Jeffrey A. Feinstein, MD, MPH

All Publications

• A probabilistic neural twin for treatment planning in peripheral pulmonary artery stenosis. International journal for numerical methods in biomedical engineering Lee, J. D., Richter, J., Pfaller, M. R., Szafron, J. M., Menon, K., Zanoni, A., Ma, M. R., Feinstein, J. A., Kreutzer, J., Marsden, A. L., Schiavazzi, D. E. 2024: e3820

  Abstract

  The substantial computational cost of high-fidelity models in numerical hemodynamics has, so far, relegated their use mainly to offline treatment planning. New breakthroughs in data-driven architectures and optimization techniques for fast surrogate modeling provide an exciting opportunity to overcome these limitations, enabling the use of such technology for time-critical decisions. We discuss an application to the repair of multiple stenosis in peripheral pulmonary artery disease through either transcatheter pulmonary artery rehabilitation or surgery, where it is of interest to achieve desired pressures and flows at specific locations in the pulmonary artery tree, while minimizing the risk for the patient. Since different degrees of success can be achieved in practice during treatment, we formulate the problem in probability, and solve it through a sample-based approach. We propose a new offline-online pipeline for probabilistic real-time treatment planning which combines offline assimilation of boundary conditions, model reduction, and training dataset generation with online estimation of marginal probabilities, possibly conditioned on the degree of augmentation observed in already repaired lesions. Moreover, we propose a new approach for the parametrization of arbitrarily shaped vascular repairs through iterative corrections of a zero-dimensional approximant. We demonstrate this pipeline for a diseased model of the pulmonary artery tree available through the Vascular Model Repository.

  View details for DOI 10.1002/cnm.3820

  View details for PubMedID 38544354

• Younger age at initiation of subcutaneous treprostinil is associated with better response in pediatric Group 1 pulmonary arterial hypertension. Pulmonary circulation Kochanski, J. J., Feinstein, J. A., Ogawa, M., Ritter, V., Hopper, R. K., Adamson, G. T. 2024; 14 (1): e12328

  Abstract

  Children with severe Group 1 pulmonary arterial hypertension (PAH) have an unpredictable response to subcutaneous treprostinil (TRE) therapy, which may be influenced by age, disease severity, or other unknown variables at time of initiation. In this retrospective single-center cohort study, we hypothesized that younger age at TRE initiation, early hemodynamic response (a decrease in pulmonary vascular resistance by ≥30% at follow-up catheterization), and less severe baseline hemodynamics (Rp:Rs < 1.1) would each be associated with better clinical outcomes. In 40 pediatric patients with Group I PAH aged 17 days-18 years treated with subcutaneous TRE, younger age (cut-off of 6-years of age, AUC 0.824) at TRE initiation was associated with superior 5-year freedom from adverse events (94% vs. 39%, p = 0.002), better WHO functional class (I or II: 88% vs. 39% p = 0.003), and better echocardiographic indices of right ventricular function at most recent follow-up. Neither early hemodynamic response nor less severe baseline hemodynamics were associated with better outcomes. Patients who did not have a significant early hemodynamic response to TRE by first follow-up catheterization were unlikely to show subsequent improvement in PVRi (1/8, 13%). These findings may help clinicians counsel families and guide clinical decision making regarding the timing of advanced therapies.

  View details for DOI 10.1002/pul2.12328

  View details for PubMedID 38348195

  View details for PubMedCentralID PMC10860541

• Event-free survival of maralixibat-treated patients with Alagille syndrome compared to a real-world cohort from GALA. Hepatology (Baltimore, Md.) Hansen, B. E., Vandriel, S. M., Vig, P., Garner, W., Mogul, D. B., Loomes, K. M., Piccoli, D. A., Rand, E. B., Jankowska, I., Czubkowski, P., Gliwicz-Miedzinska, D., Gonzales, E. M., Jacquemin, E., Bouligand, J., D'Antiga, L., Nicastro, E., Arnell, H., Fischler, B., Sokal, E., Demaret, T., Siew, S., Stormon, M., Karpen, S. J., Romero, R., Ebel, N. H., Feinstein, J. A., Roberts, A. J., Evans, H. M., Sundaram, S. S., Chaidez, A., Hardikar, W., Shankar, S., Fischer, R. T., Lacaille, F., Debray, D., Lin, H. C., Jensen, M. K., Jaramillo, C., Karthikeyan, P., Indolfi, G., Verkade, H. J., Larson-Nath, C., Quiros-Tejeira, R. E., Valentino, P. L., Rogalidou, M., Dezsofi, A., Squires, J. E., Schwarz, K., Calvo, P. L., Bernabeu, J. Q., Zizzo, A. N., Nebbia, G., Bulut, P., Santos-Silva, E., Fawaz, R., Nastasio, S., Karnsakul, W., Tamara, M. L., Busoms, C. M., Kelly, D., Sandahl, T. D., Jimenez-Rivera, C., Banales, J. M., Mujawar, Q., Li, L., She, H., Wang, J., Kim, K. M., Oh, S. H., Sanchez, M. C., Cavalieri, M. L., Lee, W. S., Hajinicolaou, C., Lertudomphonwanit, C., Waisbourd-Zinman, O., Arikan, C., Alam, S., Carvalho, E., Melere, M., Eshun, J., Onal, Z., Desai, D. M., Wiecek, S., Pinto, R. B., Wolters, V. M., Garcia, J., Beretta, M., Kerkar, N., Brecelj, J., Rock, N., Lurz, E., Blondet, N., Shah, U., Thompson, R. J., Kamath, B. M., Global ALagille Alliance (GALA) Study Group 2023

  Abstract

  BACKGROUND AND AIMS: Alagille syndrome (ALGS) is characterized by chronic cholestasis with associated pruritus and extrahepatic anomalies. Maralixibat, an ileal bile acid transporter inhibitor, is the first-approved pharmacologic therapy for cholestatic pruritus in ALGS. Since long-term placebo-controlled studies are not feasible or ethical in children with rare diseases, a novel approach was taken comparing 6-year outcomes from maralixibat trials with an aligned and harmonized natural history cohort from the Global ALagille Alliance (GALA) study.APPROACH AND RESULTS: Maralixibat trials comprise 84 patients with ALGS with≤6 years of treatment. GALA contains retrospective data from 1438 participants. GALA was filtered to align with key maralixibat eligibility criteria, yielding 469 participants. Serum bile acids (sBA) could not be included in the GALA filtering criteria as these are routinely performed in clinical practice. Index time was determined via maximum likelihood estimation in an effort to align the disease severity between the two cohorts with the initiation of maralixibat. Event-free survival (EFS), defined as time to first event of manifestations of portal hypertension (variceal bleeding, ascites requiring therapy), surgical biliary diversion, liver transplant, or death, was analyzed by Cox proportional hazards methods. Sensitivity analyses and adjustments for covariates were applied. Age, total bilirubin (TB), gamma-glutamyl transferase (GGT), and alanine aminotransferase (ALT) were balanced between groups with no statistical differences. EFS in the maralixibat cohort was significantly better than the GALA cohort (hazard ratio 0.305; 95% CI, 0.189-0.491; p<0.0001). Multiple sensitivity and subgroup analyses (including sBA availability) showed similar findings.CONCLUSIONS: This study demonstrates a novel application of a robust statistical method to evaluate outcomes in long-term intervention studies where placebo comparisons are not feasible, providing wide application for rare diseases. This comparison with real-world natural history data suggests that maralixibat improves EFS in patients with ALGS.

  View details for DOI 10.1097/HEP.0000000000000727

  View details for PubMedID 38146932

• SERUM BILE ACIDS ARE ASSOCIATED WITH NATIVE LIVER SURVIVAL IN PATIENTS WITH ALAGILLE SYNDROME: RESULTS FROM THE GALA STUDY GROUP Perez, C., Vandriel, S. M., Wang, J., Li, L., She, H., Jankowska, I., Czubkowski, P., Gliwicz-Miedzinska, D., Gonzales, E. M., Jacquemin, E., Bouligand, J., D'Antiga, L., Nicastro, E., Fischler, B., Arnell, H., Siew, S., Stormon, M. O., Loomes, K. M., Piccoli, D. A., Rand, E., Squires, J. E., Karpen, S., Romero, R., Kasahara, M., Onal, Z., Sokal, E. M., Demaret, T., Wiecek, S., Lacaille, F., Debray, D., Hardikar, W., Shankar, S., Valentino, P. L., Sundaram, S. S., Chaidez, A., Ebel, N. H., Feinstein, J. A., Mozer-Glassberg, Y., Lin, H. C., Rock, N., Verkade, H. J., Jensen, M., Jaramillo, C., Kim, K., Oh, S., Brecelj, J., Alam, S., Indolfi, G., Blondet, N., Fawaz, R. L., Nastasio, S., Calvo, P., Nebbia, G., Arikan, C., Larson-Nath, C., Zizzo, A. N., Sandahl, T., Tzivinikos, C., El-Koofy, N. M., Elmonem, M. A., Desai, D. M., Karnsakul, W., Karthikeyan, P., Bulut, P., Kerkar, N., Wolters, V. M., Roberts, A. J., Evans, H. M., Sanchez, M., Cavalieri, M., Kelly, D. A., Lee, W., Hajinicolaou, C., Lertudomphonwanit, C., Fischer, R. T., Bernabeu, J., Quiros-Tejeira, R. E., Melere, M., Carvalho, E., Eshun, J., Zellos, A., Dezsofi, A., Pinto, R., Schwarz, K. B., Rogalidou, M., Garcia, J., Tamara, M., Beretta, M., Mujawar, Q., Santos-Silva, E., Busoms, C., Lurz, E., Goncalves, C., Jimenez-Rivera, C., Banales, J. M., Shah, U., Thompson, R. J., Hansen, B. E., Kamath, B. M., Global ALagille Alliance GALA LIPPINCOTT WILLIAMS & WILKINS. 2023: S121-S124

  View details for Web of Science ID 001094865400122

• SURGICAL BILIARY DIVERSION IS ASSOCIATED WITH AN INCREASED RISK OF LIVER TRANSPLANTATION OR DEATH IN ALAGILLE SYNDROME Vandriel, S. M., Loomes, K. M., Piccoli, D. A., Rand, E., Li, L., She, H., Wang, J., Fawaz, R. L., Nastasio, S., Verkade, H. J., Jensen, M., Jaramillo, C., Rock, N., Jankowska, I., Czubkowski, P., Gliwicz-Miedzinska, D., Lin, H. C., Kelly, D. A., Larson-Nath, C., Lacaille, F., Debray, D., Karpen, S., Romero, R., Molera Busoms, C., Sokal, E. M., Demaret, T., El-Koofy, N. M., Elmonem, M. A., Sundaram, S. S., Chaidez, A., Karthikeyan, P., Karnsakul, W., Hardikar, W., Shankar, S., Quiros-Tejeira, R. E., Alam, S., Bulut, P., Hajinicolaou, C., Wolters, V. M., Onal, Z., Gonzales, E. M., Jacquemin, E., Bouligand, J., D'Antiga, L., Nicastro, E., Ebel, N. H., Feinstein, J. A., Fischler, B., Arnell, H., Siew, S., Stormon, M. O., Kim, K., Oh, S., Roberts, A. J., Evans, H. M., Camila Sanchez, M., Lorena Cavalieri, M., Lee, W., Lertudomphonwanit, C., Fischer, R. T., Waisbourd-Zinman, O., Squires, J. E., Arikan, C., Quintero Bernabeu, J., Kasahara, M., Carvalho, E., Ferreira, C., Valentino, P. L., Indolfi, G., Eshun, J., Calvo, P., Desai, D. M., Zellos, A., Dezsofi, A., Wiecek, S., Nebbia, G., Pinto, R., Rogalidou, M., Legarda Tamara, M., Zizzo, A. N., Garcia, J., Schwarz, K. B., Blondet, N., Beretta, M., Sandahl, T., Brecelj, J., Goncalves, C., Lurz, E., Santos-Silva, E., Kerkar, N., Mujawar, Q., Tzivinikos, C., Shah, U., Jimenez-Rivera, C., Banales, J. M., Thompson, R. J., Hansen, B. E., Kamath, B. M., Global ALagille Alliance GALA LIPPINCOTT WILLIAMS & WILKINS. 2023: S20-S23

  View details for Web of Science ID 001094865400013

• A computational growth and remodeling framework for adaptive and maladaptive pulmonary arterial hemodynamics. Biomechanics and modeling in mechanobiology Szafron, J. M., Yang, W., Feinstein, J. A., Rabinovitch, M., Marsden, A. L. 2023

  Abstract

  Hemodynamic loading is known to contribute to the development and progression of pulmonary arterial hypertension (PAH). This loading drives changes in mechanobiological stimuli that affect cellular phenotypes and lead to pulmonary vascular remodeling. Computational models have been used to simulate mechanobiological metrics of interest, such as wall shear stress, at single time points for PAH patients. However, there is a need for new approaches that simulate disease evolution to allow for prediction of long-term outcomes. In this work, we develop a framework that models the pulmonary arterial tree through adaptive and maladaptive responses to mechanical and biological perturbations. We coupled a constrained mixture theory-based growth and remodeling framework for the vessel wall with a morphometric tree representation of the pulmonary arterial vasculature. We show that non-uniform mechanical behavior is important to establish the homeostatic state of the pulmonary arterial tree, and that hemodynamic feedback is essential for simulating disease time courses. We also employed a series of maladaptive constitutive models, such as smooth muscle hyperproliferation and stiffening, to identify critical contributors to development of PAH phenotypes. Together, these simulations demonstrate an important step toward predicting changes in metrics of clinical interest for PAH patients and simulating potential treatment approaches.

  View details for DOI 10.1007/s10237-023-01744-z

  View details for PubMedID 37658985

• Pulmonary Vasodilator Therapy in Pediatric Patients on Ventricular Assist Device Support: A Single-Center Experience and Proposal for Use. ASAIO journal (American Society for Artificial Internal Organs : 1992) Schramm, J. E., Dykes, J. C., Hopper, R. K., Feinstein, J. A., Rosenthal, D. N., Kameny, R. J. 2023

  Abstract

  Pediatric precapillary pulmonary hypertension can develop in response to systemic atrial hypertension. Systemic atrial decompression following ventricular assist device (VAD) implantation may not sufficiently lower pulmonary vascular resistance (PVR) to consider heart transplant candidacy. Prostacyclins have been used in adult VAD patients with success, but pediatric data on safety and efficacy in this population are limited. We sought to describe our center's experience to show its safety and to present our current protocol for perioperative use. We reviewed our use of prostacyclin therapy in pediatric patients on VAD support with high PVR from 2016 to 2021. Of the 17 patients who met inclusion, 12 survived to transplant and 1 is alive with VAD in situ. All patients survived posttransplant. With continuous intravenous (IV) epoprostenol or treprostinil therapy, there were no bleeding complications or worsening of end-organ function. A significant reduction was observed in vasoactive inotropic scores by 49% in the first 24 hours post-prostacyclin initiation. The proportion of patients surviving to transplant in this high-risk cohort is favorable. In conclusion, prostacyclins may be safe to use in patients with elevated PVR as part of their VAD and transplant course and may provide a transplant option in those otherwise not candidates.

  View details for DOI 10.1097/MAT.0000000000002023

  View details for PubMedID 37556563

• Acute Hemodynamics in the Fontan Circulation: Open-Label Study of Vasopressin. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies Adamson, G. T., Yu, J., Ramamoorthy, C., Peng, L. F., Taylor, A., Lennig, M., Schmidt, A. R., Feinstein, J. A., Navaratnam, M. 2023

  Abstract

  OBJECTIVE: To describe the acute hemodynamic effect of vasopressin on the Fontan circulation, including systemic and pulmonary pressures and resistances, left atrial pressure, and cardiac index.DESIGN: Prospective, open-label, nonrandomized study (NCT04463394).SETTING: Cardiac catheterization laboratory at Lucile Packard Children's Hospital, Stanford.PATIENTS: Patients 3-50 years old with a Fontan circulation who were referred to the cardiac catheterization laboratory for hemodynamic assessment and/or intervention.INTERVENTIONS: A 0.03 U/kg IV (maximum dose 1 unit) bolus of vasopressin was administered over 5 minutes, followed by a maintenance infusion of 0.3 mU/kg/min (maximum dose 0.03 U/min).MEASUREMENTS AND MAIN RESULTS: Comprehensive cardiac catheterization measurements before and after vasopressin administration. Measurements included pulmonary artery, atrial, and systemic arterial pressures, oxygen saturations, and systemic and pulmonary flows and resistances. There were 28 patients studied. Median age was 13.5 (9.1, 17) years, and 16 (57%) patients had a single or dominant right ventricle. Following vasopressin administration, systolic blood pressure and systemic vascular resistance (SVR) increased by 17.5 (13.0, 22.8) mm Hg (Z value -4.6, p < 0.001) and 3.8 (1.8, 7.5) Wood Units (Z value -4.6, p < 0.001), respectively. The pulmonary vascular resistance (PVR) decreased by 0.4±0.4 WU (t statistic 6.2, p < 0.001), and the left atrial pressure increased by 1.0 (0.0, 2.0) mm Hg (Z value -3.5, p < 0.001). The PVR:SVR decreased by 0.04±0.03 (t statistic 8.1, p < 0.001). Neither the pulmonary artery pressure (median difference 0.0 [-1.0, 1.0], Z value -0.4, p = 0.69) nor cardiac index (0.1±0.3, t statistic -1.4, p = 0.18) changed significantly. There were no adverse events.CONCLUSIONS: In Fontan patients undergoing cardiac catheterization, vasopressin administration resulted in a significant increase in systolic blood pressure, SVR, and left atrial pressure, decrease in PVR, and no change in cardiac index or pulmonary artery pressure. These findings suggest that in Fontan patients vasopressin may be an option for treating systemic hypotension during sedation or general anesthesia.

  View details for DOI 10.1097/PCC.0000000000003326

  View details for PubMedID 37462430

• Serum bile acids are associated with native liver survival in patients with Alagille syndrome: results from the GALA study group Perez, C., Vandriel, S. M., Wang, J., Li Liting, She, H., Jankowska, I., Czubkowski, P., Gliwicz, D., Gonzales, E., Jacquemin, E., Bouligand, J., D'Antiga, L., Nicastro, E., Fischler, B., Arnell, H., Siew, S., Stormon, M., Loomes, K. M., Piccoli, D. A., Rand, E. B., Squires, J. E., Karpen, S. J., Romero, R., Kasahara, M., Onal, Z., Sokal, E., Demaret, T., Wiecek, S., Lacaille, F., Debray, D., Hardikar, W., Shankar, S., Valentino, P., Sundaram, S., Chaidez, A., Ebel, N., Feinstein, J., Mozar-Glazberg, Y., Lin, H., Rock, N., Verkade, H. J., Jensen, M. K., Jaramillo, C., Kim, K., Oh, S., Brecelj, J., Alam, S., Indolfi, G., Blondet, N., Fawaz, R., Nastasio, S., Calvo, P., Nebbia, G., Arikan, C., Larson-Nath, C., Zizzo, A. N., Sandahl, T., Tzivinikos, C., El-Koofy, N., Elmonem, M., Desai, D., Karnsakul, W., Karthikeyan, P., Bulut, P., Kerkar, N., Wolters, V., Roberts, A. J., Evans, H., Sanchez, M., Cavalieri, M., Kelly, D., Lee, W., Hajinicolaou, C., Lertudomphonwanit, C., Fischer, R., Bernabeu, J., Quiros-Tejeira, R. E., Melere, M., Carvalho, E., Eshun, J., Zellos, A., Fi, A., Pinto, R., Schwarz, K., Rogalidou, M., Garcia, J., Tamara, M., Beretta, M., Mujawar, Q., Santos-Silva, E., Busoms, C., Lurz, E., Goncalves, C., Jimenez-Rivera, C., Banales, J. M., Shah, U., Thompson, R., Hansen, B., Kamath, B. M. ELSEVIER. 2023: S971-S973

  View details for Web of Science ID 001037135104146

• A Computational Growth and Remodeling Framework for Adaptive and Maladaptive Pulmonary Arterial Hemodynamics. bioRxiv : the preprint server for biology Szafron, J. M., Yang, W., Feinstein, J. A., Rabinovitch, M., Marsden, A. L. 2023

  Abstract

  Hemodynamic loading is known to contribute to the development and progression of pulmonary arterial hypertension (PAH). This loading drives changes in mechanobiological stimuli that affect cellular phenotypes and lead to pulmonary vascular remodeling. Computational models have been used to simulate mechanobiological metrics of interest, such as wall shear stress, at single time points for PAH patients. However, there is a need for new approaches that simulate disease evolution to allow for prediction of long-term outcomes. In this work, we develop a framework that models the pulmonary arterial tree through adaptive and maladaptive responses to mechanical and biological perturbations. We coupled a constrained mixture theory-based growth and remodeling framework for the vessel wall with a morphometric tree representation of the pulmonary arterial vasculature. We show that non-uniform mechanical behavior is important to establish the homeostatic state of the pulmonary arterial tree, and that hemodynamic feedback is essential for simulating disease time courses. We also employed a series of maladaptive constitutive models, such as smooth muscle hyperproliferation and stiffening, to identify critical contributors to development of PAH phenotypes. Together, these simulations demonstrate an important step towards predicting changes in metrics of clinical interest for PAH patients and simulating potential treatment approaches.

  View details for DOI 10.1101/2023.04.20.537714

  View details for PubMedID 37131683

  View details for PubMedCentralID PMC10153237

• Serial Lung Perfusion Scintigraphy After Unifocalization and Repair of Tetralogy of Fallot With Major Aortopulmonary Collaterals. World journal for pediatric & congenital heart surgery Wise-Faberowski, L., Long, J., Ma, M., Nadel, H. R., Shek, J., Feinstein, J. A., Martin, E., Hanley, F. L., McElhinney, D. B. 2023: 21501351231162959

  Abstract

  BACKGROUND: In patients with tetralogy of Fallot and major aortopulmonary collaterals (MAPCAs), pulmonary blood supply is highly variable. Our approach to this condition emphasizes complete unifocalization of the pulmonary circulation, incorporating all lung segments and addressing stenoses out to the segmental level. Post-repair, we recommend serial lung perfusion scintigraphy (LPS) to assess short-term changes in pulmonary blood flow distribution.METHODS: We reviewed post-discharge and follow-up LPS performed through three years post-repair and analyzed serial changes in perfusion, risk factors for change, and the relationship between LPS parameters and pulmonary artery reintervention.RESULTS: Of 543 patients who had postoperative LPS results in our system, 317 (58%) had only a predischarge LPS available for review, while 226 had 1 (20%) or more (22%) follow-up scans within three years. Overall, pulmonary flow distribution prior to discharge was balanced, and there was minimal change over time; however, there was considerable patient-to-patient variation in both metrics. On multivariable mixed modeling, time after repair (P=.025), initial anatomy consisting of a ductus arteriosus to one lung (P<.001), and age at repair (P=.014) were associated with changes on serial LPS. Patients who had follow-up LPS were more likely to undergo pulmonary artery reintervention, but within that cohort, LPS parameters were not associated with reintervention risk.CONCLUSION: Serial LPS during the first year after MAPCAs repair is a noninvasive method of screening for significant post-repair pulmonary artery stenosis that occurs in a small but important minority of patients. In patients who received follow-up LPS beyond the perioperative period, there was minimal change over time in the population overall, but large changes in some patients and considerable variability. There was no statistical association between LPS findings and pulmonary artery reintervention.

  View details for DOI 10.1177/21501351231162959

  View details for PubMedID 36972512

• International practice heterogeneity in pre-transplant management of pulmonary hypertension related to pediatric left heart disease. Pediatric transplantation Hopper, R. K., van der Have, O., Hollander, S. A., Dipchand, A. I., Perez de Sa, V., Feinstein, J. A., Tran-Lundmark, K. 2023: e14461

  Abstract

  BACKGROUND: Elevated pulmonary vascular resistance (PVR) in the setting of left heart failure may contribute to poor outcomes after pediatric heart transplant (HTx), but peri-transplant management is variable.METHODS: We sought to characterize international practice by surveying physicians at pediatric HTx centers.RESULTS: We received 49 complete responses from 39 centers in 16 countries. Most respondents are pediatric cardiologists (90%), practice at centers offering heart (86%) and lung (55%) transplant, and perform pre-HTx acute vasoreactivity testing (AVT, 88%) in patients with elevated PVR. Half (51%) reported defining a PVR cutoff for HTx eligibility as ≤6WUm2 (56%) post-AVT (84%). The highest post-AVT PVR ever accepted for HTx ranged from 3-14.4 (median 6) WUm2 . To treat elevated pre-transplant PVR, phosphodiesterase type 5 inhibitors are most common (65%) followed by oxygen (31%), nitric oxide (14%), endothelin receptor antagonists (11%), and prostacyclins (6%). Nearly a third (31%) do not routinely use pulmonary vasodilators without implantation of a left ventricular assist device (LVAD). Case scenarios highlight treatment variability: in a restrictive cardiomyopathy scenario, HTx listing with post-transplant vasodilator therapy was favored, whereas in a Shone's complex patient with fixed PVR, LVAD±pulmonary vasodilators followed by repeat catheterization was most common. Management of dilated cardiomyopathy with reactive PVR was variable. Most continue vasodilator therapy until HTx (16%), PVR normalizes (16%) or ≤6months.CONCLUSIONS: Management of elevated PVR in children awaiting HTx is heterogenous. Evidence-based guidelines are needed to allow for longitudinal determination of optimal outcomes and standardized care.

  View details for DOI 10.1111/petr.14461

  View details for PubMedID 36593638

• The development and efficacy of a paediatric cardiology fellowship online preparatory course. Cardiology in the young Motonaga, K. S., Sacks, L., Olson, I., Balasubramanian, S., Chen, S., Peng, L., Feinstein, J. A., Silverman, N. H., Hanley, F. L., Axelrod, D. M., Krawczeski, C. D., Arunamata, A., Kwiatkowski, D. M., Ceresnak, S. R. 2022: 1-6

  Abstract

  BACKGROUND: The transition from residency to paediatric cardiology fellowship is challenging due to the new knowledge and technical skills required. Online learning can be an effective didactic modality that can be widely accessed by trainees. We sought to evaluate the effectiveness of a paediatric cardiology Fellowship Online Preparatory Course prior to the start of fellowship.METHODS: The Online Preparatory Course contained 18 online learning modules covering basic concepts in anatomy, auscultation, echocardiography, catheterisation, cardiovascular intensive care, electrophysiology, pulmonary hypertension, heart failure, and cardiac surgery. Each online learning module included an instructional video with pre-and post-video tests. Participants completed pre- and post-Online Preparatory Course knowledge-based exams and surveys. Pre- and post-Online Preparatory Course survey and knowledge-based examination results were compared via Wilcoxon sign and paired t-tests.RESULTS: 151 incoming paediatric cardiology fellows from programmes across the USA participated in the 3 months prior to starting fellowship training between 2017 and 2019. There was significant improvement between pre- and post-video test scores for all 18 online learning modules. There was also significant improvement between pre- and post-Online Preparatory Course exam scores (PRE 43.6 ± 11% versus POST 60.3 ± 10%, p < 0.001). Comparing pre- and post-Online Preparatory Course surveys, there was a statistically significant improvement in the participants' comfort level in 35 of 36 (97%) assessment areas. Nearly all participants (98%) agreed or strongly agreed that the Online Preparatory Course was a valuable learning experience and helped alleviate some anxieties (77% agreed or strongly agreed) related to starting fellowship.CONCLUSION: An Online Preparatory Course prior to starting fellowship can provide a foundation of knowledge, decrease anxiety, and serve as an effective educational springboard for paediatric cardiology fellows.

  View details for DOI 10.1017/S1047951122003626

  View details for PubMedID 36440543

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

  Abstract

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

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

  View details for PubMedID 36372884

• Quantification of systemic-to-pulmonary collateral flow in univentricular physiology with 4D flow MRI. Cardiology in the young Ridderbos, F. S., Chan, F. P., van Melle, J. P., Ebels, T., Feinstein, J. A., Berger, R. M., Willems, T. P. 2022: 1-9

  Abstract

  PURPOSE: Systemic-to-pulmonary collateral flow is a well-recognised phenomenon in patients with single ventricle physiology, but remains difficult to quantify. The aim was to compare the reported formula's that have been used for calculation of systemic-to-pulmonary-collateral flow to assess their consistency and to quantify systemic-to-pulmonary collateral flow in patients with a Glenn and/or Fontan circulation using four-dimensional flow MRI (4D flow MR).METHODS: Retrospective case-control study of Glenn and Fontan patients who had a 4D flow MR study. Flows were measured at the ascending aorta, left and right pulmonary arteries, left and right pulmonary veins, and both caval veins. Systemic-to-pulmonary collateral flow was calculated using two formulas: 1) pulmonary veins - pulmonary arteries and 2) ascending aorta - caval veins. Anatomical identification of collaterals was performed using the 4D MR image set.RESULTS: Fourteen patients (n = 11 Fontan, n = 3 Glenn) were included (age 26 [22-30] years). Systemic-to-pulmonary collateral flow was significantly higher in the patients than the controls (n = 10, age 31.2 [15.1-38.4] years) with both formulas: 0.28 [0.09-0.5] versus 0.04 [-0.66-0.21] l/min/m2 (p = 0.036, formula 1) and 0.67 [0.24-0.88] versus -0.07 [-0.16-0.08] l/min/m2 (p < 0.001, formula 2). In patients, systemic-to-pulmonary collateral flow differed significantly between formulas 1 and 2 (13% versus 26% of aortic flow, p = 0.038). In seven patients, veno-venous collaterals were detected and no aortopulmonary collaterals were visualised.CONCLUSION: 4D flow MR is able to detect increased systemic-to-pulmonary collateral flow and visualise collaterals vessels in Glenn and Fontan patients. However, the amount of systemic-to-pulmonary collateral flow varies with the formula employed. Therefore, further research is necessary before it could be applied in clinical care.

  View details for DOI 10.1017/S1047951122002840

  View details for PubMedID 36120930

• ISHLT consensus statement: Perioperative management of patients with pulmonary hypertension and right heart failure undergoing surgery. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation McGlothlin, D. P., Granton, J., Klepetko, W., Beghetti, M., Rosenzweig, E. B., Corris, P. A., Horn, E., Kanwar, M. K., McRae, K., Roman, A., Tedford, R., Badagliacca, R., Bartolome, S., Benza, R., Caccamo, M., Cogswell, R., Dewachter, C., Donahoe, L., Fadel, E., Farber, H. W., Feinstein, J., Franco, V., Frantz, R., Gatzoulis, M., Hwa Anne Goh, C., Guazzi, M., Hansmann, G., Hastings, S., Heerdt, P. M., Hemnes, A., Herpain, A., Hsu, C., Kerr, K., Kolaitis, N. A., Kukreja, J., Madani, M., McCluskey, S., McCulloch, M., Moser, B., Navaratnam, M., Radegran, G., Reimer, C., Savale, L., Shlobin, O. A., Svetlichnaya, J., Swetz, K., Tashjian, J., Thenappan, T., Vizza, C. D., West, S., Zuckerman, W., Zuckermann, A., De Marco, T. 2022; 41 (9): 1135-1194

  Abstract

  Pulmonary hypertension (PH) is a risk factor for morbidity and mortality in patients undergoing surgery and anesthesia. This document represents the first international consensus statement for the perioperative management of patients with pulmonary hypertension and right heart failure. It includes recommendations for managing patients with PH being considered for surgery, including preoperative risk assessment, planning, intra- and postoperative monitoring and management strategies that can improve outcomes in this vulnerable population. This is a comprehensive document that includes common perioperative patient populations and surgical procedures with unique considerations.

