Sushma Reddy

All Publications

• Cardiorenal Syndrome in Right Heart Failure Due to Pulmonary Arterial Hypertension-The Right Ventricle as a Therapeutic Target to Improve Renal Function. Cardiovascular drugs and therapy Ichimura, K., Gross, A., Mathew, R. O., Salman, L., Reddy, S., Spiekerkoetter, E., Sidhu, M. S. 2024

  Abstract

  Cardiorenal syndrome (CRS) due to right ventricular (RV) failure is a disease entity emerging as a key indicator of morbidity and mortality. The multifactorial aspects of CRS and the left-right ventricular interdependence complicate the link between RV failure and renal function. RV failure has a direct pathophysiological link to renal dysfunction by leading to systemic venous congestion in certain circumstances and low cardiac output in other situations, both leading to impaired renal perfusion. Indeed, renal dysfunction is known to be an independent predictor of mortality in patients with pulmonary arterial hypertension (PAH) and RV failure. Thus, it is important to further understand the interaction between the RV and renal function. RV adaptation is critical to long-term survival in patients with PAH. The RV is also known for its remarkable capacity to recover once the aggravating factor is addressed or mitigated. However, less is known about the renal potential for recovery following the resolution of chronic RV failure. In this review, we provide an overview of the intricate relationship between RV dysfunction and the subsequent development of CRS, with a particular emphasis on PAH. Additionally, we summarize potential RV-targeted therapies and their potential beneficial impact on renal function.

  View details for DOI 10.1007/s10557-024-07588-8

  View details for PubMedID 38847906

• 3D Imaging Reveals Complex Microvascular Remodeling in the Right Ventricle in Pulmonary Hypertension. Circulation research Ichimura, K., Boehm, M., Andruska, A. M., Zhang, F., Schimmel, K., Bonham, S., Kabiri, A., Kheyfets, V. O., Ichimura, S., Reddy, S., Mao, Y., Zhang, T., Wang, G., Santana, E. J., Tian, X., Essafri, I., Vinh, R., Tian, W., Nicolls, M. R., Yajima, S., Shudo, Y., MacArthur, J. W., Woo, Y. J., Metzger, R. J., Spiekerkoetter, E. 2024

  Abstract

  Pathogenic concepts of right ventricular (RV) failure in pulmonary arterial hypertension focus on a critical loss of microvasculature. However, the methods underpinning prior studies did not take into account the 3-dimensional (3D) aspects of cardiac tissue, making accurate quantification difficult. We applied deep-tissue imaging to the pressure-overloaded RV to uncover the 3D properties of the microvascular network and determine whether deficient microvascular adaptation contributes to RV failure.Heart sections measuring 250-µm-thick were obtained from mice after pulmonary artery banding (PAB) or debanding PAB surgery and properties of the RV microvascular network were assessed using 3D imaging and quantification. Human heart tissues harvested at the time of transplantation from pulmonary arterial hypertension cases were compared with tissues from control cases with normal RV function.Longitudinal 3D assessment of PAB mouse hearts uncovered complex microvascular remodeling characterized by tortuous, shorter, thicker, highly branched vessels, and overall preserved microvascular density. This remodeling process was reversible in debanding PAB mice in which the RV function recovers over time. The remodeled microvasculature tightly wrapped around the hypertrophied cardiomyocytes to maintain a stable contact surface to cardiomyocytes as an adaptation to RV pressure overload, even in end-stage RV failure. However, microvasculature-cardiomyocyte contact was impaired in areas with interstitial fibrosis where cardiomyocytes displayed signs of hypoxia. Similar to PAB animals, microvascular density in the RV was preserved in patients with end-stage pulmonary arterial hypertension, and microvascular architectural changes appeared to vary by etiology, with patients with pulmonary veno-occlusive disease displaying a lack of microvascular complexity with uniformly short segments.3D deep tissue imaging of the failing RV in PAB mice, pulmonary hypertension rats, and patients with pulmonary arterial hypertension reveals complex microvascular changes to preserve the microvascular density and maintain a stable microvascular-cardiomyocyte contact. Our studies provide a novel framework to understand microvascular adaptation in the pressure-overloaded RV that focuses on cell-cell interaction and goes beyond the concept of capillary rarefaction.

  View details for DOI 10.1161/CIRCRESAHA.123.323546

  View details for PubMedID 38770652

• Effect of Sodium-Glucose Cotransporter 2 Inhibitors in Adults With Congenital Heart Disease. Journal of the American College of Cardiology Neijenhuis, R. M., MacDonald, S. T., Zemrak, F., Mertens, B. J., Dinsdale, A., Hunter, A., Walker, N. L., Swan, L., Reddy, S., Rotmans, J. I., Jukema, J. W., Jongbloed, M. R., Veldtman, G. R., Egorova, A. D. 2024

  Abstract

  Heart failure (HF) is the principal cause of morbidity and mortality in adults with congenital heart disease (ACHD). Robust evidence-based treatment options are lacking.This study aims to evaluate the safety, tolerability, and short-term HF-related effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in a real-world ACHD population.All patients with ACHD treated with SGLT2i in 4 European ACHD centers were included in this retrospective study. Data were collected from 1 year before starting SGLT2i to the most recent follow-up. Data on side effects, discontinuation, mortality, and hospitalizations were collected.In total, 174 patients with ACHD were treated with SGLT2i from April 2016 to July 2023. The mean age was 48.7 ± 15.3 years, 72 (41.4%) were female, and 29 (16.7%) had type 2 diabetes mellitus. Ten (5.7%) patients had mild, 75 (43.1%) moderate, and 89 (51.1%) severe congenital heart disease. HF was the most frequent starting indication (n = 162, 93.1%), followed by type 2 diabetes (n = 11, 6.3%) and chronic kidney disease (n = 1, 0.6%). At median follow-up of 7.7 months (Q1-Q3: 3.9-13.2 months), 18 patients (10.3%) reported side effects, 12 (6.9%) permanently discontinued SGLT2i, and 4 (2.3%) died of SGLT2i-unrelated causes. A significant reduction in the HF hospitalization rate was observed from 6 months before to 6 months after starting SGLT2i (relative rate = 0.30; 95% CI: 0.14-0.62; P = 0.001).SGLT2i generally seem safe, well-tolerated, and potentially beneficial in patients with ACHD. SGLT2i was associated with a 3-fold reduction in the 6-month HF hospitalization rate. These results warrant prospective randomized investigation of the potential benefits of SGLT2i for patients with ACHD.

  View details for DOI 10.1016/j.jacc.2024.02.017

  View details for PubMedID 38530688

• Mitochondrial Targeted Therapies to Prevent Maternal Diabetes-Induced Congenital Heart Defects. JACC. Basic to translational science Reddy, S. 2024; 9 (3): 319-321

  View details for DOI 10.1016/j.jacbts.2024.01.016

  View details for PubMedID 38559633

  View details for PubMedCentralID PMC10978448

• Intraoperative and Postoperative Hemodynamic Predictors of Acute Kidney Injury in Pediatric Heart Transplant Recipients. Journal of pediatric intensive care Hollander, S. A., Chung, S., Reddy, S., Zook, N., Yang, J., Vella, T., Navaratnam, M., Price, E., Sutherland, S. M., Algaze, C. A. 2024; 13 (1): 37-45

  Abstract

  Acute kidney injury (AKI) is common after pediatric heart transplantation (HT) and is associated with inferior patient outcomes. Hemodynamic risk factors for pediatric heart transplant recipients who experience AKI are not well described. We performed a retrospective review of 99 pediatric heart transplant patients at Lucile Packard Children's Hospital Stanford from January 1, 2015, to December 31, 2019, in which clinical and demographic characteristics, intraoperative perfusion data, and hemodynamic measurements in the first 48 postoperative hours were analyzed as risk factors for severe AKI (Kidney Disease: Improving Global Outcomes [KDIGO] stage ≥ 2). Univariate analysis was conducted using Fisher's exact test, Chi-square test, and the Wilcoxon rank-sum test, as appropriate. Multivariable analysis was conducted using logistic regression. Thirty-five patients (35%) experienced severe AKI which was associated with lower intraoperative cardiac index ( p  = 0.001), higher hematocrit ( p  < 0.001), lower body temperature ( p  < 0.001), lower renal near-infrared spectroscopy ( p  = 0.001), lower postoperative mean arterial blood pressure (MAP: p  = 0.001), and higher central venous pressure (CVP; p  < 0.001). In multivariable analysis, postoperative CVP >12 mm Hg (odds ratio [OR] = 4.27; 95% confidence interval [CI]: 1.48-12.3, p  = 0.007) and MAP <65 mm Hg (OR = 4.9; 95% CI: 1.07-22.5, p  = 0.04) were associated with early severe AKI. Children with severe AKI experienced longer ventilator, intensive care, and posttransplant hospital days and inferior survival ( p  = 0.01). Lower MAP and higher CVP are associated with severe AKI in pediatric HT recipients. Patients, who experienced AKI, experienced increased intensive care unit (ICU) morbidity and inferior survival. These data may guide the development of perioperative renal protective management strategies to reduce AKI incidence and improve patient outcomes.

  View details for DOI 10.1055/s-0041-1736336

  View details for PubMedID 38571984

  View details for PubMedCentralID PMC10987224

• MicroRNA-34a-Dependent Attenuation of Angiogenesis in Right Ventricular Failure. Journal of the American Heart Association Reddy, S., Hu, D. Q., Zhao, M., Ichimura, S., Barnes, E. A., Cornfield, D. N., Alejandre Alcázar, M. A., Spiekerkoetter, E., Fajardo, G., Bernstein, D. 2024: e029427

  Abstract

  The right ventricle (RV) is at risk in patients with complex congenital heart disease involving right-sided obstructive lesions. We have shown that capillary rarefaction occurs early in the pressure-loaded RV. Here we test the hypothesis that microRNA (miR)-34a, which is induced in RV hypertrophy and RV failure (RVF), blocks the hypoxia-inducible factor-1α-vascular endothelial growth factor (VEGF) axis, leading to the attenuated angiogenic response and increased susceptibility to RV failure.Mice underwent pulmonary artery banding to induce RV hypertrophy and RVF. Capillary rarefaction occurred immediately. Although hypoxia-inducible factor-1α expression increased (0.12±0.01 versus 0.22±0.03, P=0.05), VEGF expression decreased (0.61±0.03 versus 0.22±0.05, P=0.01). miR-34a expression was most upregulated in fibroblasts (4-fold), but also in cardiomyocytes and endothelial cells (2-fold). Overexpression of miR-34a in endothelial cells increased cell senescence (10±3% versus 22±2%, P<0.05) by suppressing sirtulin 1 expression, and decreased tube formation by 50% via suppression of hypoxia-inducible factor-1α, VEGF A, VEGF B, and VEGF receptor 2. miR-34a was induced by stretch, transforming growth factor-β1, adrenergic stimulation, and hypoxia in cardiac fibroblasts and cardiomyocytes. In mice with RVF, locked nucleic acid-antimiR-34a improved RV shortening fraction and survival half-time and restored capillarity and VEGF expression. In children with congenital heart disease-related RVF, RV capillarity was decreased and miR-34a increased 5-fold.In summary, miR-34a from fibroblasts, cardiomyocytes, and endothelial cells mediates capillary rarefaction by suppressing the hypoxia-inducible factor-1α-VEGF axis in RV hypertrophy/RVF, raising the potential for anti-miR-34a therapeutics in patients with at-risk RVs.

