transplant patients followed at Stanford University between January 1998 and January 2007 were reviewed. HCR was defined as a rejection episode requiring hospitalization for heart failure. Univariate and multivariate analyses were performed to identify risk factors for death or retransplantation at 1 year.HCR occurred in 71 patients (12.9%). Death or retransplantation at 1 year occurred in 28 patients (39%). Univariate analysis identified non-cellular rejection (odds ratio [OR] = 3.20, p = 0.021), the need for inotropic support (OR = 4.80, p = 0.007), RV dysfunction (OR = 4.63, p = 0.006), left ventricular ejection fraction (OR = 0.941, p = 0.031) and acute renal failure (OR = 3.82, p = 0.010) as predictors of death or retransplantation at 1 year. Multivariate analysis identified RV dysfunction (OR = 4.80, p = 0.007) and the need for inotropic support (OR = 5.00, p = 0.009) as predictors of death or retransplantation at 1 year.In the modern era of immunosuppression, HCR remains a major complication after heart transplantation. RV dysfunction was identified as a novel risk factor for death or retransplantation following HCR.

  View details for DOI 10.1016/j.healun.2008.12.023

  View details for PubMedID 19332256

• Microvascular Dysfunction and Suboptimal Glycemic Control Predicts Poor Outcome Following Heart Transplantation 58th Annual Scientific Session of the American-College-of-Cardiology Khazanie, P., Haddad, F., Simos, A. M., Pham, M., Weisshaar, D. M., Desai, S. V., Shah, M. G., McLaughlin, T. L., Hunt, S. A., Valantine, H. A., Fearon, W. ELSEVIER SCIENCE INC. 2009: A182–A182

  View details for Web of Science ID 000263864200760

• Diabetes Does Not Affect Ventricular Repolarization and Sudden Cardiac Death Risk in Patients with Dilated Cardiomyopathy PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY Vrtovec, B., Fister, M., Poglajen, G., Starc, V., Haddad, F. 2009; 32: S146-S150

  Abstract

  We studied the effects of diabetes on ventricular repolarization parameters and sudden cardiac death in patients with dilated cardiomyopathy (DCM).We enrolled 132 consecutive patients in New York Heart Association (NYHA) heart failure functional classes II or III and left ventricular ejection fraction <40% without evidence of coronary artery disease. In 45 patients (34%), diabetes was diagnosed according to standard criteria (study group), and the remaining 87 (66%) had no diabetes (controls). All patients underwent a 5-minute high-resolution electrocardiogram recording for determination of QT variability (QTV) index and were followed for 1 year thereafter.At baseline, the two groups did not differ in age, gender, left ventricular ejection fraction, NYHA functional class, or plasma brain natriuretic peptide levels. Similarly, QTV index did not differ between the study group (-0.51 +/- 0.55) and controls (-0.48 +/- 0.51; P = 0.48). During follow-up, 18 patients (14%) died of cardiac causes. Of the 18 deaths, eight were attributed to heart failure, and 10 to sudden cardiac death. Mortality was higher in the study group (10/45, 20%) than in controls (8/87, 10%) (P = 0.03). The same was true of the heart failure mortality (6/45 [13%] vs 2/87 [2%], P = 0.01), but not of the sudden cardiac death rate (3/45 [7%] vs 7/87 [8%], P = 0.78). By multiple variable analyses, diabetes predicted total and heart failure mortality, and a high QTV predicted sudden cardiac death.Diabetes appears to increase the risk of heart failure in patients with DCM without affecting ventricular repolarization parameters and sudden cardiac death risk.

  View details for Web of Science ID 000266562900034

  View details for PubMedID 19250080

• The Right Ventricle in Cardiac Surgery, a Perioperative Perspective: II. Pathophysiology, Clinical Importance, and Management ANESTHESIA AND ANALGESIA Haddad, F., Couture, P., Tousignant, C., Denault, A. Y. 2009; 108 (2): 422-433

  Abstract

  The importance of right ventricular (RV) function in cardiovascular disease and cardiac surgery has been recognized for several years. RV dysfunction has been shown to be a significant prognostic factor in cardiac surgery and heart transplantation. In the first article of this review, key features of RV anatomy, physiology, and assessment were presented. In this second part, we review the pathophysiology, clinical importance, and management of RV failure in cardiac surgery.