  View details for DOI 10.1016/j.healun.2022.06.013

  View details for PubMedID 36123001

• Natural History of Liver Disease in a Large International Cohort of Children with Alagille syndrome: Results from The GALA Study. Hepatology (Baltimore, Md.) Vandriel, S. M., Li, L., She, H., Wang, J., Gilbert, M. A., Jankowska, I., Czubkowski, P., Gliwicz-Miedzinska, D., Gonzales, E. M., Jacquemin, E., Bouligand, J., Spinner, N. B., Loomes, K. M., Piccoli, D. A., D'Antiga, L., Nicastro, E., Sokal, E., Demaret, T., Ebel, N. H., Feinstein, J. A., Fawaz, R., Nastasio, S., Lacaille, F., Debray, D., Arnell, H., Fischler, B., Siew, S., Stormon, M., Karpen, S. J., Romero, R., Kim, K. M., Baek, W. Y., Hardikar, W., Shankar, S., Roberts, A. J., Evans, H. M., Jensen, M. K., Kavan, M., Sundaram, S. S., Chaidez, A., Karthikeyan, P., Sanchez, M. C., Cavalieri, M. L., Verkade, H. J., Lee, W. S., Squires, J. E., Hajinicolaou, C., Lertudomphonwanit, C., Fischer, R. T., Larson-Nath, C., Mozer-Glassberg, Y., Arikan, C., Lin, H. C., Quintero Bernabeu, J., Alam, S., Kelly, D., Carvalho, E., Ferreira, C. T., Indolfi, G., Quiros-Tejeira, R. E., Bulut, P., Calvo, P. L., Onal, Z., Valentino, P. L., Desai, D. M., Eshun, J., Rogalidou, M., Dezsofi, A., Wiecek, S., Nebbia, G., Borges Pinto, R., Wolters, V. M., Tamara, M. L., Zizzo, A. N., Garcia, J., Schwarz, K., Beretta, M., Sandahl, T. D., Jimenez-Rivera, C., Kerkar, N., Brecelj, J., Mujawar, Q., Rock, N., Busoms, C. M., Karnsakul, W., Lurz, E., Santos-Silva, E., Blondet, N., Bujanda, L., Shah, U., Thompson, R. J., Hansen, B. E., Kamath, B. M., Global ALagille Alliance (GALA) Study Group 2022

  Abstract

  BACKGROUND: Alagille syndrome (ALGS) is a multisystem disorder, characterized by cholestasis. Existing outcome data are largely derived from tertiary centers and real-world data are lacking. This study aimed to elucidate the natural history of liver disease in a contemporary, international, cohort of children with ALGS.METHODS: Multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born Jan-1997 - Aug-2019. Native liver survival (NLS) and event-free survival rates were assessed. Cox models were constructed to identify early biochemical predictors of clinically evident portal hypertension (CEPH) and NLS.RESULTS: 1433 children (57% male) from 67 centers in 29 countries were included. 10 and 18-years NLS rates were 54.4% and 40.3%. By 10 and 18-years, 51.5% and 66.0% of ALGS children experienced ≥1 adverse liver-related event (CEPH, transplant or death). Children (>6 and ≤12 months) with median total bilirubin (TB) levels between ≥5.0 and <10.0 mg/dL had a 4.1-fold (95% CI 1.6 - 10.8) and those ≥10.0 mg/dL had an 8.0-fold (95% CI 3.4 - 18.4) increased risk of developing CEPH compared with those <5.0 mg/dL. Median TB levels between ≥5.0 and <10.0 mg/dL and >10.0 mg/dL were associated with a 4.8 (95% CI 2.4 - 9.7) and 15.6 (95% CI 8.7 - 28.2) increased risk of transplantation relative to <5.0 mg/dL. Median TB <5.0 mg/dL were associated with higher NLS rates relative to ≥5.0 mg/dL, with 79% reaching adulthood with native liver (p<0.001).CONCLUSIONS: In this large international cohort of ALGS, only 40.3% of children reach adulthood with their native liver. A TB <5.0 mg/dL between 6-and-12-months of age is associated with better hepatic outcomes. These thresholds provide clinicians with an objective tool to assist with clinical decision-making and in the evaluation of novel therapies.

  View details for DOI 10.1002/hep.32761

  View details for PubMedID 36036223

• Pulmonary Hypertension in Children with Down Syndrome: Results from the Pediatric Pulmonary Hypertension Network Registry. The Journal of pediatrics Hopper, R. K., Abman, S. H., Elia, E. G., Avitabile, C. M., Yung, D., Mullen, M. P., Austin, E. D., Bates, A., Handler, S. S., Feinstein, J. A., Ivy, D. D., Kinsella, J. P., Mandl, K. D., Raj, J. U., Sleeper, L. A., Pediatric Pulmonary Hypertension Network Investigators 2022

  Abstract

  OBJECTIVE: To characterize distinct comorbidities, outcomes, and treatment patterns in children with Down syndrome and pulmonary hypertension) in a large, multicenter pediatric pulmonary hypertension registry.STUDY DESIGN: We analyzed data from the Pediatric Pulmonary Hypertension Network (PPHNet) Registry, comparing demographic and clinical characteristics of children with and without Down syndrome. We examined factors associated with pulmonary hypertension resolution and a composite outcome of pulmonary hypertension severity in the cohort with Down syndrome.RESULTS: Of 1475 pediatric patients with pulmonary hypertension, 158 (11%) had Down syndrome. Median age of pulmonary hypertension diagnosis in patients with Down syndrome was 0.49 years (IQR 0.21, 1.77), similar to non-Down syndrome. There was no difference in rates of cardiac catheterization and prescribed pulmonary hypertension medications in children with or without Down syndrome. Comorbidities in Down syndrome included congenital heart disease (95%, repaired in 68%), sleep apnea (56%), prematurity (49%), recurrent respiratory exacerbations (35%), gastroesophageal reflux (38%), and aspiration (31%). pulmonary hypertension resolved in 43% after 3 years, associated with pulmonary hypertension diagnosis age <6 months (54% vs 29%, p=0.002) and pre-tricuspid shunt (65% vs 38%, p=0.02). Five-year transplant-free survival was 88% (95% CI: 80-97%). Tracheostomy (HR 3.29, 95% CI 1.61-6.69) and reflux medication use (HR 2.08, 95% CI 1.11-3.90) were independently associated with for a composite outcome of severe pulmonary hypertension.CONCLUSIONS: Despite high rates of cardiac and respiratory comorbidities that influence pulmonary hypertension severity, children with Down syndrome-associated pulmonary hypertension generally have survival rates similar to children with non-Down syndrome-associated pulmonary hypertension. Pulmonary hypertension resolution is common, but reduced among children with complicated respiratory comorbidities.

  View details for DOI 10.1016/j.jpeds.2022.08.027

  View details for PubMedID 36027975

• Subcutaneous Treprostinil Improves Surgical Candidacy for Next Stage Palliation in Single Ventricle Patients With High-Risk Hemodynamics. Seminars in thoracic and cardiovascular surgery Sullivan, R. T., Handler, S. S., Feinstein, J. A., Ogawa, M., Liu, E., Ma, M., Hopper, R. K., Norris, J., Hollander, S. A., Chen, S. 2022

  Abstract

  Single ventricle (SV) patients with pulmonary vascular disease (SV-PVD) are considered poor surgical candidates for Glenn or Fontan palliation. Given limited options for Stage 1 (S1) and Stage 2 (S2) SV patients with SV-PVD, we report on the use of subcutaneous treprostinil (TRE) to treat SV-PVD in this population. This single-center, retrospective cohort study examined SV patients who were not candidates for subsequent surgical palliation due to SV-PVD and were treated with TRE. The primary outcome was ability to progress to the next surgical stage; secondary outcomes included changes in hemodynamics after TRE initiation. Between 3/2014 and 8/2021, 17 SV patients received TRE for SV-PVD: 11 after S1 and 6 after S2 (median PVR 4.1 [IQR 3.2-4.8] WU*m2, and 5.0 [IQR 1.5-6.1] WU*m2, respectively). Nine of eleven (82%) S1 progressed to S2, and 2 (18%) underwent heart transplant (HTx). Three of six (50%) S2 progressed to Fontan, 1 underwent HTx and 2 are awaiting Fontan on TRE. TRE significantly decreased PVR in S1 patients with median post-treatment PVR of 2.0 (IQR 1.5-2.6) WU*m2. TRE can allow for further surgical palliation in select pre-Fontan patients with SV-PVD, obviating the need for HTx. Improvement in PVR was significant in S1 patients and persisted beyond discontinuation of therapy for most patients.

  View details for DOI 10.1053/j.semtcvs.2022.07.011

  View details for PubMedID 35931345

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

  Abstract

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

  View details for DOI 10.1002/pul2.12125

  View details for Web of Science ID 000843054900001

  View details for PubMedID 36016669

  View details for PubMedCentralID PMC9395694

• Abnormal platelet aggregation in pediatric pulmonary hypertension PULMONARY CIRCULATION Handler, S. S., Jin, J., Ogawa, M. T., Feinstein, J. A., Lo, C. 2022; 12 (3): e12104

  Abstract

  Endogenous prostacyclin stimulates pulmonary vasodilation and inhibits platelet aggregation. For the synthetic analog treprostinil, used in the treatment of pulmonary hypertension (PH), conflicting, anecdotal evidence exists regarding its effects on clinically relevant platelet function. This study investigated whether treprostinil therapy results in inhibition of platelet aggregation in pediatric PH patients. This is a single institution, prospective, cohort study. Pediatric patients ≤18 years of age on medical therapy for PH underwent platelet function testing by light transmission aggregometry with U-46619-a stable analog of endoperoxide prostaglandin H2, exhibiting properties similar to thromboxane A2 (TXA2). Results were compared for those on continuous treprostinil therapy (TRE) versus those on other, non-prostacyclin therapies (non-TRE). Thirty-five patients were enrolled: 18 in the TRE group and 17 in the non-TRE group. There was no difference in platelet aggregation abnormalities between the two groups: 44% (n = 8) in the TRE group and 41% (n = 7) in the non-TRE group were abnormal. Furthermore, subgroup analysis showed no difference based on treprostinil dosing. This study demonstrated similar, moderately high rates of abnormal platelet aggregation in pediatric PH patients on continuous treprostinil therapy compared to those on other, non-prostacyclin therapies. The high rate of abnormal platelet aggregation in the entire cohort, however, warrants follow-up study to identify a potential inherent risk in this population.

  View details for DOI 10.1002/pul2.12104

  View details for Web of Science ID 000826721400001

  View details for PubMedID 35864911

  View details for PubMedCentralID PMC9294293

• Dissecting alveolar patterning and maintenance at single-cell resolution. FASEB journal : official publication of the Federation of American Societies for Experimental Biology Gillich, A., Brownfield, D. G., Travaglini, K. J., Zhang, F., Farmer, C. G., St Julien, K. R., Tan, S. Y., Gu, M., Zhou, B., Feinstein, J. A., Metzger, R. J., Krasnow, M. A. 2022; 36 Suppl 1

  Abstract

  In mammalian lungs gas exchange occurs in thin-walled air sacs called alveoli, which are surrounded by a dense mesh of capillaries. Defects in patterning, maintenance or repair of alveoli lead to diseases that compromise gas exchange, including chronic diseases such as bronchopulmonary dysplasia, pulmonary fibrosis and chronic obstructive pulmonary disease, as well as the acute respiratory distress syndromes accompanying severe alveolar injury or virus-induced damage, as in Covid-19. Despite the tremendous disease burden and the urgent need for therapies, the mechanisms that establish and maintain the pattern and architecture of alveoli are not well understood. Here we use mosaic genetic labeling, single-cell RNA-sequencing and high-resolution deep imaging to elucidate the three-dimensional structure and cellular composition of alveoli. We show that an alveolus in the mouse lung is composed of 10-15 cells of seven different types, each with a remarkable, distinctive structure. Two of them are intermingled capillary cell types with complex 'swiss cheese' morphologies and distinct functions. One cell type that we name the 'aerocyte' is specialized for gas exchange and unique to the lung. The other cell type, termed 'general capillary', is specialized to regulate vasomotor tone and functions as a progenitor cell in capillary maintenance and repair. By mapping alveolar development at single-cell resolution at a defined position in the lung, we find that alveoli form surprisingly early by budding of epithelial cells out from the airway stalk between enwrapping smooth muscle cells that rearrange into a ring of myofibroblasts at the alveolar entrance. Our analysis suggests a novel mechanism of alveolar formation and provides the foundation for investigations of the structure, function and maintenance of the gas exchange surface in health, disease, aging and evolution.

  View details for DOI 10.1096/fasebj.2022.36.S1.I7444

  View details for PubMedID 35560397

• International Practice Heterogeneity in Pediatric Left Heart Disease Related Pulmonary Hypertension Hopper, R. K., van der Have, O., Hollander, S. A., Dipchand, A. I., de Sa, V., Feinstein, J. A., Tran-Lundmark, K. ELSEVIER SCIENCE INC. 2022: S140-S141

  View details for Web of Science ID 000780119700305

• Virtual Transcatheter Interventions for Peripheral Pulmonary Artery Stenosis in Williams and Alagille Syndromes. Journal of the American Heart Association Lan, I. S., Yang, W., Feinstein, J. A., Kreutzer, J., Collins, R. T., Ma, M., Adamson, G. T., Marsden, A. L. 2022: e023532

  Abstract

  Background Despite favorable outcomes of surgical pulmonary artery (PA) reconstruction, isolated proximal stenting of the central PAs is common clinical practice for patients with peripheral PA stenosis in association with Williams and Alagille syndromes. Given the technical challenges of PA reconstruction and the morbidities associated with transcatheter interventions, the hemodynamic consequences of all treatment strategies must be rigorously assessed. Our study aims to model, assess, and predict hemodynamic outcomes of transcatheter interventions in these patients. Methods and Results Isolated proximal and "extensive" interventions (stenting and/or balloon angioplasty of proximal and lobar vessels) were performed in silico on 6 patient-specific PA models. Autoregulatory adaptation of the cardiac output and downstream arterial resistance was modeled in response to intervention-induced hemodynamic perturbations. Postintervention computational fluid dynamics predictions were validated in 2 stented patients and quantitatively assessed in 4 surgical patients. Our computational methods accurately predicted postinterventional PA pressures, the primary indicators of success for treatment of peripheral PA stenosis. Proximal and extensive treatment achieved median reductions of 14% and 40% in main PA systolic pressure, 27% and 56% in pulmonary vascular resistance, and 10% and 45% in right ventricular stroke work, respectively. Conclusions In patients with Williams and Alagille syndromes, extensive transcatheter intervention is required to sufficiently reduce PA pressures and right ventricular stroke work. Transcatheter therapy was shown to be ineffective for long-segment stenosis and pales hemodynamically in comparison with published outcomes of surgical reconstruction. Regardless of the chosen strategy, a virtual treatment planning platform could identify lesions most critical for optimizing right ventricular afterload.

  View details for DOI 10.1161/JAHA.121.023532

  View details for PubMedID 35253446

• Cardiac Catheterization and Hemodynamics in a Multicenter Cohort of Children with Pulmonary Hypertension. Annals of the American Thoracic Society Rosenzweig, E. B., Bates, A., Mullen, M. P., Abman, S. H., Austin, E. D., Everett, A., Fineman, J., Feinstein, J., Hopper, R. K., Kinsella, J. P., Krishnan, U. S., Lu, M., Mandl, K. D., Raj, J. U., Varghese, N., Yung, D., Handler, S. S., Sleeper, L. A., Pediatric Pulmonary Hypertension Network 1800

  Abstract

  RATIONALE: Hemodynamic assessments direct care among children with pulmonary hypertension (PH), yet the use of cardiac catheterization is highly variable, which could impact patient care and research. Objective We analyzed hemodynamic findings from right (RHC) and left heart catheterization (LHC), acute vasodilator testing (AVT) and the safety of catheterization in children with World Symposium on Pulmonary Hypertension(WSPH) Group 1 and 3 subtypes in a large multicenter North American cohort.METHODS: Of 1475 children enrolled in the Pediatric PH Network registry (2014 -2020), there were 1383 Group 1 and 3 patients, of whom 671 (48.5%) had a RHC performed at diagnosis and were included for analysis.RESULTS: Compared to those without a diagnostic RHC, these children were older, less likely to be an infant or preterm, more often female, treated with targeted PH medications at diagnosis and had advanced WHO functional class. Catheterization was performed without a difference in complication rates between WSPH Groups. PCWP was well-correlated with LVEDP and left atrial pressures. AVT using 3 different methods were comparable; positive AVT was observed in 8.0-11.8% of subjects and did not differ between WSPH Groups 1 and 3 or associated with freedom from the composite endpoint of lung transplantation or death during follow-up.CONCLUSIONS: In a large pediatric PH cohort, diagnostic RHC + LHC in WSPH Group 1 and 3 patients were performed safely at experienced pediatric PH Centers. Hemodynamic differences were noted between Group 1 and 3 subjects. Higher mean PAP and PAPm:SAPm ratio were associated with a higher risk of death/transplantation. Findings suggest overall safety and potential value of RHC as a standard diagnostic approach to guide PH management in children.

  View details for DOI 10.1513/AnnalsATS.202108-998OC

  View details for PubMedID 35049414

• APPLICATION OF REAL-WORLD EVIDENCE ANALYTICS: A 6-YEAR EVENT-FREE SURVIVAL ANALYSIS IN ALAGILLE SYNDROME OF THE GALA CLINICAL RESEARCH DATABASE AND MARALIXIBAT TREATED PATIENTS Hansen, B. E., Vandriel, S. M., Vig, P., Garner, W., Li, L., She, H., Wang, J., Gilbert, M. A., Jankowska, I., Czubkowski, P., Gliwicz-Miedzinska, D., Gonzales, E. M., Jacquemin, E., Bouligand, J., Spinner, N., Loomes, K. M., Piccoli, D. A., D'Antiga, L., Nicastro, E., Sokal, E., Demaret, T., Ebel, N., Feinstein, J. A., Fawaz, R., Nastasio, S., Lacaille, F., Debray, D., Arnell, H., Fischler, B., Siew, S., Stormon, M., Karpen, S. J., Romero, R., Kim, K., Baek, W., Hardikar, W., Shankar, S., Roberts, A. J., Evans, H. M., Jensen, M., Kavan, M., Sundaram, S. S., Chaidez, A., Karthikeyan, P., Davison, S., Sanchez, M., Cavalieri, M., Verkade, H. J., Lee, W., Squires, J. E., Hajinicolaou, C., Lertudomphonwanit, C., Fischer, R. T., Larson-Nath, C., Mozer-Glassberg, Y., Arikan, C., Lin, H. C., Bernabeu, J., Alam, S., Kelly, D., Carvalho, E., Ferreira, C., Indolfi, G., Quiros-Tejeira, R. E., Bulut, P., Calvo, P., Onal, Z., Valentino, P. L., Desai, D. M., Eshun, J., Rogalidou, M., Dezsofi, A., Wiecek, S., Nebbia, G., Pinto, R., Wolters, V. M., Tamara, M., Zizzo, A. N., Garcia, J., Schwarz, K., Beretta, M., Sandahl, T., Jimenez-Rivera, C., Kerkar, N., Brecelj, J., Mujawar, Q., Rock, N., Molera, C., Karnsakul, W., Lurz, E., Santos-Silva, E., Blondet, N., Bujanda, L., Shah, U., Thompson, R. J., Kamath, B. M. WILEY. 2021: 1387A-1389A

  View details for Web of Science ID 000727360100075

• Automated Tracing of Tricuspid Regurgitation Doppler Waveforms Pham, J., Dual, S. A., Verdonk, C., Amsallem, M., Feinstein, J. A., Haddad, F., Marsden, A. L. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for Web of Science ID 000752020002313

• Computational simulation-derived hemodynamic and biomechanical properties of the pulmonary arterial tree early in the course of ventricular septal defects. Biomechanics and modeling in mechanobiology Dong, M. L., Lan, I. S., Yang, W., Rabinovitch, M., Feinstein, J. A., Marsden, A. L. 2021

  Abstract

  Untreated ventricular septal defects (VSDs) can lead to pulmonary arterial hypertension (PAH) characterized by elevated pulmonary artery (PA) pressure and vascular remodeling, known as PAH associated with congenital heart disease (PAH-CHD). Though previous studies have investigated hemodynamic effects on vascular mechanobiology in late-stage PAH, hemodynamics leading to PAH-CHD initiation have not been fully quantified. We hypothesize that abnormal hemodynamics from left-to-right shunting in early stage VSDs affects PA biomechanical properties leading to PAH initiation. To model PA hemodynamics in healthy, small, moderate, and large VSD conditions prior to the onset of vascular remodeling, computational fluid dynamics simulations were performed using a 3D finite element model of a healthy 1-year-old's proximal PAs and a body-surface-area-scaled 0D distal PA tree. VSD conditions were modeled with increased pulmonary blood flow to represent degrees of left-to-right shunting. In the proximal PAs, pressure, flow, strain, and wall shear stress (WSS) increased with increasing VSD size; oscillatory shear index decreased with increasing VSD size in the larger PA vessels. WSS was higher in smaller diameter vessels and increased with VSD size, with the large VSD condition exhibiting WSS >100 dyn/cm[Formula: see text], well above values typically used to study dysfunctional mechanotransduction pathways in PAH. This study is the first to estimate hemodynamic and biomechanical metrics in the entire pediatric PA tree with VSD severity at the stage leading to PAH initiation and has implications for future studies assessing effects of abnormal mechanical stimuli on endothelial cells and vascular wall mechanics that occur during PAH-CHD initiation and progression.

  View details for DOI 10.1007/s10237-021-01519-4

  View details for PubMedID 34585299

• Predictive Modeling of Secondary Pulmonary Hypertension in Left Ventricular Diastolic Dysfunction. Frontiers in physiology Harrod, K. K., Rogers, J. L., Feinstein, J. A., Marsden, A. L., Schiavazzi, D. E. 2021; 12: 666915

  Abstract

  Diastolic dysfunction is a common pathology occurring in about one third of patients affected by heart failure. This condition may not be associated with a marked decrease in cardiac output or systemic pressure and therefore is more difficult to diagnose than its systolic counterpart. Compromised relaxation or increased stiffness of the left ventricle induces an increase in the upstream pulmonary pressures, and is classified as secondary or group II pulmonary hypertension (2018 Nice classification). This may result in an increase in the right ventricular afterload leading to right ventricular failure. Elevated pulmonary pressures are therefore an important clinical indicator of diastolic heart failure (sometimes referred to as heart failure with preserved ejection fraction, HFpEF), showing significant correlation with associated mortality. However, accurate measurements of this quantity are typically obtained through invasive catheterization and after the onset of symptoms. In this study, we use the hemodynamic consistency of a differential-algebraic circulation model to predict pulmonary pressures in adult patients from other, possibly non-invasive, clinical data. We investigate several aspects of the problem, including the ability of model outputs to represent a sufficiently wide pathologic spectrum, the identifiability of the model's parameters, and the accuracy of the predicted pulmonary pressures. We also find that a classifier using the assimilated model parameters as features is free from the problem of missing data and is able to detect pulmonary hypertension with sufficiently high accuracy. For a cohort of 82 patients suffering from various degrees of heart failure severity, we show that systolic, diastolic, and wedge pulmonary pressures can be estimated on average within 8, 6, and 6 mmHg, respectively. We also show that, in general, increased data availability leads to improved predictions.

  View details for DOI 10.3389/fphys.2021.666915

  View details for PubMedID 34276397

• Semi-automated Analysis of Tricuspid Regurgitation Doppler Profile for Detection and Evaluation of Pulmonary Hypertension Dual, S. A., Amsallem, M., McElhinney, D., Zamanian, R., Feinstein, J., Haddad, F., Marsden, A. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000607190401378

• PHENOTYPIC DIVERGENCE OF JAGGED1 AND NOTCH2-ASSOCIATED ALAGILLE SYNDROME: RESULTS FROM THE INTERNATIONAL MULTICENTER GALA STUDY GROUP Vandriel, S., Li, L., She, H., Wang, J., Gilbert, M. A., Spinner, N. B., Loomes, K. M., Piccoli, D. A., D'Antiga, L., Nicastro, E., Calvo, P., Hardikar, W., Shankar, S., Fawaz, R. L., Nastasio, S., Bulut, P., Jankowska, I., Czubkowski, P., Gliwicz-Miedzinska, D., Sokal, E., Demaret, T., Siew, S. M., Stormon, M., Lacaille, F., Debray, D., Kim, K., Baek, W., Feinstein, J. A., Ebel, N., Karpen, S. J., Romero, R., Karthikeyan, P., Davison, S., Arnell, H., Fischler, B., Squires, J. E., Verkade, H. J., Jensen, M., Kavan, M., Roberts, A. J., Evans, H. M., Lertudomphonwanit, C., Lee, W., Sundaram, S. S., Chaidez, A., Fischer, R. T., Mozer-Glassberg, Y., Larson-Nath, C., Lin, H., Bujanda, L., Kelly, D., Karnsakul, W., Bernabeu, J., Indolfi, G., Mujawar, Q., Valentino, P. L., Nebbia, G., Quiros-Tejeira, R. E., Kerkar, N., Schwarz, K. B., Wolters, V. M., Alam, S., Jimenez-Rivera, C., Santos-Silva, E., Brecelj, J., Sanchez, M., Cavalieri, M., Desai, D. M., Onal, Z., Tamara, M., Molera, C., Arikan, C., Wiecek, S., Gonzales, E. M., Thompson, R. J., Hansen, B. E., The, B., Gala Study Grp WILEY. 2020: 882A–884A

  View details for Web of Science ID 000574027003242

• Pharmacokinetics of Oral Treprostinil in Children with Pulmonary Arterial Hypertension. Journal of cardiovascular pharmacology Hopper, R. K., Ivy, D. D., Yung, D., Mullen, M. P., Hanna, B. D., Kirkpatrick, E., Hirsch, R., Austin, E. D., Fineman, J., Solum, D., Deng, C. Q., Feinstein, J. A. 2020

  Abstract

  As part of a clinical trial, this study examined the pharmacokinetics (PK) of oral treprostinil in children with pulmonary arterial hypertension (PAH). The trial consisted of 3 cohorts: transition from parenteral (Cohort 1) or inhaled (Cohort 2) treprostinil, or de novo addition (Cohort 3). Oral treprostinil was dosed 3 times daily (TID). PK samples were obtained prior to an oral treprostinil dose, and at 2, 4, 6 and 8 hours thereafter. The PK parameters were calculated using noncompartmental analysis. Thirty-two children (n=10 in Cohorts 1 and 2, n=12 in Cohort 3) were enrolled; median age was 12 years (range 7 to 17 years) and median weight was 42.2 kg (range 19.3 to 78 kg). Median oral treprostinil dose for all subjects was 3.8 mg (5.9, 3.5, and 4.0 mg for Cohorts 1, 2, and 3, respectively). The treprostinil concentration vs. time profile demonstrated a peak concentration at a median of 3.8 hours with wide variability. In Cohort 1, oral dosing led to higher peak (5.9 ng/mL) and lower trough (1 ng/mL) concentrations compared with parenteral (peak 5.4, trough 4.2 ng/mL), but a lower mean concentration (3.61 vs. 4.46 ng/mL), likely due to variable metabolism and noncomparable dosing. Both the area under the curve and average concentration were linearly correlated to oral treprostinil dose and dose normalized to body weight, but not weight or age alone. In pediatric patients, increased oral treprostinil dose or dose frequency may be required to minimize PK variability and achieve greater correlation with parenteral dosing.

  View details for DOI 10.1097/FJC.0000000000000842

  View details for PubMedID 32398473

• Comprehensive Echocardiographic Assessment of Ventricular Function and Pulmonary Pressure in the Neonatal Omphalocele Population. American journal of perinatology Dal Col, A. K., Bhombal, S., Tacy, T. A., Hintz, S. R., Feinstein, J., Altit, G. 2020

  Abstract

  OBJECTIVE: Pulmonary hypertension (PH) has been described in the neonatal omphalocele population. This study was aimed to describe cardiac function and PH severity using echocardiography in newborns with giant omphalocele (GO) and with non-GO and determine if right ventricular (RV) dysfunction is associated with mortality.STUDY DESIGN: Retrospective, single-center analysis of first echocardiography among neonatal omphalocele patients born between 2004 and 2017 was conducted. Multivariate logistic and univariate Cox's regression was constructed to measure hazard ratio (HR) for death outcome.RESULTS: There were 32 newborns, of whom 18 were GO and 7 died. GO had increased systolic pulmonary arterial to systolic systemic blood pressure ratio (97% [isosystemic] vs. 73% [three-fourths systemic] p=0.03). RV performance parameters (tricuspid annular plane excursion, HR=0.40; fractional area change, HR=0.90; and RV peak global longitudinal strain, HR=1.39) were associated with mortality. These RV performance parameters remained associated in a multiple logistic regression accounting for gestational age and GO status. The overall population had abnormal eccentricity index and pulmonary artery acceleration time to RV ejection time ratio, two markers of PH.CONCLUSION: Patients with omphalocele have increased pulmonary pressure, with GO being worse than non-GO. RV dysfunction at initial echocardiography was significantly associated with mortality.

  View details for DOI 10.1055/s-0040-1708048

  View details for PubMedID 32198744

• Outcomes in Patients with Alagille Syndrome and Complex Pulmonary Artery Disease. The Journal of pediatrics Luong, R. n., Feinstein, J. A., Ma, M. n., Ebel, N. H., Wise-Faberowski, L. n., Zhang, Y. n., Peng, L. F., Yarlagadda, V. V., Shek, J. n., Hanley, F. L., McElhinney, D. B. 2020

  Abstract

  To assess outcomes in a large cohort of patients with Alagille Syndrome (ALGS) who underwent pulmonary artery reconstruction surgery for complex PA disease.Patients with ALGS who underwent PA reconstruction surgery at Lucile Packard Children's Hospital Stanford were reviewed. Patients were examined as an overall cohort and based on the primary cardiovascular diagnosis: severe isolated branch PA stenosis, tetralogy of Fallot (TOF) without major aortopulmonary collateral arteries (MAPCAs), or TOF with MAPCAs RESULTS: Fifty-one patients with ALGS underwent PA surgery at our center: 22 with severe branch PA stenosis, 9 with TOF without MAPCAs, and 20 with TOF and MAPCAs. Forty-one patients (80%) achieved a complete repair. Five of the patients with TOF with MAPCAs (25%) had a complete repair at the first surgery, compared with 8 (89%) and 19 (86%) with TOF without MAPCAs and isolated branch PA stenosis, respectively. At a median follow-up of 1.7 years after the first surgery, 39 patients (76%) were alive, 36 with a complete repair and a median PA:aortic systolic pressure ratio of 0.38. Nine patients (18%), 8 with isolated branch PA stenosis, underwent liver transplantation.Most patients with ALGS and complex PA disease can undergo complete repair with low postoperative right ventricular pressure. Patients with TOF/MAPCAs had the worst outcome, with higher mortality and more frequent PA interventions compared with patients with TOF without MAPCAs or isolated branch PA stenosis. Complex PA disease is not a contraindication to liver transplantation in patients with ALGS.

  View details for DOI 10.1016/j.jpeds.2020.09.053

  View details for PubMedID 32980376

• Treprostinil improves hemodynamics and symptoms in children with mild pulmonary hypertension awaiting heart transplantation. Pediatric transplantation Hollander, S. A., Ogawa, M. T., Hopper, R. K., Liu, E. n., Chen, S. n., Rosenthal, D. N., Feinstein, J. A. 2020: e13742

  Abstract

  Treprostinil, a prostacyclin analog, is a safe and effective therapy for children with PAH; however, the use of this agent in children with mild PVR elevations related to HF, including those with SV congenital heart disease awaiting HT, is understudied. We describe the hemodynamic and symptomatic changes in pediatric patients awaiting HT treated with treprostinil.Single-center retrospective review of all patients was listed for HT who received treprostinil during the listing period. Changes in hemodynamic and functional indices between the baseline catheterization (prior to drug initiation), and prior to HT, and patient outcomes were analyzed.Among 16/17 (94%) who survived to HT, 8 (50%) were female, and 10 (63%) had SV physiology. The median age at drug initiation was 9 (IQR: 1, 14) years. The median duration of therapy prior to HT was 253 (IQR: 148, 504) days. Treprostinil significantly decreased PVR (3.8 vs 3.1 WU, P = .03), while mLA or mPCW pressure did not change (11 vs 13 mm Hg, P = .9). HF symptoms improved in 9/15 (60%) patients without VAD support prior to drug initiation, including 4/10 (40%) who did not receive a VAD any point while awaiting HT.Treprostinil may be used safely in patients with mild PAH awaiting HT, including those with SV disease. PVR falls without substantial increases in mLA/mPCW pressure. HF symptoms improve in some patients.

