Bio


Dr. Hiesinger is a board-certified, fellowship-trained specialist in adult cardiac surgery. He is also an associate professor in the Department of Cardiothoracic Surgery at Stanford University School of Medicine.

Dr. Hiesinger’s clinical focus encompasses the full spectrum of cardiothoracic conditions and treatment approaches, such as heart transplantation, mitral and aortic valve repair, surgical treatment for hypertrophic cardiomyopathy, coronary artery bypass, and complex thoracic aortic procedures. He serves as Surgical Director of the Stanford Mechanical Circulatory Support Program, where he leads and directs the surgical implantation of ventricular assist devices (VADs) in patients with end-stage heart failure.

The National Institutes of Health and the Thoracic Surgery Foundation have awarded funds to support Dr. Hiesinger’s research. In the Stanford Cardiothoracic Therapeutics and Surgery Laboratory, Dr. Hiesinger's research spans the disciplines of computer science and cardiovascular biology, and he endeavors to build novel foundational deep learning systems designed to better represent and process high-dimensional inputs and apply these systems towards clinical problems. Additionally, his lab investigates bioengineered devices, tissue engineering, and angiogenic cytokine therapy for the treatment of heart failure.

He has published extensively and his work has appeared in Nature Communications, Nature Machine Intelligence, the Journal of Heart and Lung Transplantation, Circulation Heart Failure, the Journal of Thoracic and Cardiovascular Surgery, Journal of Vascular Surgery, and elsewhere.

He teaches courses on cardiothoracic surgery skills. He also advises surgeons of the future.

Dr. Hiesinger has won awards for his research and scholarship, including the Surgical Resident of the Year Award, Jonathan E. Rhoads Research Award, Clyde F. Baker Research Prize, and I.S. Ravdin Prize, all from his alma mater, the University of Pennsylvania. He was a finalist for the Vivien Thomas Young Investigator Award from the American Heart Association.

Dr. Hiesinger is a member of the American Association For Thoracic Surgery and serves on the Cardiac Surgery Biology Club. He is also a member of the Society of Thoracic Surgeons and serves on the Workforce on Surgical Treatment of End-Stage Cardiopulmonary Disease national committee as well as the American Heart Association Council for Cardiothoracic and Vascular Surgery.

Clinical Focus


  • Heart Transplantation
  • Mechanical Circulatory Support
  • Mitral Valve Repair
  • Aortic Aneurysm
  • Minimally Invasive Cardiac Surgery
  • Cardiac Surgery
  • Complex Valve Repair Surgery
  • Aortic Valve Repair
  • Valve Replacement Surgery
  • Surgical Treatments of Cardiomyopathy
  • Heart Failure
  • Ventricular Assist Device
  • Heart-Lung Transplantation
  • Coronary Artery Bypass
  • Coronary Artery Bypass, Off-pump
  • Reoperative Cardiac Surgery
  • Clinical Device Trials
  • Lung Transplantation
  • Thoracic and Cardiovascular Surgery
  • Thoracic and Cardiac Surgery

Academic Appointments


Honors & Awards


  • Keith Reemtsma Surgical Resident of the Year Award, Department of Surgery, University of Pennsylvania (2014)
  • Jonathan E. Rhoads Research Award, Department of Surgery, University of Pennsylvania (2011)
  • Vivien Thomas Young Investigator Award Finalist, American Heart Association (2010)
  • Alpha Omega Alpha (AOA) Honor Medical Society, University of Pennsylvania (2007)
  • Clyde F. Baker Research Prize, Department of Surgery, University of Pennsylvania (2007)
  • First Place, Medical Student Research Day Basic Science Research, University of Pennsylvania (2007)
  • I. S. Ravdin Prize, Department of Surgery, University of Pennsylvania (2007)

Boards, Advisory Committees, Professional Organizations


  • Member, Society of Thoracic Surgeons Workforce on Surgical Treatment of End-Stage Cardiopulmonary Disease, National Committee (2017 - Present)
  • Reviewer, Circulation (2017 - Present)
  • Member, American Heart Association, Council for Cardiothoracic & Vascular Surgery (2017 - Present)
  • Member, Society of Thoracic Surgeons (2017 - Present)

Professional Education


  • Board Certification: American Board of Thoracic Surgery, Thoracic and Cardiac Surgery (2017)
  • Fellowship: Hospital of the University of Pennsylvania Dept of CTS (2016) PA
  • Residency: Hospital of the University of Pennsylvania General Surgery Residency (2014) PA
  • Medical Education: Perelman School of Medicine University of Pennsylvania (2007) PA
  • Board Certification: American Board of Surgery, General Surgery (2015)
  • M.D., University of Pennsylvania (2007)

Clinical Trials


  • Edwards PASCAL CLASP IID/IIF Pivotal Clinical Trial Recruiting

    To establish the safety and effectiveness of the Edwards PASCAL Transcatheter Valve Repair System in patients with degenerative mitral regurgitation (DMR) who have been determined to be at prohibitive risk for mitral valve surgery by the Heart Team, and in patients with functional mitral regurgitation (FMR) on guideline directed medical therapy (GDMT)

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  • MOMENTUM 3 Continued Access Protocol Not Recruiting

    The objective of the study is to continue to evaluate safety and clinical performance of the HM3 LVAS for the treatment of advanced, refractory, left ventricular heart failure following completion of enrollment in the the MOMENTUM 3 IDE Study.

    Stanford is currently not accepting patients for this trial.

    View full details

2024-25 Courses


Stanford Advisees


Graduate and Fellowship Programs


All Publications


  • Electrohydraulic Vascular Compression Device (e-VaC) with Integrated Sensing and Controls ADVANCED MATERIALS TECHNOLOGIES Pirozzi, I., Kight, A., Liang, X., Han, A., Ennis, D. B., Hiesinger, W., Dual, S. A., Cutkosky, M. R. 2022
  • A value-based approach to optimize red blood cell transfusion in patients receiving extracorporeal membrane oxygenation. Perfusion Shudo, Y., Cheng, N., He, H., Rosenberg, C., Hiesinger, W., Hadhazy, E., Shepard, J., Krishna, P., Resnik, J., Fong, R., Hill, C., Hsu, J. L., Maggio, P. M., Chang, S., Boyd, J. H., Woo, Y. J. 2022: 2676591221128138

    Abstract

    INTRODUCTION: The risk, cost, and adverse outcomes associated with packed red blood cell (RBC) transfusions in patients with cardiopulmonary failure requiring extracorporeal membrane oxygenation (ECMO) have raised concerns regarding the overutilization of RBC products. It is, therefore, necessary to establish optimal transfusion criteria and protocols for patients supported with ECMO. The goal of this study was to establish specific criteria for RBC transfusions in patients undergoing ECMO.METHODS: This was a retrospective cohort study conducted at Stanford University Hospital. Data on RBC utilization during the entire hospital stay were obtained, which included patients aged ≥18years who received ECMO support between 1 January 2017, and 30 June 2020 (n = 281). The primary outcome was in-hospital mortality.RESULTS: Hemoglobin (HGB) levels >10g/dL before transfusion did not improve in-hospital survival. Therefore, we revised the HGB threshold to ≤10g/dL to guide transfusion in patients undergoing ECMO. To validate this intervention, we prospectively compared the pre- and post-intervention cohorts for in-hospital mortality. Post-intervention analyses found 100% compliance for all eligible records and a decrease in the requirement for RBC transfusion by 1.2 units per patient without affecting the mortality.CONCLUSIONS: As an institution-driven value-based approach to guide transfusion in patients undergoing ECMO, we lowered the threshold HGB level. Validation of this revised intervention demonstrated excellent compliance and reduced the need for RBC transfusion while maintaining the clinical outcome. Our findings can help reform value-based healthcare in this cohort while maintaining the outcome.

    View details for DOI 10.1177/02676591221128138

    View details for PubMedID 36148806

  • A flexible electronic strain sensor for the real-time monitoring of tumor regression. Science advances Abramson, A., Chan, C. T., Khan, Y., Mermin-Bunnell, A., Matsuhisa, N., Fong, R., Shad, R., Hiesinger, W., Mallick, P., Gambhir, S. S., Bao, Z. 2022; 8 (37): eabn6550

    Abstract

    Assessing the efficacy of cancer therapeutics in mouse models is a critical step in treatment development. However, low-resolution measurement tools and small sample sizes make determining drug efficacy in vivo a difficult and time-intensive task. Here, we present a commercially scalable wearable electronic strain sensor that automates the in vivo testing of cancer therapeutics by continuously monitoring the micrometer-scale progression or regression of subcutaneously implanted tumors at the minute time scale. In two in vivo cancer mouse models, our sensor discerned differences in tumor volume dynamics between drug- and vehicle-treated tumors within 5 hours following therapy initiation. These short-term regression measurements were validated through histology, and caliper and bioluminescence measurements taken over weeklong treatment periods demonstrated the correlation with longer-term treatment response. We anticipate that real-time tumor regression datasets could help expedite and automate the process of screening cancer therapies in vivo.

    View details for DOI 10.1126/sciadv.abn6550

    View details for PubMedID 36112679

  • Randomized Comparison of Transcatheter Edge-to-Edge Repair for Degenerative Mitral Regurgitation in Prohibitive Surgical Risk Patients. JACC. Cardiovascular interventions Lim, D. S., Smith, R. L., Gillam, L. D., Zahr, F., Chadderdon, S., Makkar, R., Stephan von Bardeleben, R., Kipperman, R. M., Rassi, A. N., Szerlip, M., Goldman, S., Inglessis-Azuaje, I., Yadav, P., Lurz, P., Davidson, C. J., Mumtaz, M., Gada, H., Kar, S., Kodali, S. K., Laham, R., Hiesinger, W., Fam, N. P., KeSSler, M., O'Neill, W. W., Whisenant, B., Kliger, C., Kapadia, S., Rudolph, V., Choo, J., Hermiller, J., Morse, M. A., Schofer, N., Gafoor, S., Latib, A., Koulogiannis, K., Marcoff, L., Hausleiter, J., CLASP IID Pivotal Trial Investigators 2022

    Abstract

    BACKGROUND: Severe symptomatic degenerative mitral regurgitation (DMR) has a poor prognosis in the absence of treatment, and new transcatheter options are emerging.OBJECTIVES: The CLASP IID randomized trial (NCT03706833) is the first to evaluate the safety and effectiveness of the PASCAL system compared to the MitraClip system in patients with significant symptomatic DMR. In this report, we present the primary safety and effectiveness endpoints for the trial.METHODS: Patients with 3+ or 4+ DMR at prohibitive surgical risk were assessed by a central screening committee and randomized 2:1 (PASCAL:MitraClip). Study oversight also included an echocardiographic core laboratory and a clinical events committee. The primary safety endpoint was a composite major adverse event (MAE) rate at 30 days. The primary effectiveness endpoint was the proportion of patients with MR ≤2+ at 6 months.RESULTS: A pre-specified interim analysis in 180 patients demonstrated non-inferiority of the PASCAL system vs. MitraClip system for the primary safety and effectiveness endpoints, MAE: 3.4% vs. 4.8%, MR ≤2+: 96.5% vs. 96.8%, respectively. Functional and quality-of-life outcomes significantly improved in both groups (p<0.05). The proportion of patients with MR ≤1+ was durable in the PASCAL group from discharge to 6 months [PASCAL: 87.2% and 83.7% (p=0.317 vs. discharge); MitraClip: 88.5% and 71.2% (p=0.003 vs. discharge), respectively].CONCLUSIONS: The CLASP IID trial demonstrated safety and effectiveness of the PASCAL system and met non-inferiority endpoints, expanding transcatheter treatment options for prohibitive surgical risk patients with significant symptomatic DMR.