  View details for DOI 10.1161/JAHA.123.029427

  View details for PubMedID 38293915

• A Noninvasive Circulating Signature of Combined Right Ventricular Pressure and Volume Overload in Tetralogy of Fallot/Pulmonary Atresia/Major Aortopulmonary Collateral Arteries. World journal for pediatric & congenital heart surgery Clouthier, K. L., Taylor, A. C., Xuhuai, J., Liu, Y., Parker, S., Van Eyk, J., Reddy, S. 2023: 21501351231213626

  Abstract

  Background: Despite surgical advances, children with tetralogy of Fallot/pulmonary atresia/major aortopulmonary collaterals (TOF/PA/MAPCAs) are subject to chronic right ventricular (RV) pressure and volume overload. Current diagnostic tools do not identify adverse myocardial remodeling and cannot predict progression to RV failure. We sought to identify a noninvasive, circulating signature of the systemic response to right heart stress to follow disease progression. Methods: Longitudinal data were collected from patients with TOF/PA/MAPCAs (N = 5) at the time of (1) early RV pressure overload and (2) late RV pressure and volume overload. Plasma protein and microRNA expression were evaluated using high-throughput data-independent mass spectroscopy and Agilent miR Microarray, respectively. Results: At the time of early RV pressure overload, median patient age was 0.34 years (0.02-9.37), with systemic RV pressures, moderate-severe hypertrophy, and preserved systolic function. Late RV pressure and volume overload occurred at a median age of 4.08 years (1.51-10.83), with moderate RV hypertrophy and dilation, and low normal RV function; 277 proteins were significantly dysregulated (log2FC ≥0.6/≤-0.6, FDR≤0.05), predicting downregulation in lipid transport (apolipoproteins), fibrinolytic system, and extracellular matrix structural proteins (talin 1, profilin 1); and upregulation in the respiratory burst. Increasing RV size and decreasing RV function correlated with decreasing structural protein expression. Similarly, miR expression predicted downregulation of extracellular matrix-receptor interactions and upregulation in collagen synthesis. Conclusion: To our knowledge, we show for the first time a noninvasive protein and miR signature reflecting the systemic response to adverse RV myocardial remodeling in TOF/PA/MAPCAs which could be used to follow disease progression.

  View details for DOI 10.1177/21501351231213626

  View details for PubMedID 38128927

• Tetralogy of Fallot Across the Lifespan: A Focus on the Right Ventricle. CJC pediatric and congenital heart disease Ganni, E., Ho, S. Y., Reddy, S., Therrien, J., Kearney, K., Roche, S. L., Dimopoulos, K., Mertens, L. L., Bitterman, Y., Friedberg, M. K., Saraf, A., Marelli, A., Alonso-Gonzalez, R. 2023; 2 (6Part A): 283-300

  Abstract

  Tetralogy of Fallot is a cyanotic congenital heart disease, for which various surgical techniques allow patients to survive to adulthood. Currently, the natural history of corrected tetralogy of Fallot is underlined by progressive right ventricular (RV) failure due to pulmonic regurgitation and other residual lesions. The underlying cellular mechanisms that lead to RV failure from chronic volume overload are characterized by microvascular and mitochondrial dysfunction through various regulatory molecules. On a clinical level, these cardiac alterations are commonly manifested as exercise intolerance. The degree of exercise intolerance can be objectified and aid in prognostication through cardiopulmonary exercise testing. The timing for reintervention on residual lesions contributing to RV volume overload remains controversial; however, interval assessment of cardiac function and volumes by echocardiography and magnetic resonance imaging may be helpful. In patients who develop clinically important RV failure, clinicians should aim to maintain a euvolemic state through the use of diuretics while paying particular attention to preload and kidney function. In patients who develop signs of cardiogenic shock from right heart failure, stabilization through the use of inotropes and pressor is indicated. In special circumstances, the use of mechanical support may be appropriate. However, cardiologists should pay particular attention to residual lesions that may impact the efficacy of the selected device.

  View details for DOI 10.1016/j.cjcpc.2023.10.009

  View details for PubMedID 38161676

• Biomarkers, Socioeconomic Factors, and Right Ventricular Function After Surgical Repair for Tetralogy of Fallot. Pediatric cardiology Jones, A. L., Faerber, J., Huang, J., Ampah, S., Wang, Y., DeCost, G., Gardner, M., Naim, M. Y., Reddy, S., Goldmuntz, E., Mercer-Rosa, L. 2023

  Abstract

  Right ventricular (RV) dysfunction early after tetralogy of Fallot (TOF) increases post-operative morbidity. We investigated associations of circulating biomarkers and socioeconomic factors with early post-operative RV systolic function. Single-center prospective cohort study of infants undergoing TOF repair. Six serologic biomarkers of myocardial fibrosis and wall stress collected at the time of surgery were measured with immunoassay. Geocoding was performed for socioeconomic factors. Multivariate adaptive regression splines (MARS) models identified factors associated with RV function parameters: fractional area change (FAC), global longitudinal strain and strain rate, and free wall strain and strain rate. Seventy-one patients aged 3.5 months (IQR 2.4, 5.2) were included. Galectin-3 was the highest ranked predictor for FAC, global longitudinal strain, and free wall strain, and procollagen type-I carboxy-terminal propeptide (PICP) was the highest ranked predictor for global longitudinal strain rate and free wall strain rate. Several neighborhood characteristics were also highly ranked. Models adjusted R2 ranged from 0.71 to 0.85 (FAC, global longitudinal strain/strain rate), and 0.55-0.57 (RV free wall strain/strain rate). A combination of serologic biomarkers, socioeconomic, and clinical variables explain a significant proportion of the variability in RV function after TOF repair. These factors may inform pre-operative risk-stratification for these patients.

  View details for DOI 10.1007/s00246-023-03108-x

  View details for PubMedID 36797379

  View details for PubMedCentralID 7155423

• miR Profile of Chronic Right Ventricular Pacing: a Pilot Study in Children with Congenital Complete Atrioventricular Block. Journal of cardiovascular translational research Navarre, B. M., Clouthier, K. L., Ji, X., Taylor, A., Weldy, C. S., Dubin, A. M., Reddy, S. 2022

  Abstract

  Chronic ventricular pacing can lead to pacing-induced cardiomyopathy (PICM). Clinical data alone is insufficient to predict who will develop PICM. Our study aimed to evaluate the circulating miR profile associated with chronic right ventricular pacing in children with congenital complete AV block (CCAVB) and to identify candidate miRs for longitudinal monitoring. Clinical data and blood were collected from chronically paced children (N = 9) and compared with non-paced controls (N = 13). miR microarrays from the buffy coat revealed 488 differentially regulated miRs between groups. Pathway analysis predicted both adaptive and maladaptive miR signaling associated with chronic pacing despite preserved ventricular function. Greater profibrotic signaling (miRs-92a, 130, 27, 29) and sodium and calcium channel dysregulation (let-7) were seen in those paced > 10 years with the most dyregulation seen in a patient with sudden death vs. those paced < 10 years. These miRs may help to identify early adverse remodeling in this population.

  View details for DOI 10.1007/s12265-022-10318-w

  View details for PubMedID 36121621

• 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

• iPSC model of congenital heart disease predicts disease outcome. Cell stem cell Tripathi, D., Reddy, S. 2022; 29 (5): 659-660

  Abstract

  In this issue of Cell Stem Cell, Xu etal. demonstrate that induced pluripotent stem cell-derived cardiomyocytes from patients with hypoplastic left heart syndrome exhibit mitochondrial dysfunction and can be used for disease modeling. In addition, they show the potential to predict future heart failure and develop therapies.

  View details for DOI 10.1016/j.stem.2022.04.010

  View details for PubMedID 35523134

• Three-Dimensional Deep-Tissue Imaging of the Right Ventricle Reveals Adaptive Reconstruction of the Capillary Network in Right Heart Failure Ichimura, K., Zhang, F., Boehm, M., Andruska, A. M., Reddy, S., Kheyfets, M., Metzger, R., Spiekerkoetter, E. F. AMER THORACIC SOC. 2022

  View details for Web of Science ID 000792480405293

• Altered Cardiac Energetics and Mitochondrial Dysfunction in Hypertrophic Cardiomyopathy. Circulation Ranjbarvaziri, S., Kooiker, K. B., Ellenberger, M., Fajardo, G., Zhao, M., Vander Roest, A. S., Woldeyes, R. A., Koyano, T. T., Fong, R., Ma, N., Tian, L., Traber, G. M., Chan, F., Perrino, J., Reddy, S., Chiu, W., Wu, J. C., Woo, J. Y., Ruppel, K. M., Spudich, J. A., Snyder, M. P., Contrepois, K., Bernstein, D. 2021

  Abstract

  Background: Hypertrophic cardiomyopathy (HCM) is a complex disease partly explained by the effects of individual gene variants on sarcomeric protein biomechanics. At the cellular level, HCM mutations most commonly enhance force production, leading to higher energy demands. Despite significant advances in elucidating sarcomeric structure-function relationships, there is still much to be learned about the mechanisms that link altered cardiac energetics to HCM phenotypes. In this work, we test the hypothesis that changes in cardiac energetics represent a common pathophysiologic pathway in HCM. Methods: We performed a comprehensive multi-omics profile of the molecular (transcripts, metabolites, and complex lipids), ultrastructural, and functional components of HCM energetics using myocardial samples from 27 HCM patients and 13 normal controls (donor hearts). Results: Integrated omics analysis revealed alterations in a wide array of biochemical pathways with major dysregulation in fatty acid metabolism, reduction of acylcarnitines, and accumulation of free fatty acids. HCM hearts showed evidence of global energetic decompensation manifested by a decrease in high energy phosphate metabolites [ATP, ADP, and phosphocreatine (PCr)] and a reduction in mitochondrial genes involved in creatine kinase and ATP synthesis. Accompanying these metabolic derangements, electron microscopy showed an increased fraction of severely damaged mitochondria with reduced cristae density, coinciding with reduced citrate synthase (CS) activity and mitochondrial oxidative respiration. These mitochondrial abnormalities were associated with elevated reactive oxygen species (ROS) and reduced antioxidant defenses. However, despite significant mitochondrial injury, HCM hearts failed to upregulate mitophagic clearance. Conclusions: Overall, our findings suggest that perturbed metabolic signaling and mitochondrial dysfunction are common pathogenic mechanisms in patients with HCM. These results highlight potential new drug targets for attenuation of the clinical disease through improving metabolic function and reducing mitochondrial injury.