  View details for DOI 10.1111/petr.13742

  View details for PubMedID 32428328

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

  Abstract

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

  View details for DOI 10.1177/2045894020941343

  View details for PubMedID 33335708

  View details for PubMedCentralID PMC7724418

• Capillary cell-type specialization in the alveolus. Nature Gillich, A. n., Zhang, F. n., Farmer, C. G., Travaglini, K. J., Tan, S. Y., Gu, M. n., Zhou, B. n., Feinstein, J. A., Krasnow, M. A., Metzger, R. J. 2020

  Abstract

  In the mammalian lung, an apparently homogenous mesh of capillary vessels surrounds each alveolus, forming the vast respiratory surface across which oxygen transfers to the blood1. Here we use single-cell analysis to elucidate the cell types, development, renewal and evolution of the alveolar capillary endothelium. We show that alveolar capillaries are mosaics; similar to the epithelium that lines the alveolus, the alveolar endothelium is made up of two intermingled cell types, with complex 'Swiss-cheese'-like morphologies and distinct functions. The first cell type, which we term the 'aerocyte', is specialized for gas exchange and the trafficking of leukocytes, and is unique to the lung. The other cell type, termed gCap ('general' capillary), is specialized to regulate vasomotor tone, and functions as a stem/progenitor cell in capillary homeostasis and repair. The two cell types develop from bipotent progenitors, mature gradually and are affected differently in disease and during ageing. This cell-type specialization is conserved between mouse and human lungs but is not found in alligator or turtle lungs, suggesting it arose during the evolution of the mammalian lung. The discovery of cell type specialization in alveolar capillaries transforms our understanding of the structure, function, regulation and maintenance of the air-blood barrier and gas exchange in health, disease and evolution.

  View details for DOI 10.1038/s41586-020-2822-7

  View details for PubMedID 33057196

• Image-based scaling laws for somatic growth and pulmonary artery morphometry from infant- to adulthood. American journal of physiology. Heart and circulatory physiology Dong, M. L., Yang, W. n., Tamaresis, J. S., Chan, F. P., Zucker, E. J., Kumar, S. n., Rabinovitch, M. n., Marsden, A. L., Feinstein, J. A. 2020

  Abstract

  Pulmonary artery (PA) morphometry has been extensively explored in adults, with particular focus on intra-acinar arteries. However, scaling law relationships for length and diameter of extensive pre-acinar PAs by age have not been previously reported for in vivo human data. To understand pre-acinar PA growth spanning children to adults, we performed morphometric analyses of all PAs visible in the computed tomography (CT) and magnetic resonance (MR) images from a healthy subject cohort (n=16; age: 1-51 years; body surface area, BSA: 0.49-2.01 m2). Subject-specific anatomic PA models were constructed from CT and MR images, and morphometric information - diameter, length, tortuosity, bifurcation angle, and connectivity - was extracted and sorted into diameter-defined Strahler orders. Validation of Murray's law, describing optimal scaling exponents of radii for branching vessels, was performed to determine how closely PAs conform to this classical relationship. Using regression analyses of vessel diameters and lengths against orders and patient metrics (BSA, age, height), we found that diameters increased exponentially with order and allometrically with patient metrics, and length increased allometrically with patient metrics, albeit weakly. The average tortuosity index of all vessels was 0.026 ± 0.024, average bifurcation angle was 28.2º ± 15.1º, and average Murray's law exponent was 2.92 ± 1.07. We report a set of scaling laws for vessel diameter and length, along with other morphometric information. These provide an initial understanding of healthy structural pre-acinar PA development with age, which can be used for computational modeling studies and comparison with diseased PA anatomy.

  View details for DOI 10.1152/ajpheart.00123.2020

  View details for PubMedID 32618514

• Angiographic Anatomy of Major Aortopulmonary Collateral Arteries and Association With Early Surgical Outcomes in Tetralogy of Fallot. Journal of the American Heart Association Adamson, G. T., McElhinney, D. B., Zhang, Y. n., Feinstein, J. A., Peng, L. F., Ma, M. n., Algaze, C. A., Hanley, F. L., Perry, S. B. 2020: e017981

  Abstract

  Background Due in part to the heterogeneity of the pulmonary circulation in patients with tetralogy of Fallot and major aortopulmonary collateral arteries (MAPCAs), research on this condition has focused on relatively basic anatomic characteristics. We aimed to detail pulmonary artery (PA) and MAPCA anatomy in a large group of infants, assess relationships between anatomy and early surgical outcomes, and consider systems for classifying MAPCAs. Methods and Results All infants ( <1 year of age) undergoing first cardiac surgery for tetralogy of Fallot/MAPCAs from 2001 to 2019 at Stanford University were identified. Preoperative angiograms delineating supply to all 18 pulmonary segments were reviewed for details of each MAPCA and the arborization and size of central PAs. We studied 276 patients with 1068 MAPCAs and the following PA patterns: 152 (55%) incompletely arborizing PAs, 48 (17%) normally arborizing PAs, 45 (16%) absent PAs, and 31 (11%) unilateral MAPCAs. There was extensive anatomic variability, but no difference in early outcomes according to PA arborization or the predominance of PAs or MAPCAs. Patients with low total MAPCA and/or PA cross-sectional area were less likely to undergo complete repair. Conclusions MAPCA anatomy is highly variable and essentially unique for each patient. Though each pulmonary segment can be supplied by a MAPCA, central PA, or both, all anatomic combinations are similarly conducive to a good repair. Total cross-sectional area of central PA and MAPCA material is an important driver of outcome. We elucidate a number of novel associations between anatomic features, but the extreme variability of the pulmonary circulation makes a granular tetralogy of Fallot/MAPCA classification system unrealistic.

  View details for DOI 10.1161/JAHA.120.017981

  View details for PubMedID 33283588

• Pulmonary lung Doppler signals: normative data in a pediatric population compared with adults JOURNAL OF CLINICAL MONITORING AND COMPUTING Burstein, D. S., Hopper, R. K., McCarthy, E. K., Hall, K., Schatzberger, R., Palti, Y., Feinstein, J. A. 2019; 33 (6): 1055–60

  View details for DOI 10.1007/s10877-019-00258-3

  View details for Web of Science ID 000493607300013

• Treprositinil in Pediatric Patients Listed for Heart Transplantation Hollander, S. A., Ogawa, M. T., Liu, E., Hopper, R. K., Chen, S., Rosenthal, D. N., Feinstein, J. A. LIPPINCOTT WILLIAMS & WILKINS. 2019

  View details for Web of Science ID 000529998001373

• Diminished right ventricular function at diagnosis of pulmonary hypertension is associated with mortality in bronchopulmonary dysplasia. Pulmonary circulation Altit, G., Bhombal, S., Feinstein, J., Hopper, R. K., Tacy, T. A. 2019; 9 (3): 2045894019878598

  Abstract

  Pulmonary vascular disease and resultant pulmonary hypertension (PH) have been increasingly recognized in the preterm population, particularly among patients with bronchopulmonary dysplasia (BPD). Limited data exist on the impact of PH severity and right ventricular (RV) dysfunction at PH diagnosis on outcome. The purpose of this study was to evaluate if echocardiography measures of cardiac dysfunction and PH severity in BPD-PH were associated with mortality. The study is a retrospective analysis of the echocardiography at three months or less from time of PH diagnosis. Survival analysis using a univariate Cox proportional hazard model is presented and expressed using hazard ratios (HR). We included 52 patients with BPD and PH of which 16 (31%) died at follow-up. Average gestational age at birth was 26.3 ± 2.3 weeks. Echocardiography was performed at a median of 43.3 weeks (IQR: 39.0-54.7). The median time between PH diagnosis and death was 117 days (range: 49-262 days). Multiple measures of PH severity and RV performance were associated with mortality (sPAP/sBP: HR 1.02, eccentricity index: HR 2.02, tricuspid annular plane systolic excursion Z-score: HR 0.65, fractional area change: HR 0.88, peak longitudinal strain: HR 1.22). Hence, PH severity and underlying RV dysfunction at PH diagnosis were associated with mortality in BPD-PH patients. While absolute estimation of pulmonary pressures is not feasible in every screening echocardiography, thorough evaluation of RV function and other markers of PH may allow to discriminate the most at-risk population and should be considered as standard add-ons to the current screening at 36 weeks.

  View details for DOI 10.1177/2045894019878598

  View details for PubMedID 31662848

  View details for PubMedCentralID PMC6792284

• Diminished right ventricular function at diagnosis of pulmonary hypertension is associated with mortality in bronchopulmonary dysplasia PULMONARY CIRCULATION Altit, G., Bhombal, S., Feinstein, J., Hopper, R. K., Tacy, T. A. 2019; 9 (3)

  View details for DOI 10.1177/2045894019878598

  View details for Web of Science ID 000490128900001

• EXPRESS: Oral Treprostinil in Transition or as Add-on Therapy in Pediatric Pulmonary Arterial Hypertension. Pulmonary circulation Ivy, D. D., Feinstein, J., Yung, D., Mullen, M., Kirkpatrick, E. C., Hirsch, R., Austin, E., Fineman, J., Truong, U., Solum, D., Deng, C. Q., Hopper, R. K. 2019: 2045894019856471

  View details for DOI 10.1177/2045894019856471

  View details for PubMedID 31215336

• Evolution of hemodynamic forces in the pulmonary tree with progressively worsening pulmonary arterial hypertension in pediatric patients BIOMECHANICS AND MODELING IN MECHANOBIOLOGY Yang, W., Dong, M., Rabinovitch, M., Chan, F. P., Marsden, A. L., Feinstein, J. A. 2019; 18 (3): 779–96

  View details for DOI 10.1007/s10237-018-01114-0

  View details for Web of Science ID 000467394100015

• Patient-Specific Multiscale Modeling of the Assisted Bidirectional Glenn ANNALS OF THORACIC SURGERY Shang, J. K., Esmaily, M., Verma, A., Reinhartz, O., Figliola, R. S., Hsia, T., Feinstein, J. A., Marsden, A. L. 2019; 107 (4): 1232–40

  View details for DOI 10.1016/j.athoracsur.2018.10.024

  View details for Web of Science ID 000462308000057

• Death or resolution: the "natural history" of pulmonary hypertension in bronchopulmonary dysplasia JOURNAL OF PERINATOLOGY Altit, G., Bhombal, S., Hopper, R. K., Tacy, T. A., Feinstein, J. 2019; 39 (3): 415–25

  View details for DOI 10.1038/s41372-018-0303-8

  View details for Web of Science ID 000459549600011

• Pulmonary lung Doppler signals: normative data in a pediatric population compared with adults. Journal of clinical monitoring and computing Burstein, D. S., Hopper, R. K., McCarthy, E. K., Hall, K., Schatzberger, R., Palti, Y., Feinstein, J. A. 2019

  Abstract

  Lung Doppler signals (LDS) acquired via transthoracic echocardiography is a novel technology previously reported in adults for use in detecting pulmonary hypertension. The aim of this study was to characterize LDS in healthy children to establish normative pediatric LDS data, and compare the pediatric data to the previously published healthy adult LDS. In this prospective, two-center study, LDS were acquired in children without cardiopulmonary disease using a 2MHz transthoracic pulsed Doppler transducer. The data were processed to obtain Doppler velocity patterns corresponding to phases of the cardiac cycle. Signals were analyzed using a parametric Doppler signal-processing package and performance evaluation of the trained classifiers was performed using cross validation method. Pediatric signals were then compared to a retrospective cohort of healthy adults. Eighty-six healthy pediatric subjects (mean age 9.1±5.1years) and 79 healthy adult controls (mean age 59.7±10.7years) were included. The normative LDS velocity profiles were defined for pediatric subjects and then compared to adults; the highest discriminating LDS parameters between healthy children and adults were acceleration of atrial (A) signal contraction (46±18 vs. 90±34; p<0.001), peak systolic (S) signal velocity (10.0±3.5 vs. 11.7±3.5; p<0.001), and ratio of peak diastolic (D)-to-atrial (A) signal velocity (1.4±0.5 vs. 0.4±0.3; p<0.001). The sensitivity and specificity of this LDS based method to discern between healthy children and adult subjects was 98.6% and 97.4%, respectively. Subgroup analyses between younger (2-8years) and older (9-18years) pediatric LDS yielded significant differences between atrial (A) acceleration (43.7±33.9 vs. 47.7±42.1; p=0.04) and diastolic (D)-to-atrial (A) signal velocity (1.2±0.5 vs. 1.5±0.5; p=0.01) but not systolic (S) signals (0.14±0.05 vs. 0.14±0.05; p=0.97). In this study, we defined the normal LDS profile for healthy children and have demonstrated differences in LDS between children and adults. Specifically, healthy children had lower atrial contraction power, differences in ventricular compliance and increased chronotropic response. Further studies are warranted to investigate the application of this technology, for example as a tool to aid in the detection of pulmonary hypertension in children.

  View details for PubMedID 30661196

• Evolution of hemodynamic forces in the pulmonary tree with progressively worsening pulmonary arterial hypertension in pediatric patients. Biomechanics and modeling in mechanobiology Yang, W., Dong, M., Rabinovitch, M., Chan, F. P., Marsden, A. L., Feinstein, J. A. 2019

  Abstract

  Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling resulting in right ventricular (RV) dysfunction and ultimately RV failure. Mechanical stimuli acting on the vessel walls of the full pulmonary tree have not previously been comprehensively characterized. The goal of this study is to characterize wall shear stress (WSS) and strain in pediatric PAH patients at different stages of disease severity using computational patient-specific modeling. Computed tomography, magnetic resonance imaging and right heart catheterization data were collected and assimilated into pulmonary artery (PA) models for patients with and without PAH. Patients were grouped in three disease severity groups (control, moderate and severe) based on clinical evaluations. A finite element solver was employed to quantify hemodynamics and wall strains. To estimate WSS in the distal small PAs with diameters ranging from 50 to 500[Formula: see text], a morphometric tree model was created, with inputs coming from outlets of the 3D model. WSS in the proximal PAs decreased with disease severity (control 20.5 vs. moderate 15.8 vs. severe 6.3[Formula: see text], [Formula: see text]). Oscillatory shear index increased in the main pulmonary artery (MPA) with disease severity (0.13 vs. 0.13 vs. 0.2, [Formula: see text]). Wall strains measured by the first invariant of Green strain tensor decreased with disease severity (0.16 vs. 0.12 vs. 0.11, [Formula: see text]). Mean WSS for the distal PAs between 100 and 500[Formula: see text] significantly increased with disease severity (20 vs. 52 vs. 116 [Formula: see text], [Formula: see text]). In conclusion, 3D flow simulations showed that WSS is significantly decreased in the MPA with disease while the mathematical morphometric model suggested increased WSS in the distal small vessels. Computational models can reveal mechanical stimuli acting on vessel walls that may inform patient risk stratification and flow shear experiments.

  View details for PubMedID 30635853

• Death or resolution: the "natural history" of pulmonary hypertension in bronchopulmonary dysplasia. Journal of perinatology : official journal of the California Perinatal Association Altit, G., Bhombal, S., Hopper, R. K., Tacy, T. A., Feinstein, J. 2019

  Abstract

  OBJECTIVES: The primary objective was to describe the early "natural history" of pulmonary hypertension (PH) in the premature population. The secondary objective was to describe factors associated with poor outcomes in the premature population with PH at 36 weeks post-menstrual age (PMA).STUDY DESIGN: Retrospective chart review of patients followed at our institution from 2000 to 2017 with echocardiographic (ECHO) evidence of PH at 36 weeks PMA, and born≤32 weeks estimated gestational age (GA). Cox regression was used for survival analysis.RESULTS: Sixty-one patients with PH (26.5±1.5 weeks at birth) were included. All PH patients had bronchopulmonary dysplasia (BPD), with 89% considered severe; 38% were small for gestational age. Necrotizing enterocolitis requiring surgery was common (25%). Use of post-natal steroids (HR 11.02, p=0.01) and increased severity of PH (HR 1.05, p<0.001) were associated with mortality. Pulmonary vein stenosis (PVS) was documented in 26% of the PH cohort, but not associated with increased mortality. ECHO estimation of pulmonary artery pressure (PAP) was available in 84%. PAP was higher in those who died (sPAP/sBP ratio 1.09±27 vs 0.83±20 %, p=0.0002). At follow-up (mean 250±186 weeks PMA), 72% of the PH cohort was alive. Most survivors (66%) had resolution of their PH on their most recent ECHO; 31% remained on PH therapy.CONCLUSION: PH resolved in most survivors in this study population. Mortality in those with BPD-PH was associated with male sex, post-natal steroid use, and increased severity of PH, but not with PVS.

  View details for PubMedID 30617286

• EXPRESS: Acute Vasoreactivity Testing in Pediatric Idiopathic Pulmonary Arterial Hypertension: an international Survey on Current Practice. Pulmonary circulation Caicedo, L. n., Hopper, R. K., Garcia, H. n., Ivy, D. D., Haag, D. n., Fineman, J. n., Humpi, T. n., Al-Tamimi, O. n., Feinstein, J. n., Berger, R. M., Berman-Rosenzweig, E. n., Kashour, T. n., Diaz, G. F., Mendoza, A. n., Bobhate, P. n., Handler, S. n., Lopes, A. A., Barwad, P. n., Kumar Rahit, M. n., Krishnan, U. n., Adatia, I. T., Moledina, S. n., Abman, S. n., Cerro Marin, M. J. 2019: 2045894019857533

  View details for DOI 10.1177/2045894019857533

  View details for PubMedID 31144586

• Racial and Ethnic Differences in Pediatric Pulmonary Hypertension: An Analysis of the Pediatric Pulmonary Hypertension Network Registry. The Journal of pediatrics Ong, M. S., Abman, S. n., Austin, E. D., Feinstein, J. A., Hopper, R. K., Krishnan, U. S., Mullen, M. P., Natter, M. D., Raj, J. U., Rosenzweig, E. B., Mandl, K. D. 2019

  Abstract

  To investigate racial and ethnic differences in pulmonary hypertension subtypes and survival differences in a pediatric population.This was a retrospective analysis of a cohort of patients with pulmonary hypertension (aged ≤18 years) enrolled in the Pediatric Pulmonary Hypertension Network registry between 2014 and 2018, comprising patients at eight Pediatric Centers throughout North America (n = 1417).Among children diagnosed after the neonatal period, pulmonary arterial hypertension was more prevalent among Asians (OR, 1.83; 95% CI, 1.21-2.79; P = .0045), lung disease-associated pulmonary hypertension among blacks (OR, 2.09; 95% CI, 1.48-2.95; P < .0001), idiopathic pulmonary arterial hypertension among whites (OR, 1.58; 95% CI, 1.06-2.41; P = .0289), and pulmonary veno-occlusive disease among Hispanics (OR, 6.11; 95% CI, 1.34-31.3; P = .0184). Among neonates, persistent pulmonary hypertension of the newborn (OR, 4.07; 95% CI, 1.54-10.0; P = .0029) and bronchopulmonary dysplasia (OR, 8.11; 95% CI, 3.28-19.8; P < .0001) were more prevalent among blacks, and congenital diaphragmatic hernia was more prevalent among whites (OR, 2.29; 95% CI, 1.25-4.18; P = .0070). An increased mortality risk was observed among blacks (HR, 1.99; 95% CI, 1.03-3.84; P = .0396), driven primarily by the heightened mortality risk among those with lung disease-associated pulmonary hypertension (HR, 2.84; 95% CI, 1.15-7.04; P = .0241).We found significant racial variability in the prevalence of pulmonary hypertension subtypes and survival outcomes among children with pulmonary hypertension. Given the substantial burden of this disease, further studies to validate phenotypic differences and to understand the underlying causes of survival disparities between racial and ethnic groups are warranted.

  View details for DOI 10.1016/j.jpeds.2019.04.046

  View details for PubMedID 31176455

• Subcutaneous and Intravenous Treprostinil Pharmacokinetics in Children With Pulmonary Vascular Disease. Journal of cardiovascular pharmacology Hall, K. n., Ogawa, M. n., Sakarovitch, C. n., Hopper, R. K., Adamson, G. T., Hanna, B. n., Ivy, D. D., Miller-Reed, K. n., Yung, D. n., McCarthy, E. n., Siehr-Handler, S. L., Feinstein, J. A. 2019; 73 (6): 383–93

  Abstract

  This study evaluated the pharmacokinetics of intravenous (IV) and subcutaneous (SC) treprostinil in pediatric patients with pulmonary vascular disease, and compared them with existing adult data from a similar cohort. Blood samples were collected from pediatric patients receiving steady-state IV or SC treprostinil and were assessed for plasma treprostinil concentration using liquid chromatography and tandem mass spectrometry. Forty participants, 15 receiving IV and 25 receiving SC treprostinil, were included in the analysis. Age ranged from 0.1 to 15.6 years. The median dose of treprostinil was 45.5 ng·kg·min with a range of 8-146 ng·kg·min. There was a linear relationship between treprostinil dose and plasma concentration with an R of 0.57. On average, there were higher blood concentrations per given dose of IV treprostinil compared with those per given dose of SC, but the difference was not significant. Compared with adult data, the slope of the pediatric data was similar, but the y-intercept was significantly lower. Additionally, the concentration per dose ratio was significantly higher in adults compared with children. Pediatric patients have significantly lower average blood concentrations of treprostinil per given dose compared with adults, and higher, but not significantly so, blood concentrations when treprostinil is administered IV as compared with SC administration.

  View details for DOI 10.1097/FJC.0000000000000674

  View details for PubMedID 31162247

• Pulmonary hemorrhage in children with Alagille syndrome undergoing cardiac catheterization. Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions Adamson, G. T., Peng, L. F., Feinstein, J. A., Yarlagadda, V. V., Lin, A. n., Wise-Faberowski, L. n., McElhinney, D. B. 2019

  Abstract

  To evaluate the incidence, severity, and outcomes of pulmonary hemorrhage in children with Alagille syndrome (AGS) undergoing cardiac catheterization, and to find variables associated with hemorrhage in this population.Children with AGS have a high incidence of bleeding complications during invasive procedures. It has been our impression that catheterization-associated pulmonary hemorrhage is more common in children with AGS, but there are no published data on this topic.This was a retrospective single institution study of children with AGS undergoing catheterization from 2010 to 2018. Pulmonary hemorrhage was defined as angiographic or fluoroscopic evidence of extravasated blood in the lung parenchyma, or blood suctioned from the endotracheal tube with documentation of pulmonary hemorrhage by the anesthesiologist or intensivist. Univariate comparisons were made between catheterizations that did and did not have pulmonary hemorrhage.Thirty children with AGS underwent 87 catheterizations, 32 (37%) with interventions on the branch pulmonary arteries (PA). There were 26 (30%) procedures with hemorrhage, the majority (65%) of which were self-limited or required less than 24 hr of mechanical ventilation. Moderate and severe hemorrhage occurred only in children with tetralogy of Fallot (TOF; 5 of 14, 36%). A higher right ventricle to aorta systolic pressure ratio (1.0 [0.85-1.1] vs. 0.88 [0.59-1.0], p = .029) and interventions on the branch PAs (14 of 26, 54% vs. 18 of 61, 30%, p = .032) were associated with hemorrhage.Pulmonary hemorrhage was common in children with AGS undergoing both intervention and diagnostic cardiac catheterization, and was associated with TOF, higher RV to aorta pressure ratio, and interventions on the branch PAs.

  View details for DOI 10.1002/ccd.28508

  View details for PubMedID 31584246

• Patient-Specific Multiscale Modeling of the Assisted Bidirectional Glenn. The Annals of thoracic surgery Shang, J. K., Esmaily, M., Verma, A., Reinhartz, O., Figliola, R. S., Hsia, T., Feinstein, J. A., Marsden, A. L. 2018

  Abstract

  BACKGROUND: First-stage palliation of neonates with single-ventricle physiology is associated with poor outcomes and challenging clinical management. Prior computational modeling and invitro experiments introduced the assisted bidirectional Glenn (ABG), which increased pulmonary flow and oxygenation over the bidirectional Glenn (BDG) and the systemic-to-pulmonary shunt in idealized models. In this study, we demonstrate that the ABG achieves similar performance in patient-specific models and assess the influence of varying shunt geometry.METHODS: In a small cohort of single-ventricle prestage 2 patients, we constructed three-dimensional in silico models and tuned lumped parameter networks to match clinical measurements. Each model was modified to produce virtual BDG and ABG surgeries. We simulated the hemodynamics of the stage 1 procedure, BDG, and ABG by using multiscale computational modeling, coupling a finite-element flow solver to the lumped parameter network. Two levels of pulmonary vascular resistances (PVRs) were investigated: baseline (low) PVR of the patients and doubled (high) PVR. The shunt nozzle diameter, anastomosis location, and shape were also manipulated.RESULTS: The ABG increased the pulmonary flow rate and pressure by 15% to 20%, which was accompanied by a rise in superior vena caval pressure (2 to 3 mm Hg) at both PVR values. Pulmonary flow rate and superior vena caval pressures were most sensitive to the shunt nozzle diameter.CONCLUSIONS: Patient-specific ABG performance was similar to prior idealized simulations and experiments, with good performance at lower PVR values in the range of measured clinical data. Larger shunt outlet diameters and lower PVR led to improved ABG performance.

  View details for PubMedID 30471273

• microRNA-21 Predicts Functional Status in Children With Pulmonary Hypertension Associated With Congenital Heart Disease. Sen, S., Feinstein, J., Reddy, S. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000528619400413

• Right ventricular stroke work correlates with outcomes in pediatric pulmonary arterial hypertension PULMONARY CIRCULATION Yang, W., Marsden, A. L., Ogawa, M. T., Sakarovitch, C., Hall, K. K., Rabinovitch, M., Feinstein, J. A. 2018; 8 (3)

  View details for DOI 10.1177/2045894018780534

  View details for Web of Science ID 000434659100001

• THE DEVELOPMENT AND EFFICACY OF A PEDIATRIC CARDIOLOGY FELLOWSHIP ONLINE PREPARATORY COURSE Motonaga, K., Sacks, L., Olson, I., Balasubramanian, S., Chen, S., Peng, L., Feinstein, J., Silverman, N., Hanley, F., Axelrod, D., Krawczeski, C., Ceresnak, S. ELSEVIER SCIENCE INC. 2018: 2622

  View details for DOI 10.1016/S0735-1097(18)33163-2

  View details for Web of Science ID 000429659705072

• Computational simulation of postoperative pulmonary flow distribution in Alagille patients with peripheral pulmonary artery stenosis. Congenital heart disease Yang, W., Hanley, F. L., Chan, F. P., Marsden, A. L., Vignon-Clementel, I. E., Feinstein, J. A. 2018; 13 (2): 241-250

  Abstract

  Up to 90% of individuals with Alagille syndrome have congenital heart diseases. Peripheral pulmonary artery stenosis (PPS), resulting in right ventricular hypertension and pulmonary flow disparity, is one of the most common abnormalities, yet the hemodynamic effects are ill-defined, and optimal patient management and treatment strategies are not well established. The purpose of this pilot study is to use recently refined computational simulation in the setting of multiple surgical strategies, to examine the influence of pulmonary artery reconstruction on hemodynamics in this population.Based on computed tomography angiography and cardiac catheterization data, preoperative pulmonary artery models were constructed for 4 patients with Alagille syndrome with PPS (all male, age range: 0.6-2.9 years), and flow simulations with deformable walls were performed. Surgeon directed virtual surgery, mimicking the surgical procedure, was then performed to derive postoperative models. Postoperative simulation-derived hemodynamics and blood flow distribution were then compared with the clinical results.Simulations confirmed substantial resistance, resulting from preoperative severe ostial stenoses, and the use of newly developed adaptive outflow boundary conditions led to excellent agreement with in vivo measurements. Relief of PPS decreased pulmonary artery pressures and improved pulmonary flow distribution both in vivo and in silico with good correlation.Using adaptive outflow boundary conditions, computational simulations can estimate postoperative overall pulmonary flow distribution in patients with Alagille syndrome after pulmonary artery reconstruction. Obstruction relief along with pulmonary artery vasodilation determines postoperative pulmonary flow distribution and newer methods can incorporate these physiologic changes. Evolving blood flow simulations may be useful in surgical or transcatheter planning and in understanding the complex interplay among various obstructions in patients with peripheral pulmonary stenosis.

  View details for DOI 10.1111/chd.12556

  View details for PubMedID 29194961

• Optimization of the Assisted Bidirectional Glenn Procedure for First Stage Single Ventricle Repair. World journal for pediatric & congenital heart surgery Verma, A., Esmaily, M., Shang, J., Figliola, R., Feinstein, J. A., Hsia, T. Y., Marsden, A. L. 2018; 9 (2): 157-170

  Abstract

  First-stage single-ventricle palliation is challenging to manage, and significant interstage morbidity and mortality remain. Prior computational and in vitro studies of the assisted bidirectional Glenn (ABG), a novel first-stage procedure that has shown potential for early conversion to a more stable augmented Glenn physiology, demonstrated increased pulmonary flow and oxygen delivery while decreasing cardiac work, as compared to conventional stage-1 alternatives. This study aims to identify optimal shunt designs for the ABG to improve pulmonary flow while maintaining or decreasing superior vena caval (SVC) pressure.A representative three-dimensional model of a neonatal bidirectional Glenn (BDG) was created, with a shunt connecting the innominate artery to the SVC. The shunt design was studied as a six-parameter constrained shape optimization problem. We simulated hemodynamics for each candidate designs using a multiscale finite element flow solver and compared performance against designs with taper-less shunts, the standalone BDG, and a simplified control volume model. Three values of pulmonary vascular resistance (PVR) of 2.3, 4.3, and 7.1 WUm2 were studied.Increases in pulmonary flow were generally accompanied by increases in SVC pressure, except at low PVR (2.3 WUm2), where the optimal shunt geometry achieved a 13% increase in pulmonary flow without incurring any increase in SVC pressure. Shunt outlet area was the most influential design parameter, while others had minimal effect.Assisted bidirectional Glenn performance is sensitive to PVR and shunt outlet diameter. An increase in pulmonary flow without a corresponding increase in SVC pressure is possible only when PVR is low.

  View details for DOI 10.1177/2150135117745026

  View details for PubMedID 29544408

• Central line replacement following infection does not improve reinfection rates in pediatric pulmonary hypertension patients receiving intravenous prostanoid therapy PULMONARY CIRCULATION McCarthy, E. K., Ogawa, M. T., Hopper, R. K., Feinstein, J. A., Gans, H. A. 2018; 8 (1): 2045893218754886

  Abstract

  Treatment of pediatric pulmonary hypertension (PH) with IV prostanoids has greatly improved outcomes but requires a central line, posing inherent infection risk. This study examines the types of infections, infection rates, and importantly the effect of line management strategies on reinfection in children receiving IV prostanoids for PH. This study is a retrospective review of all pediatric PH patients receiving intravenous epoprostenol (EPO) or treprostinil (TRE) at one academic tertiary care center between 2000 and 2014. No patients declined participation in the study or were otherwise excluded. Infectious complications were characterized by organism(s), infection rates, time to next infection, and line management decisions (salvage vs. replace). Of the 40 patients followed, 13 sustained 38 infections involving 49 pathogens, with a predominance of gram-positive (GP) organisms (n = 35). The pooled infection rate was 1.06 per 1000 prostanoid days with no difference between EPO and TRE. No significant difference in reinfection rate was observed when comparing line salvage to replacement, regardless of organism type. Both overall and organism-type comparisons suggest longer time between line infections following line salvage compared with line replacement (732 vs. 410 days overall; 793 vs. 363 days for GP; 611 vs. 581 days for gram-negative [GN]; P > 0.05 for all comparisons). Central line replacement following blood stream infections in pediatric PH patients does not improve subsequent infection rates or time to next infection, and may lead to unnecessary risks associated with line replacement, including potential loss of vascular access. A revised approach to central line infections in pediatric PH is proposed.