    View details for DOI 10.1016/j.jcin.2022.09.005

    View details for PubMedID 36121247

  • Type A Aortic Dissection With Concurrent Aortic Valve Endocarditis, Subarachnoid Hemorrhage, and Disseminated Intravascular Coagulation. JACC. Case reports Elde, S. F., Guenthart, B. A., de Biasi, A., Dalal, A. R., Casselman, K. G., Hiesinger, W., Burton, E. C. 2022; 4 (14): 839-843

    Abstract

    We describe surgical repair of a Stanford Type A aortic dissection with concurrent aortic valve Streptococcus equi endocarditis in the setting of subarachnoid hemorrhage and disseminated intravascular coagulation. Multidisciplinary collaboration among specialists from a variety of disciplines is essential when treating acutely ill cardiovascular patients with multisystem involvement. (Level of Difficulty: Beginner.).

    View details for DOI 10.1016/j.jaccas.2021.05.008

    View details for PubMedID 35912321

  • Embryologic Origin Influences Smooth Muscle Cell Phenotypic Modulation Signatures in Murine Marfan Syndrome Aortic Aneurysm. Arteriosclerosis, thrombosis, and vascular biology Pedroza, A. J., Dalal, A. R., Shad, R., Yokoyama, N., Nakamura, K., Cheng, P., Wirka, R. C., Mitchel, O., Baiocchi, M., Hiesinger, W., Quertermous, T., Fischbein, M. P. 2022: 101161ATVBAHA122317381

    Abstract

    BACKGROUND: Aortic root smooth muscle cells (SMC) develop from both the second heart field (SHF) and neural crest. Disparate responses to disease-causing Fbn1 variants by these lineages are proposed to promote focal aortic root aneurysm formation in Marfan syndrome (MFS), but lineage-stratified SMC analysis in vivo is lacking.METHODS: We generated SHF lineage-traced MFS mice and performed integrated multiomic (single-cell RNA and assay for transposase-accessible chromatin sequencing) analysis stratified by embryological origin. SMC subtypes were spatially identified via RNA in situ hybridization. Response to TWIST1 overexpression was determined via lentiviral transduction in human aortic SMCs.RESULTS: Lineage stratification enabled nuanced characterization of aortic root cells. We identified heightened SHF-derived SMC heterogeneity including a subset of Tnnt2-expressing cells distinguished by altered proteoglycan expression. MFS aneurysm-associated SMC phenotypic modulation was identified in both SHF-traced and nontraced (neural crest-derived) SMCs; however, transcriptomic responses were distinct between lineages. SHF-derived modulated SMCs overexpressed collagen synthetic genes and small leucine-rich proteoglycans while nontraced SMCs activated chondrogenic genes. These modulated SMCs clustered focally in the aneurysmal aortic root at the region of SHF/neural crest lineage overlap. Integrated RNA-assay for transposase-accessible chromatin analysis identified enriched Twist1 and Smad2/3/4 complex binding motifs in SHF-derived modulated SMCs. TWIST1 overexpression promoted collagen and SLRP gene expression in vitro, suggesting TWIST1 may drive SHF-enriched collagen synthesis in MFS aneurysm.CONCLUSIONS: SMCs derived from both SHF and neural crest lineages undergo phenotypic modulation in MFS aneurysm but are defined by subtly distinct transcriptional responses. Enhanced TWIST1 transcription factor activity may contribute to enriched collagen synthetic pathways SHF-derived SMCs in MFS.

    View details for DOI 10.1161/ATVBAHA.122.317381

    View details for PubMedID 35861960

  • Controlled Comparison of Simulated Hemodynamics Across Tricuspid and Bicuspid Aortic Valves. Annals of biomedical engineering Kaiser, A. D., Shad, R., Schiavone, N., Hiesinger, W., Marsden, A. L. 2022

    Abstract

    Bicuspid aortic valve is the most common congenital heart defect, affecting 1-2% of the global population. Patients with bicuspid valves frequently develop dilation and aneurysms of the ascending aorta. Both hemodynamic and genetic factors are believed to contribute to dilation, yet the precise mechanism underlying this progression remains under debate. Controlled comparisons of hemodynamics in patients with different forms of bicuspid valve disease are challenging because of confounding factors, and simulations offer the opportunity for direct and systematic comparisons. Using fluid-structure interaction simulations, we simulate flows through multiple aortic valve models in a patient-specific geometry. The aortic geometry is based on a healthy patient with no known aortic or valvular disease, which allows us to isolate the hemodynamic consequences of changes to the valve alone. Four fully-passive, elastic model valves are studied: a tricuspid valve and bicuspid valves with fusion of the left- and right-, right- and non-, and non- and left-coronary cusps. The resulting tricuspid flow is relatively uniform, with little secondary or reverse flow, and little to no pressure gradient across the valve. The bicuspid cases show localized jets of forward flow, excess streamwise momentum, elevated secondary and reverse flow, and clinically significant levels of stenosis. Localized high flow rates correspond to locations of dilation observed in patients, with the location related to which valve cusps are fused. Thus, the simulations support the hypothesis that chronic exposure to high local flow contributes to localized dilation and aneurysm formation.

    View details for DOI 10.1007/s10439-022-02983-4

    View details for PubMedID 35748961

  • Deep Learning Preoperative Risk Stratification. The Annals of thoracic surgery Ouyang, D., Hiesinger, W., Langlotz, C. 2022

    View details for DOI 10.1016/j.athoracsur.2022.05.023

    View details for PubMedID 35661716

  • Improving nutrition practices for postoperative high-risk heart transplant and ventricular assist device implant patients in circulatory compromise: A quality improvement pre- and post-protocol intervention outcome study. Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition Modir, R., Hadhazy, E., Teuteberg, J., Hiesinger, W., Tulu, Z., Hill, C. 2022

    Abstract

    Patients undergoing heart transplant (HT) and ventricular assist device (VAD) implant may experience intra- and postoperative complications requiring high-dose vasopressor agents and/or mechanical circulatory support. These complications increase the risk of nonocclusive bowel ischemia (NOBI) and inadequate enteral nutrition (EN) delivery, and guidance for this high-risk patient population is limited. To optimize nutrition support practices in this patient population at our institution, we created the High-Risk Nutrition Support Protocol (HRNSP) to improve nutrient delivery and promote safer EN practices in the setting of NOBI risk factors after HT and VAD implant.We developed and implemented a nutrition support protocol as a quality improvement (QI) initiative. Data were obtained before (n = 62) and after (n = 52) protocol initiation. We compared nutrition and clinical outcomes between the pre- and post-intervention groups.Fewer calorie deficits (P < 0.001), fewer protein deficits (P < 0.001), a greater proportion of calorie/protein needs met (P < 0.001), zero NOBI cases (0%), and decreased intensive care unit (ICU) length of stay (LOS) (P = 0.005) were observed with 100% (n = 52 of 54) HRNSP implementation success. Increased use of parenteral nutrition did not increase central line-associated bloodstream infections (P = 0.46). There was no difference in hospital LOS (P = 0.44) or 90-day and 1-year mortality (P = 0.56, P = 0.35).This single-center, QI pre- and post-protocol intervention outcome study suggests that implementing and adhering to a nutrition support protocol for VAD implant/HT patients with hemodynamic complications increases nutrient delivery and is associated with reduced ICU LOS and NOBI.

    View details for DOI 10.1002/ncp.10854

    View details for PubMedID 35606342

  • Modeling Effects of Immunosuppressive Drugs on Human Hearts Using Induced Pluripotent Stem Cell-Derived Cardiac Organoids and Single-Cell RNA Sequencing. Circulation Sallam, K., Thomas, D., Gaddam, S., Lopez, N., Beck, A., Beach, L., Rogers, A. J., Zhang, H., Chen, I. Y., Ameen, M., Hiesinger, W., Teuteberg, J. J., Rhee, J. W., Wang, K. C., Sayed, N., Wu, J. C. 2022; 145 (17): 1367-1369

    View details for DOI 10.1161/CIRCULATIONAHA.121.054317

    View details for PubMedID 35467958

  • Keep Your Cool! One Year Outcomes with Use of a Hypothermic Preservation System Compared to Standard Storage with Ice During Heart Procurement Teuteberg, J., Henricksen, E., Khush, K., Kim, D. T., Moayedi, Y., Luikart, H., Wainwright, R., Woo, J. Y., Hiesinger, W., Koyano, T., Shudo, Y. ELSEVIER SCIENCE INC. 2022: S201
  • RVEX: Right Ventricular External Device for Biomimetic Support and Monitoring of the Right Heart ADVANCED MATERIALS TECHNOLOGIES Pirozzi, I., Kight, A., Shad, R. A., Han, A., Dual, S. A., Fong, R., Jia, A., Hiesinger, W., Yock, P., Cutkosky, M. 2022
  • Acute Induced Pressure Overload Rapidly Incites Thoracic Aortic Aneurysmal Smooth Muscle Cell Phenotype. Hypertension (Dallas, Tex. : 1979) Pedroza, A. J., Shad, R., Dalal, A. R., Yokoyama, N., Nakamura, K., Hiesinger, W., Fischbein, M. P. 2022: HYPERTENSIONAHA12118640

    View details for DOI 10.1161/HYPERTENSIONAHA.121.18640

    View details for PubMedID 35124970

  • Twelfth Interagency Registry for Mechanically Assisted Circulatory Support Report: Readmissions after LVAD. The Annals of thoracic surgery Shah, P., Yuzefpolskaya, M., Hickey, G. W., Breathett, K., Wever-Pinzon, O., Khue-Ton, V., Hiesinger, W., Koehl, D., Kirklin, J. K., Cantor, R. S., Jacobs, J. P., Habib, R. H., Pagani, F. D., Goldstein, D. J. 1800

    Abstract

    The twelfth annual report from the Society of Thoracic Surgeons (STS) Interagency Registry for Mechanically Assisted Circulatory Support (Intermacs) highlights outcomes for 26,688 continuous-flow LVAD patients over the past decade (2011-2020). In 2020, we observed the largest drop in yearly LVAD implant volumes since the registry's inception, which reflects the effects of the COVID-19 pandemic on cardiac surgical volumes in the United States. The 2018 heart transplant allocation policy change in the U.S. continues to affect LVAD implantation volumes and device strategy, with 78.1% of patients now implanted as destination therapy. Despite an older and sicker patient cohort, survival in the recent era (2016-2020) at one- and two-years continues to improve at 82.8% and 74.1%. Patient adverse event profile has also improved in the recent era, with significant reductions in stroke, gastrointestinal bleeding, infection, and device malfunction/pump thrombosis. Finally, we review the burden of readmissions after LVAD implant and highlight an opportunity to improve patient outcomes by reducing this frequent and vexing problem.