  View details for DOI 10.1161/CIRCULATIONAHA.121.053575

  View details for PubMedID 34672721

• Intraoperative and Postoperative Hemodynamic Predictors of Acute Kidney Injury in Pediatric Heart Transplant Recipients JOURNAL OF PEDIATRIC INTENSIVE CARE Hollander, S. A., Chung, S., Reddy, S., Zook, N., Yang, J., Vella, T., Navaratnam, M., Price, E., Sutherland, S. M., Algaze, C. A. 2021

  View details for DOI 10.1055/s-0041-1736336

  View details for Web of Science ID 000704825900002

• RIGHT VENTRICULAR OUTFLOW TRACT AND PULMONARY ARTERY GEOMETRY IN PATIENTS WITH REPAIRED TETRALOGY OF FALLOT PRIOR TO PULMONARY VALVE REPLACEMENT-CHARACTERIZATION AND LONGITUDINAL ASSOCIATION WITH BIOPROSTHETIC VALVE FUNCTION Arana, V., Chan, F., Schiavone, N., Reddy, S., Hanley, F., Marsden, A., McElhinney, D. ELSEVIER SCIENCE INC. 2021: 1410

  View details for Web of Science ID 000647487501418

• 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

• Transcriptomic and Functional Analyses of Mitochondrial Dysfunction in Pressure Overload-Induced Right Ventricular Failure. Journal of the American Heart Association Hwang, H. V., Sandeep, N., Nair, R. V., Hu, D., Zhao, M., Lan, I. S., Fajardo, G., Matkovich, S. J., Bernstein, D., Reddy, S. 2021: e017835

  Abstract

  Background In complex congenital heart disease patients such as those with tetralogy of Fallot, the right ventricle (RV) is subject to pressure overload, leading to RV hypertrophy and eventually RV failure. The mechanisms that promote the transition from stable RV hypertrophy to RV failure are unknown. We evaluated the role of mitochondrial bioenergetics in the development of RV failure. Methods and Results We created a murine model of RV pressure overload by pulmonary artery banding and compared with sham-operated controls. Gene expression by RNA-sequencing, oxidative stress, mitochondrial respiration, dynamics, and structure were assessed in pressure overload-induced RV failure. RV failure was characterized by decreased expression of electron transport chain genes and mitochondrial antioxidant genes (aldehyde dehydrogenase 2 and superoxide dismutase 2) and increased expression of oxidant stress markers (heme oxygenase, 4-hydroxynonenal). The activities of all electron transport chain complexes decreased with RV hypertrophy and further with RV failure (oxidative phosphorylation: sham 552.3±43.07 versus RV hypertrophy 334.3±30.65 versus RV failure 165.4±36.72pmol/(s*mL), P<0.0001). Mitochondrial fission protein DRP1 (dynamin 1-like) trended toward an increase, while MFF (mitochondrial fission factor) decreased and fusion protein OPA1 (mitochondrial dynamin like GTPase) decreased. In contrast, transcription of electron transport chain genes increased in the left ventricle of RV failure. Conclusions Pressure overload-induced RV failure is characterized by decreased transcription and activity of electron transport chain complexes and increased oxidative stress which are associated with decreased energy generation. An improved understanding of the complex processes of energy generation could aid in developing novel therapies to mitigate mitochondrial dysfunction and delay the onset of RV failure.

  View details for DOI 10.1161/JAHA.120.017835

  View details for PubMedID 33522250

• Noncanonical WNT Activation in Human Right Ventricular Heart Failure FRONTIERS IN CARDIOVASCULAR MEDICINE Edwards, J. J., Brandimarto, J., Hu, D., Jeong, S., Yucel, N., Li, L., Bedi, K. C., Wada, S., Murashige, D., Hwang, H. V., Zhao, M., Margulies, K. B., Bernstein, D., Reddy, S., Arany, Z. 2020; 7: 582407

  Abstract

  Background: No medical therapies exist to treat right ventricular (RV) remodeling and RV failure (RVF), in large part because molecular pathways that are specifically activated in pathologic human RV remodeling remain poorly defined. Murine models have suggested involvement of Wnt signaling, but this has not been well-defined in human RVF. Methods: Using a candidate gene approach, we sought to identify genes specifically expressed in human pathologic RV remodeling by assessing the expression of 28 WNT-related genes in the RVs of three groups: explanted nonfailing donors (NF, n = 29), explanted dilated and ischemic cardiomyopathy, obtained at the time of cardiac transplantation, either with preserved RV function (pRV, n = 78) or with RVF (n = 35). Results: We identified the noncanonical WNT receptor ROR2 as transcriptionally strongly upregulated in RVF compared to pRV and NF (Benjamini-Hochberg adjusted P < 0.05). ROR2 protein expression correlated linearly to mRNA expression (R2 = 0.41, P = 8.1 × 10-18) among all RVs, and to higher right atrial to pulmonary capillary wedge ratio in RVF (R2 = 0.40, P = 3.0 × 10-5). Utilizing Masson's trichrome and ROR2 immunohistochemistry, we identified preferential ROR2 protein expression in fibrotic regions by both cardiomyocytes and noncardiomyocytes. We compared RVF with high and low ROR2 expression, and found that high ROR2 expression was associated with increased expression of the WNT5A/ROR2/Ca2+ responsive protease calpain-μ, cleavage of its target FLNA, and FLNA phosphorylation, another marker of activation downstream of ROR2. ROR2 protein expression as a continuous variable, correlated strongly to expression of calpain-μ (R2 = 0.25), total FLNA (R2 = 0.67), calpain cleaved FLNA (R2 = 0.32) and FLNA phosphorylation (R2 = 0.62, P < 0.05 for all). Conclusion: We demonstrate robust reactivation of a fetal WNT gene program, specifically its noncanonical arm, in human RVF characterized by activation of ROR2/calpain mediated cytoskeleton protein cleavage.

  View details for DOI 10.3389/fcvm.2020.582407

  View details for Web of Science ID 000579825800001

  View details for PubMedID 33134326

  View details for PubMedCentralID PMC7575695

• Diagnosis and treatment of right ventricular dysfunction in congenital heart disease CARDIOVASCULAR DIAGNOSIS AND THERAPY Santens, B., Van de Bruaene, A., De Meester, P., D'Alto, M., Reddy, S., Bernstein, D., Koestenberger, M., Hansmann, G., Budts, W. 2020; 10 (5): 1625–45

  Abstract

  Right ventricular (RV) function is important for clinical status and outcomes in children and adults with congenital heart disease (CHD). In the normal RV, longitudinal systolic function is the major contributor to global RV systolic function. A variety of factors contribute to RV failure including increased pressure- or volume-loading, electromechanical dyssynchrony, increased myocardial fibrosis, abnormal coronary perfusion, restricted filling capacity and adverse interactions between left ventricle (LV) and RV. We discuss the different imaging techniques both at rest and during exercise to define and detect RV failure. We identify the most important biomarkers for risk stratification in RV dysfunction, including abnormal NYHA class, decreased exercise capacity, low blood pressure, and increased levels of NTproBNP, troponin T, galectin-3 and growth differentiation factor 15. In adults with CHD (ACHD), fragmented QRS is independently associated with heart failure (HF) symptoms and impaired ventricular function. Furthermore, we discuss the different HF therapies in CHD but given the broad clinical spectrum of CHD, it is important to treat RV failure in a disease-specific manner and based on the specific alterations in hemodynamics. Here, we discuss how to detect and treat RV dysfunction in CHD in order to prevent or postpone RV failure.

  View details for DOI 10.21037/cdt-20-370

  View details for Web of Science ID 000582467900038

  View details for PubMedID 33224777

  View details for PubMedCentralID PMC7666946

• 4HNE Impairs Myocardial Bioenergetics in Congenital Heart DiseaseInduced Right Ventricular Failure. Circulation Hwang, H. V., Sandeep, N., Paige, S. L., Ranjbarvaziri, S., Hu, D., Zhao, M., Lan, I. S., Coronado, M., Kooiker, K. B., Wu, S. M., Fajardo, G., Bernstein, D., Reddy, S. 2020

  Abstract

  Background: In patients with complex congenital heart disease, such as those with tetralogy of Fallot, the right ventricle (RV) is subject to pressure overload stress, leading to RV hypertrophy and eventually RV failure. The role of lipid peroxidation, a potent form of oxidative stress, in mediating RV hypertrophy and failure in congenital heart disease is unknown. Methods: Lipid peroxidation and mitochondrial function and structure were assessed in RV myocardium collected from patients with RV hypertrophy with normal RV systolic function (RV FAC 47.3±3.8%) and in patients with RV failure showing decreased RV systolic function (RV FAC 26.6±3.1%). The mechanism of the effect of lipid peroxidation, mediated by 4-hydroxynonenal (4HNE; a byproduct of lipid peroxidation) on mitochondrial function and structure was assessed in HL1 murine cardiomyocytes and human induced pluripotent stem cellderived cardiomyocytes. Results: RV failure was characterized by an increase in 4HNE adduction of metabolic and mitochondrial proteins (16/27 identified proteins), in particular electron transport chain proteins. Sarcomeric (myosin) and cytoskeletal proteins (desmin, tubulin) also underwent 4HNEadduction. RV failure showed lower oxidative phosphorylation [moderate RV hypertrophy 287.6±19.75 vs. RV failure 137.8±11.57 pmol/(sec*ml), p=0.0004], and mitochondrial structural damage. Using a cell model, we show that 4HNE decreases cell number and oxidative phosphorylation (control 388.1±23.54 vs. 4HNE 143.7±11.64 pmol/(sec*ml), p<0.0001). Carvedilol, a known antioxidant did not decrease 4HNE adduction of metabolic and mitochondrial proteins and did not improve oxidative phosphorylation. Conclusions: Metabolic, mitochondrial, sarcomeric and cytoskeletal proteins are susceptible to 4HNE-adduction in patients with RV failure. 4HNE decreases mitochondrial oxygen consumption by inhibiting electron transport chain complexes. Carvedilol did not improve the 4HNE-mediated decrease in oxygen consumption. Strategies to decrease lipid peroxidation could improve mitochondrial energy generation and cardiomyocyte survival and improve RV failure in patients with congenital heart disease.

  View details for DOI 10.1161/CIRCULATIONAHA.120.045470

  View details for PubMedID 32806952

• Proceedings From the 2019 Stanford Single Ventricle Scientific Summit: Advancing Science for Single Ventricle Patients: From Discovery to Clinical Applications. Journal of the American Heart Association Reddy, S., Handler, S. S., Wu, S., Rabinovitch, M., Wright, G. 2020; 9 (7): e015871

  Abstract

  Abstracts Because of remarkable advances in survival over the past 40years, the worldwide population of individuals with single ventricle heart disease living with Fontan circulation has grown to 70000, with nearly half aged >18years. Survival to at least 30years of age is now achievable for 75% of Fontan patients. On the other hand, single ventricle patients account for the largest group of the 6000 to 8000 children hospitalized with circulation failure, with or without heart failure annually in the United States, with the highest in-hospital mortality. Because there is little understanding of the underlying mechanisms of heart failure, arrhythmias, pulmonary and lymphatic vascular abnormalities, and other morbidities, there are no specific treatments to maintain long-term myocardial performance or to optimize overall patient outcomes.