  View details for PubMedID 29309237

  View details for PubMedCentralID PMC5826011

• Subcutaneous treprostinil in pediatric patients with failing single-ventricle physiology JOURNAL OF HEART AND LUNG TRANSPLANTATION Handler, S. S., Ogawa, M. T., Hopper, R. K., Sakarovitch, C., Feinstein, J. A. 2018; 37 (2): 306–7

  View details for Web of Science ID 000424293900022

• Right Ventricular Stroke Work Correlates with Outcomes in Pediatric Pulmonary Arterial Hypertension. Pulmonary circulation Yang, W., Marsden, A. L., Ogawa, M. T., Sakarovitch, C., Hall, K. K., Rabinovitch, M., Feinstein, J. A. 2018: 2045894018780534

  View details for PubMedID 29767574

• Relationship Between Pulmonary Vascular Resistance and Right Ventricular Dysfunction Assessed by MRI in Pediatric Pulmonary Arterial Hypertension Hopper, R. K., Chen, H., Ogawa, M., Feinstein, J. A. AMER THORACIC SOC. 2018

  View details for Web of Science ID 000449980303198

• Transition to Oral Treprostinil from Parenteral or Inhaled Treprostinil or as Add-On Therapy in Pediatric Subjects with Pulmonary Arterial Hypertension Ivy, D., Feinstein, J., Yung, D., Mullen, M., Kirkpatrick, E., Hirsch, R., Austin, E. D., Fineman, J., Doran, A., Solum, D., Deng, C., Hopper, R. K. AMER THORACIC SOC. 2018

  View details for Web of Science ID 000449980303195

• Optimization of the Assisted Bidirectional Glenn Procedure for First Stage Single Ventricle Repair Optimization of the Assisted Bidirectional Glenn Procedure for First Stage Single Ventricle Repair Verma, A., Esmaily, M., Shang, J., Figliola, R., Feinstein, J., Hsia, T., Marsden, A. 2018; 9 (2): 157-170

  Abstract

  First-stage single-ventricle palliation is challenging to manage, and significant interstage morbidity and mortality remain. Prior computational and in vitro studies of the assisted bidirectional Glenn (ABG), a novel first-stage procedure that has shown potential for early conversion to a more stable augmented Glenn physiology, demonstrated increased pulmonary flow and oxygen delivery while decreasing cardiac work, as compared to conventional stage-1 alternatives. This study aims to identify optimal shunt designs for the ABG to improve pulmonary flow while maintaining or decreasing superior vena caval (SVC) pressure.A representative three-dimensional model of a neonatal bidirectional Glenn (BDG) was created, with a shunt connecting the innominate artery to the SVC. The shunt design was studied as a six-parameter constrained shape optimization problem. We simulated hemodynamics for each candidate designs using a multiscale finite element flow solver and compared performance against designs with taper-less shunts, the standalone BDG, and a simplified control volume model. Three values of pulmonary vascular resistance (PVR) of 2.3, 4.3, and 7.1 WUm2 were studied.Increases in pulmonary flow were generally accompanied by increases in SVC pressure, except at low PVR (2.3 WUm2), where the optimal shunt geometry achieved a 13% increase in pulmonary flow without incurring any increase in SVC pressure. Shunt outlet area was the most influential design parameter, while others had minimal effect.Assisted bidirectional Glenn performance is sensitive to PVR and shunt outlet diameter. An increase in pulmonary flow without a corresponding increase in SVC pressure is possible only when PVR is low.

  View details for DOI 10.1177/2150135117745026

• Accelerometry: Improving Objective Assessments of Therapeutic Impact in Pediatric Pulmonary Arterial Hypertension AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Austin, E. D., Feinstein, J. A. 2017; 196 (2): 127–29

  View details for PubMedID 28707968

• Practices surrounding pulmonary hypertension and bronchopulmonary dysplasia amongst neonatologists caring for premature infants. Journal of perinatology : official journal of the California Perinatal Association Altit, G. n., Lee, H. C., Hintz, S. n., Tacy, T. A., Feinstein, J. A., Bhombal, S. n. 2017

  Abstract

  Pulmonary hypertension (PH) is associated with bronchopulmonary dysplasia (BPD). Screening strategies, a thorough investigation of co-morbidities, and multidisciplinary involvement prior to anti-PH medications have been advocated by recent guidelines. We sought to evaluate current practices of neonatologists caring for premature infants with PH.Electronic survey of American Academy of Pediatrics neonatology members.Among 306 neonatologist respondents, 38% had an institutional screening protocol for patients with BPD; 83% screened at 36 weeks for premature neonates on oxygen/mechanical ventilation. In those practicing more than 5 years, 54% noted increasing numbers of premature infants diagnosed with PH. Evaluation for PH in BPD patients included evaluations for micro-aspiration (41%), airways anomalies (29%), and catheterization (10%). Some degree of acquired pulmonary vein stenosis was encountered in 47%. A majority (90%) utilized anti-PH medications during the neonatal hospitalization.Screening for PH in BPD, and subsequent evaluation and management is highly variable.

  View details for PubMedID 29234146

• Evaluation and Management of Pulmonary Hypertension in Children with Bronchopulmonary Dysplasia. The Journal of pediatrics Krishnan, U. n., Feinstein, J. A., Adatia, I. n., Austin, E. D., Mullen, M. P., Hopper, R. K., Hanna, B. n., Romer, L. n., Keller, R. L., Fineman, J. n., Steinhorn, R. n., Kinsella, J. P., Ivy, D. D., Rosenzweig, E. B., Raj, U. n., Humpl, T. n., Abman, S. H. 2017; 188: 24–34.e1

  View details for PubMedID 28645441

• Subcutaneous treprostinil in pediatric patients with failing single-ventricle physiology. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Handler, S. S., Ogawa, M. T., Hopper, R. K., Sakarovitch, C. n., Feinstein, J. A. 2017

  View details for PubMedID 29126699

• Computational simulation of postoperative pulmonary flow distribution in Alagille patients with peripheral pulmonary artery stenosis Computational simulation of postoperative pulmonary flow distribution in Alagille patients with peripheral pulmonary artery stenosis Yang, W., Feinstein, J., Marsden, A., Vignon-Clementel, I. 2017; 00: 1–10

  View details for DOI 10.1111/chd.12556

• Right Ventricular Stroke Work Correlates With Outcomes in Pediatric Pulmonary Arterial Hypertension (PAH) Patients Quality of Care and Outcomes Research Scientific Sessions Yang, W., Marsden, A. L., Ogawa, M. T., Phillips, K. K., Rabinovitch, M., Feinstein, J. A. LIPPINCOTT WILLIAMS & WILKINS. 2016

  View details for Web of Science ID 000396815607139

• Adaptive outflow boundary conditions improve post-operative predictions after repair of peripheral pulmonary artery stenosis. Biomechanics and modeling in mechanobiology Yang, W., Feinstein, J. A., Vignon-Clementel, I. E. 2016; 15 (5): 1345-1353

  Abstract

  Peripheral pulmonary artery stenosis (PPS) is a congenital abnormality resulting in pulmonary blood flow disparity and right ventricular hypertension. Despite recent advance in catheter-based interventions, surgical reconstruction is still preferred to treat complex PPS. However optimal surgical strategies remain unclear. It would be of great benefit to be able to predict post-operative hemodynamics to assist with surgical planning toward optimizing outcomes. While image-based computational fluid dynamics has been used in cardiovascular surgical planning, most studies have focused on the impact of local geometric changes on hemodynamic performance. Previous experimental studies suggest morphological changes in the pulmonary arteries not only alter local hemodynamics but also lead to distal pulmonary adaptation. In this proof of concept study, a constant shear stress hypothesis and structured pulmonary trees are used to derive adaptive outflow boundary conditions for post-operative simulations. Patient-specific simulations showed the adaptive outflow boundary conditions by the constant shear stress model to provide better predictions of pulmonary flow distribution than the conventional strategy of maintaining outflow boundary conditions. On average, the relative difference, when compared to the gold standard clinical test, in blood flow distribution to the right lung is reduced from 20 to 4 %. This suggests adaptive outflow boundary conditions should be incorporated into post-operative modeling in patients with complex PPS.

  View details for DOI 10.1007/s10237-016-0766-5

  View details for PubMedID 26843118

• Quantification of systemic-to-pulmonary arterial collateral flow in the Fontan circulation with four dimensional flow magnetic resonance imaging Ridderbos, F. S., Chan, F. P., Bauser-Heaton, H. D., Feinstein, J. A., Berger, R. F., Willems, T. P. OXFORD UNIV PRESS. 2016: 163

  View details for Web of Science ID 000383869500532

• CT-defined phenotype of pulmonary artery stenoses in Alagille syndrome PEDIATRIC RADIOLOGY Rodriguez, R. M., Feinstein, J. A., Chan, F. P. 2016; 46 (8): 1120-1127

  Abstract

  Alagille syndrome is a rare disorder commonly associated with pulmonary artery stenosis. Studies exist discussing the cardiovascular sequela but no consistent phenotype, or pattern of pulmonary artery stenosis, has been described.The objective of this study was to characterize the distribution and severity of pulmonary artery stenosis in patients with Alagille syndrome based on computed tomography angiography.A retrospective chart review identified patients with Alagille syndrome who had undergone CT angiography. Pulmonary trunk (MPA), left main pulmonary artery (LPA) and right main pulmonary artery (RPA) diameters in Alagille patients were compared with those from matched control subjects. Stenoses at lobar and segmental pulmonary arteries were categorized as: Grade 1 (<33% stenosis), Grade 2 (33-66% stenosis) or Grade 3 (>66% stenosis). Involvement among the different lung regions was then compared.Fifteen patients ages 6 months to 17 years were identified; one had surgical augmentation of the central pulmonary arteries and was excluded from the central (main, right and left) pulmonary artery analysis. The proximal LPA and RPA, but not the MPA, were significantly smaller than those of the control subjects (P<0.01). The proximal LPA was significantly smaller than the proximal RPA (P<0.01) in the Alagille group (0.55 LPA:RPA ratio). Within the Alagille group, 75% of the lobar and segmental branches showed mild or no stenoses (Grade 1), 17% showed moderate stenosis (Grade 2) and 8% showed severe stenosis (Grade 3). While not statistically significant, the right lung demonstrated a greater percentage of Grades 2 and 3 stenoses (28%, right vs. 20% left, P=0.1). The right middle and lingula lobes of both lungs showed more Grade 2 and 3 stenoses (33% upper/middle vs. 18% lower, P<0.01).We describe a common pattern pulmonary artery stenosis in Alagille patients consisting of severe proximal LPA stenosis, heavy involvement of the lobar and segmental branches (more often right than left), and a greater involvement of the upper lobes. Knowledge of this phenotypic pattern can help in the diagnosis of Alagille syndrome in patients presenting with pulmonary artery stenosis.

  View details for DOI 10.1007/s00247-016-3580-4

  View details for PubMedID 27041277

• Hemodynamic Effects of Phenylephrine, Vasopressin, and Epinephrine in Children With Pulmonary Hypertension: A Pilot Study PEDIATRIC CRITICAL CARE MEDICINE Siehr, S. L., Feinstein, J. A., Yang, W., Peng, L. F., Ogawa, M. T., Ramamoorthy, C. 2016; 17 (5): 428-437

  Abstract

  During a pulmonary hypertensive crisis, the marked increase in pulmonary vascular resistance can result in acute right ventricular failure and death. Currently, there are no therapeutic guidelines for managing an acute crisis. This pilot study examined the hemodynamic effects of phenylephrine, arginine vasopressin, and epinephrine in pediatric patients with pulmonary hypertension.In this prospective, open-label, nonrandomized pilot study, we enrolled pediatric patients previously diagnosed with pulmonary hypertensive who were scheduled electively for cardiac catheterization. Primary outcome was a change in the ratio of pulmonary-to-systemic vascular resistance. Baseline hemodynamic data were collected before and after the study drug was administered.Eleven of 15 participants were women, median age was 9.2 years (range, 1.7-14.9 yr), and median weight was 26.8 kg (range, 8.5-55.2 kg). Baseline mean pulmonary artery pressure was 49 ± 19 mm Hg, and mean indexed pulmonary vascular resistance was 10 ± 5.4 Wood units. Etiology of pulmonary hypertensive varied, and all were on systemic pulmonary hypertensive medications.Patients 1-5 received phenylephrine 1 μg/kg; patients 6-10 received arginine vasopressin 0.03 U/kg; and patients 11-15 received epinephrine 1 μg/kg. Hemodynamics was measured continuously for up to 10 minutes following study drug administration.After study drug administration, the ratio of pulmonary-to-systemic vascular resistance decreased in three of five patients receiving phenylephrine, five of five patients receiving arginine vasopressin, and three of five patients receiving epinephrine. Although all three medications resulted in an increase in aortic pressure, only arginine vasopressin consistently resulted in a decrease in the ratio of systolic pulmonary artery-to-aortic pressure.This prospective pilot study of phenylephrine, arginine vasopressin, and epinephrine in pediatric patients with pulmonary hypertensive showed an increase in aortic pressure with all drugs although only vasopressin resulted in a consistent decrease in the ratio of pulmonary-to-systemic vascular resistance. Studies with more subjects are warranted to define optimal dosing strategies of these medications in an acute pulmonary hypertensive crisis.

  View details for DOI 10.1097/PCC.0000000000000716

  View details for PubMedID 27144689

• Accuracy of Pulse Oximeters Intended for Hypoxemic Pediatric Patients PEDIATRIC CRITICAL CARE MEDICINE Harris, B. U., Char, D. S., Feinstein, J. A., Verma, A., Shiboski, S. C., Ramamoorthy, C. 2016; 17 (4): 315-320

  Abstract

  Prior studies have shown inaccuracies in pulse oximetry readings at saturations less than 85%; however, no large studies have evaluated new sensors marketed for these low saturations. This study's purpose was to evaluate two sensors with claims of improved accuracy in children with saturations less than 85%.Prospective observational study.Single institution; cardiac catheterization laboratory, and operating room.Fifty patients weighing 3-20 kg with baseline saturations less than 90% undergoing surgical or catheterization procedure.Data collected included demographics, diagnosis, continuous saturations from three different pulse oximeters (Masimo LNCS [Masimo, Irvine, CA], Masimo Blue [Masimo], and Nellcor Max-I [Medtronic, Dublin, Ireland]) and up to four blood samples for co-oximetry as the gold-standard arterial oxygen saturation. Analysis included scatter plots, smoothed regression estimates of mean continuous saturation levels plotted against corresponding arterial oxygen saturation values, and Bland-Altman plots. Bland-Altman analysis indicated increasing levels of bias and variability for decreasing arterial oxygen saturation levels for all three sensors, with a statistically significant increase in mean difference observed for decreasing arterial oxygen saturation level. The Masimo Blue sensor had the lowest mean difference, SD and Bland-Altman limits in patients with saturations less than or equal to 85%. At saturation range of less than or equal to 85% and greater than 75%, 14% of the samples obtained from Masimo Blue, 24% of the readings from the Nellcor, and 31% from the Masimo Standard sensors were greater than or equal to 5% points difference. All three sensors had a further increase in these differences for arterial oxygen saturation values less than 75%.The Masimo Blue sensor has improved accuracy at saturations 75-85% versus the Nellcor and Masimo Standard sensors. The accuracy of peripheral capillary oxygen saturation of the Masimo Blue sensor was within 5% points of the arterial oxygen saturation the majority of the time. Currently, at saturations less than or equal to 85%, pulse oximetry alone should not be relied on in making clinical decisions.

  View details for DOI 10.1097/PCC.0000000000000660

  View details for Web of Science ID 000373211600006

• Outpatient Subcutaneous Treprostinil for Pediatric Single Ventricle Patients Siehr, S. L., Ogawa, M., Romfh, A., Rosenthal, D. N., Feinstein, J. A. ELSEVIER SCIENCE INC. 2016: S159

  View details for DOI 10.1016/j.healun.2016.01.442

  View details for Web of Science ID 000374718100412

• 2015 SPCTPD/ACC/AAP/AHA Training Guidelines for Pediatric Cardiology Fellowship Programs ( Revision of the 2005 Training Guidelines for Pediatric Cardiology Fellowship Programs): Introduction CIRCULATION Ross, R. D., Brook, M., Koenig, P., Feinstein, J. A., Lang, P., Spicer, R. L., Vincent, J. A. 2016; 133 (13): E465

  View details for DOI 10.1161/CIR.0000000000000397

  View details for Web of Science ID 000372852900009

• 2015 SPCTPD/ACC/AAP/AHA Training Guidelines for Pediatric Cardiology Fellowship Programs ( Revision of the 2005 Training Guidelines for Pediatric Cardiology Fellowship Programs) CIRCULATION Ross, R. D., Brook, M., Koenig, P., Feinstein, J. A., Lang, P., Spicer, R. L., Vincent, J. A. 2016; 133 (13): E464

  View details for DOI 10.1161/CIR.0000000000000396

  View details for Web of Science ID 000372852900008

• Recommendations for the Use of Inhaled Nitric Oxide Therapy in Premature Newborns with Severe Pulmonary Hypertension. The Journal of pediatrics Kinsella, J. P., Steinhorn, R. H., Krishnan, U. S., Feinstein, J. A., Adatia, I., Austin, E. D., Rosenzweig, E. B., Everett, A. D., Fineman, J. R., Hanna, B. D., Hopper, R. K., Humpl, T., Ivy, D. D., Keller, R. L., Mullen, M. P., Raj, J. U., Wessel, D. L., Abman, S. H. 2016; 170: 312-4

  View details for DOI 10.1016/j.jpeds.2015.11.050

  View details for PubMedID 26703869

• Pediatric Pulmonary Hypertension Guidelines From the American Heart Association and American Thoracic Society CIRCULATION Abman, S. H., Hansmann, G., Archer, S. L., Ivy, D. D., Adatia, I., Chung, W. K., Hanna, B. D., Rosenzweig, E. B., Raj, J. U., Cornfield, D., Stenmark, K. R., Steinhorn, R., Theobaud, B., Fineman, J. R., Kuehne, T., Feinstein, J. A., Friedberg, M. K., Earing, M., Barst, R. J., Keller, R. L., Kinsella, J. P., Mullen, M., Deterding, R., Kulik, T., Mallory, G., Humpl, T., Wessel, D. L. 2015; 132 (21): 2037-2099

  Abstract

  Pulmonary hypertension is associated with diverse cardiac, pulmonary, and systemic diseases in neonates, infants, and older children and contributes to significant morbidity and mortality. However, current approaches to caring for pediatric patients with pulmonary hypertension have been limited by the lack of consensus guidelines from experts in the field. In a joint effort from the American Heart Association and American Thoracic Society, a panel of experienced clinicians and clinician-scientists was assembled to review the current literature and to make recommendations on the diagnosis, evaluation, and treatment of pediatric pulmonary hypertension. This publication presents the results of extensive literature reviews, discussions, and formal scoring of recommendations for the care of children with pulmonary hypertension.

  View details for DOI 10.1161/CIR.0000000000000329

  View details for Web of Science ID 000365574600015

  View details for PubMedID 26534956

• Computational modeling and engineering in pediatric and congenital heart disease. Current opinion in pediatrics Marsden, A. L., Feinstein, J. A. 2015; 27 (5): 587-596

  Abstract

  Recent methodological advances in computational simulations are enabling increasingly realistic simulations of hemodynamics and physiology, driving increased clinical utility. We review recent developments in the use of computational simulations in pediatric and congenital heart disease, describe the clinical impact in modeling in single-ventricle patients, and provide an overview of emerging areas.Multiscale modeling combining patient-specific hemodynamics with reduced order (i.e., mathematically and computationally simplified) circulatory models has become the de-facto standard for modeling local hemodynamics and 'global' circulatory physiology. We review recent advances that have enabled faster solutions, discuss new methods (e.g., fluid structure interaction and uncertainty quantification), which lend realism both computationally and clinically to results, highlight novel computationally derived surgical methods for single-ventricle patients, and discuss areas in which modeling has begun to exert its influence including Kawasaki disease, fetal circulation, tetralogy of Fallot (and pulmonary tree), and circulatory support.Computational modeling is emerging as a crucial tool for clinical decision-making and evaluation of novel surgical methods and interventions in pediatric cardiology and beyond. Continued development of modeling methods, with an eye towards clinical needs, will enable clinical adoption in a wide range of pediatric and congenital heart diseases.

  View details for DOI 10.1097/MOP.0000000000000269

  View details for PubMedID 26262579

• Task Force 7: Pediatric Cardiology Fellowship Training in Pulmonary Hypertension, Advanced Heart Failure, and Transplantation. SPCTPD/ACC/AAP/AHA. Circulation Webber, S. A., Hsu, D. T., Ivy, D. D., Kulik, T. J., Pahl, E., Rosenthal, D. N., Morrow, W. R., Feinstein, J. A. 2015; 132 (6): e99-e106

  View details for DOI 10.1161/CIR.0000000000000198

  View details for PubMedID 25769631

• 2015 SPCTPD/ACC/AAP/AHA Training Guidelines for Pediatric Cardiology Fellowship Programs (Revision of the 2005 Training Guidelines for Pediatric Cardiology Fellowship Programs) CIRCULATION Ross, R. D., Brook, M., Koenig, P., Feinstein, J. A., Lang, P., Spicer, R. L., Vincent, J. A., Lewis, A. B., Martin, G. R., Bartz, P. J., Fischbach, P. S., Fulton, D. R., Matherne, G., Reinking, B., Spicer, R. L., Srivastava, S., Printz, B. F., Geva, T., Shirali, G. S., Weinberg, P. M., Wong, P. C., Lang, P., Armsby, L. B., Vincent, R. N., Foerster, S. R., Holzer, R. J., Moore, J. W., Marshall, A. C., Latson, L., Brook, M., Dubin, A. M., Walsh, E. P., Franklin, W., Kanter, R. J., Saul, J., Shah, M. J., Van Hare, G. F., Vincent, J. A., Feltes, T. F., Roth, S. J., Almodovar, M. C., Andropoulos, D. B., Bohn, D. J., Costello, J. M., Gajarski, R. J., Mott, A. R., Koenig, P., Stout, K., Valente, A., Bartz, P. J., Cook, S., Gurvitz, M., Saidi, A., Ross, R. D., Webber, S. A., Hsu, D. T., Ivy, D., Kulik, T. J., Pahl, E., Rosenthal, D. N., Morrow, R., Feinstein, J. A., Mahle, W. T., Murphy, A. M., Li, J. S., Law, Y. M., Newburger, J. W., Daniels, S. R., Bernstein, D., Marino, B. S., Ross, R. D., Steering Comm, Pediat Cardiol Fellowship, Pediat Cardiology Fellowship, Pediat Cardiol Fellowship, Pediat Cardiology Fellowship, Pediat Cardiology Fellowship, Pediat Cardiol Fellowship, Pediat Cardiology Fellowship, Pediat Cardiology Fellowship 2015; 132 (6): E41-E42

  View details for DOI 10.1161/CIR.0000000000000190

  View details for Web of Science ID 000359666700002

  View details for PubMedID 25777637

• 2015 SPCTPD/ACC/AAP/AHA Training Guidelines for Pediatric Cardiology Fellowship Programs (Revision of the 2005 Training Guidelines for Pediatric Cardiology Fellowship Programs): Introduction JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Ross, R. D., Brook, M., Koenig, P., Feinstein, J. A., Lang, P., Spicer, R. L., Vincent, J. A. 2015; 66 (6): 672-676

  View details for DOI 10.1016/j.jacc.2015.03.007

  View details for Web of Science ID 000359139600011

  View details for PubMedID 25777634

• 2015 SPCTPD/ACC/AAP/AHA Training Guidelines for Pediatric Cardiology Fellowship Programs (Revision of the 2005 Training Guidelines for Pediatric Cardiology Fellowship Programs): Introduction (vol 66, pg 672, 2015) JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Ross, R. D., Brook, M., Koenig, P., Feinstein, J. A., Lang, P., Spicer, R. L., Vincent, J. A. 2015; 66 (6): 761

  View details for DOI 10.1016/j.jacc.2015.06.1303

  View details for Web of Science ID 000359139600029

• Task Force 7: Pediatric Cardiology Fellowship Training in Pulmonary Hypertension, Advanced Heart Failure, and Transplantation (vol 66, pg 732, 2015) JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Webber, S. A., Hsu, D. T., Ivy, D. D., Kulik, T. J., Pahl, E., Rosenthal, D. N., Morrow, R., Feinstein, J. A. 2015; 66 (6): 763

  View details for DOI 10.1016/j.jacc.2015.06.1307

  View details for Web of Science ID 000359139600033

• Task Force 7: Pediatric Cardiology Fellowship Training in Pulmonary Hypertension, Advanced Heart Failure, and Transplantation CIRCULATION Webber, S. A., Hsu, D. T., Ivy, D. D., Kulik, T. J., Pahl, E., Rosenthal, D. N., Morrow, W. R., Feinstein, J. A. 2015; 132 (6): E99-E106

  View details for DOI 10.1161/CIR.0000000000000198

  View details for Web of Science ID 000359666700010

  View details for PubMedID 25769631

• 2015 SPCTPD/ACC/AAP/AHA Training Guidelines for Pediatric Cardiology Fellowship Programs (Revision of the 2005 Training Guidelines for Pediatric Cardiology Fellowship Programs): Introduction CIRCULATION Ross, R. D., Brook, M., Koenig, P., Feinstein, J. A., Lang, P., Spicer, R. L., Vincent, J. A. 2015; 132 (6): E43-E47

  View details for DOI 10.1161/CIR.0000000000000191

  View details for Web of Science ID 000359666700003

  View details for PubMedID 25769639

• Task Force 7: Pediatric Cardiology Fellowship Training in Pulmonary Hypertension, Advanced Heart Failure, and Transplantation JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Webber, S. A., Hsu, D. T., Ivy, D. D., Kulik, T. J., Pahl, E., Rosenthal, D. N., Morrow, W. R., Feinstein, J. A. 2015; 66 (6): 732-739

  View details for DOI 10.1016/j.jacc.2015.03.013

  View details for Web of Science ID 000359139600018

  View details for PubMedID 25777654

• A multiscale model for the study of cardiac biomechanics in single-ventricle surgeries: a clinical case. Interface focus Meoli, A., Cutrì, E., Krishnamurthy, A., Dubini, G., Migliavacca, F., Hsia, T., Pennati, G., Taylor, A., Giardini, A., Khambadkone, S., Schievano, S., De Leval, M., Hsia, T., Bove, E., Dorfman, A., Baker, G. H., Hlavacek, A., Migliavacca, F., Pennati, G., Dubini, G., Marsden, A., Feinstein, J., Vignon-Clementel, I., Figliola, R., McGregor, J. 2015; 5 (2): 20140079-?

  Abstract

  Complex congenital heart disease characterized by the underdevelopment of one ventricular chamber (single ventricle (SV) circulation) is normally treated with a three-stage surgical repair. This study aims at developing a multiscale computational framework able to couple a patient-specific three-dimensional finite-element model of the SV to a patient-specific lumped parameter (LP) model of the whole circulation, in a closed-loop fashion. A sequential approach was carried out: (i) cardiocirculatory parameters were estimated by using a fully LP model; (ii) ventricular material parameters and unloaded geometry were identified by means of the stand-alone, three-dimensional model of the SV; and (iii) the three-dimensional model of SV was coupled to the LP model of the circulation, thus closing the loop and creating a multiscale model. Once the patient-specific multiscale model was set using pre-operative clinical data, the virtual surgery was performed, and the post-operative conditions were simulated. This approach allows the analysis of local information on ventricular function as well as global parameters of the cardiovascular system. This methodology is generally applicable to patients suffering from SV disease for surgical planning at different stages of treatment. As an example, a clinical case from stage 1 to stage 2 is considered here.

  View details for DOI 10.1098/rsfs.2014.0079

  View details for PubMedID 25844151

  View details for PubMedCentralID PMC4342947

• Neonatal Pulmonary Arterial Hypertension and Noonan Syndrome: Two Fatal Cases with a Specific RAF1 Mutation AMERICAN JOURNAL OF MEDICAL GENETICS PART A Hopper, R. K., Feinstein, J. A., Manning, M. A., Benitz, W., Hudgins, L. 2015; 167A (4): 882-885

  Abstract

  Mutations in RAF1 are associated with Noonan syndrome and hypertrophic cardiomyopathy. We present two infants with Noonan syndrome and an identical RAF1 mutation, p.Ser257Leu (c.770C>T), who developed severe pulmonary arterial hypertension (PAH) that proved to be fatal. The RAF1 gene encodes Raf-1 kinase, part of the Ras/mitogen-activated kinase (MAPK) signaling pathway, which has been linked to the development of PAH. This specific mutation has been associated with dephosphorylation of a critical serine residue and constitutive activation of the Raf-1 kinase. These two cases suggest that abnormal activation of the Ras/MAPK pathway may play a significant role in the development of pulmonary vascular disease in the subset of patients with Noonan syndrome and a specific RAF1 mutation. © 2015 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.a.37024

  View details for Web of Science ID 000352019000035

• Neonatal pulmonary arterial hypertension and Noonan syndrome: two fatal cases with a specific RAF1 mutation. American journal of medical genetics. Part A Hopper, R. K., Feinstein, J. A., Manning, M. A., Benitz, W., Hudgins, L. 2015; 167A (4): 882-885

  Abstract

  Mutations in RAF1 are associated with Noonan syndrome and hypertrophic cardiomyopathy. We present two infants with Noonan syndrome and an identical RAF1 mutation, p.Ser257Leu (c.770C>T), who developed severe pulmonary arterial hypertension (PAH) that proved to be fatal. The RAF1 gene encodes Raf-1 kinase, part of the Ras/mitogen-activated kinase (MAPK) signaling pathway, which has been linked to the development of PAH. This specific mutation has been associated with dephosphorylation of a critical serine residue and constitutive activation of the Raf-1 kinase. These two cases suggest that abnormal activation of the Ras/MAPK pathway may play a significant role in the development of pulmonary vascular disease in the subset of patients with Noonan syndrome and a specific RAF1 mutation. © 2015 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.a.37024

  View details for PubMedID 25706034

• Reported sildenafil side effects in pediatric pulmonary hypertension patients. Frontiers in pediatrics Siehr, S. L., McCarthy, E. K., Ogawa, M. T., Feinstein, J. A. 2015; 3: 12-?

  Abstract

  Sildenafil, a phosphodiestase type 5 inhibitor, was approved in 2005 for the treatment of pulmonary arterial hypertension (PAH) in adults and is commonly used off-label for pediatric patients. Little is known, however, about sildenafil's side effects in this population.Single institution, longitudinal survey-based study performed in an outpatient pediatric cardiology clinic. Pediatric patients on sildenafil [alone or in combination with other pulmonary hypertension (PH) therapies] completed questionnaires regarding frequency of vascular, gastrointestinal, neurologic, and hematologic side effects.Between January 2011 and May 2014, 66 pediatric patients with PH on sildenafil filled out 214 surveys, 32 patients (96 surveys) on monotherapy, and 43 patients (118 surveys) on sildenafil plus an endothelin receptor antagonist (ERA) (bosentan or ambrisentan) and/or a prostacyclin (epoprostenol or treprostinil). Overall, 30% of respondents identified at least one side effect. For all patients on sildenafil, incidence of side effects by system was 37% gastrointestinal, 35% vascular, and 22% neurologic. For patients on sildenafil monotherapy, incidence of side effects by system was 24% gastrointestinal, 21% vascular, and 18% neurologic compared to patients on combination therapy who reported an incidence of 48% gastrointestinal, 45% vascular, and 25% neurologic.Incidence of vascular, gastrointestinal, and neurologic side effect in pediatric patients on sildenafil therapy for PAH was 30%. Side effects were more common in patients on combination therapy with an ERA and/or prostacyclin than in patients on sildenafil monotherapy.