    View details for DOI 10.1016/j.athoracsur.2021.12.011

    View details for PubMedID 35007505

  • Post-Transplant Extracorporeal Membrane Oxygenation for Severe Primary Graft Dysfunction to Support the Use of Marginal Donor Hearts. Transplant international : official journal of the European Society for Organ Transplantation Shudo, Y., Alassar, A., Wang, H., Lingala, B., He, H., Zhu, Y., Hiesinger, W., MacArthur, J. W., Boyd, J. H., Lee, A. M., Currie, M., Woo, Y. J. 2022; 35: 10176

    Abstract

    Severe primary graft dysfunction (PGD) is the leading cause of early postoperative mortality following orthotopic heart transplantation (OHT). Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) has been used as salvage therapy. This study aimed to evaluate the outcomes in adult OHT recipients who underwent VA-ECMO for severe PGD. We retrospectively reviewed 899 adult (≥18years) patients who underwent primary OHT at our institution between 1997 and 2017. Recipients treated with VA-ECMO (19, 2.1%) exhibited a higher incidence of previous cardiac surgery (p = .0220), chronic obstructive pulmonary disease (p = .0352), and treatment with a calcium channel blocker (p = .0018) and amiodarone (p = .0148). Cardiopulmonary bypass (p = .0410) and aortic cross-clamp times (p = .0477) were longer in the VA-ECMO cohort and they were more likely to have received postoperative transfusion (p = .0013); intra-aortic balloon pump (IABP, p < .0001), and reoperation for bleeding or tamponade (p < .0001). The 30-day, 1-year, and overall survival after transplantation of non-ECMO patients were 95.9, 88.8, and 67.4%, respectively, compared to 73.7, 57.9, and 47.4%, respectively in the ECMO cohort. Fourteen (73.7%) of the ECMO patients were weaned after a median of 7days following OHT (range: 1-12days). Following OHT, VA-ECMO may be a useful salvage therapy for severe PGD and can potentially support the usage of marginal donor hearts.

    View details for DOI 10.3389/ti.2022.10176

    View details for PubMedID 35340846

  • Analysis of the revised heart allocation policy and the influence of increased mechanical circulatory support on survival. The Journal of thoracic and cardiovascular surgery Elde, S., He, H., Lingala, B., Baiocchi, M., Wang, H., Hiesinger, W., MacArthur, J. W., Shudo, Y., Woo, Y. J. 1800

    Abstract

    OBJECTIVES: In 2018, the new United Network for Organ Sharing heart allocation policy took effect. This study evaluated waitlist mortality, mechanical circulatory support utilization, and its influence on posttransplant survival.METHODS: Two 12-month cohorts matched for time of year before and after the policy change were defined by inclusion criteria of first-time transplant recipients aged 18years or older who were listed and underwent transplant during the same era. Student t test and Wilcoxon rank-sum test were used for mean and median differences, respectively. Categorical variables were compared using chi2 or Fisher exact test. Kaplan-Meier curves were used to characterize survival, including time-to-event analysis with the log-rank test. Fine-Gray modeling was used to characterize waitlist mortality. Cox proportional-hazard models were used for multivariate analysis.RESULTS: Waitlist mortality in the new era is significantly improved based on a competing-risks model (Gray test P=.0064). Unadjusted 180-day posttransplant mortality increased from 5.8% during the old era to 8.0% during the new (P=.0134). However, time-to-event analysis showed similar 180-day survival in both eras. After risk adjustment, the hazard ratio for posttransplant 180-day mortality during the new era was 1.18 (95% CI, 0.85-1.64; P=.333). The posttransplant 180-day mortality of the extracorporeal membrane oxygenation bridge-to-transplant subgroup improved from 28.6% in the old era to 8.4% in the new era (P=.0103; log-rank P=.0021). Patients with an intra-aortic balloon pump at the time of transplant had similar 180-day posttransplant mortality between eras (5.4% vs 7.0%; P=.4831).CONCLUSIONS: The United Network for Organ Sharing policy change is associated with reduced waitlist mortality and similar risk adjusted posttransplant 180-day mortality. The new era is also associated with improved 180-day survival in patientsundergoing bridge to transplant with extracorporeal membrane oxygenation.

    View details for DOI 10.1016/j.jtcvs.2021.11.076

    View details for PubMedID 35027214

  • Commentary: Bespoke tricuspid tailoring-bringing patient-specific valve repair to the forgotten valve JTCVS TECHNIQUES Shad, R., Hiesinger, W. 2021; 10: 296-297
  • Commentary: Evidence-based management of infections on patients requiring left ventricular assist device support-a pipe dream? JTCVS open Shad, R., Hiesinger, W. 2021; 8: 412-413

    View details for DOI 10.1016/j.xjon.2021.09.029

    View details for PubMedID 36004170

  • Postcardiotomy shock extracorporeal membrane oxygenation: Peripheral or central? JTCVS open Bowles, C., Hiesinger, W. 2021; 8: 66-69

    View details for DOI 10.1016/j.xjon.2021.10.020

    View details for PubMedID 36004095

  • Commentary: Bespoke tricuspid tailoring-bringing patient-specific valve repair to the forgotten valve. JTCVS techniques Shad, R., Hiesinger, W. 2021; 10: 296-297

    View details for DOI 10.1016/j.xjtc.2021.07.010

    View details for PubMedID 34977741

    View details for PubMedCentralID PMC8690905

  • Designing clinically translatable artificial intelligence systems for high-dimensional medical imaging NATURE MACHINE INTELLIGENCE Shad, R., Cunningham, J. P., Ashley, E. A., Langlotz, C. P., Hiesinger, W. 2021; 3 (11): 929-935
  • A design-based model of the aortic valve for fluid-structure interaction. Biomechanics and modeling in mechanobiology Kaiser, A. D., Shad, R., Hiesinger, W., Marsden, A. L. 2021

    Abstract

    This paper presents a new method for modeling the mechanics of the aortic valve and simulates its interaction with blood. As much as possible, the model construction is based on first principles, but such that the model is consistent with experimental observations. We require that tension in the leaflets must support a pressure, then derive a system of partial differential equations governing its mechanical equilibrium. The solution to these differential equations is referred to as the predicted loaded configuration; it includes the loaded leaflet geometry, fiber orientations and tensions needed to support the prescribed load. From this configuration, we derive a reference configuration and constitutive law. In fluid-structure interaction simulations with the immersed boundary method, the model seals reliably under physiological pressures and opens freely over multiple cardiac cycles. Further, model closure is robust to extreme hypo- and hypertensive pressures. Then, exploiting the unique features of this model construction, we conduct experiments on reference configurations, constitutive laws and gross morphology. These experiments suggest the following conclusions: (1) The loaded geometry, tensions and tangent moduli primarily determine model function. (2) Alterations to the reference configuration have little effect if the predicted loaded configuration is identical. (3) The leaflets must have sufficiently nonlinear material response to function over a variety of pressures. (4) Valve performance is highly sensitive to free edge length and leaflet height. These conclusions suggest appropriate gross morphology and material properties for the design of prosthetic aortic valves. In future studies, our aortic valve modeling framework can be used with patient-specific models of vascular or cardiac flow.

    View details for DOI 10.1007/s10237-021-01516-7

    View details for PubMedID 34549354

  • Extended Static Hypothermic Preservation In Cardiac Transplantation: A Case Report. Transplantation proceedings Guenthart, B. A., Krishnan, A., Koyano, T., La Francessca, S., Chan, J., Alassar, A., Macarthur, J. W., Shudo, Y., Hiesinger, W., Woo, Y. J. 2021

    Abstract

    BACKGROUND: The donor shortage poses a major limitation to use of heart transplantation. Novel strategies such as use of expanded-criteria donors with prolonged ischemia times are being employed to address this need. Recent developments in static hypothermia have allowed for the safe use of cardiac allografts with prolonged ischemic times.CASE REPORT: We present the case of a 68-year-old woman with valvular cardiomyopathy refractory to medical therapy who underwent orthotopic heart transplantation with a cardiac allograft exposed to elevated ischemic times. This was achieved through use of the federally approved SherpaPak Cardiac Transport System for transportation of the allograft. This method of static hypothermic organ preservation allowed for a 330-minute total ischemic time, including 283 minutes of storage within the preservation system. The patient tolerated the procedure well and was discharged on postoperative day 10, with excellent graft function and no evidence of rejection 3 months postoperatively.CONCLUSIONS: Though traditionally ischemic times of 240 minutes or less are recommended for cardiac allografts, we demonstrate, to our knowledge, the longest reported ischemic time of 330 minutes via use of a novel method of static hypothermia for organ preservation. The recipient had an excellent outcome postoperatively, demonstrating the potential for this new organ preservation system to expand the donor pool and improve access and use of heart transplantation.

    View details for DOI 10.1016/j.transproceed.2021.08.021

    View details for PubMedID 34521542

  • Patient-Specific Computational Fluid Dynamics Reveal Localized Flow Patterns Predictive of Post-Left Ventricular Assist Device Aortic Incompetence. Circulation. Heart failure Shad, R., Kaiser, A. D., Kong, S., Fong, R., Quach, N., Bowles, C., Kasinpila, P., Shudo, Y., Teuteberg, J., Woo, Y. J., Marsden, A. L., Hiesinger, W. 2021: CIRCHEARTFAILURE120008034

    Abstract

    BACKGROUND: Progressive aortic valve disease has remained a persistent cause of concern in patients with left ventricular assist devices. Aortic incompetence (AI) is a known predictor of both mortality and readmissions in this patient population and remains a challenging clinical problem.METHODS: Ten left ventricular assist device patients with de novo aortic regurgitation and 19 control left ventricular assist device patients were identified. Three-dimensional models of patients' aortas were created from their computed tomography scans, following which large-scale patient-specific computational fluid dynamics simulations were performed with physiologically accurate boundary conditions using the SimVascular flow solver.RESULTS: The spatial distributions of time-averaged wall shear stress and oscillatory shear index show no significant differences in the aortic root in patients with and without AI (mean difference, 0.67 dyne/cm2 [95% CI, -0.51 to 1.85]; P=0.23). Oscillatory shear index was also not significantly different between both groups of patients (mean difference, 0.03 [95% CI, -0.07 to 0.019]; P=0.22). The localized wall shear stress on the leaflet tips was significantly higher in the AI group than the non-AI group (1.62 versus 1.35 dyne/cm2; mean difference [95% CI, 0.15-0.39]; P<0.001), whereas oscillatory shear index was not significantly different between both groups (95% CI, -0.009 to 0.001; P=0.17).CONCLUSIONS: Computational fluid dynamics serves a unique role in studying the hemodynamic features in left ventricular assist device patients where 4-dimensional magnetic resonance imaging remains unfeasible. Contrary to the widely accepted notions of highly disturbed flow, in this study, we demonstrate that the aortic root is a region of relatively stagnant flow. We further identified localized hemodynamic features in the aortic root that challenge our understanding of how AI develops in this patient population.

    View details for DOI 10.1161/CIRCHEARTFAILURE.120.008034

    View details for PubMedID 34139862

  • Impact of thoracotomy approach on right ventricular failure and length of stay in left ventricular assist device implants: an intermacs registry analysis. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Lampert, B. C., Teuteberg, J. J., Cowger, J., Mokadam, N. A., Cantor, R. S., Benza, R. L., Ganapathi, A. M., Myers, S. L., Hiesinger, W., Woo, J., Pagani, F., Kirklin, J. K., Whitson, B. A. 2021

    Abstract

    INTRODUCTION: Traditionally, implantation of Left Ventricular Assist Devices (LVADs) is performed via median sternotomy. Recently, less invasive thoracotomy approaches are growing in popularity as they involve less surgical trauma, potentially less bleeding, and may preserve right ventricular function. We hypothesized implantation of LVADs via thoracotomy has less perioperative right ventricular failure (RVF) and shorter postoperative length of stay (LOS).METHODS: Continuous flow LVAD implants from Intermacs between February 6, 2014 - December 31, 2018 were identified. Patients implanted via thoracotomy were propensity matched in a 1:1 ratio with patients implanted via sternotomy. Outcomes were compared between sternotomy and thoracotomy approach and by device type (axial, centrifugal-flow with hybrid levitation (CF-HL), centrifugal-flow with full magnetic levitation devices (CF-FML)). The primary outcome was time to first moderate or severe RVF. Secondary outcomes included survival and LOS.RESULTS: Overall 978 thoracotomy patients were matched with 978 sternotomy patients. Over the study period, 242 thoracotomy patients and 219 sternotomy patients developed RVF with no significant difference in time to first moderate to severe RVF by surgical approach overall (p=0.27) or within CF-HL (p=0.36) or CF-FML devices (p=0.25). Survival did not differ by implant technique (150 deaths in thoracotomy group, 154 deaths in sternotomy group; p=0.58). However, sternotomy approach was associated with a significantly shorter LOS (17 Vs 18 days, p=0.009).CONCLUSION: As compared to sternotomy, implantation of continuous flow LVADs via thoracotomy approach does not reduce moderate to severe RVF or improve survival but does reduce post-operative LOS. Device type did not influence outcomes and most centers did a small volume of thoracotomy implants.