  View details for DOI 10.1161/JAHA.119.015871

  View details for PubMedID 32188306

• Characterizing the Molecular and Histological Events That Govern Right Ventricular Recovery in a Novel Mouse Model of PA De-Banding Boehm, M., Tian, X., Mao, Y., Ichimura, K., Dufva, M., Ali, M. K., Prosseda, S., Shi, Y., Kuramoto, K., Reddy, S., Kheyfets, V. O., Metzger, R. J., Spiekerkoetter, E. AMER THORACIC SOC. 2020

  View details for Web of Science ID 000556622802402

• Circulating whole genome miRNA expression corresponds to progressive right ventricle enlargement and systolic dysfunction in adults with tetralogy of Fallot. PloS one Weldy, C. S., Syed, S. A., Amsallem, M., Hu, D., Ji, X., Punn, R., Taylor, A., Navarre, B., Reddy, S. 2020; 15 (11): e0241476

  Abstract

  INTRODUCTION: The adult congenital heart disease population with repaired tetralogy of Fallot (TOF) is subject to chronic volume and pressure loading leading to a 40% probability of right ventricular (RV) failure by the 3rd decade of life. We sought to identify a non-invasive signature of adverse RV remodeling using peripheral blood microRNA (miRNA) profiling to better understand the mechanisms of RV failure.METHODS: Demographic, clinical data, and blood samples were collected from adults with repaired TOF (N = 20). RNA was isolated from the buffy coat of peripheral blood and whole genome miRNA expression was profiled using Agilent's global miRNA microarray platform. Fold change, pathway analysis, and unbiased hierarchical clustering of miRNA expression was performed and correlated to RV size and function assessed by echocardiography performed at or near the time of blood collection.RESULTS: MiRNA expression was profiled in the following groups: 1. normal RV size (N = 4), 2. mild/moderate RV enlargement (N = 11) and 3. severe RV enlargement (N = 5). 267 miRNAs were downregulated, and 66 were upregulated across the three groups (fold change >2.0, FDR corrected p<0.05) as RV enlargement increased and systolic function decreased. qPCR validation of a subset of these miRNAs identified increasing expression of miRNA 28-3p, 433-3p, and 371b-3p to be associated with increasing RV size and decreasing RV systolic function. Unbiased hierarchical clustering of all patients based on miRNA expression demonstrates three distinct patient clusters that largely coincide with progressive RV enlargement. Pathway analysis of dysregulated miRNAs demonstrates up and downregulation of cell cycle pathways, extracellular matrix proteins and fatty acid synthesis. HIF 1alpha signaling was downregulated while p53 signaling was predicted to be upregulated.CONCLUSION: Adults with TOF have a distinct miRNA profile with progressive RV enlargement and dysfunction implicating cell cycle dysregulation and upregulation in extracellular matrix and fatty acid metabolism. These data suggest peripheral blood miRNA can provide insight into the mechanisms of RV failure and can potentially be used for monitoring disease progression and to develop RV specific therapeutics to prevent RV failure in TOF.

  View details for DOI 10.1371/journal.pone.0241476

  View details for PubMedID 33175850

• FK506 Requires ALK1 to Attenuate Stimulus-Induced Collagen Production in Human Cardiac Fibroblasts Ali, M., Tian, X., Boehm, M., Andruska, A. M., Zhao, M., Kuramoto, K., Bernstein, D., Metzger, R., Reddy, S., Spiekerkoetter, E. F. AMER THORACIC SOC. 2020

  View details for Web of Science ID 000556393501501

• Delineating the molecular and histological events that govern right ventricular recovery using a novel mouse model of PA de-banding. Cardiovascular research Boehm, M., Tian, X., Mao, Y., Ichimura, K., Dufva, M. J., Ali, K., Prosseda, S. D., Shi, Y., Kuramoto, K., Reddy, S., Kheyfets, V. O., Metzger, R. J., Spiekerkoetter, E. 2019

  Abstract

  AIMS: The temporal sequence of events underlying functional right ventricular (RV) recovery after improvement of pulmonary hypertension-associated pressure overload are unknown. We sought to establish a novel mouse model of gradual RV recovery from pressure overload and use it to delineate RV reverse-remodeling events.METHODS AND RESULTS: Surgical pulmonary artery banding (PAB) around a 26G needle induced RV dysfunction with increased RV pressures, reduced exercise capacity and caused liver congestion, hypertrophic, fibrotic and vascular myocardial remodeling within 5 weeks of chronic RV pressure overload in mice. Gradual reduction of the afterload burden through PA band absorption (de-PAB) - after RV dysfunction and structural remodeling were established - initiated recovery of RV function (cardiac output, exercise capacity) along with rapid normalization in RV hypertrophy (RV/LV+S, cardiomyocyte area) and RV pressures (RVSP). RV fibrotic (collagen, elastic fibers, vimentin+ fibroblasts) and vascular (capillary density) remodeling were equally reversible, however reversal occurred at a later time-point after de-PAB, when RV function was already completely restored. Microarray gene expression (ClariomS, Thermo Fisher) along with gene ontology analyses in RV tissues revealed growth factors, immune modulators and apoptosis mediators as major cellular components underlying functional RV recovery.CONCLUSIONS: We established a novel gradual de-PAB mouse model and used it to demonstrate that established pulmonary hypertension-associated RV dysfunction is fully reversible. Mechanistically, we link functional RV improvement to hypertrophic normalization that precedes fibrotic and vascular reverse-remodeling events.TRANSLATIONAL PERSPECTIVE: The right ventricle (RV) in pulmonary arterial hypertension possesses a remarkable ability to recover after lung transplantation. Yet, some transplant centers prefer a heart-lung instead of lung transplantation when the RV function is severely impaired because knowledge is lacking whether fibrotic and vascular myocardial remodeling are completely reversible once the increased afterload burden is relieved. We have developed a mouse model to study gradual unloading of the RV and identified key molecular components and the timing of RV reverse-remodeling events with the ultimate goal to understand the RV recovery process and identify ways how to support the RV during recovery.

  View details for DOI 10.1093/cvr/cvz310

  View details for PubMedID 31738411

• Bleeding and Thrombosis With Pediatric Extracorporeal Life Support: A Roadmap for Management, Research, and the Future From the Pediatric Cardiac Intensive Care Society (Part Two). Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies Penk, J. S., Reddy, S., Polito, A., Cisco, M. J., Allan, C. K., Bembea, M., Giglia, T. M., Cheng, H. H., Thiagarajan, R. R., Dalton, H. J. 2019

  Abstract

  OBJECTIVES: To make recommendations on improving understanding of bleeding and thrombosis with pediatric extracorporeal life support including future research directions.DATA SOURCES: Evaluation of literature and consensus conferences of pediatric critical care and extracorporeal life support experts.STUDY SELECTION: A team of 10 experts with pediatric cardiac and extracorporeal membrane oxygenation experience and expertise met through the Pediatric Cardiac Intensive Care Society to review current knowledge and make recommendations for future research to establish "best practice" for anticoagulation management related to extracorporeal life support.DATA EXTRACTION/DATA SYNTHESIS: This white paper focuses on clinical understanding and limitations of current strategies to monitor anticoagulation. For each test of anticoagulation, limitations of current knowledge are addressed and future research directions suggested.CONCLUSIONS: No consensus on best practice for anticoagulation monitoring exists. Structured scientific evaluation to answer questions regarding anticoagulation monitoring and bleeding and thrombotic events should occur in multicenter studies using standardized approaches and well-defined endpoints. Outcomes related to need for component change, blood product administration, healthcare outcome, and economic assessment should be incorporated into studies. All centers should report data on patient receiving extracorporeal life support to a registry.

  View details for DOI 10.1097/PCC.0000000000002104

  View details for PubMedID 31517728

• Right ventricular failure in congenital heart disease. Current opinion in pediatrics Friedberg, M. K., Reddy, S. 2019

  Abstract

  PURPOSE OF REVIEW: We aim to review select literature pertaining to congenital heart disease (CHD)-induced right ventricular (RV) function and failure.RECENT FINDINGS: We review recent findings pertaining to children and adults with repaired tetralogy of Fallot (rTOF), systemic RV and hypoplastic left heart syndrome (HLHS). We emphasize pathophysiological mechanisms contributing to RV dysfunction in these conditions, the risk factors for adverse outcomes and the continuing challenges in treating these patients. We discuss how recent pathology findings, as well as developments in imaging and computer modeling have broadened our understanding of the pathophysiology of these conditions. We further review developments in the molecular and cellular basis of RV failure; and in particular, the RV molecular response to stress in repaired tetralogy of Fallot (rTOF). We highlight some of the genetic complexities in HLHS and how these may influence the long-term outcomes in these patients.SUMMARY: Recent literature has led to new understandings in the pathology, pathophysiology, risk factors for adverse outcomes, molecular and genetic basis for RV dysfunction and failure in CHD. Although these findings provide new therapeutic targets, the treatment of RV failure at this time remains limited.

  View details for DOI 10.1097/MOP.0000000000000804

  View details for PubMedID 31356354

• Bleeding and Thrombosis With Pediatric Extracorporeal Life Support: A Roadmap for Management, Research, and the Future From the Pediatric Cardiac Intensive Care Society (Part 1). Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies Penk, J. S., Reddy, S., Polito, A., Cisco, M. J., Allan, C. K., Bembea, M. M., Giglia, T. M., Cheng, H. H., Thiagarajan, R. R., Dalton, H. J. 2019

  Abstract

  OBJECTIVES: To make practical and evidence-based recommendations on improving understanding of bleeding and thrombosis with pediatric extracorporeal life support and to make recommendations for research directions.DATA SOURCES: Evaluation of literature and consensus conferences of pediatric critical care and extracorporeal life support experts.STUDY SELECTION: A team of 10 experts with pediatric cardiac and extracorporeal membrane oxygenation experience and expertise met through the Pediatric Cardiac Intensive Care Society to review current knowledge and make recommendations for future research to establish "best practice" for anticoagulation management related to extracorporeal life support.DATA EXTRACTION/SYNTHESIS: The first of a two-part white article focuses on clinical understanding and limitations of medications in use for anticoagulation, including novel medications. For each medication, limitations of current knowledge are addressed and research recommendations are suggested to allow for more definitive clinical guidelines in the future.CONCLUSIONS: No consensus on best practice for anticoagulation exists. Structured scientific evaluation to answer questions regarding anticoagulant medication and bleeding and thrombotic events should occur in multicenter studies using standardized approaches and well-defined endpoints. Outcomes related to need for component change, blood product administration, healthcare outcome, and economic assessment should be incorporated into studies. All centers should report data on patients receiving extracorporeal life support to a registry. The Extracorporeal Life Support Organization registry, designed primarily for quality improvement purposes, remains the primary and most successful data repository to date.

  View details for DOI 10.1097/PCC.0000000000002054

  View details for PubMedID 31274779

• Loss of Endothelium-Derived Wnt5a Is Associated With Reduced Pericyte Recruitment and Small Vessel Loss in Pulmonary Arterial Hypertension CIRCULATION Yuan, K., Shamskhou, E. A., Orcholski, M. E., Nathan, A., Reddy, S., Honda, H., Mani, V., Zeng, Y., Ozen, M. O., Wang, L., Demirci, U., Tian, W., Nicolls, M. R., Perez, V. 2019; 139 (14): 1710–24

  View details for DOI 10.1161/CIRCULATIONAHA.118.037642

  View details for Web of Science ID 000469320000018

• Overexpression of Hypoxia Inducible Factors in Pulmonary Artery Smooth Muscle Cells Mitigates Hypoxia-Induced Pulmonary Hypertension Barnes, E. A., Che, X., Ito, R., Reddy, S., Cornfield, D. N. AMER THORACIC SOC. 2019

  View details for Web of Science ID 000466776701480

• A process for academic societies to develop scientific statements and white papers: experience of the Pediatric Cardiac Intensive Care Society. Cardiology in the young Reddy, S., Polito, A., Staveski, S., Dalton, H. 2018: 1–4

  Abstract

  There are substantial knowledge gaps, practice variation, and paucity of controlled trials owing to the relatively small number of patients with critical heart disease. The Pediatric Cardiac Intensive Care Society has recognised this knowledge gap as an area needing a more comprehensive and evidence-based approach to the management of the critically ill child with heart disease. To address this, the Pediatric Cardiac Intensive Care Society created a scientific statements and white papers committee. Scientific statements and white papers will present the current state-of-the-art in areas where controversy exists, providing clinicians with guidance in diagnostic and therapeutic strategies, particularly where evidence-based data are lacking. This paper provides a template for other societies and organisations faced with the task of developing scientific statements and white papers. We describe the methods used to perform a systematic literature search and evidence rating that will be used by all scientific statements and white papers emerging from the Pediatric Cardiac Intensive Care Society. The Pediatric Cardiac Intensive Care Society aims to revolutionise the care of children with heart disease by shifting our efforts from individual institution-based practices to national standardised protocols and to lay the ground work for multicentre high-impact research directions.