  View details for DOI 10.3389/fped.2015.00012

  View details for PubMedID 25806361

  View details for PubMedCentralID PMC4353247

• Reported sildenafil side effects in pediatric pulmonary hypertension patients FRONTIERS IN PEDIATRICS Siehr, S. L., McCarthy, E. K., Ogawa, M. T., Feinstein, J. A. 2015; 3

  Abstract

  Sildenafil, a phosphodiestase type 5 inhibitor, was approved in 2005 for the treatment of pulmonary arterial hypertension (PAH) in adults and is commonly used off-label for pediatric patients. Little is known, however, about sildenafil's side effects in this population.Single institution, longitudinal survey-based study performed in an outpatient pediatric cardiology clinic. Pediatric patients on sildenafil [alone or in combination with other pulmonary hypertension (PH) therapies] completed questionnaires regarding frequency of vascular, gastrointestinal, neurologic, and hematologic side effects.Between January 2011 and May 2014, 66 pediatric patients with PH on sildenafil filled out 214 surveys, 32 patients (96 surveys) on monotherapy, and 43 patients (118 surveys) on sildenafil plus an endothelin receptor antagonist (ERA) (bosentan or ambrisentan) and/or a prostacyclin (epoprostenol or treprostinil). Overall, 30% of respondents identified at least one side effect. For all patients on sildenafil, incidence of side effects by system was 37% gastrointestinal, 35% vascular, and 22% neurologic. For patients on sildenafil monotherapy, incidence of side effects by system was 24% gastrointestinal, 21% vascular, and 18% neurologic compared to patients on combination therapy who reported an incidence of 48% gastrointestinal, 45% vascular, and 25% neurologic.Incidence of vascular, gastrointestinal, and neurologic side effect in pediatric patients on sildenafil therapy for PAH was 30%. Side effects were more common in patients on combination therapy with an ERA and/or prostacyclin than in patients on sildenafil monotherapy.

  View details for DOI 10.3389/fped.2015.00012

  View details for Web of Science ID 000209897400010

  View details for PubMedCentralID PMC4353247

• Technical feasibility and intermediate outcomes of using a handcrafted, area-preserving, bifurcated Y-graft modification of the Fontan procedure JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Martin, M. H., Feinstein, J. A., Chan, F. P., Marsden, A. L., Yang, W., Reddy, V. M. 2015; 149 (1): 239-U381

  Abstract

  To demonstrate the technical feasibility and describe intermediate outcomes for the initial patients undergoing handcrafted, area-preserving, Y-graft modification of the Fontan procedure.A retrospective review of a pilot study was undertaken to describe preoperative, intraoperative, and postoperative results.Six patients underwent successful procedures and remain alive 3 to 4 years later. The median age at operation was 3.3 years, and median weight was 13.2 kg. Five operations were done without cardiopulmonary bypass and no intraoperative pressure gradients were found. Five patients were extubated by postoperative day 1, Fontan pressures were 12 to 14 mm Hg, transpulmonary gradients were 6 to 8 mm Hg, and no renal or hepatic function abnormalities were found. Length of stay was 10 to 64 days. One patient required venovenous extracorporeal membrane oxygenation for previously undiagnosed plastic bronchitis (64-day stay); another required reoperation for an incidentally diagnosed aortic thrombus (44-day stay). One patient had occlusion of a Y-graft limb noted on magnetic resonance imaging follow-up at 3 months. Catheterization showed excellent hemodynamic parameters and no Fontan obstruction. Occlusion was believed to be due to right-sided pulmonary arteriovenous malformations and widely discrepant flow (80%) to the right lung leading to low flow in the left limb.The area-preserving, bifurcated Y-graft Fontan modification is technically feasible and shows excellent intermediate outcomes. Additional study is required to determine whether the advantages seen in the computational models will be realized in patients over the long-term, and to optimize patient selection for each of the various Fontan options now available.

  View details for DOI 10.1016/j.jtcvs.2014.08.058

  View details for Web of Science ID 000350550100068

  View details for PubMedID 25439786

• Technical feasibility and intermediate outcomes of using a handcrafted, area-preserving, bifurcated Y-graft modification of the Fontan procedure. journal of thoracic and cardiovascular surgery Martin, M. H., Feinstein, J. A., Chan, F. P., Marsden, A. L., Yang, W., Reddy, V. M. 2015; 149 (1): 239-45 e1

  Abstract

  To demonstrate the technical feasibility and describe intermediate outcomes for the initial patients undergoing handcrafted, area-preserving, Y-graft modification of the Fontan procedure.A retrospective review of a pilot study was undertaken to describe preoperative, intraoperative, and postoperative results.Six patients underwent successful procedures and remain alive 3 to 4 years later. The median age at operation was 3.3 years, and median weight was 13.2 kg. Five operations were done without cardiopulmonary bypass and no intraoperative pressure gradients were found. Five patients were extubated by postoperative day 1, Fontan pressures were 12 to 14 mm Hg, transpulmonary gradients were 6 to 8 mm Hg, and no renal or hepatic function abnormalities were found. Length of stay was 10 to 64 days. One patient required venovenous extracorporeal membrane oxygenation for previously undiagnosed plastic bronchitis (64-day stay); another required reoperation for an incidentally diagnosed aortic thrombus (44-day stay). One patient had occlusion of a Y-graft limb noted on magnetic resonance imaging follow-up at 3 months. Catheterization showed excellent hemodynamic parameters and no Fontan obstruction. Occlusion was believed to be due to right-sided pulmonary arteriovenous malformations and widely discrepant flow (80%) to the right lung leading to low flow in the left limb.The area-preserving, bifurcated Y-graft Fontan modification is technically feasible and shows excellent intermediate outcomes. Additional study is required to determine whether the advantages seen in the computational models will be realized in patients over the long-term, and to optimize patient selection for each of the various Fontan options now available.

  View details for DOI 10.1016/j.jtcvs.2014.08.058

  View details for PubMedID 25439786

• Flow simulations and validation for the first cohort of patients undergoing the Y-graft Fontan procedure JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Yang, W., Chan, F. P., Reddy, V. M., Marsden, A. L., Feinstein, J. A. 2015; 149 (1): 247-255

  Abstract

  In this study, with the use of computational fluid dynamics, we evaluate the postoperative hemodynamic performance of the first cohort of patients undergoing a handcrafted Y-graft Fontan procedure and validate simulation predictions of hepatic blood flow distribution against in vivo clinical data.An 18-12 × 2-mm handcrafted Y-graft modification of the Fontan procedure was performed in 6 patients. Early (at the time of discharge) and 6-month postoperative 3-dimensional magnetic resonance imaging data were collected. Patient-specific models were constructed for flow simulations.Hepatic blood flow distribution varied among patients. Lung perfusion data (n = 3) showed good agreement with simulations. Postoperative asymmetry in hepatic blood flow distribution was reduced 6 months postoperatively. In 1 patient, low wall shear stress was found in the left limb of the Y-graft, corresponding to the location of subsequent thrombosis in the patient.The credibility and accuracy of simulation-based predictions of postoperative hepatic flow distribution for the Fontan surgery have been validated by in vivo lung perfusion data. The performance of the Y-graft design is highly patient-specific. The anastomosis location is likely the most important factor influencing hepatic blood flow distribution. Although the development of thrombosis is multifactorial, the occurrence in 1 patient suggests that simulations should not solely consider the hepatic blood flow distribution but also aim to avoid low wall shear stress in the limbs.

  View details for DOI 10.1016/j.jtcvs.2014.08.069

  View details for PubMedID 25439766

• Computed Tomography Angiography Can Replace Cardiac Catheterization in the Surgical Planning of Select Neonates with Major Aortopulmonary Collaterals Bauser-Heaton, H., Peng, L., Perry, S. B., Feinstein, J. A., Hanley, F. L., Chan, F. P. LIPPINCOTT WILLIAMS & WILKINS. 2014

  View details for Web of Science ID 000209790200072

• Quantification of local hemodynamic alterations caused by virtual implantation of three commercially available stents for the treatment of aortic coarctation. Pediatric cardiology Kwon, S., Feinstein, J. A., Dholakia, R. J., LaDisa, J. F. 2014; 35 (4): 732-740

  Abstract

  Patients with coarctation of the aorta (CoA) are prone to morbidity including atherosclerotic plaque that has been shown to correlate with altered wall shear stress (WSS) in the descending thoracic aorta (dAo). We created the first patient-specific computational fluid dynamics (CFD) model of a CoA patient treated by Palmaz stenting to date, and compared resulting WSS distributions to those from virtual implantation of Genesis XD and modified NuMED CP stents, also commonly used for CoA. CFD models were created from magnetic resonance imaging, fluoroscopy and blood pressure data. Simulations incorporated vessel deformation, downstream vascular resistance and compliance to match measured data and generate blood flow velocity and time-averaged WSS (TAWSS) results. TAWSS was quantified longitudinally and circumferentially in the stented region and dAo. While modest differences were seen in the distal portion of the stented region, marked differences were observed downstream along the posterior dAo and depended on stent type. The Genesis XD model had the least area of TAWSS values exceeding the threshold for platelet aggregation in vitro, followed by the Palmaz and NuMED CP stents. Alterations in local blood flow patterns and WSS imparted on the dAo appear to depend on the type of stent implanted for CoA. Following confirmation in larger studies, these findings may aid pediatric interventional cardiologists in selecting the most appropriate stent for each patient, and ultimately reduce long-term morbidity following treatment for CoA by stenting.

  View details for DOI 10.1007/s00246-013-0845-7

  View details for PubMedID 24259013

  View details for PubMedCentralID PMC3959287

• A PUBLIC REPOSITORY OF IMAGE-BASED COMPUTATIONAL MODELS AND PATIENT-SPECIFIC BLOOD FLOW SIMULATION RESULTS Wilson, N. M., Ortiz, A. K., Johnson, A. B., Feinstein, J. A., LaDisa, J. F., Marsden, A., ASME AMER SOC MECHANICAL ENGINEERS. 2014

  View details for Web of Science ID 000359389200185

• Hot Topics in Tetralogy of Fallot JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Villafane, J., Feinstein, J. A., Jenkins, K. J., Vincent, R. N., Walsh, E. P., Dubin, A. M., Geva, T., Towbin, J. A., Cohen, M. S., Fraser, C., Dearani, J., Rosenthal, D., Kaufman, B., Graham, T. P. 2013; 62 (23): 2155-2166

  Abstract

  Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect. We explore "hot topics" to highlight areas of emerging science for clinicians and scientists in moving toward a better understanding of the long-term management of patients with repaired TOF. From a genetic perspective, the etiology of TOF is multifactorial, with a familial recurrence risk of 3%. Cardiac magnetic resonance is the gold standard assessment tool based on its superior imaging of the right ventricular (RV) outflow tract, pulmonary arteries, aorta, and aortopulmonary collaterals, and on its ability to quantify biventricular size and function, pulmonary regurgitation (PR), and myocardial viability. Atrial re-entrant tachycardia will develop in more than 30% of patients, and high-grade ventricular arrhythmias will be seen in about 10% of patients. The overall incidence of sudden cardiac death is estimated at 0.2%/yr. Risk stratification, even with electrophysiologic testing and cardiac magnetic resonance, remains imperfect. Drug therapy has largely been abandoned, and defibrillator placement, despite its high risks for complications and inappropriate discharges, is often recommended for patients at higher risk. Definitive information about optimal surgical strategies for primary repair to preserve RV function, reduce arrhythmia, and optimize functional status is lacking. Post-operative lesions are often amenable to transcatheter intervention. In selected cases, PR may be treated with transcatheter valve insertion. Ongoing surveillance of RV function is a crucial component of clinical assessment. Except for resynchronization with biventricular pacing, no medical therapies have been shown to be effective after RV dysfunction occurs. In patients with significant PR with RV dilation, optimal timing of pulmonary valve replacement remains uncertain, although accepted criteria are emerging.

  View details for DOI 10.1016/j.jacc.2013.07.100

  View details for Web of Science ID 000328073000002

  View details for PubMedID 24076489

• Food and drug administration (FDA) postmarket reported side effects and adverse events associated with pulmonary hypertension therapy in pediatric patients. Pediatric cardiology Maxey, D. M., Ivy, D. D., Ogawa, M. T., Feinstein, J. A. 2013; 34 (7): 1628-1636

  Abstract

  Because most medications for pediatric pulmonary hypertension (PH) are used off label and based on adult trials, little information is available on pediatric-specific adverse events (AEs). Although drug manufacturers are required to submit postmarket AE reports to the Food and Drug Administration (FDA), this information is rarely transmitted to practitioners. In the setting of a recent FDA warning for sildenafil, the authors sought to give a better description of the AEs associated with current therapies in pediatric PH. In January 2010, a written request was made to the Food and Drug Administration for AE records of commonly used PH medications. Reports were screened for pediatric patients, analyzed in terms of AEs, and compared with the medical literature. Arbitrarily, AEs that could be attributed to concomitant medications were not attributed to the PH medication in question. Adverse events occurring in more than 5 % of events for each drug were assumed to be associated with the targeted PH medication. Between November 1997 and December 2009, 588 pediatric AE reports (death in 257 cases) were reported for the three most commonly used therapies: bosentan, epoprostenol, and sildenafil. Many of the AEs were similar to those reported previously. However, 27 AEs not previously reported in the literature (e.g., pulmonary hemorrhage, hemoptysis, and pneumonia) were found. The FDA postmarket records for PH medications in pediatric patients show a significant number of AEs. The discovery of AEs not previously reported will better inform those caring for these complex and critically ill children, and the large number of deaths suggest they may be underreported in current literature.

  View details for DOI 10.1007/s00246-013-0688-2

  View details for PubMedID 23532466

• Diagnostic evaluation of paediatric pulmonary hypertension in current clinical practice EUROPEAN RESPIRATORY JOURNAL Beghetti, M., Berger, R. M., Schulze-Neick, I., Day, R. W., Pulido, T., Feinstein, J., Barst, R. J., Humpl, T. 2013; 42 (3): 689-700

  Abstract

  Current paediatric pulmonary hypertension (PH) diagnostic algorithms include some testing specifically for paediatrics, but it is unclear if this is used in clinical practice. We describe the current diagnostic workup of the TOPP (Tracking Outcomes and Practice in Paediatric Pulmonary hypertension) registry for suspected PH. We investigated 456 patients enrolled until February 2010. The majority had ECGs (94%), echocardiograms (96%) and/or chest radiographs (89%) performed and these were the noninvasive tests most frequently used for evaluation of suspected PH. No patient had all three tests considered normal, suggesting the potential for the combined use to rule out PH. For evaluation of complications associated with heart catheterisation (HC) we analysed a total of 908 HCs reported until February 2012. Of these, 554 were at diagnosis and 354 in follow-up. Complications were reported in 5.9% with five deaths considered related to HC, suggesting a higher rate of HC complications compared to adult studies. However, current recommendations support HC in paediatric PH. A proper application of the risk/benefit ratio for HC requires further data. Most children did not undergo the diagnostic workup currently recommended for adults, which highlights either incomplete awareness of current guidelines and/or challenges their appropriateness for children.

  View details for DOI 10.1183/09031936.00140112

  View details for Web of Science ID 000326160500019

  View details for PubMedID 23563261

• Children with pulmonary arterial hypertension and prostanoid therapy: Long-term hemodynamics JOURNAL OF HEART AND LUNG TRANSPLANTATION Siehr, S. L., Ivy, D. D., Miller-Reed, K., Ogawa, M., Rosenthal, D. N., Feinstein, J. A. 2013; 32 (5): 546-552

  Abstract

  Pediatric patients with severe pulmonary arterial hypertension (PAH) are treated with intravenous epoprostenol or intravenous or subcutaneous treprostinil. Little is known about longitudinal hemodynamics and outcomes of epoprostenol, treprostinil, and transitions from epoprostenol to treprostinil.This was retrospective study of 77 pediatric patients (47 idiopathic PAH, 24 congenital heart disease-PAH) receiving epoprostenol or treprostinil from 1992 to 2010 at 2 centers. Outcomes were defined as living vs dead/transplant.Mean age at baseline was 7.7 ± 5.2 years, with follow-up of 4.3 ± 3.4 years. Thirty-seven patients were treated with epoprostenol, 20 with treprostinil, and 20 were transitioned from epoprostenol to treprostinil. Mean pulmonary-to-systemic vascular resistance ratio (Rp/Rs) for epoprostenol was 1.0 ± 0.4, 0.8 ± 0.4, 0.8 ± 0.4, 1.0 ± 0.4, and 1.2 ± 0.4, respectively, at baseline, 1, 2, 3, and 4 years. For treprostinil, Rp/Rs was 0.9 ± 0.3, 0.7 ± 0.3, 0.5 ± 0.2, (p < 0.01 vs baseline), and 1.1 ± 0.2, respectively, at baseline, 1, 2, and 3 to 4 years, respectively. There were similar changes in mean pulmonary artery pressure and pulmonary vascular resistance index. The Rp/Rs 1 year after epoprostenol to treprostinil transition increased from 0.6 to 0.8 (n = 7). Changes not statistically significant unless noted. Eight patients died or received a transplant within 2 years of baseline; compared with the rest of the cohort, mean baseline Rp/Rs, right atrial pressure, and pulmonary vascular resistance index were significantly worse in this group. Thirty-nine patients remain on prostanoids, 17 are off, 16 died, and 5 received heart-lung transplant. Kaplan-Meier 5-year transplant-free survival was 70% (95% confidence interval, 56%-80%).There was improvement in Rp/Rs on both therapies at 1 to 2 years that was not sustained. The 5-year transplant-free survival was better than in similar adult studies.

  View details for DOI 10.1016/j.healun.2013.01.1055

  View details for PubMedID 23453572

• Validation of the Innocor Device for Noninvasive Measurement of Oxygen Consumption in Children and Adults PEDIATRIC CARDIOLOGY Sheth, S. S., Maxey, D. M., Drain, A. E., Feinstein, J. A. 2013; 34 (4): 847-852

  Abstract

  Outpatient measurements of oxygen consumption (VO2) and cardiac output (CO) are valuable in the management of pediatric cardiac disease. Current methods are inaccurate and cumbersome or require invasive procedures. New devices to measure these variables in adults have not been rigorously tested for children. The Innocor system uses a photoacoustic analyzer to measure gas content for noninvasive measurement of VO2 and CO. This study sought to validate Innocor-derived VO2 measurements in children and adults by comparing them against the gold standard Douglas bag method. Subjects were tested in an outpatient setting. Adaptations were made for pediatric patients based on weight. Resting VO2 measurements were obtained simultaneously by the Innocor system and Douglas bag during 3 min. The study enrolled 31 children (mean age, 12.2 years; range, 7-17 years, 17 girls) and 29 adults (mean age, 36.7 years; range, 19-57 years; 17 women). Strong correlation between the two techniques was seen for both the adults (R (2) = 0.88) and the children (R (2) = 0.82). The average discrepancy between the Innocor and Douglas bag measurements was 1.7 % (range, 0.6-19.1 %) for the adults, and 5.4 % (range, 0.1-32.2 %) for the children. The discrepancy was more than 15 % for 17 % of the adults and 22 % of the children, with the Innocor device tending to overestimate VO2 in children compared with the Douglas bag. This trend was not seen in adults. The Innocor system has excellent correlation with the Douglas bag and shows promise for noninvasive measurement of VO2 and CO in the school-age pediatric population.

  View details for DOI 10.1007/s00246-012-0555-6

  View details for PubMedID 23108483

• Magnetic resonance imaging of the right ventricle in pediatric pulmonary arterial hypertension PULMONARY CIRCULATION Blalock, S., Chan, F., Rosenthal, D., Ogawa, M., Maxey, D., Feinstein, J. 2013; 3 (2): 350-355

  Abstract

  Pulmonary arterial hypertension (PAH) causes changes in the right ventricle (RV), affecting RV size and function, ultimately leading to death. These changes have been evaluated by cardiac MRI (CMR) in adults with PAH, but not in children. Using CMR in pediatric patients with PAH, we examined how RV size and function (1) compare to normal data, (2) change over time, and (3) compare to similar studies in the adult population. Data from two institutions were retrospectively reviewed. Subjects with PAH and a CMR were included. Baseline CMR variables (right and left ventricular end-diastolic and end-systolic volumes indexed for body surface area, and calculated stroke volume and ejection fraction) were compared to normative data and follow-up CMR data. Twenty-six subjects (15 female), age 2-16 (mean 11) years, with idiopathic PAH were included. All patients were on PAH medication, and 65% on prostacyclin therapy. The baseline 6-Minute Walk Distance (6MWD; 481 ± 137) was normal. RV volumes and ejection fraction were markedly abnormal compared to normal data (P < 0.001). Follow-up CMRs were analyzed in 15 patients. RV volumes and function and LV stroke volume showed no significant change over one year. Our pediatric patients with PAH have markedly abnormal right ventricles by CMR but have normal walk distances. The lack of change in CMR parameters over one year may represent a stable cohort and is different than similar studies in adults.

  View details for DOI 10.4103/2045-8932.114763

  View details for Web of Science ID 000209981500008

  View details for PubMedCentralID PMC3757829

• Magnetic resonance imaging of the right ventricle in pediatric pulmonary arterial hypertension. Pulmonary circulation Blalock, S., Chan, F., Rosenthal, D., Ogawa, M., Maxey, D., Feinstein, J. 2013; 3 (2): 350-355

  Abstract

  Pulmonary arterial hypertension (PAH) causes changes in the right ventricle (RV), affecting RV size and function, ultimately leading to death. These changes have been evaluated by cardiac MRI (CMR) in adults with PAH, but not in children. Using CMR in pediatric patients with PAH, we examined how RV size and function (1) compare to normal data, (2) change over time, and (3) compare to similar studies in the adult population. Data from two institutions were retrospectively reviewed. Subjects with PAH and a CMR were included. Baseline CMR variables (right and left ventricular end-diastolic and end-systolic volumes indexed for body surface area, and calculated stroke volume and ejection fraction) were compared to normative data and follow-up CMR data. Twenty-six subjects (15 female), age 2-16 (mean 11) years, with idiopathic PAH were included. All patients were on PAH medication, and 65% on prostacyclin therapy. The baseline 6-Minute Walk Distance (6MWD; 481 ± 137) was normal. RV volumes and ejection fraction were markedly abnormal compared to normal data (P < 0.001). Follow-up CMRs were analyzed in 15 patients. RV volumes and function and LV stroke volume showed no significant change over one year. Our pediatric patients with PAH have markedly abnormal right ventricles by CMR but have normal walk distances. The lack of change in CMR parameters over one year may represent a stable cohort and is different than similar studies in adults.

  View details for DOI 10.4103/2045-8932.114763

  View details for PubMedID 24015335

  View details for PubMedCentralID PMC3757829

• Implications of the U.S. Food and Drug Administration Warning against the Use of Sildenafil for the Treatment of Pediatric Pulmonary Hypertension AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Abman, S. H., Kinsella, J. P., Rosenzweig, E. B., Krishnan, U., Kulik, T., Mullen, M., Wessel, D. L., Steinhorn, R., Adatia, I., Hanna, B., Feinstein, J., Fineman, J., Raj, U., Humpl, T. 2013; 187 (6): 572-575

  Abstract

  Pulmonary arterial hypertension (PAH) contributes to disability and death in children with diverse cardiac, pulmonary, or systemic diseases, and therapeutic options are currently limited. Data from adult studies provide the basis for most PAH-specific therapies; however, many of these medications are commonly used in children on an off-label basis due to the life-threatening nature of PAH. Although currently approved for use in adult PAH, sildenafil is used extensively off-label for the treatment of neonates, infants, and children with PAH. Past studies have generally suggested favorable effects and outcomes in infants and young children with PAH, but these reports are generally uncontrolled observations, except for one single-center trial for persistent pulmonary hypertension of the newborn. Despite extensive clinical experience with sildenafil therapy in children and approval by the European Medicines Agency for its pediatric use in Europe, the U.S. Food and Drug Administration recently issued a warning against the use of sildenafil for pediatric PAH between 1 and 17 years of age due to an apparent increase in mortality during long-term therapy. Although these data are extremely limited, this U.S. Food and Drug Administration review challenges the pediatric PAH community to further assess the efficacy and safety of sildenafil, especially with chronic treatment. Although low doses of sildenafil are likely safe in pediatric PAH, further studies should carefully examine its role in the long-term therapy of children, especially with diverse causes of PAH. Pediatric patients with PAH require close surveillance and frequent monitoring, and persistent sildenafil monotherapy is likely insufficient with disease progression.

  View details for DOI 10.1164/rccm.201210-1928PP

  View details for Web of Science ID 000316423800005

  View details for PubMedID 23220921

• Computational fluid dynamic simulations for determination of ventricular workload in aortic arch obstructions. journal of thoracic and cardiovascular surgery Coogan, J. S., Chan, F. P., LaDisa, J. F., Taylor, C. A., Hanley, F. L., Feinstein, J. A. 2013; 145 (2): 489-495 e1

  Abstract

  The cardiac workload associated with various types of aortic obstruction was determined using computational fluid dynamic simulations.Computed tomography image data were collected from 4 patients with 4 distinct types of aortic arch obstructions and 4 controls. The categorization of arch hypoplasia corresponded to the "A, B, C" nomenclature of arch interruption; a type "D" was added to represent diffuse arch hypoplasia. Measurements of the vessel diameter were compared against the normal measurements to determine the degree of narrowing. Three-dimensional models were created for each patient, and additional models were created for type A and B hypoplasia to represent 25%, 50%, and 75% diameter narrowing. The boundary conditions for the computational simulations were chosen to achieve realistic flow and pressures in the control cases. The simulations were then repeated after changing the boundary conditions to represent a range of cardiac and vascular adaptations. The resulting cardiac workload was compared with the control cases.Of the 4 patients investigated, 1 had aortic coarctation and 3 had aortic hypoplasia. The cardiac workload of the patients with 25% narrowing type A and B hypoplasia was not appreciably different from that of the control. When comparing the different arch obstructions, 75% type A, 50% type B, and 50% type D hypoplasia required a greater workload increase than 75% coarctation.The present study has determined the hemodynamic significance of aortic arch obstruction using computational simulations to calculate the cardiac workload. These results suggest that all types of hypoplasia pose more of a workload challenge than coarctation with an equivalent degree of narrowing.

  View details for DOI 10.1016/j.jtcvs.2012.03.051

  View details for PubMedID 22516390

• Computational fluid dynamic simulations for determination of ventricular workload in aortic arch obstructions JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Coogan, J. S., Chan, F. P., LaDisa, J. F., Taylor, C. A., Hanley, F. L., Feinstein, J. A. 2013; 145 (2): 489-U535

  View details for DOI 10.1016/j.jtcvs.2012.03.051

  View details for Web of Science ID 000313634700032

  View details for PubMedID 22516390

• Chronic effects of pulmonary artery stenosis on hemodynamic and structural development of the lungs. American journal of physiology. Lung cellular and molecular physiology Razavi, H., Stewart, S. E., Xu, C., Sawada, H., Zarafshar, S. Y., Taylor, C. A., Rabinovitch, M., Feinstein, J. A. 2013; 304 (1): L17-28

  Abstract

  Pulmonary artery (PA) stenosis is a difficult obstructive defect to manage since clinicians cannot know a priori which obstructions to treat and when. Prognosis of PA stenosis and its chronic effects on lung development are poorly understood. This study aimed to characterize the hemodynamic and structural effects of PA stenosis during development. Fourteen male Sprague-Dawley rats underwent left PA (LPA) banding at age 21 days, and 13 underwent sham operation. Hemodynamic and structural impacts were studied longitudinally at 20, 36, 52, 100, and 160 days. Chronic LPA banding resulted in a significant reduction in LPA flow (P < 0.0001) and size of both proximal LPA (P < 0.0001) and distal LPA (P < 0.01), as well as a significant increase in flow and size of the right PA (P < 0.05) throughout development. Flows and sizes adapted such that normal levels of wall shear were restored after banding. At 160 days, LPA banding resulted in a significant decrease in left lung volume and an increase in right lung volume but no significant differences in total lung volume. There was an elevation of proximal LPA pressure as well as right ventricular hypertrophy in the banded animals. The banded lung exhibited arterial disorganization, loss of vessels, and enlargement of its bronchial arteries, whereas the contralateral lung showed signs of vascular pathology. There are consequences on development of both lungs in the presence of an LPA stenosis at young age. These results suggest that early intervention may be necessary to optimize left lung growth and minimize right lung vascular pathology.

  View details for DOI 10.1152/ajplung.00412.2011

  View details for PubMedID 23043077

• Optimization of a Y-Graft Design for Improved Hepatic Flow Distribution in the Fontan Circulation JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME Yang, W., Feinstein, J. A., Shadden, S. C., Vignon-Clementel, I. E., Marsden, A. L. 2013; 135 (1)

  Abstract

  Single ventricle heart defects are among the most serious congenital heart diseases, and are uniformly fatal if left untreated. Typically, a three-staged surgical course, consisting of the Norwood, Glenn, and Fontan surgeries is performed, after which the superior vena cava (SVC) and inferior vena cava (IVC) are directly connected to the pulmonary arteries (PA). In an attempt to improve hemodynamic performance and hepatic flow distribution (HFD) of Fontan patients, a novel Y-shaped graft has recently been proposed to replace the traditional tube-shaped extracardiac grafts. Previous studies have demonstrated that the Y-graft is a promising design with the potential to reduce energy loss and improve HFD. However these studies also found suboptimal Y-graft performance in some patient models. The goal of this work is to determine whether performance can be improved in these models through further design optimization. Geometric and hemodynamic factors that influence the HFD have not been sufficiently investigated in previous work, particularly for the Y-graft. In this work, we couple Lagrangian particle tracking to an optimal design framework to study the effects of boundary conditions and geometry on HFD. Specifically, we investigate the potential of using a Y-graft design with unequal branch diameters to improve hepatic distribution under a highly uneven RPA/LPA flow split. As expected, the resulting optimal Y-graft geometry largely depends on the pulmonary flow split for a particular patient. The unequal branch design is demonstrated to be unnecessary under most conditions, as it is possible to achieve the same or better performance with equal-sized branches. Two patient-specific examples show that optimization-derived Y-grafts effectively improve the HFD, compared to initial nonoptimized designs using equal branch diameters. An instance of constrained optimization shows that energy efficiency slightly increases with increasing branch size for the Y-graft, but that a smaller branch size is preferred when a proximal anastomosis is needed to achieve optimal HFD.

  View details for DOI 10.1115/1.4023089

  View details for PubMedID 23363213

• Chronic effects of pulmonary artery stenosis on hemodynamic and structural development of the lungs AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Razavi, H., Stewart, S. E., Xu, C., Sawada, H., Zarafshar, S. Y., Taylor, C. A., Rabinovitch, M., Feinstein, J. A. 2013; 304 (1): L17-L28

  Abstract

  Pulmonary artery (PA) stenosis is a difficult obstructive defect to manage since clinicians cannot know a priori which obstructions to treat and when. Prognosis of PA stenosis and its chronic effects on lung development are poorly understood. This study aimed to characterize the hemodynamic and structural effects of PA stenosis during development. Fourteen male Sprague-Dawley rats underwent left PA (LPA) banding at age 21 days, and 13 underwent sham operation. Hemodynamic and structural impacts were studied longitudinally at 20, 36, 52, 100, and 160 days. Chronic LPA banding resulted in a significant reduction in LPA flow (P < 0.0001) and size of both proximal LPA (P < 0.0001) and distal LPA (P < 0.01), as well as a significant increase in flow and size of the right PA (P < 0.05) throughout development. Flows and sizes adapted such that normal levels of wall shear were restored after banding. At 160 days, LPA banding resulted in a significant decrease in left lung volume and an increase in right lung volume but no significant differences in total lung volume. There was an elevation of proximal LPA pressure as well as right ventricular hypertrophy in the banded animals. The banded lung exhibited arterial disorganization, loss of vessels, and enlargement of its bronchial arteries, whereas the contralateral lung showed signs of vascular pathology. There are consequences on development of both lungs in the presence of an LPA stenosis at young age. These results suggest that early intervention may be necessary to optimize left lung growth and minimize right lung vascular pathology.