    View details for DOI 10.1016/j.healun.2021.05.022

    View details for PubMedID 34229917

  • Computational fluid dynamics simulations to predict false lumen enlargement after surgical repair of Type-A aortic dissection. Seminars in thoracic and cardiovascular surgery Shad, R., Kong, S., Fong, R., Quach, N., Kasinpila, P., Bowles, C., Lee, A., Hiesinger, W. 2021

    Abstract

    We aim to use computational fluid dynamics to investigate the hemodynamic conditions that may predispose to false lumen enlargement in this patient population. Nine patients who received surgical repairs of their type-A aortic dissections between 2017-2018 were retrospectively identified. Multiple contrast-enhanced post-operative CT scans were used to construct 3D models of aortic geometries. Computational fluid dynamics simulations of the models were run on a high-performance computing cluster using SimVascular - an open source simulation package. Physiological pulsatile flow conditions (4.9 L/min) were used at the aortic true lumen inlet, and physiological vascular resistances were applied at the distal vascular ends. Exploratory analyses showed no correlation between rate of false lumen growth and blood pressure, immediate post-op aortic diameter, or the number of fenestrations (p = 0.2). 1-year post-operative CT scans showed a median (IQR) false lumen growth rate of 4.31 (3.66, 14.67) mm/year Median (Interquartile range) peak systolic, mid-diastolic, and late diastolic velocity magnitudes were 0.90 (1.40); 0.10 (0.16); and 0.06 (0.06) cm/s respectively. Spearman's ranked correlations between fenestration velocity and 1-year false lumen growth rates were found to be statistically significant: Velocity magnitude at peak systolic (p = 0.025; rho = 0.75), mid diastolic (p = 0.025; rho = 0.75) and late diastolic phases of the cardiac cycle (p = 0.006; rho = 0.85). We have shown that false lumen growth is strongly correlated to fenestration flow velocity, which has potential implications for post-operative surveillance and risk stratification.

    View details for DOI 10.1053/j.semtcvs.2021.05.012

    View details for PubMedID 34091015

  • The Perfect Candidate? The Stanford Integrated Psychosocial Assessment for Transplant Henricksen, E. J., Stott, K., Ilango, S., Moayedi, Y., Waddell, K., Luikart, H. I., Twiggs, J., Lee, R., Zhang, B. M., Hiesinger, W., Khush, K. K., Teuteberg, J. J. WILEY. 2021: 596
  • Long-term survival in patients with post-LVAD right ventricular failure: multi-state modelling with competing outcomes of heart transplant. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Shad, R., Fong, R., Quach, N., Bowles, C., Kasinpila, P., Li, M., Callon, K., Castro, M., Guha, A., Suarez, E. E., Lee, S., Jovinge, S., Boeve, T., Shudo, Y., Langlotz, C. P., Teuteberg, J., Hiesinger, W. 2021

    Abstract

    BACKGROUND: Multicenter data on long term survival following LVAD implantation that make use of contemporary definitions of RV failure are limited. Furthermore, traditional survival analyses censor patients who receive a bridge to heart transplant. Here we compare the outcomes of LVAD patients who develop post-operative RV failure accounting for the transitional probability of receiving an interim heart transplantation.METHODS: We use a retrospective cohort of LVAD patients sourced from multiple high-volume centers based in the United States. Five- and ten-year survival accounting for transition probabilities of receiving a heart transplant were calculated using a multi-state Aalen Johansen survival model.RESULTS: Of the 897 patients included in the study, 238 (26.5%) developed post-operative RV failure at index hospitalization. At 10 years the probability of death with post-op RV failure was 79.28% vs 61.70% in patients without (HR 2.10; 95% CI 1.72 - 2.57; p=< .001). Though not significant, patients with RV failure were less likely to be bridged to a heart transplant (HR 0.87, p=.4). Once transplanted the risk of death between both patient groups remained equivalent; the probability of death after a heart transplant was 3.97% in those with post-operative RV failure shortly after index LVAD implant, as compared to 14.71% in those without.CONCLUSIONS AND RELEVANCE: Long-term durable mechanical circulatory support is associated with significantly higher mortality in patients who develop post-operative RV failure. Improving outcomes may necessitate expeditious bridge to heart transplant wherever appropriate, along with critical reassessment of organ allocation policies.

    View details for DOI 10.1016/j.healun.2021.05.002

    View details for PubMedID 34167863

  • The Use of Factor Eight Inhibitor Bypass Activity (FEIBA) for the Treatment of Perioperative Hemorrhage in Left Ventricular Assist Device Implantation. Journal of cardiothoracic and vascular anesthesia O'Donnell, C., Rodriguez, A. J., Madhok, J., Sharifi, H., Wang, H., O'Brien, C. G., Boyd, J., Hiesinger, W., Hsu, J., Hill, C. C. 2021

    Abstract

    OBJECTIVE: To test the hypothesis that factor eight inhibitor bypassing activity (FEIBA) can be used to control bleeding following left ventricular assist device (LVAD) implantation without increasing the 14-day composite thrombotic outcome of pump thrombus, ischemic cerebrovascular accidents, pulmonary embolism, and deep venous thrombosis.DESIGN: Retrospective cohort study.SETTING: Academic hospital.PARTICIPANTS: Three hundred nineteen consecutive patients who underwent LVAD implantation (December 1, 2009 to December 30, 2018).INTERVENTION: FEIBA administered to control perioperative hemorrhage.MEASUREMENTS AND MAIN RESULTS: The 82 patients (25.7%) in the FEIBA cohort had more risk factors for perioperative hemorrhage, such as lower preoperative platelet count (169 ± 66 v 194 ± 68 * 103/mL, p = 0.004), prior cardiac surgery (36.6% v 21.9%, p = 0.008), and longer cardiopulmonary bypass (CPB) time (100.3 v 75.2 minutes, p = 0.001) than the 237 controls. After 16.6 units (95% CI: 14.3-18.9) of blood products were given, 992 units (95% CI: 821-1163) of FEIBA were required to control bleeding in the FEIBA cohort. Compared to the controls, there were no differences in the 14-day composite thrombotic outcome (11.0% v 7.6%, p = 0.343) or mortality rate (3.7% v 1.3%, p = 0.179). Multivariate logistical regression identified preoperative international normalized ratio (odds ratio [OR]: 1.30, 95% CI: 1.04-1.62) and CPB time (OR: 1.11, 95% CI: 1.02-1.20) as risk factors for 14-day thrombotic events, but FEIBA usage was not associated with an increased risk.CONCLUSIONS: In this retrospective cohort study, the use of FEIBA (1,000 units, 13 units/kg) to control perioperative hemorrhage following LVAD implantation was not associated with increases in mortality or composite thrombotic outcome.

    View details for DOI 10.1053/j.jvca.2021.04.030

    View details for PubMedID 34034934

  • Very Temporary Mechanical Support Prior to Heart Transplant: Post-Transplant Outcomes as Status 1-2 versus 3-6 in the Setting of Short Wait Times Teuteberg, J., Waddell, K., Henricksen, E., Khush, K., Luikart, H., Resurreccion, C., Marks, P., Packard, H., Woo, J., Jimenez, S., Hiesinger, W. ELSEVIER SCIENCE INC. 2021: S258
  • Longest Storage Period with Static Hypothermic Preservation in Cardiac Transplantation: Initial Experience in the West Coast Guenthart, B. A., Alassar, A., Koyano, T., La Francesca, S., Chan, J. L., Krishnan, A., MacArthur, J. W., Shudo, Y., Hiesinger, W., Woo, Y. ELSEVIER SCIENCE INC. 2021: S471
  • Racial Disparities in Advanced Heart Failure Therapies: Are Outcomes the Correct Metric? Bowles, C., Shad, R., Fong, R., Quach, N., Kasinpila, P., Lingala, B., Zhu, Y., MacArthur, J. W., Shudo, Y., Hiesinger, W. ELSEVIER SCIENCE INC. 2021: S272
  • An Analysis of Driveline Infections with Left Ventricular Assist Devices Utilizing Carbothane versus Pellethane Driveline Sheaths Ravichandran, A. K., Cowger, J. A., Feller, E. D., Mahr, C., Hiesinger, W., Klein, L., Jacoski, M. V., Lampert, B., Moazami, N. ELSEVIER SCIENCE INC. 2021: S434–S435
  • Race by Gender after Mechanical Circulatory Support: Impact on Survival and Adverse Events Teuteberg, J. J., Pamboukian, S., Lee, S., Tatooles, A., Hiesinger, W., Milano, C., McGee, E., Cotts, W. ELSEVIER SCIENCE INC. 2021: S424–S425
  • The Utility of Preoperative Nutrition Screenings and Postoperative Nutrition Protocols in Patients with Ventricular Assist Devices and Heart Transplantation Modir, R., Teuteberg, J., Hiesinger, W., Hadhazy, E., Wei, J., Tulu, Z., Hill, C. ELSEVIER SCIENCE INC. 2021: S289
  • Thoracic Epidural Analgesia Improves Outcomes after Lung Transplant Bowles, C., Keeyapaj, W., Brodt, J., Dhillon, G., Woo, Y. J., Hiesinger, W., MacArthur, J. W. ELSEVIER SCIENCE INC. 2021: S355
  • Predicting post-operative right ventricular failure using video-based deep learning. Nature communications Shad, R., Quach, N., Fong, R., Kasinpila, P., Bowles, C., Castro, M., Guha, A., Suarez, E. E., Jovinge, S., Lee, S., Boeve, T., Amsallem, M., Tang, X., Haddad, F., Shudo, Y., Woo, Y. J., Teuteberg, J., Cunningham, J. P., Langlotz, C. P., Hiesinger, W. 2021; 12 (1): 5192

    Abstract

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

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

    View details for PubMedID 34465780

  • Impact of using higher-risk donor hearts for candidates with pre-transplant mechanical circulatory support. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Han, J., Moayedi, Y., Yang, W., Henricksen, E. J., Lee, R., Purewal, S., Chang, E., Duclos, S., Lyapin, A., Feng, K., Hiesinger, W., Teuteberg, J. J., Khush, K. K. 2021

    Abstract

    We evaluated post-heart transplant (HTx) outcomes after use of higher-risk donor hearts for candidates supported with pre-HTx mechanical circulatory support (MCS).In this retrospective analysis of the national United Network for Organ Sharing registry, a total of 9,915 adult candidates on MCS underwent HTx from January 1, 2010 to March 31, 2019. Multi-organ, re-transplant, and congenital heart disease patients were excluded. Higher-risk donor organs met at least one of the following criteria: left ventricular ejection fraction <50%, donor to recipient predicted heart mass ratio <0.86, donor age >55 years, or ischemic time >4 hours. Primary outcome was 1 year post-transplant survival.Among HTx recipients, 3688 (37.2%) received higher-risk donor hearts. Candidates supported with pre-HTx extracorporeal membrane oxygenation or biventricular assist device (n = 374, 3.8%) who received higher-risk donor hearts had comparable 1 year survival (HR: 1.14, 95% CI: [0.67-1.93], p = 0.64) to recipients of standard-risk donor hearts, when adjusted for recipient age and sex. In candidates supported with intra-aortic balloon pump (n = 1391, 14.6%), transplantation of higher-risk donor hearts did not adversely affect 1 year survival (HR: 0.80, 95% CI: [0.52-1.22], p = 0.30). Patients on durable left ventricular assist devices (LVAD) who received higher-risk donor hearts had comparable 1 year survival to continued LVAD support on the waitlist, but mortality was increased compared to those who received standard-risk donor hearts (HR: 1.37, 95% CI: [1.11-1.70], p = 0.004).Patients requiring pre-HTx temporary MCS who received higher-risk donor hearts had comparable 1 year post-transplant survival to those who received standard-risk donor hearts. Stable patients on durable LVADs may benefit from waiting for standard-risk donor hearts.