  View details for PubMedID 30511598

• Cardiovascular Disease in the Young Council's Science and Clinical Education Lifelong Learning Committee: Year in Review JOURNAL OF THE AMERICAN HEART ASSOCIATION Reddy, S., Marino, B. S., Baker-Smith, C. M., Beaton, A., Krawczeski, C. D., Miyake, C. Y., Cnota, J. F., Glatz, A. C., Feingold, B., Romano, J. C., Cabrera, A. G., John, A. S., Cohen, M. S. 2018; 7 (21): e010617

  View details for PubMedID 30571390

• Renin-Angiotensin-Aldosterone System Inhibitors for Right Ventricular Dysfunction in Tetralogy of Fallot Quo Vadis? CIRCULATION Reddy, S., Bernstein, D., Newburger, J. W. 2018; 137 (14): 1472–74

  View details for PubMedID 29610128

  View details for PubMedCentralID PMC5886745

• Physiological Mitochondrial Fragmentation Is a Normal Cardiac Adaptation to Increased Energy Demand. Circulation research Coronado, M. n., Fajardo, G. n., Nguyen, K. n., Zhao, M. n., Kooiker, K. n., Jung, G. n., Hu, D. Q., Reddy, S. n., Sandoval, E. n., Stotland, A. n., Gottlieb, R. A., Bernstein, D. n. 2018; 122 (2): 282–95

  Abstract

  Mitochondria play a dual role in the heart, responsible for meeting energetic demands and regulating cell death. Paradigms have held that mitochondrial fission and fragmentation are the result of pathological stresses, such as ischemia, are an indicator of poor mitochondrial health, and lead to mitophagy and cell death. However, recent studies demonstrate that inhibiting fission also results in decreased mitochondrial function and cardiac impairment, suggesting that fission is important for maintaining cardiac and mitochondrial bioenergetic homeostasis.The purpose of this study is to determine whether mitochondrial fission and fragmentation can be an adaptive mechanism used by the heart to augment mitochondrial and cardiac function during a normal physiological stress, such as exercise.We demonstrate a novel role for cardiac mitochondrial fission as a normal adaptation to increased energetic demand. During submaximal exercise, physiological mitochondrial fragmentation results in enhanced, rather than impaired, mitochondrial function and is mediated, in part, by β1-adrenergic receptor signaling. Similar to pathological fragmentation, physiological fragmentation is induced by activation of dynamin-related protein 1; however, unlike pathological fragmentation, membrane potential is maintained and regulators of mitophagy are downregulated. Inhibition of fission with P110, Mdivi-1 (mitochondrial division inhibitor), or in mice with cardiac-specific dynamin-related protein 1 ablation significantly decreases exercise capacity.These findings demonstrate the requirement for physiological mitochondrial fragmentation to meet the energetic demands of exercise, as well as providing additional support for the evolving conceptual framework, where mitochondrial fission and fragmentation play a role in the balance between mitochondrial maintenance of normal physiology and response to disease.

  View details for PubMedID 29233845

  View details for PubMedCentralID PMC5775047

• Loss of Endothelial Derived WNT5A is Associated with Reduced Pericyte Recruitment and Small Vessel Loss in Pulmonary Arterial Hypertension. Circulation Yuan, K. n., Shamskhou, E. A., Orcholski, M. E., Nathan, A. n., Reddy, S. n., Honda, H. n., Mani, V. n., Zeng, Y. n., Ozen, M. O., Wang, L. n., Demirci, U. n., Tian, W. n., Nicolls, M. R., de Jesus Perez, V. A. 2018

  Abstract

  Pulmonary arterial hypertension (PAH) is a life-threatening disorder of the pulmonary circulation associated with loss and impaired regeneration of microvessels. Reduced pericyte coverage of pulmonary microvessels is a pathological feature of PAH and is partly due to the inability of pericytes to respond to signaling cues from neighboring pulmonary microvascular endothelial cells (PMVECs). We have shown that activation of the Wnt/PCP pathway is required for pericyte recruitment but whether production and release of specific Wnt ligands by PMVECs is responsible for Wnt/PCP activation in pericytes is unknown.Isolation of pericytes and PMVECs from healthy donor and PAH lungs was carried out using 3G5 or CD31 antibody conjugated magnetic beads. Wnt expression profile of PMVECs was documented via qPCR using a Wnt primer library. Exosome purification from PMVEC media was carried out using the ExoTIC device. Hemodynamic profile, right ventricular function and pulmonary vascular morphometry were obtained in a conditional endothelial specific Wnt5a knockout ( Wnt5aECKO) mouse model under normoxia, chronic hypoxia and hypoxia recovery.Quantification of Wnt ligand expression in healthy PMVECs co-cultured with pericytes demonstrated a 35-fold increase in Wnt5a, a known Wnt/PCP ligand. This Wnt5a spike was not seen in PAH PMVECs, which correlated with inability to recruit pericytes in matrigel co-culture assays. Exosomes purified from media demonstrated an increase in Wnt5a content when healthy PMVECs were co-cultured with pericytes, a finding that was not observed in exosomes of PAH PMVECs. Furthermore, the addition of either recombinant Wnt5a or purified healthy PMVEC exosomes increased pericyte recruitment to PAH PMVECs in co-culture studies. While no differences were noted in normoxia and chronic hypoxia, Wnt5aECKO mice demonstrated persistent pulmonary hypertension and right ventricular failure four weeks after recovery from chronic hypoxia, which correlated with significant reduction, muscularization and decreased pericyte coverage of microvessels.We identify Wnt5a as a key mediator for the establishment of pulmonary endothelial-pericyte interactions and its loss could contribute to PAH by reducing the viability of newly formed vessels. We speculate that therapies that mimic or restore Wnt5a production could help prevent loss of small vessels in PAH.

  View details for PubMedID 30586764

• miR-21 is associated with fibrosis and right ventricular failure. JCI insight Reddy, S., Hu, D., Zhao, M., Blay, E., Sandeep, N., Ong, S., Jung, G., Kooiker, K. B., Coronado, M., Fajardo, G., Bernstein, D. 2017; 2 (9)

  Abstract

  Combined pulmonary insufficiency (PI) and stenosis (PS) is a common long-term sequela after repair of many forms of congenital heart disease, causing progressive right ventricular (RV) dilation and failure. Little is known of the mechanisms underlying this combination of preload and afterload stressors. We developed a murine model of PI and PS (PI+PS) to identify clinically relevant pathways and biomarkers of disease progression. Diastolic dysfunction was induced (restrictive RV filling, elevated RV end-diastolic pressures) at 1 month after generation of PI+PS and progressed to systolic dysfunction (decreased RV shortening) by 3 months. RV fibrosis progressed from 1 month (4.4% ± 0.4%) to 3 months (9.2% ± 1%), along with TGF-β signaling and tissue expression of profibrotic miR-21. Although plasma miR-21 was upregulated with diastolic dysfunction, it was downregulated with the onset of systolic dysfunction), correlating with RV fibrosis. Plasma miR-21 in children with PI+PS followed a similar pattern. A model of combined RV volume and pressure overload recapitulates the evolution of RV failure unique to patients with prior RV outflow tract surgery. This progression was characterized by enhanced TGF-β and miR-21 signaling. miR-21 may serve as a plasma biomarker of RV failure, with decreased expression heralding the need for valve replacement.

  View details for DOI 10.1172/jci.insight.91625

  View details for PubMedID 28469078

• Institution of Veno-arterial Extracorporeal Membrane Oxygenation Does Not Lead to Increased Wall Stress in Patients with Impaired Myocardial Function PEDIATRIC CARDIOLOGY Koth, A. M., Axelrod, D. M., Reddy, S., Roth, S. J., Tacy, T. A., Punn, R. 2017; 38 (3): 539-546

  Abstract

  The effect of veno-arterial extracorporeal membrane oxygenation (VA ECMO) on wall stress in patients with cardiomyopathy, myocarditis, or other cardiac conditions is unknown. We set out to determine the circumferential and meridional wall stress (WS) in patients with systemic left ventricles before and during VA ECMO. We established a cohort of patients with impaired myocardial function who underwent VA ECMO therapy from January 2000 to November 2013. Demographic and clinical data were collected and inotropic score calculated. Measurements were taken on echocardiograms prior to the initiation of VA ECMO and while on full-flow VA ECMO, in order to derive wall stress (circumferential and meridional), VCFc, ejection fraction, and fractional shortening. A post hoc sub-analysis was conducted, separating those with pulmonary hypertension (PH) and those with impaired systemic output. Thirty-three patients met inclusion criteria. The patients' median age was 0.06 years (range 0-18.7). Eleven (33%) patients constituted the organ failure group (Gr2), while the remaining 22 (66%) patients survived to discharge (Gr1). WS and all other echocardiographic measures were not different when comparing patients before and during VA ECMO. Ejection and shortening fraction, WS, and VCFc were not statistically different comparing the survival and organ failure groups. The patients' position on the VCFc-WS curve did not change after the initiation of VA ECMO. Those with PH had decreased WS as well as increased EF after ECMO initiation, while those with impaired systemic output showed no difference in those parameters with initiation of ECMO. The external workload on the myocardium as indicated by WS is unchanged by the institution of VA ECMO support. Furthermore, echocardiographic measures of cardiac function do not reflect the changes in ventricular performance inherent to VA ECMO support. These findings are informative for the interpretation of echocardiograms in the setting of VA ECMO. ECMO may improve ventricular mechanics in those with PH as the primary diagnosis.

  View details for DOI 10.1007/s00246-016-1546-9

  View details for Web of Science ID 000398030200013

• Compassionate deactivation of ventricular assist devices in pediatric patients JOURNAL OF HEART AND LUNG TRANSPLANTATION Hollander, S. A., Axelrod, D. M., Bernstein, D., Cohen, H. J., Sourkes, B., Reddy, S., Magnus, D., Rosenthal, D. N., Kaufman, B. D. 2016; 35 (5): 564-567

  Abstract

  Despite greatly improved survival in pediatric patients with end-stage heart failure through the use of ventricular assist devices (VADs), heart failure ultimately remains a life-threatening disease with a significant symptom burden. With increased demand for donor organs, liberalizing the boundaries of case complexity, and the introduction of destination therapy in children, more children can be expected to die while on mechanical support. Despite this trend, guidelines on the ethical and pragmatic issues of compassionate deactivation of VAD support in children are strikingly absent. As VAD support for pediatric patients increases in frequency, the pediatric heart failure and palliative care communities must work toward establishing guidelines to clarify the complex issues surrounding compassionate deactivation. Patient, family and clinician attitudes must be ascertained and education regarding the psychological, legal and ethical issues should be provided. Furthermore, pediatric-specific planning documents for use before VAD implantation as well as deactivation checklists should be developed to assist with decision-making at critical points during the illness trajectory. Herein we review the relevant literature regarding compassionate deactivation with a specific focus on issues related to children.