  View details for DOI 10.1152/ajplung.00412.2011

  View details for Web of Science ID 000313043000003

  View details for PubMedID 23043077

• Wall shear stress is decreased in the pulmonary arteries of patients with pulmonary arterial hypertension: An image-based, computational fluid dynamics study. Pulmonary circulation Tang, B. T., Pickard, S. S., Chan, F. P., Tsao, P. S., Taylor, C. A., Feinstein, J. A. 2012; 2 (4): 470-476

  Abstract

  Previous clinical studies in pulmonary arterial hypertension (PAH) have concentrated predominantly on distal pulmonary vascular resistance, its contribution to the disease process, and response to therapy. However, it is well known that biomechanical factors such as shear stress have an impact on endothelial health and dysfunction in other parts of the vasculature. This study tested the hypothesis that wall shear stress is reduced in the proximal pulmonary arteries of PAH patients with the belief that reduced shear stress may contribute to pulmonary endothelial cell dysfunction and as a result, PAH progression. A combined MRI and computational fluid dynamics (CFD) approach was used to construct subject-specific pulmonary artery models and quantify flow features and wall shear stress (WSS) in five PAH patients with moderate-to-severe disease and five age- and sex-matched controls. Three-dimensional model reconstruction showed PAH patients have significantly larger main, right, and left pulmonary artery diameters (3.5 ± 0.4 vs. 2.7 ± 0.1 cm, P = 0.01; 2.5 ± 0.4 vs. 1.9 ± 0.2 cm, P = 0.04; and 2.6 ± 0.4 vs. 2.0 ± 0.2 cm, P = 0.01, respectively), and lower cardiac output (3.7 ± 1.2 vs. 5.8 ± 0.6 L/min, P = 0.02.). CFD showed significantly lower time-averaged central pulmonary artery WSS in PAH patients compared to controls (4.3 ± 2.8 vs. 20.5 ± 4.0 dynes/cm(2), P = 0.0004). Distal WSS was not significantly different. A novel method of measuring WSS was utilized to demonstrate for the first time that WSS is altered in some patients with PAH. Using computational modeling in patient-specific models, WSS was found to be significantly lower in the proximal pulmonary arteries of PAH patients compared to controls. Reduced WSS in proximal pulmonary arteries may play a role in the pathogenesis and progression of PAH. This data may serve as a basis for future in vitro studies of, for example, effects of WSS on gene expression.

  View details for DOI 10.4103/2045-8932.105035

  View details for PubMedID 23372931

• Electrical and mechanical dyssynchrony in pediatric pulmonary hypertension JOURNAL OF HEART AND LUNG TRANSPLANTATION Hill, A. C., Maxey, D. M., Rosenthal, D. N., Siehr, S. L., Hollander, S. A., Feinstein, J. A., Dubin, A. M. 2012; 31 (8): 825-830

  Abstract

  Electrical and mechanical dyssynchrony are often seen in patients with left ventricular failure. In pediatric pulmonary hypertension (PH), right ventricular failure predominates; however, the prevalence of electrical and/or mechanical dyssynchrony in these patients is unknown. We examined the prevalence of electrical and mechanical dyssynchrony in pediatric PH patients.Medical records (including, functional status, electrocardiograms and echocardiograms) of pediatric PH patients were reviewed. QRS duration z-scores were calculated to determine electrical dyssynchrony. Echo vector velocity imaging was used to calculate the mechanical dyssynchrony index (DI).Seventy-seven PH patients (idiopathic pulmonary arterial hypertension [IPAH]: n = 26; congenital heart disease: n = 41; other: n = 10) were studied. Electrical dyssynchrony was seen in 84% (p < 0.01 vs historic controls), with a mean z-score of 4.3 (95% CI 3.5 to 5.1). There was no difference between those with IPAH, z = 3.6 (95% CI 2.5 to 4.6), and those without, z = 4.7 (95% CI 3.6 to 5.8). Mechanical dyssynchrony was seen in 76% of patients (mean DI = 66 ± 47 vs 18 ± 8 milliseconds in historic controls, p < 0.01) in both IPAH and non-IPAH patients. Post-operative congenital heart disease patients had the largest dyssynchrony index. No correlation was found among electrical or mechanical dyssynchrony, hemodynamics or disease severity.Significant electrical and mechanical dyssynchrony is present in pediatric PH patients, regardless of etiology. The overall effect of electrical and mechanical dyssynchrony on outcomes in this patient population is still unknown. Select patients may benefit from resynchronization therapy.

  View details for DOI 10.1016/j.healun.2012.04.004

  View details for PubMedID 22682994

• Pulmonary reperfusion injury after the unifocalization procedure for tetralogy of Fallot, pulmonary atresia, and major aortopulmonary collateral arteries JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Maskatia, S. A., Feinstein, J. A., Newman, B., Hanley, F. L., Roth, S. J. 2012; 144 (1): 184-189

  Abstract

  The aims of our study are to describe the incidence, clinical profile, and risk factors for pulmonary reperfusion injury after the unifocalization procedure for tetralogy of Fallot, pulmonary atresia, and major aortopulmonary collateral arteries. We hypothesized the following: (1) Pulmonary reperfusion injury is more likely to occur after unifocalization procedures in which a septated circulation is not achieved, (2) pulmonary reperfusion injury is directly related to the severity of stenosis in major aortopulmonary collateral arteries, and (3) pulmonary reperfusion injury leads to longer intubation time and longer hospitalization.Consecutive patients with tetralogy of Fallot/pulmonary atresia/major aortopulmonary collateral arteries who underwent unifocalization procedures over a 5-year period were identified in our institutional database. Chest radiographs before the unifocalization procedure, from postoperative days 0 to 4, and from 2 weeks after the unifocalization procedure or at discharge were evaluated by a pediatric radiologist for localized pulmonary edema. Determination of stenosis severity was based on review of preoperative angiograms. Statistical analyses using multivariate repeated-measures analyses were performed with generalized estimating equations.Pulmonary reperfusion injury was present after 42 of 65 (65%) unifocalization procedures. In 36 of 42 cases of reperfusion injury, unilateral injury was present. Risk factors for the development of reperfusion injury included bilateral unifocalization (P = .01) and degree of stenosis (P = .03). We did not identify an association between pulmonary reperfusion injury and time to tracheal extubation or hospital discharge.Pulmonary reperfusion injury is common after the unifocalization procedure for tetralogy of Fallot/pulmonary atresia/major aortopulmonary collateral arteries. Severity of stenosis and bilateral unifocalization are associated with the development of reperfusion injury.

  View details for DOI 10.1016/j.jtcvs.2011.12.030

  View details for Web of Science ID 000305412200031

  View details for PubMedID 22244564

• Fluid-structure interaction simulations of the Fontan procedure using variable wall properties INTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN BIOMEDICAL ENGINEERING Long, C. C., Hsu, M., Bazilevs, Y., Feinstein, J. A., Marsden, A. L. 2012; 28 (5): 513-527

  Abstract

  Children born with single ventricle heart defects typically undergo a staged surgical procedure culminating in a total cavopulmonary connection (TCPC) or Fontan surgery. The goal of this work was to perform physiologic, patient-specific hemodynamic simulations of two post-operative TCPC patients by using fluid-structure interaction (FSI) simulations. Data from two patients are presented, and post-op anatomy is reconstructed from MRI data. Respiration rate, heart rate, and venous pressures are obtained from catheterization data, and inflow rates are obtained from phase contrast MRI data and are used together with a respiratory model. Lumped parameter (Windkessel) boundary conditions are used at the outlets. We perform FSI simulations by using an arbitrary Lagrangian-Eulerian finite element framework to account for motion of the blood vessel walls in the TCPC. This study is the first to introduce variable elastic properties for the different areas of the TCPC, including a Gore-Tex conduit. Quantities such as wall shear stresses and pressures at critical locations are extracted from the simulation and are compared with pressure tracings from clinical data as well as with rigid wall simulations. Hepatic flow distribution and energy efficiency are also calculated and compared for all cases. There is little effect of FSI on pressure tracings, hepatic flow distribution, and time-averaged energy efficiency. However, the effect of FSI on wall shear stress, instantaneous energy efficiency, and wall motion is significant and should be considered in future work, particularly for accurate prediction of thrombus formation.

  View details for DOI 10.1002/cnm.1485

  View details for Web of Science ID 000303441300002

• Hepatic blood flow distribution and performance in conventional and novel Y-graft Fontan geometries: A case series computational fluid dynamics study JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Yang, W., Vignon-Clementel, I. E., Troianowski, G., Reddy, V. M., Feinstein, J. A., Marsden, A. L. 2012; 143 (5): 1086-1097

  Abstract

  A novel Y-shaped baffle has been proposed for the Fontan operation with promising initial results. However, previous studies have relied either on idealized models or a single patient-specific model. The objective of this study is to comprehensively compare the hemodynamic performance and hepatic blood flow distribution of the Y-graft Fontan baffle with 2 current designs using multiple patient-specific models.Y-shaped and tube-shaped grafts were virtually implanted into 5 patient-specific Glenn models forming 3 types of Fontan geometries: Y-graft, T-junction, and offset. Unsteady flow simulations were performed at rest and at varying exercise conditions. The hepatic flow distribution between the right and left lungs was carefully quantified using a particle tracking method. Other physiologically relevant parameters such as energy dissipation, superior vena cava pressure, and wall shear stress were evaluated.The Fontan geometry significantly influences the hepatic flow distribution. The Y-graft design improves the hepatic flow distribution effectively in 4 of 5 patients, whereas the T-junction and offset designs may skew as much as 97% of hepatic flow to 1 lung in 2 cases. Sensitivity studies show that changes in pulmonary flow split can affect the hepatic flow distribution dramatically but that some Y-graft and T-junction designs are relatively less sensitive than offset designs. The Y-graft design offers moderate improvements over the traditional designs in power loss and superior vena cava pressure in all patients.The Y-graft Fontan design achieves overall superior hemodynamic performance compared with traditional designs. However, the results emphasize that no one-size-fits-all solution is available that will universally benefit all patients and that designs should be customized for individual patients before clinical application.

  View details for DOI 10.1016/j.jtcvs.2011.06.042

  View details for PubMedID 21962841

• A method for quantitative characterization of growth in the 3-D structure of rat pulmonary arteries MICROVASCULAR RESEARCH Razavi, H., Dusch, M. N., Zarafshar, S. Y., Taylor, C. A., Feinstein, J. A. 2012; 83 (2): 146-153

  Abstract

  Understanding mechanisms causing pulmonary vascular disease (PVD) frequently requires a thorough understanding of the underlying structural changes in the pulmonary circulation. Animal models have been used extensively to study different forms of PVD but conventional experimental techniques are limited in their ability to allow the study of the whole pulmonary vasculature at once. In this study, we introduce novel techniques of arterial casting, high-resolution imaging and tree analysis to study the pulmonary circulation in rodent models. Male Sprague-Dawley rats were used at 20, 36, 52, 100 and 160 days of age. A technique involving arterial casting with Microfil silicone polymer, high-resolution micro-computed tomography (micro-CT) at 12.5 μm resolution and image data analysis involving segmentation and skeletonization was developed to both qualitatively and quantitatively describe the changes in the pulmonary vasculature with increasing age. Parameters identified to affect the quality of pulmonary arterial casting included polymer flow rate, total injected volume, polymer viscosity and polymerization time. By optimizing these parameters, we successfully created arterial casts of the pulmonary circulation in rats of different ages and demonstrated the feasibility of quantitatively characterizing the changes in the number of vessels with postnatal growth. These preliminary data suggest that the number of vessels with lumen diameters of 50-200 μm increases rapidly in both lungs between 52 and 100 days of age. With this new technique, the pulmonary vasculature can now be studied in a whole lung animal model to better understand the global effects of disease on vascular structure.

  View details for DOI 10.1016/j.mvr.2011.12.003

  View details for PubMedID 22230111

• Sildenafil for Severe Lymphatic Malformations NEW ENGLAND JOURNAL OF MEDICINE Swetman, G. L., Berk, D. R., Vasanawala, S. S., Feinstein, J. A., Lane, A. T., Bruckner, A. L. 2012; 366 (4): 384-386

  View details for Web of Science ID 000299464100029

  View details for PubMedID 22276841

• Hypoplastic Left Heart Syndrome Current Considerations and Expectations JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Feinstein, J. A., Benson, D. W., Dubin, A. M., Cohen, M. S., Maxey, D. M., Mahle, W. T., Pahl, E., Villafane, J., Bhatt, A. B., Peng, L. F., Johnson, B. A., Marsden, A. L., Daniels, C. J., Rudd, N. A., Caldarone, C. A., Mussatto, K. A., Morales, D. L., Ivy, D. D., Gaynor, J. W., Tweddell, J. S., Deal, B. J., Furck, A. K., Rosenthal, G. L., Ohye, R. G., Ghanayem, N. S., Cheatham, J. P., Tworetzky, W., Martin, G. R. 2012; 59 (1): S1-S42

  Abstract

  In the recent era, no congenital heart defect has undergone a more dramatic change in diagnostic approach, management, and outcomes than hypoplastic left heart syndrome (HLHS). During this time, survival to the age of 5 years (including Fontan) has ranged from 50% to 69%, but current expectations are that 70% of newborns born today with HLHS may reach adulthood. Although the 3-stage treatment approach to HLHS is now well founded, there is significant variation among centers. In this white paper, we present the current state of the art in our understanding and treatment of HLHS during the stages of care: 1) pre-Stage I: fetal and neonatal assessment and management; 2) Stage I: perioperative care, interstage monitoring, and management strategies; 3) Stage II: surgeries; 4) Stage III: Fontan surgery; and 5) long-term follow-up. Issues surrounding the genetics of HLHS, developmental outcomes, and quality of life are addressed in addition to the many other considerations for caring for this group of complex patients.

  View details for DOI 10.1016/j.jacc.2011.09.022

  View details for PubMedID 22192720

• The Adult Congenital and Pediatric Cardiology Section Increasing the Opportunities for the Congenital Heart Disease Community Within the American College of Cardiology JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Martin, G. R., Mitchell, S., Beekman, R. H., Feinstein, J. A., Jenkins, K. J., Landzberg, M., Webb, G. 2012; 59 (1): 84-87

  Abstract

  The Adult Congenital and Pediatric Cardiology (AC/PC) Section was established to develop a clear voice within the American College of Cardiology and address the myriad issues facing the congenital heart disease profession. The Section is governed by the AC/PC Council, which includes pediatric cardiologists, adult congenital cardiologists, a cardiac care associate, and a fellow-in-training member. The Council is responsible for bidirectional communication between the College's Board of Trustees and the AC/PC Section members. Since its founding in 2004, Section objectives have been defined by the College's mission: to advocate for quality cardiovascular care through education, research promotion, and the development and application of standards and guidelines and to influence health care policy. The pillars of the College-advocacy, quality, education, and member engagement-serve as the defining template for the Section's strategy. The Section has developed work groups in advocacy, clinical practice, education and training, quality, and publications. A separate leadership group has been developed for adult congenital heart disease. Work groups are open to all Section members. Recognition of the importance of lifelong care in congenital heart disease led Section leaders to incorporate pediatric cardiology and adult congenital heart disease content into each of the work groups. There are more than 1,200 Section members, with nearly 400 members actively contributing to Section activities. This article outlines Section efforts to date and highlights significant successes to date.

  View details for DOI 10.1016/j.jacc.2011.08.060

  View details for Web of Science ID 000298369800013

  View details for PubMedID 22192673

• COMPARISON OF CLINICAL AND SIMULATION RESULTS FOR THE STANFORD Y-GRAFT FONTAN PILOT TRIAL ASME Summer Bioengineering Conference (SBC) Yang, W., Feinstein, J. A., Reddy, V. M., Chan, F. P., Marsden, A. L. AMER SOC MECHANICAL ENGINEERS. 2012: 463–464

  View details for Web of Science ID 000325036600231

• A PUBLIC REPOSITORY OF IMAGE-BASED COMPUTATIONAL MODELS FOR PATIENT-SPECIFIC BLOOD FLOW SIMULATION ASME Summer Bioengineering Conference (SBC) Wilson, N. M., Ortiz, A. K., Johnson, A. B., Arko, F. R., Feinstein, J. A., LaDisa, J. F., Marsden, A. AMER SOC MECHANICAL ENGINEERS. 2012: 969–970

  View details for Web of Science ID 000325036600484

• Virtual surgeries in patients with congenital heart disease: a multi-scale modelling test case PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY A-MATHEMATICAL PHYSICAL AND ENGINEERING SCIENCES BARETTA, A., Corsini, C., Yang, W., Vignon-Clementel, I. E., Marsden, A. L., Feinstein, J. A., Hsia, T., Dubini, G., Migliavacca, F., Pennati, G. 2011; 369 (1954): 4316-4330

  Abstract

  The objective of this work is to perform a virtual planning of surgical repairs in patients with congenital heart diseases--to test the predictive capability of a closed-loop multi-scale model. As a first step, we reproduced the pre-operative state of a specific patient with a univentricular circulation and a bidirectional cavopulmonary anastomosis (BCPA), starting from the patient's clinical data. Namely, by adopting a closed-loop multi-scale approach, the boundary conditions at the inlet and outlet sections of the three-dimensional model were automatically calculated by a lumped parameter network. Successively, we simulated three alternative surgical designs of the total cavopulmonary connection (TCPC). In particular, a T-junction of the venae cavae to the pulmonary arteries (T-TCPC), a design with an offset between the venae cavae (O-TCPC) and a Y-graft design (Y-TCPC) were compared. A multi-scale closed-loop model consisting of a lumped parameter network representing the whole circulation and a patient-specific three-dimensional finite volume model of the BCPA with detailed pulmonary anatomy was built. The three TCPC alternatives were investigated in terms of energetics and haemodynamics. Effects of exercise were also investigated. Results showed that the pre-operative caval flows should not be used as boundary conditions in post-operative simulations owing to changes in the flow waveforms post-operatively. The multi-scale approach is a possible solution to overcome this incongruence. Power losses of the Y-TCPC were lower than all other TCPC models both at rest and under exercise conditions and it distributed the inferior vena cava flow evenly to both lungs. Further work is needed to correlate results from these simulations with clinical outcomes.

  View details for DOI 10.1098/rsta.2011.0130

  View details for Web of Science ID 000295458900010

  View details for PubMedID 21969678

• Three-Dimensional Simulations in Glenn Patients: Clinically Based Boundary Conditions, Hemodynamic Results and Sensitivity to Input Data JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME Troianowski, G., Taylor, C. A., Feinstein, J. A., Vignon-Clementel, I. E. 2011; 133 (11)

  Abstract

  While many congenital heart defects can be treated without significant long term sequelae, some achieve successful palliation as their definitive endpoints. The single-ventricle defect is one such defect and leaves the child with only one operational ventricle, requiring the systemic and the pulmonary circulations to be placed in series through several operations performed during early childhood. Numerical simulations may be used to investigate these hemodynamic conditions and their relation to post-operative sequelae; however, they rely heavily on boundary condition prescription. In this study, we investigate the impact of hemodynamic input data uncertainties on simulation results. Imaged-based patient-specific models of the multi-branched pulmonary arteries and superior vena cava were built for five cavopulmonary connection (i.e. Glenn) patients. Magnetic resonance imaging and catheterization data were acquired for each patient prior to their Fontan surgery. Inflow and outflow boundary conditions were constructed to match available clinical data and resulted in the development of a framework to incorporate these types of clinical data into patient-specific simulations. Three-dimensional computational fluid dynamics simulations were run and hemodynamic indicators were computed. Power loss was low (and efficiency very high) and a linear correlation was found between power loss and cardiac index among the five patients. Other indicators such as low wall shear stress were considered to better characterize these patients. Flow was complex and oscillatory near the anastomosis, and laminar in the smaller branches. While common trends were seen among patients, results showed differences among patients, especially in the 3D maps, strengthening the importance of patient-specific simulations. A sensitivity analysis was performed to investigate the impact of input data (clinical and modeling) to construct boundary conditions on several indicators. Overall, the sensitivity of the output indicators to the input data was small but non-negligible. The sensitivity of commonly used hemodynamic indicators to compare patients is discussed in this context. Power efficiency was much more sensitive to pressure variation than power loss. To increase the precision of such indicators, mean flow split between right and left lungs needs to be measured with more accuracy with higher priority than refining the model of how the flow is distributed on average among the smaller branches. Although ± 10% flow split imprecision seemed reasonable in terms of patient comparison, this study suggests that the common practice of imposing a right pulmonary artery/left pulmonary artery flow split of 55%/45% when performing patient specific simulations should be avoided. This study constitutes a first step towards understanding the hemodynamic differences between pre- and post Fontan surgery, predicting these differences, and evaluating surgical outcomes based on preoperative data.

  View details for DOI 10.1115/1.4005377

  View details for PubMedID 22168738

• Computational Simulations for Aortic Coarctation: Representative Results From a Sampling of Patients JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME LaDisa, J. F., Figueroa, C. A., Vignon-Clementel, I. E., Kim, H. J., Xiao, N., Ellwein, L. M., Chan, F. P., Feinstein, J. A., Taylor, C. A. 2011; 133 (9)

  Abstract

  Treatments for coarctation of the aorta (CoA) can alleviate blood pressure (BP) gradients (Δ), but long-term morbidity still exists that can be explained by altered indices of hemodynamics and biomechanics. We introduce a technique to increase our understanding of these indices for CoA under resting and nonresting conditions, quantify their contribution to morbidity, and evaluate treatment options. Patient-specific computational fluid dynamics (CFD) models were created from imaging and BP data for one normal and four CoA patients (moderate native CoA: Δ12 mmHg, severe native CoA: Δ25 mmHg and postoperative end-to-end and end-to-side patients: Δ0 mmHg). Simulations incorporated vessel deformation, downstream vascular resistance and compliance. Indices including cyclic strain, time-averaged wall shear stress (TAWSS), and oscillatory shear index (OSI) were quantified. Simulations replicated resting BP and blood flow data. BP during simulated exercise for the normal patient matched reported values. Greatest exercise-induced increases in systolic BP and mean and peak ΔBP occurred for the moderate native CoA patient (SBP: 115 to 154 mmHg; mean and peak ΔBP: 31 and 73 mmHg). Cyclic strain was elevated proximal to the coarctation for native CoA patients, but reduced throughout the aorta after treatment. A greater percentage of vessels was exposed to subnormal TAWSS or elevated OSI for CoA patients. Local patterns of these indices reported to correlate with atherosclerosis in normal patients were accentuated by CoA. These results apply CFD to a range of CoA patients for the first time and provide the foundation for future progress in this area.

  View details for DOI 10.1115/1.4004996

  View details for Web of Science ID 000295882200008

  View details for PubMedID 22010743

• Computational Simulations Demonstrate Altered Wall Shear Stress in Aortic Coarctation Patients Treated by Resection with End-to-end Anastomosis CONGENITAL HEART DISEASE LaDisa, J. F., Dholakia, R. J., Figueroa, C. A., Vignon-Clementel, I. E., Chan, F. P., Samyn, M. M., Cava, J. R., Taylor, C. A., Feinstein, J. A. 2011; 6 (5): 432-443

  Abstract

  Atherosclerotic plaque in the descending thoracic aorta (dAo) is related to altered wall shear stress (WSS) for normal patients. Resection with end-to-end anastomosis (RWEA) is the gold standard for coarctation of the aorta (CoA) repair, but may lead to altered WSS indices that contribute to morbidity.Computational fluid dynamics (CFD) models were created from imaging and blood pressure data for control subjects and age- and gender-matched CoA patients treated by RWEA (four males, two females, 15 ± 8 years). CFD analysis incorporated downstream vascular resistance and compliance to generate blood flow velocity, time-averaged WSS (TAWSS), and oscillatory shear index (OSI) results. These indices were quantified longitudinally and circumferentially in the dAo, and several visualization methods were used to highlight regions of potential hemodynamic susceptibility.The total dAo area exposed to subnormal TAWSS and OSI was similar between groups, but several statistically significant local differences were revealed. Control subjects experienced left-handed rotating patterns of TAWSS and OSI down the dAo. TAWSS was elevated in CoA patients near the site of residual narrowings and OSI was elevated distally, particularly along the left dAo wall. Differences in WSS indices between groups were negligible more than 5 dAo diameters distal to the aortic arch.Localized differences in WSS indices within the dAo of CoA patients treated by RWEA suggest that plaque may form in unique locations influenced by the surgical repair. These regions can be visualized in familiar and intuitive ways allowing clinicians to track their contribution to morbidity in longitudinal studies.

  View details for DOI 10.1111/j.1747-0803.2011.00553.x

  View details for Web of Science ID 000294919100005

  View details for PubMedID 21801315

  View details for PubMedCentralID PMC3208403

• Quantitative characterization of postnatal growth trends in proximal pulmonary arteries in rats by phase-contrast magnetic resonance imaging AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Razavi, H., Zarafshar, S. Y., Sawada, H., Taylor, C. A., Feinstein, J. A. 2011; 301 (3): L368-L379

  Abstract

  Malformations of the pulmonary arteries can increase right heart workload and result in morbidity, heart failure, and death. With the increased use of murine models to study these malformations, there is a pressing need for an accurate and noninvasive experimental technique that is capable of characterizing pulmonary arterial hemodynamics in these animals. We describe the growth trends of pulmonary arteries in 13 male Sprague-Dawley rats at 20, 36, 52, 100, and 160 days of age with the introduction of phase-contrast MRI as such a technique. PCMRI results correlated closely with cardiac output measurements by ultrasound echocardiography and with fluorescent microspheres in right-left lung flow split (flow partition). Mean flow, average cross-sectional area, distensibility, and shear rates for the right and left pulmonary arteries (RPA and LPA) were calculated. The RPA was larger and received more flow at all times than the LPA (P < 0.0001). Right-left flow split did not change significantly with age, and arterial distensibility was not significantly different between RPA and LPA, except at 160 days (P < 0.01). Shear rates were much higher for the LPA than the RPA (P < 0.0001) throughout development. The RPA and LPA showed different structure-function relationships but obeyed similar allometric scaling laws, with scaling exponents comparable to those of the main pulmonary artery. This study is the first to quantitatively describe changes in RPA and LPA flows and sizes with development and to apply phase-contrast MRI techniques to pulmonary arteries in rats.

  View details for DOI 10.1152/ajplung.00069.2011

  View details for Web of Science ID 000295356900014

  View details for PubMedID 21665961

• Indications for Cardiac Catheterization and Intervention in Pediatric Cardiac Disease A Scientific Statement From the American Heart Association CIRCULATION Feltes, T. F., Bacha, E., Beekman, R. H., Cheatham, J. P., Feinstein, J. A., Gomes, A. S., Hijazi, Z. M., Ing, F. F., de Moor, M., Morrow, W. R., Mullins, C. E., Taubert, K. A., Zahn, E. M. 2011; 123 (22): 2607-2652

  View details for DOI 10.1161/CIR.0b013e31821b1f10

  View details for Web of Science ID 000291306600024

  View details for PubMedID 21536996

• A Rapid and Computationally Inexpensive Method to Virtually Implant Current and Next-Generation Stents into Subject-Specific Computational Fluid Dynamics Models ANNALS OF BIOMEDICAL ENGINEERING Gundert, T. J., Shadden, S. C., Williams, A. R., Koo, B., Feinstein, J. A., LaDisa, J. F. 2011; 39 (5): 1423-1437

  Abstract

  Computational modeling is often used to quantify hemodynamic alterations induced by stenting, but frequently uses simplified device or vascular representations. Based on a series of Boolean operations, we developed an efficient and robust method for assessing the influence of current and next-generation stents on local hemodynamics and vascular biomechanics quantified by computational fluid dynamics. Stent designs were parameterized to allow easy control over design features including the number, width and circumferential or longitudinal spacing of struts, as well as the implantation diameter and overall length. The approach allowed stents to be automatically regenerated for rapid analysis of the contribution of design features to resulting hemodynamic alterations. The applicability of the method was demonstrated with patient-specific models of a stented coronary artery bifurcation and basilar trunk aneurysm constructed from medical imaging data. In the coronary bifurcation, we analyzed the hemodynamic difference between closed-cell and open-cell stent geometries. We investigated the impact of decreased strut size in stents with a constant porosity for increasing flow stasis within the stented basilar aneurysm model. These examples demonstrate the current method can be used to investigate differences in stent performance in complex vascular beds for a variety of stenting procedures and clinical scenarios.

  View details for DOI 10.1007/s10439-010-0238-5

  View details for Web of Science ID 000289243100005

  View details for PubMedID 21203844

• Computational Fluid Dynamic Simulations of Aortic Coarctation Comparing the Effects of Surgical- and Stent-Based Treatments on Aortic Compliance and Ventricular Workload CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS Coogan, J. S., Chan, F. P., Taylor, C. A., Feinstein, J. A. 2011; 77 (5): 680-691

  Abstract

  In this work, we examine the effects of stent-induced aortic stiffness on cardiac workload and blood pressure using computational fluid dynamic simulations.Treatment of aortic coarctation (CoA) consists of either open, surgical repair or angioplasty with or without stenting. Although stenting is a minimally invasive alternative to surgery, aortic stiffness increases in the stented section. Concern over this increased stiffness has long been argued to be detrimental to the overall vascular health of the patient.MR imaging was performed on a 15-year-old female with CoA. A 3D model of the large thoracic arteries was created, and the heart and downstream vasculature were represented by lumped parameter models at the model inlet and outlets, respectively. A deformable wall assumption was used in conjunction with variable wall properties and tissue support, and 3D velocity, pressure, and wall dynamics were computed. The lumped parameter values and wall properties were tuned to match the mean flow and aortic deformation as measured by MRI. The CoA was then virtually removed from the model representing an end-to-end surgical correction. In a second model, the repaired section was prescribed to be nearly rigid, representing stenting. All other variables remained the same.When compared to surgery, stenting resulted in clinically negligible increases in cardiac work (0.4%) and no change in mean blood pressure.This pilot study suggests CoA stenting may not affect cardiac work to any significant degree as is commonly believed in the clinical community.

  View details for DOI 10.1002/ccd.22878

  View details for PubMedID 21061250

• Three-Dimensional Hemodynamics in the Human Pulmonary Arteries Under Resting and Exercise Conditions ANNALS OF BIOMEDICAL ENGINEERING Tang, B. T., Fonte, T. A., Chan, F. P., Tsao, P. S., Feinstein, J. A., Taylor, C. A. 2011; 39 (1): 347-358

  Abstract

  The biomechanical forces associated with blood flow have been shown to play a role in pulmonary vascular cell health and disease. Therefore, the quantification of human pulmonary artery hemodynamic conditions under resting and exercise states can be useful in investigating the physiology of disease development and treatment outcomes. In this study, a combined magnetic resonance imaging and computational fluid dynamics approach was used to quantify pulsatile flow fields, wall shear stress (WSS), oscillations in WSS (OSI), and energy efficiency in six subject-specific models of the human pulmonary vasculature with high spatial and temporal resolution. Averaging over all subjects, WSS was found to increase from 19.8±4.0 to 51.8±6.7 dynes/cm2, and OSI was found to decrease from 0.094±0.016 to 0.081±0.015 in the proximal pulmonary arteries between rest and exercise conditions (p<0.05). These findings demonstrate the localized, biomechanical effects of exercise. Furthermore, an average decrease of 10% in energy efficiency was noted between rest and exercise. These data indicate the amount of energy dissipation that typically occurs with exercise and may be useful in future surgical planning applications.

  View details for DOI 10.1007/s10439-010-0124-1

  View details for PubMedID 20640512

• Introduction PROGRESS IN PEDIATRIC CARDIOLOGY Feinstein, J. A., Marsden, A. 2010; 30 (1-2): 1

  View details for DOI 10.1016/j.ppedcard.2010.09.001

  View details for Web of Science ID 000213519300001

• A primer on computational simulation in congenital heart disease for the clinician PROGRESS IN PEDIATRIC CARDIOLOGY Vignon-Clementel, I. E., Marsden, A. L., Feinstein, J. A. 2010; 30 (1-2): 3–13

  View details for DOI 10.1016/j.ppedcard.2010.09.002

  View details for Web of Science ID 000213519300002

• Computational Simulation of the Pulmonary Arteries and its Role in the Study of Pediatric Pulmonary Hypertension. Progress in pediatric cardiology Hunter, K. S., Feinstein, J. A., Ivy, D. D., Shandas, R. 2010; 30 (1-2): 63-69

  Abstract

  The hemodynamic state of the pulmonary arteries is challenging to routinely measure in children due to the vascular circuit's position in the lungs. The resulting relative scarcity of quantitative clinical diagnostic and prognostic information impairs management of diseases such as pulmonary hypertension, or high blood pressure of the pulmonary circuit, and invites new techniques of measurement. Here we examine recent applications of macro-scale computational mechanics methods for fluids and solids - traditionally used by engineers in the design and virtual testing of complex metal and composite structures - applied to study the pulmonary vasculature, both in healthy and diseased states. In four subject areas, we briefly outline advances in computational methodology and provide examples of clinical relevance.