    View details for DOI 10.1016/j.healun.2021.09.016

    View details for PubMedID 34815161

  • First lung and kidney multi-organ transplant following COVID-19 Infection. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Guenthart, B. A., Krishnan, A., Alassar, A., Madhok, J., Kakol, M., Miller, S., Cole, S. P., Rao, V. K., Acero, N. M., Hill, C. C., Cheung, C., Jackson, E. C., Feinstein, I., Tsai, A. H., Mooney, J. J., Pham, T., Elliott, I. A., Liou, D. Z., La Francesca, S., Shudo, Y., Hiesinger, W., MacArthur, J. W., Brar, N., Berry, G. J., McCarra, M. B., Desai, T. J., Dhillon, G. S., Woo, Y. J. 2021

    Abstract

    As the world responds to the global crisis of the COVID-19 pandemic an increasing number of patients are experiencing increased morbidity as a result of multi-organ involvement. Of these, a small proportion will progress to end-stage lung disease, become dialysis dependent, or both. Herein, we describe the first reported case of a successful combined lung and kidney transplantation in a patient with COVID-19. Lung transplantation, isolated or combined with other organs, is feasible and should be considered for select patients impacted by this deadly disease.

    View details for DOI 10.1016/j.healun.2021.02.015

    View details for PubMedID 34059432

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

    Abstract

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

    View details for DOI 10.1097/MAT.0000000000001383

    View details for PubMedID 34570726

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

    Abstract

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

    View details for DOI 10.1053/j.semtcvs.2021.01.001

    View details for PubMedID 33444763

  • Single-Cell Transcriptomic Profiling of Vascular Smooth Muscle Cell Phenotype Modulation in Marfan Syndrome Aortic Aneurysm. Arteriosclerosis, thrombosis, and vascular biology Pedroza, A. J., Tashima, Y., Shad, R., Cheng, P., Wirka, R., Churovich, S., Nakamura, K., Yokoyama, N., Cui, J. Z., Iosef, C., Hiesinger, W., Quertermous, T., Fischbein, M. P. 2020: ATVBAHA120314670

    Abstract

    OBJECTIVE: To delineate temporal and spatial dynamics of vascular smooth muscle cell (SMC) transcriptomic changes during aortic aneurysm development in Marfan syndrome (MFS). Approach and Results: We performed single-cell RNA sequencing to study aortic root/ascending aneurysm tissue from Fbn1C1041G/+ (MFS) mice and healthy controls, identifying all aortic cell types. A distinct cluster of transcriptomically modulated SMCs (modSMCs) was identified in adult Fbn1C1041G/+ mouse aortic aneurysm tissue only. Comparison with atherosclerotic aortic data (ApoE-/- mice) revealed similar patterns of SMC modulation but identified an MFS-specific gene signature, including plasminogen activator inhibitor-1 (Serpine1) and Kruppel-like factor 4 (Klf4). We identified 481 differentially expressed genes between modSMC and SMC subsets; functional annotation highlighted extracellular matrix modulation, collagen synthesis, adhesion, and proliferation. Pseudotime trajectory analysis of Fbn1C1041G/+ SMC/modSMC transcriptomes identified genes activated differentially throughout the course of phenotype modulation. While modSMCs were not present in young Fbn1C1041G/+ mouse aortas despite small aortic aneurysm, multiple early modSMCs marker genes were enriched, suggesting activation of phenotype modulation. modSMCs were not found in nondilated adult Fbn1C1041G/+ descending thoracic aortas. Single-cell RNA sequencing from human MFS aortic root aneurysm tissue confirmed analogous SMC modulation in clinical disease. Enhanced expression of TGF (transforming growth factor)-beta-responsive genes correlated with SMC modulation in mouse and human data sets.CONCLUSIONS: Dynamic SMC phenotype modulation promotes extracellular matrix substrate modulation and aortic aneurysm progression in MFS. We characterize the disease-specific signature of modSMCs and provide temporal, transcriptomic context to the current understanding of the role TGF-beta plays in MFS aortopathy. Collectively, single-cell RNA sequencing implicates TGF-beta signaling and Klf4 overexpression as potential upstream drivers of SMC modulation.

    View details for DOI 10.1161/ATVBAHA.120.314670

    View details for PubMedID 32698686

  • Donors after circulatory death heart trial. Future cardiology Shudo, Y., Benjamin-Addy, R., Koyano, T. K., Hiesinger, W., MacArthur, J. W., Woo, Y. J. 2020

    Abstract

    Orthotopic heart transplantation is the gold standard treatment for end-stage heart failure. However, the persistent shortage of available donor organs has resulted in an ever-increasing waitlist and longer waiting periods for transplantation. On the contrary, increasing the number of heart transplants by preserving extended criteria donors and donation after circulatory deathhearts with the Organ Care System (OCS) Heart System has the potential to provide the goldstandard, life-saving treatment to patients with end-stage heart failure. The objective of the Donation After Circulatory Death Heart Trial is to evaluate the effectiveness of the OCS Heart System to preserve and assess hearts donated after circulatory death for transplantation to increase the pool of donor hearts available for transplantation, which can potentially provide patients with end-stage heart failure with the life-saving treatment. Clinical Trial Registration: NCT03831048 (ClinicalTrials.gov).

    View details for DOI 10.2217/fca-2020-0070

    View details for PubMedID 32628044

  • Open-Chest Ablation of Incessant Ventricular Tachycardia During Left Ventricular Assist Device Implantation. JACC. Clinical electrophysiology Shah, R. L., Hiesinger, W., Badhwar, N. 2020; 6 (7): 901–2

    View details for DOI 10.1016/j.jacep.2020.03.012

    View details for PubMedID 32703578

  • Relation of Length of Survival After Orthotopic Heart Transplantation to Age of the Donor. The American journal of cardiology Shudo, Y., Guenther, S. P., Lingala, B., He, H., Hiesinger, W., MacArthur, J. W., Currie, M. E., Lee, A. M., Boyd, J. H., Woo, Y. J. 2020

    Abstract

    We aim to evaluate the impact of donor age on the outcomes in orthotropic heart transplantation recipients. The United Network for Organ Sharing database was queried for adult patients (age; ≥60) underwent first-time orthotropic heart transplantation between 1987 and 2019 (n = 18,447). We stratified the cohort by donor age; 1,702 patients (9.2%) received a heart from a donor age of <17 years; 11,307 patients (61.3%) from a donor age of 17 ≥, < 40; 3,525 patients (19.1%) from a donor age of 40 ≥, < 50); and 1,913 patients (10.4%) from a donor age of ≥50. There was a significant difference in the survival likelihood (p < 0.0001) based on donor's age-based categorized cohort, however, the median survival was 10.5 years in the cohort in whom the donor was <17, 10.3 years in whom the donor was 17 ≥, < 40, 9.4 years in whom the donor was 40 ≥, < 50, and 9.0 years in whom the donor was ≥ 50. Additionally, there was no significant difference in the episode of acute rejection (p = 0.19) nor primary graft failure (p = 0.24). In conclusion, this study demonstrated that patients receiving hearts from the donor age of ≥50 years old showed slight inferior survival likelihood, but appeared to be equivalent median survival.

    View details for DOI 10.1016/j.amjcard.2020.06.036

    View details for PubMedID 32736794

  • More Frequent Hospitalizations and Worse Quality of Life with Late Right Heart Failure Compared to Early Right Heart Failure after Left Ventricular Assist as Destination Therapy Teuteberg, J., Hiesinger, W., Cowger, J. A., Rich, J., Najjar, S. S., Jacoski, M., Markham, D., Rogers, J. ELSEVIER SCIENCE INC. 2020: S91–S92
  • Severe Primary Graft Dysfunction: Impact of the New UNOS Heart Allocation System Han, J., Moayedi, Y., Yang, W., Henricksen, E. J., Lee, R., Purewal, S., Chang, E., Duclos, S., Lyapin, A., Tremblay-Gravel, M., Alexander, K. M., Kawana, M., Hiesinger, W., Teuteberg, J. J., Khush, K. K. ELSEVIER SCIENCE INC. 2020: S173–S174
  • Thoracotomy Approach is Associated with Less Right Ventricular Failure and Shorter Length of Stay: An Intermacs Analysis of Nearly 1000 Implants via Thoracotomy Lampert, B. C., Teuteberg, J. J., Mokadam, N. A., Myers, S., Hiesinger, W., Woo, Y., Kirklin, J. K., Whitson, B. A. ELSEVIER SCIENCE INC. 2020: S121–S122
  • Take the First Available Heart: Use of Higher-Risk Donors in Recipients with Pre-Transplant Mechanical Circulatory Support Han, J., Moayedi, Y., Yang, W., Henricksen, E. J., Lee, R., Purewal, S., Chang, E., Duclos, S., Lyapin, A., Feng, K. Y., Hiesinger, W., Teuteberg, J. J., Khush, K. K. ELSEVIER SCIENCE INC. 2020: S42
  • To SIPAT or Not to SIPAT: The Stanford Integrated Psychosocial Assessment for Transplant Moayedi, Y., Yang, W. A., Mueller, B., Fan, C. S., Purewal, S., Ramirez, N., Han, J., Henricksen, E. J., Lee, R., Duclos, S., Lyapin, A., Wainwright, R., Hiesinger, W., Ross, H. J., Khush, K. K., Teuteberg, J. J. ELSEVIER SCIENCE INC. 2020: S39–S40
  • More Money and More Miles: The Hidden Costs of Donor Procurement with the New Heart Allocation System Lampert, B. C., Ravichandran, A. K., Teuteberg, J. J., Patel, C., Shah, P., Hiesinger, W., Campbell, D. A., Slivnick, J., Hasan, A. K., Salerno, C., Thomas, J., Seasor, E., Schroder, J. N., Ganapathi, A. M., Whitson, B. A., Mokadam, N. A. ELSEVIER SCIENCE INC. 2020: S175
  • Moving towards an Induction-Free Era: Short-Term Renal and Infectious Outcomes Moayedi, Y., Henricksen, E. J., Lafreniere-Roula, M., Fan, C. S., Multani, A., Puing, A., Couture-Cosette, A., Quintero, O., Han, J., Feng, K. Y., Lee, R., Duclos, S., Lyapin, A., Purewal, S., Subramanian, A., Ross, H. J., Hiesinger, W., Khush, K. K., Teuteberg, J. J. ELSEVIER SCIENCE INC. 2020: S274–S275
  • A Decade of Single Center HeartWare (TM) HVAD (TM) Experience Guenther, S. P., Fong, R., Abovwe, N., Shad, R., MacArthur, J. W., Teuteberg, J., Woo, Y., Shudo, Y., Hiesinger, W. ELSEVIER SCIENCE INC. 2020: S339
  • Novel Methods for Donor and Recipient Size Matching in Heart Transplantation Miller, R. J., Hedman, K., Vrotec, B., Ingelsson, E., Heidenreich, P., Hiesinger, W., Oyer, P., Teuteberg, J., Haddad, F. ELSEVIER SCIENCE INC. 2020: S50
  • Use of direct oral anticoagulants after heart transplantation. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Henricksen, E. J., Tremblay-Gravel, M., Moayedi, Y., Yang, W., Lee, R., Ross, H. J., Hiesinger, W., Teuteberg, J. J., Khush, K. K. 2020