  View details for DOI 10.1016/j.healun.2016.03.020

  View details for Web of Science ID 000376951900004

  View details for PubMedID 27197773

• 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

• Time-dependent evolution of functional vs. remodeling signaling in induced pluripotent stem cell-derived cardiomyocytes and induced maturation with biomechanical stimulation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology Jung, G., Fajardo, G., Ribeiro, A. J., Kooiker, K. B., Coronado, M., Zhao, M., Hu, D. Q., Reddy, S., Kodo, K., Sriram, K., Insel, P. A., Wu, J. C., Pruitt, B. L., Bernstein, D. 2015

  Abstract

  Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a powerful platform for uncovering disease mechanisms and assessing drugs for efficacy/toxicity. However, the accuracy with which hiPSC-CMs recapitulate the contractile and remodeling signaling of adult cardiomyocytes is not fully known. We used β-adrenergic receptor (β-AR) signaling as a prototype to determine the evolution of signaling component expression and function during hiPSC-CM maturation. In "early" hiPSC-CMs (less than or equal to d 30), β2-ARs are a primary source of cAMP/PKA signaling. With longer culture, β1-AR signaling increases: from 0% of cAMP generation at d 30 to 56.8 ± 6.6% by d 60. PKA signaling shows a similar increase: 15.7 ± 5.2% (d 30), 49.8 ± 0.5% (d 60), and 71.0 ± 6.1% (d 90). cAMP generation increases 9-fold from d 30 to 60, with enhanced coupling to remodeling pathways (e.g., Akt and Ca(2+)/calmodulin-dependent protein kinase type II) and development of caveolin-mediated signaling compartmentalization. By contrast, cardiotoxicity induced by chronic β-AR stimulation, a major component of heart failure, develops much later: 5% cell death at d 30 vs. 55% at d 90. Moreover, β-AR maturation can be accelerated by biomechanical stimulation. The differential maturation of β-AR functional vs. remodeling signaling in hiPSC-CMs has important implications for their use in disease modeling and drug testing. We propose that assessment of signaling be added to the indices of phenotypic maturation of hiPSC-CMs.-Jung, G., Fajardo, G., Ribeiro, A. J. S., Kooiker, K. B., Coronado, M., Zhao, M., Hu, D.-Q., Reddy, S., Kodo, K., Sriram, K., Insel, P. A., Wu, J. C., Pruitt, B. L., Bernstein, D. Time-dependent evolution of functional vs. remodeling signaling in induced pluripotent stem cell-derived cardiomyocytes and induced maturation with biomechanical stimulation.

  View details for DOI 10.1096/fj.15-280982

  View details for PubMedID 26675706

• Molecular Mechanisms of Right Ventricular Failure. Circulation Reddy, S., Bernstein, D. 2015; 132 (18): 1734-1742

  Abstract

  An abundance of data has provided insight into the mechanisms underlying the development of left ventricular (LV) hypertrophy and its progression to LV failure. In contrast, there is minimal data on the adaptation of the right ventricle (RV) to pressure and volume overload and the transition to RV failure. This is a critical clinical question, because the RV is uniquely at risk in many patients with repaired or palliated congenital heart disease and in those with pulmonary hypertension. Standard heart failure therapies have failed to improve function or survival in these patients, suggesting a divergence in the molecular mechanisms of RV versus LV failure. Although, on the cellular level, the remodeling responses of the RV and LV to pressure overload are largely similar, there are several key differences: the stressed RV is more susceptible to oxidative stress, has a reduced angiogenic response, and is more likely to activate cell death pathways than the stressed LV. Together, these differences could explain the more rapid progression of the RV to failure versus the LV. This review will highlight known molecular differences between the RV and LV responses to hemodynamic stress, the unique stressors on the RV associated with congenital heart disease, and the need to better understand these molecular mechanisms if we are to develop RV-specific heart failure therapeutics.

  View details for DOI 10.1161/CIRCULATIONAHA.114.012975

  View details for PubMedID 26527692

  View details for PubMedCentralID PMC4635965

• The vulnerable right ventricle. Current opinion in pediatrics Reddy, S., Bernstein, D. 2015; 27 (5): 563-568

  Abstract

  The right ventricle (RV) is uniquely at risk in many patients with repaired or palliated congenital heart disease (CHD) such as tetralogy of Fallot, corrected transposition, single right ventricle, and in those with pulmonary hypertension. These patients live with abnormal cardiac loading conditions throughout their life, predisposing them to right heart failure.Standard heart failure therapies, developed to treat left ventricular failure, have failed to improve function or survival in patients with RV failure, suggesting a divergence in the molecular mechanisms of right versus left ventricular failure. As surgical techniques for repair of the most complex forms of RV-affecting CHDs continue to improve, more children with CHD will survive into adulthood. Long-term survival and quality of life will ultimately depend on our ability to preserve RV function.The purpose of this review is to highlight the differences between the right and left ventricular responses to stress, our current knowledge of how the RV adapts to the unique hemodynamic stressors experienced by patients with CHD, and the need to better understand the molecular mechanisms of RV failure, providing new targets for the development of RV-specific heart failure therapeutics.

  View details for DOI 10.1097/MOP.0000000000000268

  View details for PubMedID 26262580

• BMPR2 Preserves Mitochondrial Function and DNA during Reoxygenation to Promote Endothelial Cell Survival and Reverse Pulmonary Hypertension CELL METABOLISM Diebold, I., Hennigs, J. K., Miyagawa, K., Li, C. G., Nickel, N. P., Kaschwich, M., Cao, A., Wang, L., Reddy, S., Chen, P., Nakahira, K., Alcazar, M. A., Hopper, R. K., Ji, L., Feldman, B. J., Rabinovitch, M. 2015; 21 (4): 596-608

  Abstract

  Mitochondrial dysfunction, inflammation, and mutant bone morphogenetic protein receptor 2 (BMPR2) are associated with pulmonary arterial hypertension (PAH), an incurable disease characterized by pulmonary arterial (PA) endothelial cell (EC) apoptosis, decreased microvessels, and occlusive vascular remodeling. We hypothesized that reduced BMPR2 induces PAEC mitochondrial dysfunction, promoting a pro-inflammatory or pro-apoptotic state. Mice with EC deletion of BMPR2 develop hypoxia-induced pulmonary hypertension that, in contrast to non-transgenic littermates, does not reverse upon reoxygenation and is associated with reduced PA microvessels and lung EC p53, PGC1α and TFAM, regulators of mitochondrial biogenesis, and mitochondrial DNA. Decreasing PAEC BMPR2 by siRNA during reoxygenation represses p53, PGC1α, NRF2, TFAM, mitochondrial membrane potential, and ATP and induces mitochondrial DNA deletion and apoptosis. Reducing PAEC BMPR2 in normoxia increases p53, PGC1α, TFAM, mitochondrial membrane potential, ATP production, and glycolysis, and induces mitochondrial fission and a pro-inflammatory state. These features are recapitulated in PAECs from PAH patients with mutant BMPR2.

  View details for DOI 10.1016/j.cmet.2015.03.010

  View details for Web of Science ID 000352500800014

  View details for PubMedID 25863249

• Adrenergic receptor genotype influences heart failure severity and ß-blocker response in children with dilated cardiomyopathy. Pediatric research Reddy, S., Fung, A., Manlhiot, C., Selamet Tierney, E. S., Chung, W. K., Blume, E., Kaufman, B. D., Goldmuntz, E., Colan, S., Mital, S. 2015; 77 (2): 363-369

  Abstract

  Adrenergic receptor (ADR) genotypes are associated with heart failure (HF) and β-blocker response in adults. We assessed the influence of ADR genotypes in children with dilated cardiomyopathy (DCM).Ninety-one children with advanced DCM and 44 with stable DCM were genotyped for three ADR genotypes associated with HF risk in adults: α2cdel322-325, β1Arg389, and β2Arg16. Data were analyzed by genotype and β-blocker use. Mean age at enrollment was 8.5 y.One-year event-free survival was 51% in advanced and 80% in stable DCM. High-risk genotypes were associated with higher left ventricular (LV) filling pressures, higher systemic and pulmonary vascular resistance, greater decline in LV ejection fraction (P < 0.05), and a higher frequency of mechanical circulatory support while awaiting transplant (P = 0.05). While β-blockers did not reduce HF severity in the overall cohort, in the subset with multiple high-risk genotypes, those receiving β-blockers showed better preservation of cardiac function and hemodynamics compared with those not receiving β-blockers (interaction P < 0.05).Our study identifies genetic risk markers that may help in the identification of patients at risk for developing decompensated HF and who may benefit from early institution of β-blocker therapy before progression to decompensated HF.

  View details for DOI 10.1038/pr.2014.183

  View details for PubMedID 25406899

  View details for PubMedCentralID PMC4298011

• Variability of characteristics and outcomes following cardiopulmonary resuscitation events in diverse ICU settings in a single, tertiary care children's hospital*. Pediatric critical care medicine Gupta, P., Yan, K., Chow, V., Dao, D. T., Gossett, J. M., Leong, K., Franzon, D., Halamek, L. P., Reddy, S., Berg, R. A., Roth, S. J., Nadkarni, V. M. 2014; 15 (3): e128-41

  Abstract

  The primary objective of this study was to compare and contrast the characteristics and survival outcomes of cardiopulmonary resuscitation for "monitored" events in pediatric patients treated with chest compressions more than or equal to 1 minute in varied ICU settings.Retrospective observational study.Three different specialized ICUs in a single, tertiary care, academic children's hospital.We collected demographic information, preexisting conditions, preevent characteristics, event characteristics, and outcome data. The primary outcome measure was survival to hospital discharge. Secondary outcome measures included return of spontaneous circulation, 24-hour survival, and survival with good neurologic outcome.None.Four hundred eleven patients treated with chest compressions for more than or equal to 1 minute were included in the analysis: 170 patients were located in the cardiovascular ICU, 157 patients in the neonatal ICU, and 84 patients in the PICU. Arrest durations were longer in the cardiovascular ICU than other ICUs. Use of extracorporeal cardiopulmonary resuscitation was more prevalent in the cardiovascular ICU (cardiovascular ICU, 17%; neonatal ICU, 3%; PICU, 4%). Return of spontaneous circulation, 24-hour survival, survival to hospital discharge, and good neurologic outcome were highest among neonatal ICU patients (survival to discharge, 53%) followed by cardiovascular ICU patients (survival to discharge, 46%) and PICU patients (survival to discharge, 36%). In a multivariable model controlling for patient and event characteristics, using cardiovascular ICU as reference, adjusted odds of survival in PICU were 0.33 (95% CI, 0.14-0.76; p = 0.009) and odds of survival in neonatal ICU were 0.80 (95% CI, 0.31-2.11; p = 0.65).Comparative analysis of pediatric patients undergoing cardiopulmonary resuscitation in three different ICU settings demonstrated a significant variation in baseline, preevent, and event characteristics. Although outcomes vary significantly among the three different ICUs, it was difficult to ascertain if this difference was due to variation in the disease process or variation in the location of the patient.

  View details for DOI 10.1097/PCC.0000000000000067

  View details for PubMedID 24413318

• Atherosclerosis causing recurrent catastrophic aortopulmonary shunt dehiscence in a patient with Alagille syndrome. Pediatric cardiology May, L., Hanley, F. L., Connolly, A. J., Reddy, S. 2013; 34 (8): 1945-1948

  Abstract

  Alagille syndrome (ALGS) is an autosomal dominant disorder associated with cholestatic liver disease, pulmonary valvar stenosis or atresia, vasculopathy, and renal disease. Although the liver and cardiac manifestations contribute to overall morbidity and mortality during their life span, these patients also carry a burden of important but often underappreciated vascular abnormalities. This report describes a 3 year-old girl with Alagille syndrome, hepatic cholestasis, systemic hypertension, hypercholesterolemia, hypertriglyceridemia, and tetralogy of Fallot, pulmonary atresia, and major aortopulmonary collaterals (TOF/PA/MAPCAs). She presented for bilateral pulmonary artery plasty and central shunt upsizing. She then experienced three shunt dehiscence episodes, necessitating emergent intervention. Autopsy showed diffuse atherosclerosis and significant atherosclerotic plaque at the site of shunt dehiscence. This is the first reported case of ALGS with TOF/PA/MAPCAs and catastrophic shunt dehiscence due to significant generalized vasculopathy caused by dyslipidemia and atherosclerosis. Dyslipidemia, a known comorbidity in ALGS, is one of few modifiable risk factors that should be screened for and treated, particularly before cardiac surgery.