  View details for PubMedID 21499523

  View details for PubMedCentralID PMC3076725

• AORTIC COARCTATION: RECENT DEVELOPMENTS IN EXPERIMENTAL AND COMPUTATIONAL METHODS TO ASSESS TREATMENTS FOR THIS SIMPLE CONDITION. Progress in pediatric cardiology LaDisa, J. F., Taylor, C. A., Feinstein, J. A. 2010; 30 (1): 45-49

  Abstract

  Coarctation of the aorta (CoA) is often considered a relatively simple disease, but long-term outcomes suggest otherwise as life expectancies are decades less than in the average population and substantial morbidity often exists. What follows is an expanded version of collective work conducted by the authors' and numerous collaborators that was presented at the 1st International Conference on Computational Simulation in Congenital Heart Disease pertaining to recent advances for CoA. The work begins by focusing on what is known about blood flow, pressure and indices of wall shear stress (WSS) in patients with normal vascular anatomy from both clinical imaging and the use of computational fluid dynamics (CFD) techniques. Hemodynamic alterations observed in CFD studies from untreated CoA patients and those undergoing surgical or interventional treatment are subsequently discussed. The impact of surgical approach, stent design and valve morphology are also presented for these patient populations. Finally, recent work from a representative experimental animal model of CoA that may offer insight into proposed mechanisms of long-term morbidity in CoA is presented.

  View details for PubMedID 21152106

  View details for PubMedCentralID PMC2997687

• Congenital extrahepatic portosystemic shunt associated with heterotaxy and polysplenia PEDIATRIC RADIOLOGY Newman, B., Feinstein, J. A., Cohen, R. A., Feingold, B., Kreutzer, J., Patel, H., Chan, F. P. 2010; 40 (7): 1222-1230

  Abstract

  Heterotaxy with polysplenia is associated with many cardiovascular anomalies including the occasional occurrence of congenital extrahepatic portosystemic shunts (CEPS). Missing this anomaly can lead to inappropriate and ineffective therapy.To emphasize the importance and associated anatomy of CEPS in conjunction with heterotaxy with polysplenia.Review of three young children who presented with cyanosis and pulmonary hypertension without a cardiac etiology. They were known (1) or discovered (2) to have heterotaxy with polysplenia.There was absence of the intrahepatic inferior vena cava (IVC) with azygos or hemiazygos continuation in all three cases. In spite of normal liver function, they were discovered to have large portosystemic shunts, splenorenal in location, along with diffuse peripheral pulmonary arterial dilatation suggestive of CEPS (Abernethy malformation) with hepatopulmonary or, more accurately, portopulmonary syndrome. All CEPS were ipsilateral to the spleens. Patency of the portal veins in these cases allowed for percutaneous shunt closure with resolution of cyanosis.CEPS is associated with heterotaxy with polysplenia and can be symptomatic because of pulmonary arteriovenous (AV) shunting. Portal and hepatic vein patency are critical for determining feasibility of CEPS closure.

  View details for DOI 10.1007/s00247-009-1508-y

  View details for PubMedID 20069288

• New Insights into Pacemaker Lead-Induced Venous Occlusion: Simulation-Based Investigation of Alterations in Venous Biomechanics CARDIOVASCULAR ENGINEERING Lonyai, A., Dubin, A. M., Feinstein, J. A., Taylor, C. A., Shadden, S. C. 2010; 10 (2): 84-90

  Abstract

  Venous obstruction is a major complication of transvenous pacemaker placement. Despite the increasing use of pacemakers and implantable cardiac defibrillators, a lack of understanding remains with regard to risk factors for the development of device-associated venous obstruction. We hypothesize that computational fluid dynamics simulations can reveal prothrombogenic locations and define thrombosis risk based on patient-specific anatomies. Using anatomic data derived from computed tomography, computer models of the superior vena cava, subclavian, innominate, and internal jugular veins were constructed for three adult patients with transvenous pacemakers. These models were used to perform patient-specific simulations examining blood flow velocity, wall shear stress, and blood pressure, both with and without the presence of the pacing leads. To better quantify stasis, mean exposure time fields were computed from the venous blood flow data. In comparing simulations with leads to those without, evident increases in stasis at locations between the leads and along the surface of the vessels closest to the leads were found. These locations correspond to regions at known risk for thrombosis. This work presents a novel application of computational methods to study blood flow changes induced by pacemaker leads and possible complications such as venous occlusion and thrombosis. This methodology may add to our understanding of the development of lead-induced thrombosis and occlusion in the clinical arena, and enable the development of new strategies to avoid such complications.

  View details for DOI 10.1007/s10558-010-9096-x

  View details for PubMedID 20514553

• Pulmonary Hypertension Associated With Congenital Heart Disease Pulmonary Vascular Disease: The Global Perspective CHEST Adatia, I., Kothari, S. S., Feinstein, J. A. 2010; 137 (6): 52S-61S

  Abstract

  The incidence of congenital heart disease is approximately 8/1,000 live births and appears to be constant around the world. The currently accepted paradigm for the development of pulmonary vascular disease associated with congenital heart disease maintains that increased pulmonary blood flow and pressure trigger unfavorable vascular remodeling. Endothelial cell dysfunction, abnormal shear stress, circumferential wall stretch, and an imbalance in vasoactive mediators conspire to promote vasoconstriction, inflammation, thrombosis, cell proliferation, impaired apoptosis, and fibrosis. We estimate that worldwide 3 million children are at risk for the development of pulmonary vascular disease due to congenital heart disease. The majority of children at risk globally will have a reparable heart defect, such as an isolated atrial septal or ventricular septal defect or patent ductus arteriosus. Cardiac repair in the first 2 years of life would prevent the development of Eisenmenger syndrome, the most advanced form of pulmonary vascular disease secondary to congenital heart disease. Worldwide, only a small fraction of those at risk are offered surgical repair. Thus, access to timely medical care would eliminate the vast majority of suffering, disability, and death from Eisenmenger syndrome. Globally, pulmonary vascular disease associated with congenital heart disease may be the most preventable cause of pulmonary artery hypertension and related mortality and morbidity.

  View details for DOI 10.1378/chest.09-2861

  View details for Web of Science ID 000278561500007

  View details for PubMedID 20522580

• Majewski Osteodysplastic Primordial Dwarfism Type II (MOPD II): Expanding the Vascular Phenotype AMERICAN JOURNAL OF MEDICAL GENETICS PART A Bober, M. B., Khan, N., Kaplan, J., Lewis, K., Feinstein, J. A., Scott, C. I., Steinberg, G. K. 2010; 152A (4): 960-965

  Abstract

  Majewski Osteodysplastic Primordial Dwarfism, Type II (MOPD II) is a rare, autosomal recessive disorder. Features include severe intrauterine growth retardation (IUGR), poor postnatal growth (adult stature approximately 100 cm), severe microcephaly, skeletal dysplasia, characteristic facial features, and normal or near normal intelligence. An Institutional Review Board (IRB) approved registry was created and currently follows 25 patients with a diagnosis of MOPD II. Based on previous studies, a neurovascular screening program was implemented and 13 (52%) of these patients have been found to have cerebral neurovascular abnormalities including moyamoya angiopathy and/or intracranial aneurysms. The typical moyamoya pathogenesis begins with vessel narrowing in the supraclinoid internal carotid artery, anterior cerebral (A1) or middle cerebral (M1) artery segments. The narrowing may predominate initially on one side, progresses to bilateral stenosis, with subsequent occlusion of the vessels and collateral formation. We present four patients who, on neurovascular screening, were found to have cerebrovascular changes. Two were asymptomatic, one presented with a severe headache and projectile vomiting related to a ruptured aneurysm, and one presented after an apparent decline in cognitive functioning. Analysis of the registry suggests screening for moyamoya disease be performed at the time of MOPD II diagnosis and at least every 12-18 months using MRA or computerized tomographic angiography (CTA). We believe this is imperative. If diagnosed early enough, re-vascularization and aneurysm treatment in skilled hands can be performed safely and prevent or minimize long-term sequelae in this population. Emergent evaluation is also needed when other neurologic or cardiac symptoms are present.

  View details for DOI 10.1002/ajmg.a.33252

  View details for Web of Science ID 000276754000025

  View details for PubMedID 20358609

• A New Multiparameter Approach to Computational Simulation for Fontan Assessment and Redesign CONGENITAL HEART DISEASE Marsden, A. L., Reddy, V. M., Shadden, S. C., Chan, F. P., Taylor, C. A., Feinstein, J. A. 2010; 5 (2): 104-117

  Abstract

  Despite an abundance of prior Fontan simulation articles, there have been relatively few clinical advances that are a direct result of computational methods. We address a few key limitations of previous Fontan simulations as a step towards increasing clinical relevance. Previous simulations have been limited in scope because they have primarily focused on a single energy loss parameter. We present a multi-parameter approach to Fontan modeling that establishes a platform for clinical decision making and comprehensive evaluation of proposed interventions.Time-dependent, 3-D blood flow simulations were performed on six patient-specific Fontan models. Key modeling advances include detailed pulmonary anatomy, catheterization-derived pressures, and MRI-derived flow with respiration. The following performance parameters were used to rank patients at rest and simulated exercise from best to worst performing: energy efficiency, inferior and superior vena cava (IVC, SVC) pressures, wall shear stress, and IVC flow distribution.Simulated pressures were well matched to catheterization data, but low Fontan pressure did not correlate with high efficiency. Efficiency varied from 74% to 96% at rest, and from 63% to 91% with exercise. Distribution of IVC flow ranged from 88%/12% (LPA/RPA) to 53%/47%. A "transcatheter" virtual intervention demonstrates the utility of computation in evaluating interventional strategies, and is shown to result in increased energy efficiency.A multiparameter approach demonstrates that each parameter results in a different ranking of Fontan performance. Ranking patients using energy efficiency does not correlate with the ranking using other parameters of presumed clinical importance. As such, current simulation methods that evaluate energy dissipation alone are not sufficient for a comprehensive evaluation of new Fontan designs.

  View details for DOI 10.1111/j.1747-0803.2010.00383.x

  View details for Web of Science ID 000289417500004

  View details for PubMedID 20412482

• Perioperative complications in children with pulmonary hypertension undergoing general anesthesia with ketamine PEDIATRIC ANESTHESIA Williams, G. D., Maan, H., Ramamoorthy, C., Kamra, K., Bratton, S. L., Bair, E., Kuan, C. C., Hammer, G. B., Feinstein, J. A. 2010; 20 (1): 28-37

  Abstract

  Pulmonary arterial hypertension (PAH) is associated with significant perioperative risk for major complications in children, including pulmonary hypertensive crisis and cardiac arrest. Uncertainty remains about the safety of ketamine anesthesia in this patient population.Retrospectively review the medical records of children with PAH to ascertain the nature and frequency of peri-procedural complications and to determine whether ketamine administration was associated with peri-procedural complications.Children with PAH (mean pulmonary artery pressure > or =25 mmHg and pulmonary vascular resistance index > or =3 Wood units) who underwent general anesthesia for procedures during a 6-year period (2002-2008) were enrolled. Details about the patient, PAH, procedure, anesthetic and postprocedural course were noted, including adverse events during or within 48 h of the procedure. Complication rates were reported per procedure. Association between ketamine and peri-procedural complications was tested.Sixty-eight children (median age 7.3 year, median weight 22 kg) underwent 192 procedures. Severity of PAH was mild (23%), moderate (37%), and severe (40%). Procedures undertaken were major surgery (n = 20), minor surgery (n = 27), cardiac catheterization (n = 128) and nonsurgical procedures (n = 17). Ketamine was administered during 149 procedures. Twenty minor and nine major complications were noted. Incidence of cardiac arrest was 0.78% for cardiac catheterization procedures, 10% for major surgical procedures and 1.6% for all procedures. There was no procedure-related mortality. Ketamine administration was not associated with increased complications.Ketamine appears to be a safe anesthetic option for children with PAH. We report rates for cardiopulmonary resuscitation and mortality that are more favorable than those previously reported.

  View details for DOI 10.1111/j.1460-9592.2009.03166.x

  View details for PubMedID 20078799

• VIRTUAL DESIGN FOR THE FONTAN PROCEDURE: FROM IDEALIZED TO PATIENT SPECIFIC MODELS USING CFD AND DERIVATIVE-FREE OPTIMIZATION 12th ASME Summer Bioengineering Conference Yang, W., Troianowski, G., Birolleau, A., Vignon-Clementel, I., Feinstein, J. A., Marsden, A. L. AMER SOC MECHANICAL ENGINEERS. 2010: 425–426

  View details for Web of Science ID 000290705300213

• A COMPUTATIONAL FRAMEWORK FOR OPTIMIZATION AND UNCERTAINTY QUANTIFICATION IN SURGICAL DESIGN FOR PEDIATRIC CARDIOLOGY 12th ASME Summer Bioengineering Conference Marsden, A. L., Yang, W., Sankaran, S., Feinstein, J. A. AMER SOC MECHANICAL ENGINEERS. 2010: 249–250

  View details for Web of Science ID 000290705300125

• Constrained optimization of an idealized Y-shaped baffle for the Fontan surgery at rest and exercise COMPUTER METHODS IN APPLIED MECHANICS AND ENGINEERING Yang, W., Feinstein, J. A., Marsden, A. L. 2010; 199 (33-36): 2135-2149

  View details for DOI 10.1016/j.cma.2010.03.012

  View details for Web of Science ID 000279365100005

• Pulmonary arterial hypertension in children: Diagnostic work-up and challenges. Progress in pediatric cardiology Rosenzweig, E. B., Feinstein, J. A., Humpl, T., Ivy, D. D. 2009; 27 (1): 4-11

  Abstract

  The diagnostic evaluation of a pediatric patient with suspected pulmonary arterial hypertension (PAH) is extensive but essential, given the rapid progression of the disease if left undiagnosed and untreated. The major goals of performing a complete diagnostic work-up are to confirm the diagnosis of PAH, assess disease severity, rule out associated diseases, and begin to formulate an individualized treatment plan for the pediatric patient with pulmonary hypertension. This article will provide a comprehensive review of the diagnostic work-up of the child with suspected PAH as well as a review of some of the challenges faced when assessing a child for PAH.

  View details for PubMedID 21691442

  View details for PubMedCentralID PMC3117303

• Pulmonary arterial hypertension in children: Diagnostic work-up and challenges PROGRESS IN PEDIATRIC CARDIOLOGY Rosenzweig, E. B., Feinstein, J. A., Humpl, T., Ivy, D. D. 2009; 27 (1-2): 7-11

  View details for DOI 10.1016/j.ppedcard.2009.09.003

  View details for Web of Science ID 000213516300003

• Editorial / Introduction PROGRESS IN PEDIATRIC CARDIOLOGY Feinstein, J. A. 2009; 27 (1-2): 1

  View details for DOI 10.1016/j.ppedcard.2009.09.001

  View details for Web of Science ID 000213516300001

• Non-congenital heart disease associated pediatric pulmonary arterial hypertension. Progress in pediatric cardiology Ivy, D. D., Feinstein, J. A., Humpl, T., Rosenzweig, E. B. 2009; 27 (1-2): 13-23

  Abstract

  Recognition of causes of pulmonary hypertension other than congenital heart disease is increasing in children. Diagnosis and treatment of any underlying cause of pulmonary hypertension is crucial for optimal management of pulmonary hypertension. This article discusses the available knowledge regarding several disorders associated with pulmonary hypertension in children: idiopathic pulmonary arterial hypertension (IPAH), pulmonary capillary hemangiomatosis, pulmonary veno-occlusive disease, hemoglobinopathies, hepatopulmonary syndrome, portopulmonary hypertension and HIV. Three classes of drugs have been extensively studied for the treatment of IPAH in adults: prostanoids (epoprostenol, treprostinil, iloprost, beraprost), endothelin receptor antagonists (bosentan, sitaxsentan, ambrisentan), and phosphodiesterase inhibitors (Sildenafil, tadalafil). These medications have been used in treatment of children with pulmonary arterial hypertension, although randomized clinical trial data is lacking. As pulmonary vasodilator therapy in certain diseases may be associated with adverse outcomes, further study of these medications is needed before widespread use is encouraged.

  View details for PubMedID 21852894

  View details for PubMedCentralID PMC3156479

• On Coupling a Lumped Parameter Heart Model and a Three-Dimensional Finite Element Aorta Model ANNALS OF BIOMEDICAL ENGINEERING Kim, H. J., Vignon-Clementel, I. E., Figueroa, C. A., LaDisa, J. F., Jansen, K. E., Feinstein, J. A., Taylor, C. A. 2009; 37 (11): 2153-2169

  Abstract

  Aortic flow and pressure result from the interactions between the heart and arterial system. In this work, we considered these interactions by utilizing a lumped parameter heart model as an inflow boundary condition for three-dimensional finite element simulations of aortic blood flow and vessel wall dynamics. The ventricular pressure-volume behavior of the lumped parameter heart model is approximated using a time varying elastance function scaled from a normalized elastance function. When the aortic valve is open, the coupled multidomain method is used to strongly couple the lumped parameter heart model and three-dimensional arterial models and compute ventricular volume, ventricular pressure, aortic flow, and aortic pressure. The shape of the velocity profiles of the inlet boundary and the outlet boundaries that experience retrograde flow are constrained to achieve a robust algorithm. When the aortic valve is closed, the inflow boundary condition is switched to a zero velocity Dirichlet condition. With this method, we obtain physiologically realistic aortic flow and pressure waveforms. We demonstrate this method in a patient-specific model of a normal human thoracic aorta under rest and exercise conditions and an aortic coarctation model under pre- and post-interventions.

  View details for DOI 10.1007/s10439-009-9760-8

  View details for PubMedID 19609676

• ACC 2009 Survey Results and Recommendations: Addressing the Cardiology Workforce Crisis A Report of the ACC Board of Trustees Workforce Task Force JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Rodgers, G. P., Conti, J. B., Feinstein, J. A., Griffin, B. P., Kennett, J. D., Shah, S., Walsh, M. N., Williams, E. S., Williams, J. L. 2009; 54 (13): 1195-1208

  View details for DOI 10.1016/j.jacc.2009.08.001

  View details for Web of Science ID 000269823300019

  View details for PubMedID 19761949

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

  Abstract

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

  View details for DOI 10.1016/j.healun.2008.12.008

  View details for PubMedID 19416787

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

  Abstract

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

  View details for DOI 10.1016/j.echo.2009.01.021

  View details for PubMedID 19307098

• Use of magnetic resonance imaging and computed tomography CARDIOLOGY IN THE YOUNG Feinstein, J. A., Gatzoulis, M. A. 2009; 19: 16-22

  View details for DOI 10.1017/S1047951109003904

  View details for PubMedID 19419601

• Short- and Long-Term Outcomes of Necrotizing Enterocolitis in Infants With Congenital Heart Disease PEDIATRICS Pickard, S. S., Feinstein, J. A., Popat, R. A., Huang, L., Dutta, S. 2009; 123 (5): E901-E906

  Abstract

  Congenital heart disease is a significant risk factor for necrotizing enterocolitis in the term infant. We compared the short- and long-term necrotizing enterocolitis-specific outcomes of infants with congenital heart disease with those of neonates without congenital heart disease.A retrospective study of 202 patients with necrotizing enterocolitis treated at our center from May 1999 to August 2007 was conducted. Infants with necrotizing enterocolitis were grouped according to the presence (n = 76) or absence (n = 126) of congenital heart disease. Demographic and necrotizing enterocolitis-specific outcomes were recorded. The groups were compared by nonparametric and chi(2) analyses. Univariate and multivariate odds ratios were determined for each outcome.The average birth weight and gestational age of the 2 groups were not significantly different. The initial necrotizing enterocolitis severity, as determined by Bell stage, was less for necrotizing enterocolitis subjects with congenital heart disease compared with those without congenital heart disease. When controlling for birth weight and gestational age, the congenital heart disease group had decreased risk of perforation, need for a bowel operation, strictures, need for a stoma, sepsis, and short bowel syndrome compared with the non-congenital heart disease group. Although not statistically significant, subjects with congenital heart disease had a trend toward decreased risk of death from necrotizing enterocolitis, recurrent necrotizing enterocolitis, and need for peritoneal drainage.Infants with congenital heart disease and necrotizing enterocolitis have decreased risk of major short- and long-term negative outcomes associated with necrotizing enterocolitis compared with neonates without congenital heart disease. Differences in initial severity, range of age at diagnosis, and prognoses between subjects with necrotizing enterocolitis with and without cardiac disease suggest that necrotizing enterocolitis in the cardiac patient is a distinct disease process and should be labeled cardiogenic necrotizing enterocolitis.

  View details for DOI 10.1542/peds.2008-3216

  View details for PubMedID 19403484

• Evaluation of a novel Y-shaped extracardiac Fontan baffle using computational fluid dynamics JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Marsden, A. L., Bernstein, A. J., Reddy, V. M., Shadden, S. C., Spilker, R. L., Chan, F. P., Taylor, C. A., Feinstein, J. A. 2009; 137 (2): 394-U187

  Abstract

  The objective of this work is to evaluate the hemodynamic performance of a new Y-graft modification of the extracardiac conduit Fontan operation. The performance of the Y-graft design is compared to two designs used in current practice: a t-junction connection of the venae cavae and an offset between the inferior and superior venae cavae.The proposed design replaces the current tube grafts used to connect the inferior vena cava to the pulmonary arteries with a Y-shaped graft. Y-graft hemodynamics were evaluated at rest and during exercise with a patient-specific model from magnetic resonance imaging data together with computational fluid dynamics. Four clinically motivated performance measures were examined: Fontan pressures, energy efficiency, inferior vena cava flow distribution, and wall shear stress. Two variants of the Y-graft were evaluated: an "off-the-shelf" graft with 9-mm branches and an "area-preserving" graft with 12-mm branches.Energy efficiency of the 12-mm Y-graft was higher than all other models at rest and during exercise, and the reduction in efficiency from rest to exercise was improved by 38%. Both Y-graft designs reduced superior vena cava pressures during exercise by as much as 5 mm Hg. The Y-graft more equally distributed the inferior vena cava flow to both lungs, whereas the offset design skewed 70% of the flow to the left lung. The 12-mm graft resulted in slightly larger regions of low wall shear stress than other models; however, minimum shear stress values were similar.The area-preserving 12-mm Y-graft is a promising modification of the Fontan procedure that should be clinically evaluated. Further work is needed to correlate our performance metrics with clinical outcomes, including exercise intolerance, incidence of protein-losing enteropathy, and thrombus formation.

  View details for DOI 10.1016/j.jtcvs.2008.06.043

  View details for Web of Science ID 000262919000020

  View details for PubMedID 19185159

• OPTIMIZATION OF AN IDEALIZED Y-GRAFT FOR THE FONTAN PROCEDURE USING CFD AND A DERIVATIVE-FREE OPTIMIZATION ALGORITHM ASME Summer Bioengineering Conference Yang, W., Feinstein, J. A., Reddy, V. M., Marsden, A. L. AMER SOC MECHANICAL ENGINEERS. 2009: 449–450

  View details for Web of Science ID 000280089000225

• A COMPUTATIONAL TECHNIQUE FOR UNCERTAINTY QUANTIFICATION AND ROBUST DESIGN IN CARDIOVASCULAR SYSTEMS ASME Summer Bioengineering Conference Sankaran, S., Feinstein, J. A., Marsden, A. L. AMER SOC MECHANICAL ENGINEERS. 2009: 17–18

  View details for Web of Science ID 000280089000009

• A TECHNIQUE FOR QUANTITATIVE CHARACTERIZATION OF PULMONARY VASCULAR MORPHOLOGY AND APPLICATION IN A NORMAL RAT ASME Summer Bioengineering Conference Razavi, H., Zarafshar, S. Y., Xu, C., Feinstein, J. A., Taylor, C. A. AMER SOC MECHANICAL ENGINEERS. 2009: 309–310

  View details for Web of Science ID 000263364700155

• Evaluation, risk stratification, and management of pulmonary hypertension in patients with congenital heart disease. Seminars in thoracic and cardiovascular surgery. Pediatric cardiac surgery annual Feinstein, J. A. 2009: 106-111

  Abstract

  Surgical outcomes for patients with congenital heart disease have improved dramatically over the past few decades due, in part, to improvements in preoperative and postoperative management, cardiopulmonary bypass and intraoperative technique, and the development of pediatric cardiology as a subspecialty. Patients with pulmonary hypertension, however, remain a particularly challenging subgroup worldwide. Determination of operability and, when reasonable, timing of surgery, remains at times difficult. An overview of the evaluation process for this patient population is presented along with a review of evidence for risk stratification and a generalized account of the current state of medical therapy.

  View details for DOI 10.1053/j.pcsu.2009.01.010

  View details for PubMedID 19349023

• Extension of Doppler-derived echocardiographic measures of pulmonary vascular resistance to patients with moderate or severe pulmonary vascular disease JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY Vlahos, A. P., Feinstein, J. A., Schiller, N. B., Silverman, N. H. 2008; 21 (6): 711-714

  Abstract

  Pulmonary vascular resistance (PVR) is a critical parameter in the assessment and treatment of patients with pulmonary hypertension, regardless of origin. Noninvasive estimation of PVR could be helpful.Consecutive patients with known or suggested pulmonary hypertension referred for cardiac catheterization were evaluated prospectively and the PVR was calculated invasively. Subsequently, the tricuspid regurgitation velocity (TRV), the velocity-time integral (mean of 3 measurements) of the right ventricular outflow tract (VTIm), and the right ventricular outflow tract diameter were recorded noninvasively.The TRV/VTIm ratio and the TRV/VTIm corrected for the indexed RVOT diameter correlated well with the PVR at catheterization with R(2) = 0.711 and R(2) = 0.731, respectively, including patients with very high values of PVR. A TRV/VTI(RVOT) value of 38 provided a specificity of 100% for a PVR of 8 Woods units.Noninvasive estimation is feasible over a broad range of PVR values and could be a useful tool to estimate and longitudinally tracked changes in PVR.

  View details for DOI 10.1016/j.echo.2007.10.004

  View details for Web of Science ID 000256283900008

  View details for PubMedID 18187297

• A computational framework for derivative-free optimization of cardiovascular geometries COMPUTER METHODS IN APPLIED MECHANICS AND ENGINEERING Marsden, A. L., Feinstein, J. A., Taylor, C. A. 2008; 197 (21-24): 1890-1905

  View details for DOI 10.1016/j.cma.2007.12.009

  View details for Web of Science ID 000254931400004

• Ketamine does not increase pulmonary vascular resistance in children with pulmonary hypertension undergoing sevoflurane anesthesia and spontaneous ventilation ANESTHESIA AND ANALGESIA Williams, G. D., Philip, B. M., Chu, L. F., Boltz, M. G., Kamra, K., Terwey, H., Hammer, G. B., Perry, S. B., Feinstein, J. A., Ramamoorthy, C. 2007; 105 (6): 1578-1584

  Abstract

  The use of ketamine in children with increased pulmonary vascular resistance is controversial. In this prospective, open label study, we evaluated the hemodynamic responses to ketamine in children with pulmonary hypertension (mean pulmonary artery pressure >25 mm Hg).Children aged 3 mo to 18 yr with pulmonary hypertension, who were scheduled for cardiac catheterization with general anesthesia, were studied. Patients were anesthetized with sevoflurane (1 minimum alveolar anesthetic concentration [MAC]) in air while breathing spontaneously via a facemask. After baseline catheterization measurements, sevoflurane was reduced (0.5 MAC) and ketamine (2 mg/kg IV over 5 min) was administered, followed by a ketamine infusion (10 microg x kg(-1) x min(-1)). Catheterization measurements were repeated at 5, 10, and 15 min after completion of ketamine load. Data at various time points were compared (ANOVA, P < 0.05).Fifteen patients (age 147, 108 mo; median, interquartile range) were studied. Diagnoses included idiopathic pulmonary arterial hypertension (5), congenital heart disease (9), and diaphragmatic hernia (1). At baseline, median (interquartile range) baseline pulmonary vascular resistance index was 11.3 (8.2) Wood units; 33% of patients had suprasystemic mean pulmonary artery pressures. Heart rate (99, 94 bpm; P = 0.016) and Pao2 (95, 104 mm Hg; P = 007) changed after ketamine administration (baseline, 15 min after ketamine; P value). There were no significant differences in mean systemic arterial blood pressure, mean pulmonary artery pressure, systemic or pulmonary vascular resistance index, cardiac index, arterial pH, or Paco2.In the presence of sevoflurane, ketamine did not increase pulmonary vascular resistance in spontaneously breathing children with severe pulmonary hypertension.

  View details for DOI 10.1213/01.ane.0000287656.29064.89

  View details for PubMedID 18042853

• Noninherited risk factors and congenital cardiovascular defects: Current knowledge a scientific statement from the American Heart Association Council on cardiovascular disease in the young CIRCULATION Jenkins, K. J., Correa, A., Feinstein, J. A., Botto, L., Britt, A. E., Daniels, S. R., Elixson, M., Warnes, C. A., Webb, C. L. 2007; 115 (23): 2995-3014

  Abstract

  Prevention of congenital cardiovascular defects has been hampered by a lack of information about modifiable risk factors for abnormalities in cardiac development. Over the past decade, there have been major breakthroughs in the understanding of inherited causes of congenital heart disease, including the identification of specific genetic abnormalities for some types of malformations. Although relatively less information has been available on noninherited modifiable factors that may have an adverse effect on the fetal heart, there is a growing body of epidemiological literature on this topic. This statement summarizes the currently available literature on potential fetal exposures that might alter risk for cardiovascular defects. Information is summarized for periconceptional multivitamin or folic acid intake, which may reduce the risk of cardiac disease in the fetus, and for additional types of potential exposures that may increase the risk, including maternal illnesses, maternal therapeutic and nontherapeutic drug exposures, environmental exposures, and paternal exposures. Information is highlighted regarding definitive risk factors such as maternal rubella; phenylketonuria; pregestational diabetes; exposure to thalidomide, vitamin A cogeners, or retinoids; and indomethacin tocolysis. Caveats regarding interpretation of possible exposure-outcome relationships from case-control studies are given because this type of study has provided most of the available information. Guidelines for prospective parents that could reduce the likelihood that their child will have a major cardiac malformation are given. Issues related to pregnancy monitoring are discussed. Knowledge gaps and future sources of new information on risk factors are described.

  View details for DOI 10.1161/CIRCULATIONAHA.106.183216

  View details for Web of Science ID 000247153300015

  View details for PubMedID 17519397

• Morphometry-based impedance boundary conditions for patient-specific modeling of blood flow in pulmonary arteries ANNALS OF BIOMEDICAL ENGINEERING Spilker, R. L., Feinstein, J. A., Parker, D. W., Reddy, V. M., Taylor, C. A. 2007; 35 (4): 546-559

  Abstract

  Patient-specific computational models could aid in planning interventions to relieve pulmonary arterial stenoses common in many forms of congenital heart disease. We describe a new approach to simulate blood flow in subject-specific models of the pulmonary arteries that consists of a numerical model of the proximal pulmonary arteries created from three-dimensional medical imaging data with terminal impedance boundary conditions derived from linear wave propagation theory applied to morphometric models of distal vessels. A tuning method, employing numerical solution methods for nonlinear systems of equations, was developed to modify the distal vasculature to match measured pressure and flow distribution data. One-dimensional blood flow equations were solved with a finite element method in image-based pulmonary arterial models using prescribed inlet flow and morphometry-based impedance at the outlets. Application of these methods in a pilot study of the effect of removal of unilateral pulmonary arterial stenosis induced in a pig showed good agreement with experimental measurements for flow redistribution and main pulmonary arterial pressure. Next, these methods were applied to a patient with repaired tetralogy of Fallot and predicted insignificant hemodynamic improvement with relief of the stenosis. This method of coupling image-based and morphometry-based models could enable increased fidelity in pulmonary hemodynamic simulation.