    View details for DOI 10.1016/j.healun.2019.12.007

    View details for PubMedID 32007373

  • Impact of Surgical Approach in Double Lung Transplantation: Median Sternotomy vs Clamshell Thoracotomy. Transplantation proceedings Shudo, Y. n., Rinewalt, D. n., Lingala, B. n., Kim, F. Y., He, H. n., Boyd, J. H., Lee, A. M., Hiesinger, W. n., Currie, M. E., MacArthur, J. W., Woo, Y. J. 2020

    Abstract

    Double lung transplantation (DLT) remains the gold standard for end-stage lung disease. Although DLT was historically performed via clamshell thoracotomy, recently the median sternotomy has emerged as a viable alternative. As the ideal surgical approach remains unclear, the aim of our study was to compare the short- and long-term outcomes of these 2 surgical approaches in DLT.We retrospectively reviewed 192 consecutive adult patients who underwent primary DLT at our institution between 2012 and 2017 (sternotomy, n = 147; clamshell, n = 45). The impact of each surgical approach on post-transplant morbidity was investigated, and the overall survival probability analyses were performed.There were no significant differences in recipients' baseline and donors' characteristics and bilateral allograft ischemic time. Freedom from primary graft dysfunction, acute rejection episodes, postoperative prolonged ventilator support, tracheostomy, postoperative stroke, and airway dehiscence were comparable between these 2 groups. The duration of cardiopulmonary bypass and operative time were significantly longer in the clamshell thoracotomy group. Postoperative extracorporeal membrane oxygenation usage tended to be more frequent in the clamshell thoracotomy group than the median sternotomy group, despite no statistical significance. Length of hospital and intensive care unit stay were not influenced by the type of incision. There was no significant difference in overall survival between these 2 procedure groups (P = .61, log-rank test).The median sternotomy approach in DLT decreases operative time and more importantly leads to a shorter duration of cardiopulmonary bypass. The type of surgical approach did not show any statistically significant impact on adult DLT recipients' morbidity and survival.

    View details for DOI 10.1016/j.transproceed.2019.10.018

    View details for PubMedID 31911057

  • Use of patient-specific computational models for optimization of aortic insufficiency after implantation of left ventricular assist device. The Journal of thoracic and cardiovascular surgery Kasinpila, P. n., Kong, S. n., Fong, R. n., Shad, R. n., Kaiser, A. D., Marsden, A. L., Woo, Y. J., Hiesinger, W. n. 2020

    Abstract

    Aortic incompetence (AI) is observed to be accelerated in the continuous-flow left ventricular assist device (LVAD) population and is related to increased mortality. Using computational fluid dynamics (CFD), we investigated the hemodynamic conditions related to the orientation of the LVAD outflow in these patients.We identified 10 patients with new aortic regurgitation, and 20 who did not, after LVAD implantation between 2009 and 2018. Three-dimensional models of patients' aortas were created from their computed tomography scans. The geometry of the LVAD outflow graft in relation to the aorta was quantified using azimuth angles (AA), polar angles (PAs), and distance from aortic root. The models were used to run CFD simulations, which calculated the pressures and wall shear stress (rWSS) exerted on the aortic root.The AA and PA were found to be similar. However, for combinations of high values of AA and low values of PA, there were no patients with AI. The distance from aortic root to the outflow graft was also smaller in patients who developed AI (3.39 ± 0.7 vs 4.07 ± 0.77 cm, P = .04). There was no significant difference in aortic root pressures in the 2 groups. The rWSS was greater in AI patients (4.60 ± 5.70 vs 2.37 ± 1.20 dyne/cm2, P < .001). Qualitatively, we observed a trend of greater perturbations, regions of high rWSS, and flow eddies in the AI group.Using CFD simulations, we demonstrated that patients who developed de novo AI have greater rWSS at the aortic root, and their outflow grafts were placed closer to the aortic roots than those patients without de novo AI.

    View details for DOI 10.1016/j.jtcvs.2020.04.164

    View details for PubMedID 32653292

  • Type A Aortic Dissection-Experience Over 5 Decades: JACC Historical Breakthroughs in Perspective. Journal of the American College of Cardiology Zhu, Y. n., Lingala, B. n., Baiocchi, M. n., Tao, J. J., Toro Arana, V. n., Khoo, J. W., Williams, K. M., Traboulsi, A. A., Hammond, H. C., Lee, A. M., Hiesinger, W. n., Boyd, J. n., Oyer, P. E., Stinson, E. B., Reitz, B. A., Mitchell, R. S., Miller, D. C., Fischbein, M. P., Woo, Y. J. 2020; 76 (14): 1703–13

    Abstract

    The Stanford classification of aortic dissection was described in 1970. The classification proposed that type A aortic dissection should be surgically repaired immediately, whereas type B aortic dissection can be treated medically. Since then, diagnostic tools and management of acute type A aortic dissection (ATAAD) have undergone substantial evolution. This paper evaluated historical changes of ATAAD repair at Stanford University since the establishment of the aortic dissection classification 50 years ago. The surgical approaches to the proximal and distal extent of the aorta, cerebral perfusion methods, and cannulation strategies were reviewed. Additional analyses using patients who underwent ATAAD repair at Stanford University from 1967 through December 2019 were performed to further illustrate the Stanford experience in the management of ATAAD. While technical complexity increased over time, post-operative survival continued to improve. Further investigation is warranted to delineate factors associated with the improved outcomes observed in this study.

    View details for DOI 10.1016/j.jacc.2020.07.061

    View details for PubMedID 33004136

  • OUTCOMES OF PATIENTS WITH INFECTION RELATED TO VENTRICULAR ASSIST DEVICE AFTER HEART TRANSPLANTATION Moayedi, Y., Multani, A., Bunce, P., Tremblay-Gravel, M., Gomez, C., Garvert, D., Duclos, S., Hiesinger, W., Ross, H., Khush, K., Montoya, J., Teuteberg, J. WILEY. 2019: 55
  • "Cheese Wire" Fenestration of Dissection Intimal Flap to Facilitate Thoracic Endovascular Aortic Repair in Chronic Dissection. Journal of vascular and interventional radiology : JVIR Iwakoshi, S., Watkins, C. A., Ogawa, Y., Fischbein, M., Lee, A., Lee, J. T., Hiesinger, W., Dake, M. D. 2019

    Abstract

    Thoracic endovascular aortic repair (TEVAR) for aneurysmal chronic dissection is often complicated by retrograde filling of the false lumen and dissected distal landing zone. A "cheese wire"-style fenestration of the dissection intimal flap can create a landing zone facilitating TEVAR. This technique successfully aided TEVAR in 3 patients with an average age of 57.3 years. Complications included type III endoleak requiring relining and renal artery occlusion requiring stent placement. Average duration of clinical follow-up was 19 ± 4 months. Imaging follow-up was 8 ± 10 months. All patients have survived for more than 1 year without aneurysm enlargement.

    View details for DOI 10.1016/j.jvir.2019.06.004

    View details for PubMedID 31542270

  • Outcomes of patients with infection related to a ventricular assist device after Heart Transplantation. Clinical transplantation Moayedi, Y., Multani, A., Bunce, P. E., Henricksen, E., Lee, R., Yang, W., Gomez, C. A., Garvert, D. W., Tremblay-Gravel, M., Duclos, S., Hiesinger, W., Ross, H. J., Khush, K. K., Montoya, J. G., Teuteberg, J. J. 2019: e13692

    Abstract

    BACKGROUND: Despite significant advances in durable mechanical support survival, infectious complications remain the most common adverse event after ventricular assist device (VAD) implantation and the leading cause of early death after transplantation. In this study, we aim to describe our local infectious epidemiology and review short term survival and infectious incidence rates in the post transplantation period and assess risk factors for infectious episodes after transplantation.METHODS: Retrospective single-center study of all consecutive adult heart transplant patients from 2008-2017. Survival data was estimated and summarized using the Kaplan-Meier method. We quantified and evaluated the difference in the incidence rate between patients with and without infection using a Fine-Gray model. The outcome of interest is the time to first infection diagnosis with post-transplant death as the competing event.RESULTS: Among 282 heart transplantations, 74 (26.5%) underwent LVAD implantation. Twenty-one patients (28.3%) developed an infection while supported by an LVAD. When compared to patients supported by an LVAD without a preceding infection, BMI was significantly greater (31.2 vs. 27.8 kg/m2, p=0.03). Median follow-up post transplantation was 3.01 years. Significant risk factors for the competing risk regression for infection after heart transplantation include LVAD infection (HR 1.94, [95% CI] 1.11-3.39, p=0.020) and recipient COPD (HR 2.14, [95% CI] 1.39-3.32, p=0.001) when adjusted for recipient age, gender, hypertension, diabetes mellitus and body mass index.CONCLUSIONS: Patients with LVAD-related infection had a significantly increased risk of infectious complications after heart transplantation. Further research on the avoidance of induction agents and reduced maintenance immunosuppression in this patient population is warranted This article is protected by copyright. All rights reserved.

    View details for DOI 10.1111/ctr.13692

    View details for PubMedID 31403741

  • A modified implantation technique for temporary right ventricular assist device: Enabling ambulation and less invasive decannulation. Journal of cardiac surgery Rinewalt, D., Shudo, Y., MacArthur, J. W., Woo, Y. J., Hiesinger, W. 2019

    Abstract

    This report describes our unique temporary right ventricular assist device (RVAD) implantation technique, which enables early mobilization even during biventricular support and subsequent less invasive RVAD removal without needing resternotomy upon recovery.

    View details for DOI 10.1111/jocs.14193

    View details for PubMedID 31389624

  • Risk of reoperative valve surgery for endocarditis associated with drug use. The Journal of thoracic and cardiovascular surgery Mori, M., Bin Mahmood, S. U., Schranz, A. J., Sultan, I., Axtell, A. L., Sarsour, N., Hiesinger, W., Boskovski, M. T., Hirji, S., Kaneko, T., Woo, J., Tang, P., Jassar, A. S., Atluri, P., Whitson, B. A., Gleason, T., Geirsson, A. 2019

    Abstract

    BACKGROUND: We aimed to quantify incidence and operative risks associated with reoperative valve surgeries (RVS) in patients with drug-associated infective endocarditis in a multi-center setting.METHODS: We formed a registry of patients with drug-associated infective endocarditis who underwent valve surgeries at 8 US centers between 2011 and 2017. Outcomes of first-time valve surgery (FVS) and RVS were compared. Multivariable logistic regression models related RVS to 30-day mortality. Poisson regression models were fitted to evaluate temporal trends in overall case volume and proportions of patients undergoing RVS.RESULTS: The cohort consisted of 925 patients with drug-associated infective endocarditis who underwent a valve surgery, of which 652 were FVS and 273 were RVS. Patients undergoing FVS had fewer comorbidities than those undergoing RVS. Overall case volume increased from 108 in 2012 to 229 cases in 2017 (P<.001). The proportion of redo valve cases increased from 19% in 2012 to 28% in 2017 (P<.001). The 30-day mortality in RVS was higher compared with FVS (8.1% vs 4.8%; P=.049). An increase in unadjusted mortality rates were observed as the number of prior cardiac surgeries increased, from 4.8% in FVS to 11.8% in ≥3 RVS. Multivariable model demonstrated that RVS was associated with an increased risk of 30-day mortality (odds ratio, 2.22; 95% confidence interval, 1.22-4.06; P=.010).CONCLUSIONS: An increasing proportion of valve surgery for drug-associated infective endocarditis is for RVS. Despite being young and harboring few comorbidities, the RVS cohort is still susceptible to increased risk of 30-day mortality compared with those undergoing FVS.