  View details for DOI 10.1213/ane.0b013e31818d8b92

  View details for Web of Science ID 000262590000005

  View details for PubMedID 19151265

• Changing Trends in Infectious Complications among Heart Transplant Recipients 29th Annual Meeting and Scientific Session of the International-Society-for-Heart-and-Lung-Transplantation Haddad, F., Deuse, T., Rosso, P., Pham, M., Khazanie, P., Luikart, H., Valantine, H. A., Hunt, S. A., Vu, T., Oyer, P. E., Robbins, R. C., Montoya, J. G. ELSEVIER SCIENCE INC. 2009: S237–S238

  View details for Web of Science ID 000263539800490

• Microvascular Drysfunction and Suboptimal Glycemic Control Predicts Poor Outcome Following Heart Transplantation 29th Annual Meeting and Scientific Session of the International-Society-for-Heart-and-Lung-Transplantation Khazanie, P., Haddad, F., Simos, A. M., Weissbaar, D. M., Desai, S. V., Pham, M., McLaugblin, T. L., Shah, M. G., Hunt, S. A., Valantine, H. A., Fearon, W. ELSEVIER SCIENCE INC. 2009: S228–S228

  View details for Web of Science ID 000263539800464

• The Right Ventricle in Cardiac Surgery, a Perioperative Perspective: I. Anatomy, Physiology, and Assessment ANESTHESIA AND ANALGESIA Haddad, F., Couture, P., Tousignant, C., Denault, A. Y. 2009; 108 (2): 407-421

  Abstract

  The importance of right ventricular (RV) function in cardiovascular disease and cardiac surgery has been recognized for several years. RV dysfunction has been shown to be a significant prognostic factor in heart failure, congenital heart disease, valvular disease, and cardiac surgery. In the first of our two articles, we will review key features of RV anatomy, physiology, and assessment. In the first article, the main discussion will be centered on the echographic assessment of RV structure and function. In the second review article, pathophysiology, clinical importance, and management of RV failure in cardiac surgery will be discussed.

  View details for DOI 10.1213/ane.0b013e31818f8623

  View details for Web of Science ID 000262590000004

  View details for PubMedID 19151264

• Intergenic transcription and developmental regulation of cardiac myosin heavy chain genes AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Haddad, F., Qin, A. X., Bodell, P. W., Jiang, W., Giger, J. M., Baldwin, K. M. 2008; 294 (1): H29-H40

  Abstract

  Cardiac myosin heavy chain (MHC) gene expression undergoes a rapid transition from beta- to alpha-MHC during early rodent neonatal development (0-21 days of age). Thyroid hormone (3,5,3'-triiodothyronine, T(3)) is a major player in this developmental shift; however, the exact mechanism underlying this transition is poorly understood. The goal of this study was to conduct a more thorough analysis of transcriptional activity of the cardiac MHC gene locus during the early postnatal period in the rodent, in order to gain further insight on the regulation of cardiac MHC genes. We analyzed the expression of alpha- and beta-MHC at protein, mRNA, and pre-mRNA levels at birth and 7, 10, 15, and 21 days after birth in euthyroid and hypothyroid rodents. Using novel technology, we also analyzed RNA expression across the cardiac gene locus, and we discovered that the intergenic (IG) region between the two cardiac genes possesses bidirectional transcriptional activity. This IG transcription results in an antisense RNA product as described previously, which is thought to exert an inhibitory effect on beta-MHC gene transcription. On the second half of the IG region, sense transcription occurs, resulting in expression of a sense IG RNA that merges with the alpha-MHC pre-mRNA. This sense IG RNA transcription was detected in the alpha-MHC gene promoter, approximately -1.8 kb relative to the alpha-MHC transcription start site. Both sense and antisense IG RNAs were developmentally regulated and responsive to a hypothyroid state (11, 14). This novel observation provides more complexity to the cooperative regulation of the two genes, suggesting the involvement of epigenetic processes in the regulation of cardiac MHC gene locus.