  View details for DOI 10.1007/s10439-006-9240-3

  View details for PubMedID 17294117

• Noninvasive assessment of pulmonary arterial capacitance by echocardiography JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY Friedberg, M. K., Feinstein, J. A., Rosenthal, D. N. 2007; 20 (2): 186-190

  Abstract

  Pulmonary arterial capacitance (PAC) has been associated with right ventricular (RV) workload and mortality in pulmonary hypertension, but is not routinely evaluated in children. We investigated whether PAC can be estimated noninvasively by echocardiography.We retrospectively determined PAC in 31 children with pulmonary hypertension, using echocardiography, and compared the results with those obtained at cardiac catheterization.PAC derived from echocardiography was similar to that derived from catheterization (mean +/- SD 1.16 +/- 1.0 vs 1.10 +/- 0.95 mL(3) x mm Hg(-1), P = not significant) and the two correlated well (r = 0.74, P < .0001). There was a highly significant polynomial relationship between PAC and RV anterior wall thickness indexed to body surface area (R(2) = 0.54, P < .0001), but not between pulmonary vascular resistance and RV wall thickness. Pulmonary vascular resistance and PAC did not correlate.Echocardiography can reliably estimate PAC, which strongly correlates with RV hypertrophy, a surrogate for RV work.

  View details for DOI 10.1016/j.echo.2006.08.009

  View details for PubMedID 17275705

• Effects of exercise and respiration on hemodynamic efficiency in CFD simulations of the total cavopulmonary connection ANNALS OF BIOMEDICAL ENGINEERING Marsden, A. L., Vignon-Clementel, I. E., Chan, F. P., Feinstein, J. A., Taylor, C. A. 2007; 35 (2): 250-263

  Abstract

  Congenital heart defects with a single functional ventricle, such as hypoplastic left heart syndrome and tricuspid atresia, require a staged surgical approach to separate the systemic and pulmonary circulations. Ultimately, the venous or pulmonary side of the heart is bypassed by directly connecting the vena cava to the pulmonary arteries with a modified t-shaped junction. The Fontan procedure (total cavopulmonary connection, TCPC) completes this process of separation. To date, computational fluid dynamics (CFD) simulations in this low pressure, passive flow, intrathoracic system have neglected the presumed important effects of respiration on physiology and higher "stress" states such as with exercise have never been considered. We hypothesize that incorporating effects of respiration and exercise would provide more realistic estimates of TCPC performance. Time-dependent, 3D blood flow simulations are performed by a custom finite element solver for two patient-specific Fontan models with a novel respiration model, developed to generate physiologic time-varying flow conditions. Blood flow features, pressure, and energy efficiency are analyzed at rest and with increasing flow rates to simulate exercise conditions. The simulations produce realistic pressure and flow data, comparable to that measured by catheterization and echocardiography, and demonstrate substantial increases in energy dissipation (i.e. decreased performance) with exercise and respiration due to increasing intensity of small scale vortices in the flow. As would be expected, these changes are highly dependent on patient-specific anatomy and Fontan geometry. We propose that respiration and exercise should be incorporated into TCPC CFD simulations to provide increasingly realistic evaluations of TCPC performance.

  View details for DOI 10.1007/s10439-006-9224-3

  View details for PubMedID 17171509

• Evaluation of hemodynamic efficiency in a new "Y-graft" design for the Fontan operation ASME Summer Bioengineering Conference Bernstein, A. J., Marsden, A. L., Spilker, R. L., Reddy, V. M., Taylor, C. A., Feinstein, J. A. AMER SOC MECHANICAL ENGINEERS. 2007: 473–474

  View details for Web of Science ID 000252105700237

• Use of computational fluid dynamics for the replication of clinical blood flow and pressure measurements and characterization of hemodynamics in the normal ascending and thoracic aorta ASME Summer Bioengineering Conference LaDisa, J. F., Figueroa, C. A., Vignon-Clernentel, I. E., Chan, F. P., Feinstein, J. A., Taylor, C. A. AMER SOC MECHANICAL ENGINEERS. 2007: 511–512

  View details for Web of Science ID 000252105700256

• Percutaneous translurninal coronary angioplasty in a two-month old with coronary stenosis presenting as congenital cardiomyopathy: Acute results and intermediate follow-up CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS Cheng, C. W., Lee, D. P., Rosenthal, D. N., Feinstein, J. A. 2006; 68 (4): 632-636

  Abstract

  Congenital or nonsurgically acquired obstructive coronary artery disease in infancy is exceedingly rare, and previous reports of catheter-based therapies in very young patients have been solely in patients having undergone arterial switch or other cardiovascular surgical procedures. We describe a previously unreported cause for ventricular dysfunction and heart failure in an infant, isolated congenital circumflex coronary artery stenosis, and successful treatment with percutaneous transluminal coronary angioplasty. Technical considerations, immediate results, and 3-year follow-up are provided.

  View details for DOI 10.1002/ccd.20750

  View details for PubMedID 16969876

• Unifocalization of major aortopulmonary collaterals in single-ventricle patients 42nd Annual Meeting of the Society-of-Thoracic-Surgeons Reinhartz, O., Reddy, V. M., Petrossian, E., Suleman, S., Mainwaring, R. D., Rosenthal, D. N., Feinstein, J. A., Gulati, R., Hanley, F. L. ELSEVIER SCIENCE INC. 2006: 934–39

  Abstract

  Unifocalization of major aortopulmonary collateral arteries (MAPCAs) in pulmonary atresia with ventricular septal defect and intracardiac repair has become the standard of care. However, there are no reports addressing unifocalization of MAPCAs in single-ventricle patients. It is unknown whether their pulmonary vascular bed can be reconstructed and low enough pulmonary vascular resistance achieved to allow for superior or total cavopulmonary connections.We reviewed data on all patients with functional single ventricles and unifocalization procedures of MAPCAs. From 1997 to 2005, 14 consecutive children with various single-ventricle anatomies were operated on.Patients had a median of three surgical procedures (range, 1 to 5). Two patients had absent, all others diminutive central pulmonary arteries, with an average of 3.5 +/- 1.2 MAPCAs. Seven patients (50%) had bidirectional Glenn procedures, and 3 of these had Fontan procedures. Median postoperative pulmonary artery pressures measured 12.5 mm Hg (Glenn) and 14 mm Hg (Fontan), respectively. Six patients are alive today (46%), with 1 patient lost to follow-up. Three patients died early and 3 late after initial unifocalization to shunts. One other patient survived unifocalization, but was not considered a candidate for a Glenn procedure and died after high-risk two-ventricle repair. Another patient with right-ventricle-dependent coronary circulation died of sepsis late after Glenn.In selected patients with functional single ventricles and MAPCAs, the pulmonary vascular bed can be reconstructed sufficiently to allow for cavopulmonary connections. Venous flow to the pulmonary vasculature decreases cardiac volume load and is likely to increase life expectancy and quality of life for these patients.

  View details for DOI 10.1016/j.athoracsur.2006.03.063

  View details for PubMedID 16928512

• Relative lung perfusion distribution in normal lung scans: observations and clinical implications. Congenital heart disease Cheng, C. P., Taur, A. S., Lee, G. S., Goris, M. L., Feinstein, J. A. 2006; 1 (5): 210-216

  Abstract

  While relative lung perfusion distributions are cited in clinical decision making for congenital and acquired pulmonary vascular diseases, normal values and ranges have not been published for a large population of normally perfused lungs. These values of normal relative perfusion will be useful for establishing what is abnormal and for clinical decisions related to various pulmonary vascular diseases.Relative perfusion distributions were quantified for the top, middle, and bottom thirds of the right and left lungs with a semiautomatic algorithm in 206 normal scintigraphy lung studies (45 +/- 18 years, 149 female, 57 male) acquired between January 1, 2000 and March 30, 2004 in the Nuclear Medicine Division at Stanford Hospital and Clinics.The perfusion data were found to be highly non-Gaussian in nature (necessitating the use of Wilcoxon statistical comparisons), and the right/left perfusion ratio was found to be 52.5/47.5 (+/-2.1%) rather than the often quoted 55/45 split. While this right/left split was consistent between the genders, males had proportionally less perfusion in the lower left lung as compared with females (P < .05).The long-standing 55/45 right/left perfusion ratio assumption was found to be more than 1 standard deviation greater than the mean, and the population variance is very small. Relative pulmonary perfusion distribution varies significantly with lung region, gender, and age, and should be considered when making clinical decisions based on pulmonary perfusion.

  View details for DOI 10.1111/j.1747-0803.2006.00037.x

  View details for PubMedID 18377528

• A novel echocardiographic Doppler method for estimation of pulmonary arterial pressures JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY Friedberg, M. K., Feinstein, F. A., Rosenthal, D. N. 2006; 19 (5): 559-562

  Abstract

  Current noninvasive methods for estimating diastolic and mean pulmonary artery pressures (PAp) in children are cumbersome and have limited accuracy. We hypothesized that systolic PAp correlates with diastolic and mean PAp, and that this correlation can be used to estimate diastolic and mean PAp from Doppler flow data.We recorded PAp in 112 patients 30 years or younger catheterized for heart failure, heart transplant, pulmonary hypertension, or congenital heart disease. We derived the relationship of systolic PAp to diastolic and mean PAp. We then applied these relations to systolic PAp measured by tricuspid regurgitation (TR) Doppler flow in a subset of 17 patients with pulmonary hypertension to predict mean and diastolic PAp, and correlated the results.An excellent linear relation was found between systolic PAp and both the diastolic and mean PAp measured at cardiac catheterization (r = 0.95, P < .0001; r = 0.98, P < .0001, respectively). The calculated diastolic PAp calculated from TR Doppler correlated well with invasive data (31 +/- 13 vs 30 +/- 11 mm Hg, respectively, not significant; r = 0.85, P < .0001) and surpassed existing methods that are based on pulmonary regurgitation for predicting diastolic PAp. Similarly, mean PAp calculated from TR Doppler flow correlated well with invasive data (r = 0.86, P < .0001).A strong linear relationship between systolic and diastolic PAp allows for easy and accurate noninvasive estimation of diastolic and mean PAp from TR Doppler flow.

  View details for DOI 10.1016/j.echo.2005.12.020

  View details for PubMedID 16644441

• Percutaneous pulmonary valve placement in a 10-month-old patient using a hand crafted stent-mounte d porcine valve CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS Feinstein, J. A., Kim, N., Reddy, V. M., Perry, S. B. 2006; 67 (4): 644-649

  Abstract

  Percutaneous replacement of the pulmonary valve in a right ventricle to pulmonary artery (RV-PA) conduit using bovine jugular valves has recently been described as an alternative to surgical options in selected patients weighing >or=20 kg. We report the first case of transcatheter pulmonary valve implantation in an infant and the first use of "off the shelf" components. A 12-mm (Hancock) porcine valve was sutured into a predilated Genesis 2510b stent. The valved stent was manually crimped and mounted on a 12-mm balloon. Snare-assisted deployment in the middle of the RV-PA conduit was accomplished without the use of a long sheath. After the initial deployment, a 14-mm balloon was used to further approximate the stent to the walls of the conduit. Short-term (11 month) follow-up has demonstrated continued valve integrity, markedly decreased right ventricular size and improved function and symptomatic improvement. At 10 months of age, this case represents the youngest patient to undergo percutaneous valve placement and documents the technical feasibility of the procedure.

  View details for DOI 10.1002/ccd.20668

  View details for PubMedID 16532496

• AngioJet catheter-based thrombectomy in a neonate with postoperative pulmonary embolism CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS Feldman, J. R., Feinstein, J. A., Lamberti, J. J., Perry, S. B. 2005; 66 (3): 442-445

  Abstract

  A 2-day-old male with pulmonary atresia and an intact ventricular septum underwent central aortopulmonary shunt placement and right ventricular outflow tract reconstruction. Postoperatively, the patient had difficulty weaning from mechanical ventilation and was found to have a large thrombus occluding the entire right lower pulmonary artery. The patient underwent successful percutaneous catheter-based thrombectomy in the early postoperative period with the Possis AngioJet catheter. The patient had immediate improvement in gas exchange and was able to be weaned from the ventilator shortly thereafter. This represents the first published use of mechanical thrombectomy in a postoperative neonate.

  View details for DOI 10.1002/ccd.20518

  View details for PubMedID 16216022

• Surgical and interventional therapies for pulmonary arterial hypertension SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE Olsson, J. K., Zamanian, R. T., Feinstein, J. A., Doyle, R. L. 2005; 26 (4): 417-428

  Abstract

  Surgical and interventional therapies for pulmonary arterial hypertension (PAH) in appropriately selected patients have the potential to dramatically improve or, in some cases, cure PAH. These include atrial septostomy, a palliative procedure or bridge to transplantation in patients with refractory right heart failure, pulmonary thromboendarterectomy for pulmonary hypertension associated with chronic thromboembolic disease, and closure of congenital systemic-pulmonary shunts in patients with PAH but without significant pulmonary vascular disease. Lung transplantation should be considered for patients with all forms of PAH who demonstrate advanced or progressive disease.

  View details for PubMedID 16121319

• Experience of percutaneous coronary intervention in the management of pediatric cardiac allograft vasculopathy JOURNAL OF HEART AND LUNG TRANSPLANTATION Tham, E. B., Yeung, A. C., Cheng, C. W., Bernstein, D., Chin, C., Feinstein, J. A. 2005; 24 (6): 769-773

  Abstract

  In a retrospective study, we examined the procedural success rate and the short-, intermediate-, and long-term outcomes of coronary interventional procedures in children with cardiac allograft vasculopathy. Seven patients underwent 13 interventional procedures: balloon angioplasty alone (n = 3), angioplasty with stenting (n = 9), or angioplasty with brachytherapy (n = 1), with procedural success in all. Two major complications (cardiac arrest) and a single death occurred in the immediate postprocedural period. Five (83%) of the remaining 6 patients developed moderate to severe restenosis, diffuse disease, or progressive vasculopathy; 3 have been retransplanted, 1 died from progressive cardiac allograft vasculopathy, and 1 is awaiting retransplantation, 40 months after the procedure.

  View details for DOI 10.1016/j.healun.2004.04.009

  View details for PubMedID 15949739

• Proximal pulmonary artery blood flow characteristics in healthy subjects measured in an upright posture using MRI: The effects of exercise and age 12th Annual Meeting of the International-Society-for-Magnetic-Resonance-in-Medicine Cheng, C. P., Herfkens, R. J., Taylor, C. A., Feinstein, J. A. JOHN WILEY & SONS INC. 2005: 752–58

  Abstract

  To use MRI to quantify blood flow conditions in the proximal pulmonary arteries of healthy children and adults at rest and during exercise in an upright posture.Cine phase-contrast MRI was used to calculate mean flow and reverse flow index (RFI) in the main (MPA), right (RPA), and left (LPA) pulmonary arteries in healthy children and adults in an open-MRI magnet equipped with an upright MRI-compatible ergometer.From rest to exercise (150% resting heart rate), blood flow (liters/minute/m2) increased in the RPA (1.4+/-0.3 vs. 2.5+/-0.4; P<0.001), LPA (1.1+/-0.3 vs. 2.2+/-0.6; P<0.001), and MPA (2.7+/-0.5 vs. 4.9+/-0.5; P<0.001). RFI decreased in the LPA (0.040+/-0.030 vs. 0.017+/-0.018; P<0.02) and MPA (0.025+/-0.024 vs. 0.008+/-0.007; P<0.03). Adults experienced greater retrograde flow in the MPA than the children (0.042+/-0.029 vs. 0.014+/-0.012; P<0.02).It appears that at both rest and during exercise, in children and adults alike, RPA/LPA mean blood flow distribution is predominantly determined by distal vascular resistance, while retrograde flow is affected by proximal pulmonary bifurcation geometry.

  View details for DOI 10.1002/jmri.20333

  View details for PubMedID 15906332

• Regression of severe pulmonary arteriovenous malformations after Fontan revision and "Hepatic factor" rerouting ANNALS OF THORACIC SURGERY Pike, N. A., Vricella, L. A., Feinstein, J. A., Black, M. D., Reitz, B. A. 2004; 78 (2): 697-699

  Abstract

  Although previously described in patients undergoing staged palliation for univentricular heart disease, the mechanism by which hepatic venous flow prevents development of pulmonary arteriovenous malformations is still not completely understood. We present a case in which successful H-type Fontan revision with rerouting of hepatic venous flow through a hemiazygous vein successfully reversed the progression of severe left pulmonary arteriovenous malformations.

  View details for DOI 10.1016/j.athorascur.2004.02.003

  View details for Web of Science ID 000222999300055

  View details for PubMedID 15276554

• Blood flow conditions in the proximal pulmonary arteries and vena cavae: healthy children during upright cycling exercise AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Cheng, C. P., Herfkens, R. J., Lightner, A. L., Taylor, C. A., Feinstein, J. A. 2004; 287 (2): H921-H926

  Abstract

  Diagnostic testing in patients with congenital heart disease is usually performed supine and at rest, conditions not representative of their typical hemodynamics. Upright exercise measurements of blood flow may prove valuable in the assessment of these patients, but data in normal subjects are first required. With the use of a 0.5-T open magnet, a magnetic resonance-compatible exercise cycle, and cine phase-contrast techniques, time-dependent blood flow velocities were measured in the right (RPA), left (LPA), and main (MPA) pulmonary arteries and superior (SVC) and inferior (IVC) vena cavae of 10 healthy 10- to 14-yr-old subjects. Measurements were made at seated rest and during upright cycling exercise (150% resting heart rate). Mean blood flow (l/min) and reverse flow index were computed from the velocity data. With exercise, RPA and LPA mean flow increased 2.0 +/- 0.5 to 3.7 +/- 0.7 (P < 0.05) and 1.6 +/- 0.4 to 2.9 +/- 0.8 (P < 0.05), respectively. Pulmonary reverse flow index (rest vs. exercise) decreased with exercise as follows: MPA: 0.014 +/- 0.012 vs. 0.006 +/- 0.006 [P = not significant (NS)], RPA: 0.005 +/- 0.004 vs. 0.000 +/- 0.000 (P < 0.05), and LPA: 0.041 +/- 0.019 vs. 0.014 +/- 0.016 (P < 0.05). SVC and IVC flow increased from 1.5 +/- 0.2 to 1.9 +/- 0.6 (P = NS) and 1.6 +/- 0.4 to 4.9 +/- 1.3 (P < 0.05), respectively. A 56/44% RPA/LPA flow distribution at both rest and during exercise suggests blood flow distribution is dominated by distal pulmonary resistance. Reverse flow in the MPA appears to originate solely from the LPA while the RPA is in relative isolation. During seated rest, the SVC-to-IVC venous return ratio is 50/50%. With light/moderate cycling exercise, IVC flow increases by threefold, whereas SVC remains essentially constant.

  View details for DOI 10.1152/ajpheart.00022.2004

  View details for PubMedID 15031121

• Identifying cardiac transplant rejection in children: Diagnostic utility of echocardiography, right heart catheterization and endomyocardial biopsy data JOURNAL OF HEART AND LUNG TRANSPLANTATION Rosenthal, D. N., Chin, C., Nishimura, K., Perry, S. B., Robbins, R. C., Reitz, B., Bernstein, D., Feinstein, J. A. 2004; 23 (3): 323-329

  Abstract

  There has been a continued search for alternative diagnostic techniques that do not necessitate endomyocardial biopsy for diagnosing rejection in cardiac transplant recipients. The purpose of this study is to evaluate the role of echocardiography and hemodynamic catheterization data compared with endomyocardial biopsy results, in rejection surveillance for the pediatric heart transplant recipient.A prospective, blinded evaluation was performed utilizing echocardiographic and standard right heart catheterization parameters to predict acute rejection episodes.Forty-nine patients underwent 281 biopsies. Two groups were defined: those with Grade <2 rejection and those with grade > or =2 rejection. None of the echocardiographic variables showed significant differences between the study groups and all group data were within normal limits. Mixed venous saturation, mean right atrial pressure, right ventricular end-diastolic pressure and mean pulmonary artery pressure were found to be statistically significant between groups. Receiver-operator characteristic (ROC) curves were constructed to determine the extent to which the various parameters were clinically useful. The ROC found little clinical usefulness for all variables, including those found to be statistically significant.Differences in both echocardiographic and hemodynamic data were not clinically significant between the 2 groups of patients. Although many of the catheterization-derived parameters were statistically significant, they did not permit effective discrimination between groups. This is the only clinically relevant application of such data and may explain the conflicting previous reports. It is only through analyses such as ROC that the clinical application (or lack thereof) can be appreciated in this population.

  View details for DOI 10.1016/S1053-2498(03)00209-2

  View details for PubMedID 15019642

• Transcatheter closure of postinfarction ventricular septal defects using the new Amplatzer muscular VSD occluder: Results of a US registry CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS Holzer, R., Balzer, D., Amin, Z., Ruiz, C. E., Feinstein, J., Bass, J., Vance, M., Cao, Q. L., Hijazi, Z. M. 2004; 61 (2): 196-201

  Abstract

  The objective of this study was to assess the immediate and mid-term results of transcatheter closure of postinfarct muscular ventricular septal defects (VSDs) using the new Amplatzer postinfarct muscular VSD device (PIMVSD). Ventricular septal rupture occurs in 0.2% of myocardial infarcts and remains associated with very high morbidity and mortality. Data were prospectively collected for 18 patients who underwent attempted device closure of postinfarction VSDs between 2000 and 2003. Five patients underwent the closure in the acute phase (within 6 days from the infarct); the remaining patients underwent closure on day 14-95 after the diagnosis of the infarct. Outcome parameters included procedural success, evidence of residual shunts on echocardiography, and occurrence of procedure-related complications. The procedure was successful in deploying a device across the VSD in 16 of 18 patients. The 30-day mortality was 28%. Eleven patients are still alive and have been followed up for a median of 332 days. Two patients required a second procedure to close a residual VSD. At the most recent outpatient follow-up, the VSD was completely closed in two patients, six patients had a trivial or small residual shunt, and two patients had a moderate residual shunt. We conclude that percutaneous device closure of postinfarction VSDs using the Amplatzer PIMVSD occluder appears to be safe and effective. Further trials are required to assess long-term efficacy and compare the results with those of surgical closure.

  View details for DOI 10.1002/ccd.10784

  View details for Web of Science ID 000188807400008

  View details for PubMedID 14755811

• Electrical resynchronization - A novel therapy for the failing right ventricle CIRCULATION Dubin, A. M., Feinstein, J. A., Reddy, V. M., Hanley, F. L., Van Hare, G. F., Rosenthal, D. N. 2003; 107 (18): 2287-2289

  Abstract

  Many patients with congenital heart disease develop right ventricular (RV) failure due to anatomy and prior therapy. RV problems may include right bundle-branch block (RBBB), volume loading, and chamber enlargement. Because the failing RV may have regional dyskinesis, we hypothesized that resynchronization therapy might augment its performance.We studied 7 patients with RV dysfunction and RBBB, using a predefined pacing protocol. QRS duration, cardiac index (CI), and RV dP/dt were measured in 4 different pacing states. Atrioventricular pacing improved CI and RV dP/dtmax and decreased QRS duration as compared with atrial pacing or sinus rhythm.Atrioventricular pacing in patients with RBBB and RV dysfunction augments RV and systemic performance. RV resynchronization is a promising novel therapy for patients with RV failure.

  View details for DOI 10.1161/01.CIR.0000070930.33499.9F

  View details for PubMedID 12732607

• Usefulness of epoprostenol therapy in the severely ill adolescent/adult with Eisenmenger physiology AMERICAN JOURNAL OF CARDIOLOGY Fernandes, S. M., Newburger, J. W., Lang, P., Pearson, D. D., Feinstein, J. A., Gauvreau, K., Landzberg, M. J. 2003; 91 (5): 632-635

  View details for DOI 10.1016/S0002-9149(02)03328-3

  View details for Web of Science ID 000181537800031

  View details for PubMedID 12615282

• Temporary IVC filtration before patent foramen ovale closure in a patient with paradoxic embolism JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY Lewis-Carey, M. B., Kee, S. T., Feinstein, J. A. 2002; 13 (12): 1275-1278

  Abstract

  Pulmonary embolism (PE) and associated acute peripheral ischemia suggest the diagnosis of paradoxic embolism. The most common intracardiac defect associated with paradoxic emboli is a patent foramen ovale (PFO). Therapeutic options include anticoagulation, thrombolysis, inferior vena cava (IVC) filtration, and closure of the intracardiac defect. The authors discuss the diagnosis and treatment of a young female athlete who presented with massive PE complicated by a paradoxic embolus to the right subclavian artery. Systemic and catheter-directed thrombolysis, IVC filtration, and percutaneous closure of a PFO were performed in an effort to return the patient to the level of competitiveness she desired.

  View details for PubMedID 12471194

• Comparison of contrast echocardiography versus cardiac catheterization for detection of pulmonary arteriovenous malformations AMERICAN JOURNAL OF CARDIOLOGY Feinstein, J. A., Moore, P., Rosenthal, D. N., Puchalski, M., Brook, M. M. 2002; 89 (3): 281-285

  Abstract

  Because clinical diagnosis of pulmonary arteriovenous malformations (AVMs) is difficult and cardiac catheterization invasive, contrast echo has been used to aid in the diagnosis. Correlation between contrast echo and catheterization data in these patients remains poorly defined. We examined the ability to detect pulmonary AVMs by contrast echocardiography, pulmonary angiography, and pulmonary vein saturations in patients who have undergone cavopulmonary (Glenn) shunts. Pulmonary vein saturations were obtained from catheterization reports. Blinded observers reviewed angiographic and contrast echo data retrospectively in 27 patients who had undergone a Glenn shunt and in 19 controls with biventricular hearts. Contrast echo was positive in 68 of 99 lungs (69%). Angiography showed AVMs in 65 of 98 lungs (66%). Pulmonary vein desaturation was found in 13 of 45 lungs sampled (29%). Only 10 of 38 lungs with positive contrast echo had pulmonary vein desaturation, but only 1 patient had pulmonary vein desaturation without positive contrast echo. The degree of desaturation did not correlate with severity of contrast echo return; 6 of 11 patients with 3+ contrast echo studies had normal pulmonary vein saturations. In a control group of patients with biventricular hearts, only 1 of 19 (5.3%) contrast echos was weakly positive. Contrast echo correlates poorly with angiography and pulmonary vein saturation for evaluation of AVMs. Contrast echo is extremely sensitive and often positive despite normal pulmonary vein saturation. Assessment of pulmonary vein desaturation in 100% oxygen may improve its sensitivity and correlation with contrast echo. Additional studies are needed to follow patients with mildly positive contrast echo studies to enable determination of their clinical relevance.

  View details for PubMedID 11809429

• A technique for maintenance of airway access in infants with a difficult airway following tracheal extubation PAEDIATRIC ANAESTHESIA Hammer, G. B., Funck, N., Rosenthal, D. N., Feinstein, J. A. 2001; 11 (5): 622-625

  Abstract

  Tracheal extubation of patients with a difficult airway represents a challenge to anaesthesiologists and intensive care physicians. While a variety of techniques designed to maintain access to the airway in case of the need for tracheal reintubation have been described in adults, no reports have been published in infants and young children. We describe an approach to this issue in a young child with severe micrognathia.

  View details for PubMedID 11696131

• Balloon pulmonary angioplasty for treatment of chronic thromboembolic pulmonary hypertension CIRCULATION Feinstein, J. A., Goldhaber, S. Z., Lock, J. E., Ferndandes, S. R., Landzberg, M. J. 2001; 103 (1): 10-13

  Abstract

  Although pulmonary thromboendarterectomy is increasingly successful for the definitive treatment of chronic thromboembolic pulmonary hypertension (CTEPH), not all patients have surgically accessible disease. Others are poor surgical candidates because of comorbid illness. Therefore, for selected patients, we defined and implemented an alternative interventional strategy of balloon pulmonary angioplasty (BPA).Eighteen patients (mean age, 51.8 years; range, 14 to 75 years) with CTEPH underwent BPA; they averaged 2.6 procedures (range, 1 to 5) and 6 dilations (range, 1 to 12). Selection of pulmonary artery segments for dilation required (1) complete occlusion, (2) filling defects, or (3) signs of intravascular webs. After an average of 36 months of follow-up (range, 0.5 to 66 months), the average New York Heart Association class improved from 3.3 to 1.8 (P:<0.001), and 6-minute walking distances increased from 209 to 497 yards (P:<0.0001). Pulmonary artery mean pressures decreased from 43.0+/-12.1 to 33. 7+/-10.2 mm Hg (P:=0.007). Eleven patients developed reperfusion pulmonary edema; 3 required mechanical ventilation.BPA reduces pulmonary artery hypertension in patients with CTEPH and is associated with long-term improvement in New York Heart Association class and 6-minute walking distances. BPA is a promising interventional technique that warrants randomized comparison with medical therapy in CTEPH patients who are not surgical candidates.

  View details for Web of Science ID 000166287300006

  View details for PubMedID 11136677

• Angiogenic growth factor levels are abnormal in patients with severe pulmonary hypertension Benisty, J. I., Folkman, J., Conners, S., Feinstein, J. A., Landzberg, M. J. ELSEVIER SCIENCE INC. 2000: 286A

  View details for Web of Science ID 000085209701102

• Preoperative management of pulmonary venous hypertension in hypoplastic left heart syndrome with restrictive atrial septal defect AMERICAN JOURNAL OF CARDIOLOGY Atz, A. M., Feinstein, J. A., Jonas, R. A., Perry, S. B., Wessel, D. L. 1999; 83 (8): 1224-1228

  Abstract

  A severely restrictive atrial septal defect (ASD) in neonates with hypoplastic left heart syndrome (HLHS) results in pulmonary venous hypertension, pulmonary edema, and intractable hypoxia. Between January 1983 and June 1998, 21 of 355 neonates presenting with HLHS (5.9%) underwent cardiac catheterization at median age 1 day (range 0 to 25), for creation or enlargement of a restrictive or absent interatrial communication. One patient died during preliminary angiography. Three underwent blade septostomy with 2 procedure-related deaths, and 1 had balloon atrial septostomy (BAS); all 4 died before surgical intervention. Fifteen underwent Brockenbrough atrial septoplasty with transatrial needle puncture and serial balloon dilations of the new ASD, 5 after unsuccessful BAS. The most recent patient had a stent placed across the atrial septum after transatrial needle puncture. In the 16 patients treated with septoplasty or stent, oxygen saturation increased from 50 +/- 4% to 83 +/- 2% (p <0.0001) and transatrial pressure gradient decreased from 16 +/- 1 to 6 +/- 1 mm Hg (p <0.0001). One patient died awaiting transplantation, supportive care only was requested in 1, and 14 underwent stage 1 palliation. Eight of 14 (57%) survived to hospital discharge. Six of 7 (86%) survived bidirectional Glenn and the 3 who have undergone fenestrated Fontan are alive. In neonates with HLHS, a restrictive ASD resulting in profound cyanosis demands urgent intervention. BAS is frequently unsuccessful and blade septostomy has high mortality. Pulmonary venous hypertension can be adequately relieved by Brockenbrough atrial septoplasty or stenting, allowing stabilization before reconstructive surgery or while awaiting transplant.

  View details for Web of Science ID 000079659100016

  View details for PubMedID 10215289

• Using cardiac phase to order reconstruction [CAPTOR]: A method to improve diastolic images JMRI-JOURNAL OF MAGNETIC RESONANCE IMAGING Feinstein, J. A., Epstein, F. H., Arai, A. E., Foo, T. K., Hartley, M. R., Balaban, R. S., Wolff, S. D. 1997; 7 (5): 794-798

  Abstract

  A method is proposed to reconstruct multiphase images that accurately depicts the entire cardiac cycle. A segmented, gradient-recalled-echo sequence (FASTCARD) was modified to acquire data continuously. Images were reconstructed retrospectively by selecting views from each heartbeat based on cardiac phase rather than the time elapsed from the QRS complex. Cardiac phase was calculated using a model that compensates for beat-to-beat heart rate changes. Images collected using cardiac phase to order reconstruction (CAPTOR) depict the entire cardiac cycle and lack the temporal gap that is characteristic of prospectively reconstructed sequences. Time-volume curves of the left ventricle capture the contribution of atrial contraction to end-diastolic volume (EDV). Transmitral phase-contrast flow measurements show a second peak inflow (alpha wave) that is absent in the standard sequence. Because atrial contraction contributes to ventricular EDV, images using CAPTOR potentially may provide a more reliable measure of EDV, stroke volume, and ejection fraction than standard techniques.

  View details for Web of Science ID A1997XW88300004

  View details for PubMedID 9307903

• Transposition of the great arteries: Summary of operative data, pediatric cardiac care consortium, 1984-1993. Feinstein, J. A., Moller, J. H., Hougen, T. J. AMER ACAD PEDIATRICS. 1996: 12

  View details for Web of Science ID A1996VG26500013