    View details for DOI 10.1016/j.jtcvs.2019.06.055

    View details for PubMedID 31420136

  • Predicting Transfusions During Left Ventricular Assist Device Implant: Peri-Operative Transfusions with LVAD Implantation. Seminars in thoracic and cardiovascular surgery Miller, R. J., Gregory, A. J., Kent, W., Banerjee, D., Hiesinger, W., Clarke, B. 2019

    Abstract

    OBJECTIVE: Perioperative bleeding and transfusion cause morbidity and mortality in patients receiving left ventricular assist devices (LVADs). We assessed factors associated with transfusions within 30 days of durable LVAD implantation and the clinical outcomes associated with transfusions.METHODS: A retrospective cohort study of patients undergoing initial durable LVAD implantation between 2014 and 2016 was performed. Rates of packed red blood cell (PRBC) or other blood product transfusions (platelets or fresh frozen plasma [FFP]) were asssessed. Ordinal multivariable regression analysis was performed to determine factors independently associated with transfusion.RESULTS: Analysis included 156 patients, mean age 54.6 years and 74.4% male, who received a mean of 11.7 units of PRBC and 10.0 units of other products within 30-days. Pre-implant mechanical ventilation, dialysis, higher INR, previous sternotomy, higher model for end-stage liver disease score and lower hemoglobin were associated with increased PRBC transfusion rates. Higher pre-operative central venous pressure (CVP), mechanical ventilation, concomitant surgical procedures, previous sternotomy, and lower hemoglobin were associated with increased PRBC transfusion rates within 48 hours of implant (adjusted OR 1.46, p=0.013 per 5mmHg). There were no significant associations with ferritin (adjusted OR 1.00, p=0.236) or transferrin saturation (adjusted OR 1.17, p=0.068) . Transfusions were associated with an increase in ventilation duration, intensive care unit length of stay, re-operation for bleeding and all-cause mortality.CONCLUSIONS: In patients undergoing LVAD implantation, peri-operative blood product exposure is common and associated with increased morbidity and mortality. Elevated CVP and anemia are potentially modifiable factors associated with increased early PRBC transfusion rates.

    View details for DOI 10.1053/j.semtcvs.2019.05.015

    View details for PubMedID 31128255

  • Comprehensive Analysis of Differential Expressed Genes Related with Myocardial Reverse Remodeling Following HeartWare Ventricular Assist Device Implantation Shudo, Y., Jaatinen, K. J., NIshiga, M., Chen, I. Y., Greene, C. L., Koyano, T. K., Fong, R. W., Boyd, J. H., Lee, A. M., Hiesinger, W., Woo, J. ELSEVIER SCIENCE INC. 2019: S244
  • Impact of Concomitant Valvular Surgery on Patients Undergoing LVAD Implantation Mulumba, K. Y., Kasinpila, P., Fong, R., Kong, S., Hecker, L., Nissan, R., Banerjee, D., Teuteberg, J., Shudo, Y., Woo, Y., Hiesinger, W. ELSEVIER SCIENCE INC. 2019: S72–S73
  • Improving Nutrition Practices for Critically Ill Postoperative Heart Transplant and Ventricular Assist Device Implant Patients Modir, R., Rao, V., Teuteberg, J., Banerjee, D., Oyer, P., Tulu, Z., Hadhazy, E., Hiesinger, W., Jimenez, S., Tu, L., Hill, C. ELSEVIER SCIENCE INC. 2019: S217
  • The Gift That Keeps on Giving? The Impact of Donor Coronary Atherosclerosis on the Development of Coronary Allograft Vasculopathy by IVUS Moayedi, Y., Fan, C. S., Miller, R. J., Tremblay-Gravel, M., Kawana, M., Luikart, H. I., D'Emilio, N., Gordon, J., Parizo, J. T., Oro, G., Wainwright, R., Hiesinger, W., Manlhiot, C., Ross, H. J., Khush, K. K., Teuteberg, J. J. ELSEVIER SCIENCE INC. 2019: S218–S219
  • Directly to a DOAC? Safety of Alternatives to Warfarin for Anticoagulation in Heart Transplantation Tremblay-Gravel, M., Alexander, K. M., Czobor, P., Lee, R., Foroutan, F., Yang, W. A., Hayes, A., Hiesinger, W., Ross, H. J., Khush, K. K., Teuteberg, J. J., Moayedi, Y. ELSEVIER SCIENCE INC. 2019: S389
  • Contemporary Use of Glycoprotein IIb/IIIa Inhibitors in Patients with Left Ventricular Assist Devices Duclos, S., Matsuda, K., Jimenez, S., Wheeler, M., Sallam, K., Hiesinger, W., Banerjee, D. ELSEVIER SCIENCE INC. 2019: S423–S424
  • Impact of Surgical Approach in Double Lung Transplantation: Median Sternotomy Decreases Operative and Cardiopulmonary Bypass Time Compared to Clamshell Thoracotomy Shudo, Y., Rinewalt, D., Lingala, B., Kim, F. Y., He, H., Boyd, J. H., Lee, A. M., Hiesinger, W., Currie, M. E., MacArthur, J. W., Woo, J. ELSEVIER SCIENCE INC. 2019: S414
  • Evaluation of Risk Factors for Heart-Lung Transplant Recipient Outcome: An Analysis of the United Network for Organ Sharing Database. Circulation Shudo, Y. n., Wang, H. n., Lingala, B. n., He, H. n., Kim, F. Y., Hiesinger, W. n., Lee, A. M., Boyd, J. H., Currie, M. n., Woo, Y. J. 2019; 140 (15): 1261–72

    Abstract

    Heart-lung transplantation (HLTx) is an effective treatment for patients with advanced cardiopulmonary failure. However, no large multicenter study has focused on the relationship between donor and recipient risk factors and post-HLTx outcomes. Thus, we investigated this issue using data from the United Network for Organ Sharing database.All adult patients (age ≥18 years) registered in the United Network for Organ Sharing database who underwent HLTx between 1987 and 2017 were included (n=997). We stratified the cohort by patients who were alive without retransplant at 1 year (n=664) and patients who died or underwent retransplant within 1 year of HLTx (n=333). The primary outcome was the influence of donor and recipient characteristics on 1-year post-HLTx recipient death or retransplant. Kaplan-Meier curves were created to assess overall freedom from death or retransplant. To obtain a better effect estimation on hazard and survival time, the parametric Accelerated Failure Time model was chosen to perform time-to-event modeling analyses.Overall graft survival at 1-year post-HLTx was 66.6%. Of donors, 53% were male, and the mean age was 28.2 years. Univariable analysis showed advanced donor age, recipient male sex, recipient creatinine, recipient history of prior cardiac or lung surgery, recipient extracorporeal membrane oxygenation support, transplant year, and transplant center volume were associated with 1-year post-HLTx death or retransplant. On multivariable analysis, advanced donor age (hazard ratio [HR], 1.017; P=0.0007), recipient male sex (HR, 1.701; P=0.0002), recipient extracorporeal membrane oxygenation support (HR, 4.854; P<0.0001), transplant year (HR, 0.962; P<0.0001), and transplantation at low-volume (HR, 1.694) and medium-volume centers (HR, 1.455) in comparison with high-volume centers (P=0.0007) remained as significant predictors of death or retransplant. These predictors were incorporated into an equation capable of estimating the preliminary probability of graft survival at 1-year post-HLTx on the basis of preoperative factors alone.HLTx outcomes may be improved by considering the strong influence of donor age, recipient sex, recipient hemodynamic status, and transplant center volume. Marginal donors and recipients without significant factors contributing to poor post-HLTx outcomes may still be considered for transplantation, potentially with less impact on the risk of early postoperative death or retransplant.

    View details for DOI 10.1161/CIRCULATIONAHA.119.040682

    View details for PubMedID 31589491

  • Successful Repair of Type A Aortic Dissection in an Octogenarian With Double Aortic Arch. The Annals of thoracic surgery Zeigler, S. M., Hiesinger, W. 2019; 107 (1): e19–e21

    Abstract

    An 80-year-old woman was transferred to our institution with a subacute type A aortic dissection and a previously undiagnosed double aortic arch. The patient underwent successful repair with aortic valve resuspension, ascending aortic replacement, and repair of the proximal right-sided arch. This is the first reported case of a type A dissection associated with a double aortic arch in the United States.

    View details for PubMedID 30558737

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

    Abstract

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

    View details for DOI 10.1097/MAT.0000000000001016

    View details for PubMedID 31192848

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

    Abstract

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

    View details for PubMedID 30539717

  • Planned Concomitant Left and Right Ventricular Assist Device Insertion to Avoid Long-term Biventricular Mechanical Support: Bridge to Right Ventricular Recovery. The heart surgery forum Salna, M., Shudo, Y., Teuteberg, J. J., Banerjee, D., Ha, R. V., Woo, Y. J., Hiesinger, W. 2018; 21 (5): E412–E414

    Abstract

    INTRODUCTION: The planned use of a temporary right ventricular assist device (RVAD) at the time of left ventricular assist device (LVAD) implantation may prevent the need for a permanent biventricular assist device (BiVAD). Herein we describe our RVAD weaning protocol that was effectively employed in 4 patients to prevent the need for permanent BiVAD.METHODS: Four patients in refractory cardiogenic shock underwent planned RVAD insertion during LVAD implantation due to severely depressed right ventricular function with dilation preoperatively. A standardized RVAD weaning protocol was employed in these 4 patients in preparation for decannulation.RESULTS: Temporary RVADs were successfully placed in all 4 patients at the time of LVAD implantation. All patients survived to RVAD decannulation and discharge and were alive at the time of most recent follow-up (range, 528-742 days post-RVAD decannulation).CONCLUSION: Planned implantation of a temporary RVAD in high risk patients may avoid the need for biventricular mechanical support in the future.

    View details for PubMedID 30311895

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

    Abstract

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

    View details for PubMedID 30482529

  • Transplant Outcomes in Destination Therapy vs Bridge to Transplant LVAD Patients Miller, R. J., Moyaedi, Y., Sharma, A., Zarafshar, S., Varr, B., Haddad, F., Hiesinger, W., Banerjee, D. ELSEVIER SCIENCE INC. 2018: S434–S435
  • RIGHT VENTRICULAR LOAD ADAPTABILITY IN PATIENTS UNDERGOING CONTINUOUS-FLOW LEFT VENTRICULAR ASSIST DEVICE IMPLANTATION Amsallem, M., Aymami, M., Hiesinger, W., Zeigler, S., Moneghetti, K., Marques, M., Wheeler, M., Teuteberg, J., Ha, R., Banerjee, D., Haddad, F. ELSEVIER SCIENCE INC. 2018: 1624
  • Prolonged veno-arterial extracorporeal life support for cardiac failure. The International journal of artificial organs Guenther, S. P., Shudo, Y. n., Hiesinger, W. n., Banerjee, D. n. 2018: 391398818777359

    Abstract

    In intractable cardiogenic shock, extracorporeal life support frequently is the last treatment option. Outcomes of prolonged veno-arterial extracorporeal life support for cardiac failure are poorly defined.We retrospectively analyzed 10 patients (4 females, age = 36 ± 16 years) who underwent prolonged extracorporeal life support (≥7 days) from December 2015 to March 2017 for cardiogenic shock. The primary endpoint was survival to hospital discharge.Etiologies included ischemic cardiomyopathy with non ST-segment elevation myocardial infarction (n = 1), dilated (n = 3), hypertrophic (n = 1), postpartum cardiomyopathy (n = 1), and others (n = 4). Heart failure was left or biventricular in 80.0% (left ventricular ejection fraction = 15.6 ± 5.5%). Among the 10 patients, 80.0% underwent femoral and 20.0% central cannulation, 40.0% required changes in the cannulation strategy, and 80.0% underwent left ventricular venting. No technical malfunctions occurred, but 50.0% required circuit exchanges for thrombus formation. 80.0% suffered from infections. 60.0% could be decannulated after 717 ± 830 (168-2301) h of support, and survival to hospital discharge was 40.0%. Longest follow-up available is 160 ± 175 (12-409) days after discharge, with 30.0% alive and in satisfying functional condition.Prolonged veno-arterial extracorporeal life support for cardiac failure is feasible with low technical complication rates. Survival rates are acceptable, yet inferior to short-term support. We observed a shift from initial shock-related complications to infections during prolonged support. Since recovery and thus weaning is rather unlikely after a prolonged need for extracorporeal life support, this form of support should be limited to centers offering the full spectrum of interdisciplinary cardiac care including ventricular assist device implantation and transplantation.