  View details for DOI 10.1152/ajpheart.01125.2007

  View details for Web of Science ID 000252261200007

  View details for PubMedID 17982008

• Outcome in cardiac recipients of donor hearts with increased left ventricular wall thickness AMERICAN JOURNAL OF TRANSPLANTATION Kuppahally, S. S., Valantine, H. A., Weisshaar, D., Parekh, H., Hung, Y. Y., Haddad, F., Fowler, M., Vagelos, R., Perlroth, M. G., Robbins, R. C., Hunt, S. A. 2007; 7 (10): 2388-2395

  Abstract

  The ongoing shortage of donors for cardiac transplantation has led to a trend toward acceptance of donor hearts with some structural abnormalities including left ventricular hypertrophy. To evaluate the outcome in recipients of donor hearts with increased left ventricular wall thickness (LVWT), we retrospectively analyzed data for 157 cardiac donors and respective recipients from January 2001 to December 2004. There were 47 recipients of donor heart with increased LVWT >or=1.2 cm, which constituted the study group and 110 recipients of a donor heart with normal LVWT < 1.2 cm that formed the control group. At 3 +/- 1.5 years, recipient survival was lower (50% vs. 82%, p = 0.0053) and incidence of allograft vasculopathy was higher (50% vs. 22%, p = 0.05) in recipients of donor heart with LVWT > 1.4 cm as compared to LVWT 1.4 cm (p = 0.003), recipient preoperative ventricular assist device (VAD) support (p = 0.04) and bypass time > 150 min (p = 0.05) were predictors of reduced survival. Our results suggest careful consideration of donor hearts with echocardiographic evidence of increased LVWT in the absence of hypovolemia, because they may be associated with poorer outcomes; such hearts should potentially be reserved only for the most desperately ill recipients.

  View details for DOI 10.1111/j.1600-6143.2007.01930.x

  View details for Web of Science ID 000249167000022

  View details for PubMedID 17845572

• Management strategies for patients with pulmonary hypertension in the intensive care unit CRITICAL CARE MEDICINE Zamanian, R. T., Haddad, F., Doyle, R. L., Weinacker, A. B. 2007; 35 (9): 2037-2050

  Abstract

  Pulmonary hypertension may be encountered in the intensive care unit in patients with critical illnesses such as acute respiratory distress syndrome, left ventricular dysfunction, and pulmonary embolism, as well as after cardiothoracic surgery. Pulmonary hypertension also may be encountered in patients with preexisting pulmonary vascular, lung, liver, or cardiac diseases. The intensive care unit management of patients can prove extremely challenging, particularly when they become hemodynamically unstable. The objective of this review is to discuss the pathogenesis and physiology of pulmonary hypertension and the utility of various diagnostic tools, and to provide recommendations regarding the use of vasopressors and pulmonary vasodilators in intensive care.We undertook a comprehensive review of the literature regarding the management of pulmonary hypertension in the setting of critical illness. We performed a MEDLINE search of articles published from January 1970 to March 2007. Medical subject headings and keywords searched and cross-referenced with each other were: pulmonary hypertension, vasopressor agents, therapeutics, critical illness, intensive care, right ventricular failure, mitral stenosis, prostacyclin, nitric oxide, sildenafil, dopamine, dobutamine, phenylephrine, isoproterenol, and vasopressin. Both human and animal studies related to pulmonary hypertension were reviewed.Pulmonary hypertension presents a particular challenge in critically ill patients, because typical therapies such as volume resuscitation and mechanical ventilation may worsen hemodynamics in patients with pulmonary hypertension and right ventricular failure. Patients with decompensated pulmonary hypertension, including those with pulmonary hypertension associated with cardiothoracic surgery, require therapy for right ventricular failure. Very few human studies have addressed the use of vasopressors and pulmonary vasodilators in these patients, but the use of dobutamine, milrinone, inhaled nitric oxide, and intravenous prostacyclin have the greatest support in the literature. Treatment of pulmonary hypertension resulting from critical illness or chronic lung diseases should address the primary cause of hemodynamic deterioration, and pulmonary vasodilators usually are not necessary.