  View details for DOI 10.1007/s00246-012-0484-4

  View details for PubMedID 22923029

• Deletion of the beta 2-adrenergic receptor prevents the development of cardiomyopathy in mice JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY Fajardo, G., Zhao, M., Urashima, T., Farahani, S., Hu, D., Reddy, S., Bernstein, D. 2013; 63: 155-164

  Abstract

  Beta adrenergic receptor (β-AR) subtypes act through diverse signaling cascades to modulate cardiac function and remodeling. Previous in vitro studies suggest that β1-AR signaling is cardiotoxic whereas β2-AR signaling is cardioprotective, and may be the case during ischemia/reperfusion in vivo. The objective of this study was to assess whether β2-ARs also play a cardioprotective role in the pathogenesis of non-ischemic forms of cardiomyopathy. To dissect the role of β1 vs β2-ARs in modulating MLP (Muscle LIM Protein) cardiomyopathy, we crossbred MLP-/- with β1-/- or β2-/- mice. Deletion of the β2-AR improved survival, cardiac function, exercise capacity and myocyte shortening; by contrast haploinsufficency of the β1-AR reduced survival. Pathologic changes in Ca(2+) handling were reversed in the absence of β2-ARs: peak Ca(2+) and SR Ca(2+) were decreased in MLP-/- and β1+/-/MLP-/- but restored in β2-/-MLP-/-. These changes were associated with reversal of alterations in troponin I and phospholamban phosphorylation. Gi inhibition increased peak and baseline Ca(2+), recapitulating changes observed in the β2-/-/MLP-/-. The L-type Ca(2+) blocker verapamil significantly decreased cardiac function in β2-/-MLP-/- vs WT. We next tested if the protective effects of β2-AR ablation were unique to the MLP model using TAC-induced heart failure. Similar to MLP, β2-/- mice demonstrated delayed progression of heart failure with restoration of myocyte shortening and peak Ca(2+) and Ca(2+) release. Deletion of β2-ARs prevents the development of MLP-/- cardiomyopathy via positive modulation of Ca(2+) due to removal of inhibitory Gi signaling and increased phosphorylation of troponin I and phospholamban. Similar effects were seen after TAC. Unlike previous models where β2-ARs were found to be cardioprotective, in these two models, β2-AR signaling appears to be deleterious, potentially through negative regulation of Ca(2+) dynamics.

  View details for DOI 10.1016/j.yjmcc.2013.07.016

  View details for Web of Science ID 000325387300017

  View details for PubMedID 23920331

  View details for PubMedCentralID PMC3791213

• FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. journal of clinical investigation Spiekerkoetter, E., Tian, X., Cai, J., Hopper, R. K., Sudheendra, D., Li, C. G., El-Bizri, N., Sawada, H., Haghighat, R., Chan, R., Haghighat, L., de Jesus Perez, V., Wang, L., Reddy, S., Zhao, M., Bernstein, D., Solow-Cordero, D. E., Beachy, P. A., Wandless, T. J., ten Dijke, P., Rabinovitch, M. 2013; 123 (8): 3600-3613

  Abstract

  Dysfunctional bone morphogenetic protein receptor-2 (BMPR2) signaling is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). We used a transcriptional high-throughput luciferase reporter assay to screen 3,756 FDA-approved drugs and bioactive compounds for induction of BMPR2 signaling. The best response was achieved with FK506 (tacrolimus), via a dual mechanism of action as a calcineurin inhibitor that also binds FK-binding protein-12 (FKBP12), a repressor of BMP signaling. FK506 released FKBP12 from type I receptors activin receptor-like kinase 1 (ALK1), ALK2, and ALK3 and activated downstream SMAD1/5 and MAPK signaling and ID1 gene regulation in a manner superior to the calcineurin inhibitor cyclosporine and the FKBP12 ligand rapamycin. In pulmonary artery endothelial cells (ECs) from patients with idiopathic PAH, low-dose FK506 reversed dysfunctional BMPR2 signaling. In mice with conditional Bmpr2 deletion in ECs, low-dose FK506 prevented exaggerated chronic hypoxic PAH associated with induction of EC targets of BMP signaling, such as apelin. Low-dose FK506 also reversed severe PAH in rats with medial hypertrophy following monocrotaline and in rats with neointima formation following VEGF receptor blockade and chronic hypoxia. Our studies indicate that low-dose FK506 could be useful in the treatment of PAH.

  View details for DOI 10.1172/JCI65592

  View details for PubMedID 23867624

• Altered ubiquitin-proteasome signaling in right ventricular hypertrophy and failure. American journal of physiology. Heart and circulatory physiology Rajagopalan, V., Zhao, M., Reddy, S., Fajardo, G., Wang, X., Dewey, S., Gomes, A. V., Bernstein, D. 2013; 305 (4): H551-62

  Abstract

  Alterations in the ubiquitin-proteasome system (UPS) have been described in left ventricular hypertrophy and failure, although results have been inconsistent. The role of the UPS in right ventricular (RV) hypertrophy (RVH) and RV failure (RVF) is unknown. Given the greater percent increase in RV mass associated with RV afterload stress, as present in many congenital heart lesions, we hypothesized that alterations in the UPS could play an important role in RVH/RVF. UPS expression and activity were measured in the RV from mice with RVH/RVF secondary to pulmonary artery constriction (PAC). Epoxomicin and MG132 were used to inhibit the proteasome, and overexpression of the 11S PA28α subunit was used to activate the proteasome. PAC mice developed RVH (109.3% increase in RV weight to body weight), RV dilation with septal shift, RV dysfunction, and clinical RVF. Proteasomal function (26S β5 chymotrypsin-like activity) was decreased 26% (P < 0.05). Protein expression of 19S subunit Rpt5 (P < 0.05), UCHL1 deubiquitinase (P < 0.0001), and Smurf1 E3 ubiquitin ligase (P < 0.01) were increased, as were polyubiquitinated proteins (P < 0.05) and free-ubiquitins (P = 0.05). Pro-apoptotic Bax was increased (P < 0.0001), whereas anti-apoptotic Bcl-2 decreased (P < 0.05), resulting in a sixfold increase in the Bax/Bcl-2 ratio. Proteasomal inhibition did not accelerate RVF. However, proteasome enhancement by cardiac-specific proteasome overexpression partially improved survival. Proteasome activity is decreased in RVH/RVF, associated with upregulation of key UPS regulators and pro-apoptotic signaling. Enhancement of proteasome function partially attenuates RVF, suggesting that UPS dysfunction contributes to RVF.

  View details for DOI 10.1152/ajpheart.00771.2012

  View details for PubMedID 23729213

• Physiologic and molecular characterization of a murine model of right ventricular volume overload. American journal of physiology. Heart and circulatory physiology Reddy, S., Zhao, M., Hu, D., Fajardo, G., Katznelson, E., Punn, R., Spin, J. M., Chan, F. P., Bernstein, D. 2013; 304 (10): H1314-27

  Abstract

  Pulmonary insufficiency (PI) is a common long-term sequel after repair of tetralogy of Fallot, causing progressive right ventricular (RV) dilation and failure. We describe the physiologic and molecular characteristics of the first murine model of RV volume overload. PI was created by entrapping the pulmonary valve leaflets with sutures. Imaging, catheterization, and exercise testing were performed at 1, 3, and 6 mo and compared with sham controls. RNA from the RV free wall was hybridized to Agilent whole genome oligonucleotide microarrays. Volume overload resulted in RV enlargement, decreased RV outflow tract shortening fraction at 1 mo followed by normalization at 3 and 6 mo (39 ± 2, 44 ± 2, and 41 ± 2 vs. 46 ± 3% in sham), early reversal of early and late diastolic filling velocities (E/A ratio) followed by pseudonormalization (0.87 ± 0.08, 0.82 ± 0.08, and 0.96 ± 0.08 vs. 1.04 ± 0.03; P < 0.05), elevated end-diastolic pressure (7.6 ± 0.7, 6.9 ± 0.8, and 7 ± 0.5 vs. 2.7 ± 0.2 mmHg; P < 0.05), and decreased exercise duration (26 ± 0.4, 26 ± 1, and 22 ± 1.3 vs. 30 ± 1.1 min; P < 0.05). Subendocardial RV fibrosis was evident by 1 mo. At 1 mo, 372 genes were significantly downregulated. Mitochondrial pathways and G protein-coupled receptor signaling were the most represented categories. At 3 mo, 434 genes were upregulated and 307 downregulated. While many of the same pathways continued to be downregulated, TNF-α, transforming growth factor-β(1) (TGF-β(1)), p53-signaling, and extracellular matrix (ECM) remodeling transitioned from down- to upregulated. We describe a novel murine model of chronic RV volume overload recapitulating aspects of the clinical disease with gene expression changes suggesting early mitochondrial bioenergetic dysfunction, enhanced TGF-β signaling, ECM remodeling, and apoptosis.

  View details for DOI 10.1152/ajpheart.00776.2012

  View details for PubMedID 23504182

• Hypoxia-inducible factor-1a in pulmonary artery smooth muscle cells lowers vascular tone by decreasing Myosin light chain phosphorylation. Circulation research Kim, Y., Barnes, E. A., Alvira, C. M., Ying, L., Reddy, S., Cornfield, D. N. 2013; 112 (9): 1230-1233

  View details for DOI 10.1161/CIRCRESAHA.112.300646

  View details for PubMedID 23513056

• Dynamic microRNA expression during the transition from right ventricular hypertrophy to failure PHYSIOLOGICAL GENOMICS Reddy, S., Zhao, M., Hu, D., Fajardo, G., Hu, S., Ghosh, Z., Rajagopalan, V., Wu, J. C., Bernstein, D. 2012; 44 (10): 562-575

  Abstract

  MicroRNAs (miRs) are small, noncoding RNAs that are emerging as crucial regulators of cardiac remodeling in left ventricular hypertrophy (LVH) and failure (LVF). However, there are no data on their role in right ventricular hypertrophy (RVH) and failure (RVF). This is a critical question given that the RV is uniquely at risk in patients with congenital right-sided obstructive lesions and in those with systemic RVs. We have developed a murine model of RVH and RVF using pulmonary artery constriction (PAC). miR microarray analysis of RV from PAC vs. control demonstrates altered miR expression with gene targets associated with cardiomyocyte survival and growth during hypertrophy (miR 199a-3p) and reactivation of the fetal gene program during heart failure (miR-208b). The transition from hypertrophy to heart failure is characterized by apoptosis and fibrosis (miRs-34, 21, 1). Most are similar to LVH/LVF. However, there are several key differences between RV and LV: four miRs (34a, 28, 148a, and 93) were upregulated in RVH/RVF that are downregulated or unchanged in LVH/LVF. Furthermore, there is a corresponding downregulation of their putative target genes involving cell survival, proliferation, metabolism, extracellular matrix turnover, and impaired proteosomal function. The current study demonstrates, for the first time, alterations in miRs during the process of RV remodeling and the gene regulatory pathways leading to RVH and RVF. Many of these alterations are similar to those in the afterload-stressed LV. miRs differentially regulated between the RV and LV may contribute to the RVs increased susceptibility to heart failure.

  View details for DOI 10.1152/physiolgenomics.00163.2011

  View details for Web of Science ID 000304367600003

  View details for PubMedID 22454450

  View details for PubMedCentralID PMC3426410

• Recipient Genotype Is a Predictor of Allograft Cytokine Expression and Outcomes After Pediatric Cardiac Transplantation 80th Annual Scientific Session of the American-Heart-Association (AHA) Auerbach, S. R., Manlhiot, C., Reddy, S., Kinnear, C., Richmond, M. E., Gruber, D., McCrindle, B. W., Deng, L., Chen, J. M., Addonizio, L. J., Chung, W. K., Mital, S. ELSEVIER SCIENCE INC. 2009: 1909–17

  Abstract

  This study sought to investigate the influence of recipient renin-angiotensin-aldosterone system (RAAS) genotype on cardiac function, rejection, and outcomes after heart transplantation.The RAAS influences cardiac function and up-regulates inflammatory/immune pathways. Little is known about the effect of recipient RAAS polymorphisms in pediatric cardiac transplantation.Patients <25 years of age, after cardiac transplantation, were enrolled (2003 to 2008) and genotyped for polymorphisms in genes associated with RAAS upregulation: AGT-G, ACE-D, AGTR1-C, CYP11B2-G, and CMA-A. Presence of at least 1 high-risk allele was defined as a high-risk genotype. Univariable and multivariable associations between genotypes and outcomes were assessed in time-dependent models using survival, logistic, or linear regression models. Biopsy samples were immunostained for interleukin (IL)-6, transforming growth factor (TGF)-beta, and tumor necrosis factor (TNF)-alpha during rejection and quiescence.A total of 145 patients were studied, 103 primary cohort and 42 replication cohort; 81% had rejection, 51% had graft dysfunction, and 13% had vasculopathy, 7% died and 8% underwent re-transplantation. A higher number of homozygous high-risk RAAS genotypes was associated with a higher risk of graft dysfunction (hazard ratio [HR]: 1.5, p = 0.02) and a higher probability of death (HR: 2.5, p = 0.04). The number of heterozygous high-risk RAAS genotypes was associated with frequency of rejection (+0.096 events/year, p < 0.001) and rejection-associated graft dysfunction (+0.37 events/year, p = 0.002). IL-6 and TGF-beta were markedly upregulated during rejection in patients with >/=2 high-risk RAAS genotypes.Recipient RAAS polymorphisms are associated with a higher risk of rejection, graft cytokine expression, graft dysfunction, and a higher mortality after cardiac transplantation. This may have implications for use of RAAS inhibitors in high-risk patients after transplantation.

  View details for DOI 10.1016/j.jacc.2009.02.027

  View details for Web of Science ID 000266236600012

  View details for PubMedID 19442892

• Genomic Profiling of Left and Right Ventricular Hypertrophy in Congenital Heart Disease 53rd Annual Scientific Session of the American-College-of-Cardiology Kaufman, B. D., Desai, M., Reddy, S., Osorio, J. C., Chen, J. M., Mosca, R. S., Ferrante, A. W., Mital, S. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2008: 760–67

  Abstract

  The right ventricle (RV) has a lower ability than the left ventricle (LV) to adapt to systemic load. The molecular basis of these differences is not known. We compared hypertrophy-signaling pathways between the RV and the LV in patients with congenital heart disease (CHD).Gene expression was measured using DNA microarrays in myocardium from children with CHD with LV or RV obstructive lesions undergoing surgery. The expression of 175 hypertrophy-signaling genes was compared between the LV (n=7) and the RV (n=11). Hierarchic clustering was performed.Seventeen genes (10%) were differentially expressed between the LV and the RV. Expression of genes for angiotensin, adrenergic, G-proteins, cytoskeletal, and contractile components was lower (P < .05) and expression of maladaptive factors (fibroblast growth factors, transforming growth factor-beta, caspases, ubiquitin) was higher in the RV compared with the LV (P < .05). Five of 7 LV samples clustered together. Only 4 of 11 RV samples clustered with the LV. Genes critical to adaptive remodeling correlated with the degree of LV hypertrophy but not RV hypertrophy.The transcription of pathways of adaptive remodeling was lower in the RV compared with the LV. This may explain the lower ability of the RV to adapt to hemodynamic load in CHD.

  View details for DOI 10.1016/j.cardfail.2008.06.002

  View details for Web of Science ID 000261269800008

  View details for PubMedID 18995181

• Pyloric Stenosis AAP Textbook on Pediatric Care Sushma Reddy, Deepak M Kamat 2008; Chapter315
• RAAS gene polymorphisms influence progression of pediatric hypertrophic cardiomyopathy 77th Scientific Meeting of the American-Heart-Association Kaufman, B. D., Auerbach, S., Reddy, S., Manlhiot, C., Deng, L., Prakash, A., Printz, B. F., Gruber, D., Papavassiliou, D. P., Hsu, D. T., Sehnert, A. J., Chung, W. K., Mital, S. SPRINGER. 2007: 515–23

  Abstract

  Hypertrophic Cardiomyopathy (HCM) is a disease with variable rate of progression. Young age is an independent risk factor for poor outcome in HCM. The influence of renin-angiotensin-aldosterone (RAAS) genotype on the progression of HCM in children is unknown. Children with HCM (n = 65) were enrolled prospectively across two centers (2001-2005). All subjects were genotyped for five RAAS gene polymorphisms previously associated with LV hypertrophy (pro-LVH): AGT M235T, ACE DD, CMA-1903 A/G, AGTR1 1666 A/C and CYP11B2-344 C/T. Linear regression models, based on maximum likelihood estimates, were created to assess the independent effect of RAAS genotype on LV hypertrophy (LVH). Forty-six subjects were homozygous for <2 and 19 were homozygous for > or =2 pro-LVH RAAS polymorphisms. Mean age at presentation was 9.6 +/- 6 years. Forty children had follow-up echocardiograms after a median of 1.5 years. Indexed LV mass (LVMI) and LV mass z-scores were higher at presentation and follow-up in subjects with > or =2 pro-LVH genotypes compared to those with <2 (P < 0.05). Subjects with > or =2 pro-LVH genotypes also demonstrated a greater increase in septal thickness (IVST) and in LV outflow tract (LVOT) obstruction on follow-up (P < 0.05). On multivariate analysis, a higher number of pro-LVH genotypes was associated with a larger effect size (P < 0.05). Pro-LVH RAAS gene polymorphisms are associated with progressive septal hypertrophy and LVOT obstruction in children with HCM. Identification of RAAS modifier genes may help to risk-stratify patients with HCM.

  View details for DOI 10.1007/s00439-007-0429-9

  View details for Web of Science ID 000251143900011

  View details for PubMedID 17851694

• Failure of right ventricular adaptation in children with tetralogy of Fallot 78th Annual Scientific Session of the American-Heart-Association Reddy, S., Osorio, J. C., Duque, A. M., Kaufman, B. D., Phillips, A. B., Chen, J. M., Quaegebeur, J., Mosca, R. S., Mital, S. LIPPINCOTT WILLIAMS & WILKINS. 2006: I37–I42

  Abstract

  The left ventricle (LV) adapts to chronic hypoxia by expressing protective angiogenic, metabolic, and antioxidant genes to improve O2 delivery and energy production, and to minimize reoxygenation injury. The ability of the right ventricle (RV) to adapt to hypoxia in children with tetralogy of Fallot (TOF) is unknown.Gene expression using real-time polymerase chain reaction was measured in RV myocardium obtained during surgical repair of TOF from 23 patients: 13 cyanotic and 10 acyanotic. Results were compared between the 2 groups and correlated with age at surgery, severity of cyanosis, and early postoperative course. The cyanotic patients were younger at surgery compared with acyanotic (5+/-3 versus 9+/-4 months; P=0.01), had higher hematocrit (43+/-4 versus 38+/-3 grams/dL; P=0.004), and lower O2 saturations (84+/-4% versus 98+/-2%; (P<0.001). Cyanotic patients had a significantly lower expression of vascular endothelial growth factor (VEGF), glycolytic enzymes, and glutathione peroxidase (GPX) (P<0.05), and a higher expression of collagen (P<0.01) compared with acyanotic patients. Gene expression correlated inversely with severity of cyanosis ie, preoperative hematocrit (P<0.01) and positively with preoperative saturation (P<0.05). The relationship between gene expression and cyanosis was independent of age at surgery. Ca2+ handling genes did not correlate with the severity of hypoxia. Lower angiogenic, glycolytic, and antioxidant gene expression correlated with increasing postoperative lactate (P<0.05).The RV fails to up regulate adaptive pathways in response to increasing hypoxia in children with TOF. The implications of an early maladaptive response of the RV on long-term RV function require further investigation.

  View details for DOI 10.1161/CIRCULATIONAHA.105.001248

  View details for Web of Science ID 000238688200008

  View details for PubMedID 16820602

• Inlet patch: Heterotopic gastric mucosa - Another contributor to supraesophageal symptoms? JOURNAL OF PEDIATRICS Macha, S., Reddy, S., Rabah, R., Thomas, R., Tolia, V. 2005; 147 (3): 379-382

  Abstract

  To determine prospectively the incidence of an inlet patch (IP) in children requiring esophagogastroduodenoscopy (EGD) and assess the prevalence of presenting symptoms between children with and without an IP.All patients undergoing EGD in a 2-year period were assessed for the presence of an IP with biopsy confirmation. IP, distal esophagus, and stomach biopsy specimens were blindly reviewed by a pathologist for the presence and degree of inflammation and intestinal metaplasia. Symptoms from children with and without an IP were compared.From 407 EGDs done by a single endoscopist, 24 patients had confirmed IP (incidence of 5.9%). The presence and degree of inflammation were always relatively greater in the columnar mucosa of the IP than in the antral/body gastric mucosa in the same patient (P = .0027) Inflammation was similar in the squamous epithelium around the IP and in the distal esophagus (P=.46). Two patients had intestinal metaplasia of the IP. The patients with IPs had a higher prevalence of respiratory symptoms than the control group (P = .03).Children with IPs may have a higher frequency of respiratory symptoms. Periodic surveillance should be performed in children with intestinal metaplasia of an IP.

  View details for DOI 10.1016/j.jpeds.2005.03.002

  View details for Web of Science ID 000232412100023

  View details for PubMedID 16182679

• Restrictive interatrial communication in hypoplastic left heart syndrome after modified Fontan repair ANNALS OF THORACIC SURGERY Nemeh, H. W., Reddy, S., Walters, H. L., Hakimi, M., Ross, R. D. 2003; 76 (6): 2089-2091

  Abstract

  The occurrence of pulmonary venous obstruction after total cavopulmonary connection with intraatrial lateral tunnel is a rare occurrence. We present two cases of hypoplastic left heart syndrome with restrictive interatrial communication presenting late after this type of modified Fontan repair. This occurred even after complete excision of the atrial septum at the time of Stage 1 Norwood in both cases. A novel approach to this problem of resecting the roof of the coronary sinus was utilized to enlarge the interatrial communication.

  View details for DOI 10.1016/S0003-4975(03)01173-1

  View details for Web of Science ID 000186986500072

  View details for PubMedID 14667654