  View details for DOI 10.1097/01.CCM.0000280433.74246.9E

  View details for PubMedID 17855818

• Active bacterial myocarditis: A case report and review of the literature JOURNAL OF HEART AND LUNG TRANSPLANTATION Haddad, F., Berry, G., Doyle, R. L., Martineau, P., Leung, T., Racine, N. 2007; 26 (7): 745-749

  Abstract

  Bacterial myocarditis (BM) is an uncommon cause of infectious myocarditis. BM is usually seen in the context of overwhelming sepsis or as part of a specific bacterial syndrome. The definitive diagnosis of bacterial myocarditis requires biopsy or morphologically proven active myocarditis with evidence of bacterial invasion or positive tissue cultures. The management of bacterial myocarditis consists of aggressive and early antibiotic or anti-toxin treatment, appropriate hemodynamic support, and treatment of arrhythmias or mechanical complications. We present a case of acute Listeria monocytogenes myocarditis in an immunocompetent patient and highlight the challenges in the diagnosis and treatment of bacterial myocarditis.

  View details for DOI 10.1016/j.healun.2007.04.010

  View details for Web of Science ID 000248195700014

  View details for PubMedID 17613408

• Long term outcomes in adult heart transplant recipients treated with OKT3 versus daclizumab induction therapy. 7th American Transplant Congress Virani, S. A., Ransohoff, K., Haddad, F., Valantine, H. A., Chin, C. WILEY-BLACKWELL. 2007: 424–424

  View details for Web of Science ID 000246370201514

• Pulmonary nocardiosis in a heart transplant patient: Case report and review of the literature JOURNAL OF HEART AND LUNG TRANSPLANTATION Haddad, F., Hunt, S. A., Perlroth, M., Valantine, H., Doyle, R., Montoya, J. 2007; 26 (1): 93-97

  Abstract

  Pulmonary infection with Nocardia is an uncommon but serious infection found in immunocompromised patients. We describe a rapidly progressive pulmonary nocardiosis in a heart transplant patient. We then review the common clinical features of Nocardia infection in transplant recipients, outlining the challenges in its diagnosis and management. We also review the differences between Pneumocystis jiroveci prophylaxis regimens with respect to concomitant prophylaxis of Nocardia and other opportunistic infections.

  View details for DOI 10.1016/j.healun.2006.11.002

  View details for PubMedID 17234524

• Inhaled milrinone: a new alternative in cardiac surgery? Seminars in cardiothoracic and vascular anesthesia Denault, A. Y., Lamarche, Y., Couture, P., Haddad, F., Lambert, J., Tardif, J., Perrault, L. P. 2006; 10 (4): 346-360

  Abstract

  The administration of milrinone through inhalation has been studied in only a few animal and human studies. Compared to the intravenous administration, inhaled milrinone has been shown to reduce pulmonary artery pressure without systemic hypotension. Therefore, this approach could represent an alternative to nitric oxide. This current state of knowledge of intravenous and inhaled milrinone is presented and summarized.

  View details for PubMedID 17200091

• Giant coronary aneurysms in heart transplantation: an unusual presentation of cardiac allograft vasculopathy JOURNAL OF HEART AND LUNG TRANSPLANTATION Haddad, F., Perez, M., Fleischmann, D., Valantine, H., Hunt, S. A. 2006; 25 (11): 1367-1370

  Abstract

  Cardiac allograft vasculopathy is a leading cause of death during long-term follow-up of heart transplant recipients. We report 2 cases of cardiac allograft vasculopathy associated with giant coronary aneurysms. To our knowledge, these are the first reported cases of spontaneous giant coronary aneurysms in heart transplant recipients.

  View details for DOI 10.1016/j.healun.2006.07.006

  View details for Web of Science ID 000242222100015

  View details for PubMedID 17097503

• Left and right ventricular diastolic dysfunction as predictors of difficult separation from cardiopulmonary bypass CANADIAN JOURNAL OF ANAESTHESIA-JOURNAL CANADIEN D ANESTHESIE Denault, A. Y., Couture, P., Buithieu, J., Haddad, F., Carrier, M., Babin, D., Levesque, S., Tardif, J. 2006; 53 (10): 1020-1029

  Abstract

  As the evaluation of diastolic function can be complex in the setting of a busy cardiac operating room, its assessment may benefit from an algorithmic approach using transesophageal echocardiography. We developed a diagnostic algorithm which was then applied in a series of cardiac surgery patients to determine whether moderate to severe left ventricular diastolic dysfunction (LVDD) and right ventricular diastolic dysfunction (RVDD) can predict difficult separation from cardiopulmonary bypass (DSB).An algorithm using pulsed-wave Doppler interrogation of the mitral and tricuspid valve, the pulmonary and hepatic venous flow, and tissue Doppler interrogation of the mitral and tricuspid annulus was developed. The study was divided in two phases involving two groups of patients undergoing cardiac surgery. In phase I, echocardiographic evaluations of patients (n = 74) were used to test the reproducibility of the algorithm and to evaluate inter-observer variability using Cohen's kappa values which were calculated in three specific periods. In phase II, the algorithm was applied to a second group of patients (validation group, n = 179) to explore its prognostic significance. The primary end-point in phase II was DSB.In phase I, the kappa coefficients for LVDD and RVDD algorithms were 0.77 and 0.82, respectively. In phase II, moderate or severe degrees of LVDD were observed in 29 patients (16%) and moderate to severe RVDD was observed in 18 patients (10%) before cardiac surgery. Both moderate and severe LVDD (P = 0.017) and RVDD (P = 0.049) before surgery were observed more frequently in patients with DSB.Moderate and severe LVDD and RVDD can be identified with very good reproducibility, and both degrees of diastolic dysfunction are associated with DSB.

  View details for Web of Science ID 000241350900012

  View details for PubMedID 16987858

• Dynamic right ventricular outflow tract obstruction in cardiac surgery JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Denault, A. Y., Chaput, M., Couture, P., Hebert, Y., Haddad, F., Tardif, J. 2006; 132 (1): 43-49

  Abstract

  Right ventricular outflow tract obstruction can be a cause of hemodynamic instability but it has not been described in non-congenital cardiac surgery.The prevalence of right ventricular outflow tract obstruction was retrospectively studied in 670 consecutive patients undergoing cardiac surgery. Significant right ventricular outflow tract obstruction was diagnosed if the right ventricular systolic to pulmonary artery peak gradient was more than 25 mm Hg. The diagnosis was based on measurement of the right ventricular and pulmonary artery systolic pressure through the paceport and distal opening of the pulmonary artery catheter. To further validate the prevalence and the importance of right ventricular outflow tract obstruction, 130 patients were prospectively studied over a 12-month period.In the retrospective cohort, 6 patients (1%) undergoing various types of cardiac surgical procedures were found to have significant dynamic right ventricular outflow tract obstruction with a mean gradient of 31 +/- 4 mm Hg (26 to 35 mm Hg). In the prospective study significant dynamic right ventricular outflow tract obstruction was identified in 5 patients (4%) (average peak: 37 +/- 15 mm Hg; range: 27 to 60 mm Hg). The typical transesophageal echocardiography finding was end-systolic obliteration of the right ventricular outflow tract. In patients with significant dynamic right ventricular outflow tract obstruction, hemodynamic instability was present in 10/11 patients (91%).Right ventricular outflow tract obstruction is easily diagnosed using the paceport of the pulmonary artery catheter and should be considered as a potential cause of hemodynamic instability especially when transesophageal echocardiography reveals systolic right ventricular cavity obliteration.

  View details for DOI 10.1016/j.jtcvs.2006.03.014

  View details for Web of Science ID 000238522000011

  View details for PubMedID 16798301

• Applying Cardiopulmonary Exercise Testing to the Evaluation of Left Ventricular Function for Patients Ventricular Assist Device Therapy American College of Sports Medicine Christle, J. W., Moneghetti , K. J., Haddad, F., Banerjee, D., Myers, J., 2017: 533

  View details for DOI 10.1249/01.mss.0000518376.31161.d1