    View details for PubMedID 29896993

  • Injectable Bioengineered Hydrogel Therapy in the Treatment of Ischemic Cardiomyopathy. Current treatment options in cardiovascular medicine MacArthur, J. W., Steele, A. N., Goldstone, A. B., Cohen, J. E., Hiesinger, W., Woo, Y. J. 2017; 19 (4): 30-?

    Abstract

    Over the past two decades, the field of cardiovascular medicine has seen the rapid development of multiple different modalities for the treatment of ischemic myocardial disease. Most research efforts have focused on strategies aimed at coronary revascularization, with significant technological advances made in percutaneous coronary interventions as well as coronary artery bypass graft surgery. However, recent research efforts have shifted towards ways to address the downstream effects of myocardial infarction on both cellular and molecular levels. To this end, the broad application of injectable hydrogel therapy after myocardial infarction has stimulated tremendous interest. In this article, we will review what hydrogels are, how they can be bioengineered in unique ways to optimize therapeutic potential, and how they can be used as part of a treatment strategy after myocardial infarction.

    View details for DOI 10.1007/s11936-017-0530-x

    View details for PubMedID 28337717

  • Operative technique and pitfalls in donor heart procurement. Asian cardiovascular & thoracic annals Shudo, Y., Hiesinger, W., Oyer, P. E., Woo, Y. J. 2017; 25 (1): 80-82

    Abstract

    We describe a simple and reproducible donor heart procurement technique in sequential steps. A detailed understanding of procurement and organ preservation techniques should be an essential part of a heart transplant training program.

    View details for DOI 10.1177/0218492316678716

    View details for PubMedID 28074702

  • An innovative biologic system for photon-powered myocardium in the ischemic heart. Science advances Cohen, J. E., Goldstone, A. B., Paulsen, M. J., Shudo, Y. n., Steele, A. N., Edwards, B. B., Patel, J. B., MacArthur, J. W., Hopkins, M. S., Burnett, C. E., Jaatinen, K. J., Thakore, A. D., Farry, J. M., Truong, V. N., Bourdillon, A. T., Stapleton, L. M., Eskandari, A. n., Fairman, A. S., Hiesinger, W. n., Esipova, T. V., Patrick, W. L., Ji, K. n., Shizuru, J. A., Woo, Y. J. 2017; 3 (6): e1603078

    Abstract

    Coronary artery disease is one of the most common causes of death and disability, afflicting more than 15 million Americans. Although pharmacological advances and revascularization techniques have decreased mortality, many survivors will eventually succumb to heart failure secondary to the residual microvascular perfusion deficit that remains after revascularization. We present a novel system that rescues the myocardium from acute ischemia, using photosynthesis through intramyocardial delivery of the cyanobacterium Synechococcus elongatus. By using light rather than blood flow as a source of energy, photosynthetic therapy increases tissue oxygenation, maintains myocardial metabolism, and yields durable improvements in cardiac function during and after induction of ischemia. By circumventing blood flow entirely to provide tissue with oxygen and nutrients, this system has the potential to create a paradigm shift in the way ischemic heart disease is treated.

    View details for PubMedID 28630913

  • Biochemically engineered stromal cell-derived factor 1-alpha analog increases perfusion in the ischemic hind limb. Journal of vascular surgery Edwards, B. B., Fairman, A. S., Cohen, J. E., Macarthur, J. W., Goldstone, A. B., Woo, J. B., Hiesinger, W., Woo, Y. J. 2016; 64 (4): 1093-1099

    Abstract

    Despite promising therapeutic innovation over the last decade, peripheral arterial disease remains a prevalent morbidity, as many patients are still challenged with peripheral ischemia. We hypothesized that delivery of engineered stromal cell-derived factor 1-alpha (ESA) in an ischemic hind limb will yield significant improvement in perfusion.Male rats underwent right femoral artery ligation, and animals were randomized to receive a 100 μL injection of saline (n = 9) or 6 μg/kg dosage of equal volume of ESA (n = 12) into the ipsilateral quadriceps muscle. Both groups of animals were also given an intraperitoneal injection of 40 μg/kg of granulocyte macrophage colony-stimulating factor (GMCSF). Perfusion was quantified using a laser Doppler imaging device preoperatively, and on postoperative days 0, 7, and 14. Immunohistochemistry was performed to quantify angiogenesis on day 14, and an mRNA profile was evaluated for angiogenic and inflammatory markers.Compared with the saline/GMCSF group at day 14, the ESA/GMCSF-injected animals had greater reperfusion ratios (Saline/GMCSF, 0.600 ± 0.140 vs ESA/GMCSF, 0.900 ± 0.181; group effect P = .006; time effect P < .0001; group×time effect P < .0001), elevated capillary density (10×; Saline/GMCSF, 6.40 ± 2.01 vs ESA/GMCSF, 18.55 ± 5.30; P < .01), and increased mRNA levels of vascular endothelial growth factor-A (Saline/GMCSF [n = 6], 0.298 ± 0.205 vs ESA/GMCSF [n = 8], 0.456 ± 0.139; P = .03).Delivery of ESA significantly improves perfusion in a rat model of peripheral arterial disease via improved neovasculogenesis, a finding which may prove beneficial in the treatment strategy for this debilitating disease.

    View details for DOI 10.1016/j.jvs.2015.06.140

    View details for PubMedID 26372192

  • Cell transplantation in heart failure: where do we stand in 2016? EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY MacArthur, J. W., Goldstone, A. B., Cohen, J. E., Hiesinger, W., Woo, Y. 2016; 50 (3): 396–99

    View details for PubMedID 27587719

  • Hybrid coronary revascularization: Ready for prime time, but who should star? JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Hiesinger, W., Atluri, P. 2016; 151 (4): 1090–91

    View details for DOI 10.1016/j.jtcvs.2015.12.015

    View details for Web of Science ID 000372436900056

    View details for PubMedID 26809426

  • Building a better bridge: Remodeling, recovery, and a better understanding of the biologic foundation of mechanical circulatory support JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Hiesinger, W., Atluri, P. 2015; 150 (5): 1342–43

    View details for DOI 10.1016/j.jtcvs.2015.09.042

    View details for Web of Science ID 000365038900062

    View details for PubMedID 26546204

  • A Tissue-Engineered Chondrocyte Cell Sheet Induces Extracellular Matrix Modification to Enhance Ventricular Biomechanics and Attenuate Myocardial Stiffness in Ischemic Cardiomyopathy TISSUE ENGINEERING PART A Shudo, Y., Cohen, J. E., MacArthur, J. W., Goldstone, A. B., Otsuru, S., Trubelja, A., Patel, J., Edwards, B. B., Hung, G., Fairman, A. S., Brusalis, C., Hiesinger, W., Atluri, P., Hiraoka, A., Miyagawa, S., Sawa, Y., Woo, Y. J. 2015; 21 (19-20): 2515-2525

    Abstract

    There exists a substantial body of work describing cardiac support devices to mechanically support the left ventricle (LV); however, these devices lack biological effects. To remedy this, we implemented a cell sheet engineering approach utilizing chondrocytes, which in their natural environment produce a relatively elastic extracellular matrix (ECM) for a cushioning effect. Therefore, we hypothesized that a chondrocyte cell sheet applied to infarcted and borderzone myocardium will biologically enhance the ventricular ECM and increase elasticity to augment cardiac function in a model of ischemic cardiomyopathy (ICM). Primary articular cartilage chondrocytes of Wistar rats were isolated and cultured on temperature-responsive culture dishes to generate cell sheets. A rodent ICM model was created by ligating the left anterior descending coronary artery. Rats were divided into two groups: cell sheet transplantation (1.0 × 10(7) cells/dish) and no treatment. The cell sheet was placed onto the surface of the heart covering the infarct and borderzone areas. At 4 weeks following treatment, the decreased fibrotic extension and increased elastic microfiber networks in the infarct and borderzone areas correlated with this technology's potential to stimulate ECM formation. The enhanced ventricular elasticity was further confirmed by the axial stretch test, which revealed that the cell sheet tended to attenuate tensile modulus, a parameter of stiffness. This translated to increased wall thickness in the infarct area, decreased LV volume, wall stress, mass, and improvement of LV function. Thus, the chondrocyte cell sheet strengthens the ventricular biomechanical properties by inducing the formation of elastic microfiber networks in ICM, resulting in attenuated myocardial stiffness and improved myocardial function.

    View details for DOI 10.1089/ten.tea.2014.0155

    View details for PubMedID 26154752

  • A "Repair-All" Strategy for Degenerative Mitral Valve Disease Safely Minimizes Unnecessary Replacement ANNALS OF THORACIC SURGERY Goldstone, A. B., Cohen, J. E., Howard, J. L., Edwards, B. B., Acker, A. L., Hiesinger, W., MacArthur, J. W., Atluri, P., Woo, Y. J. 2015; 99 (6): 1983-1991

    Abstract

    We examined the feasibility and efficacy of a "repair-all" strategy applied in all patients with degenerative mitral regurgitation, regardless of valve complexity, risk profile, and surgical approach.Between 2002 and 2011, 4,241 patients underwent mitral operations at our institution. Analysis was limited to 525 consecutive patients with mitral regurgitation due to leaflet prolapse (posterior, 75%; anterior, 5%; bileaflet, 20%) who underwent isolated mitral operations. A right minithoracotomy was used in 46% of procedures. Propensity scores identified 153 well-matched patient pairs for evaluation of the effect of surgical approach on valve reparability.Mitral repair was successful in 99% (520 of 525) of patients. The location of the leaflet prolapse did not significantly influence the repair rate or the need for intraoperative revision of the initial repair. The repair rate and the need for intraoperative repair revision also did not significantly differ by surgical approach. Intraoperative revision did not confer a greater risk of perioperative morbidity or longer length of stay. At 8 years, freedom from severe mitral regurgitation was 97% ± 2%. Development of residual mitral regurgitation did not differ by location of the leaflet prolapse, need for repair revision, or surgical approach. After discharge, the survival trend did not differ between patients who did and did not require intraoperative repair revision.In experienced centers, a "repair-all" strategy for degenerative mitral regurgitation can be used with nearly 100% repair rates and excellent outcomes, regardless of valve complexity. When necessary, intraoperative revision of the initial repair may be performed in most patients without a significant incremental risk, thereby further enhancing repair rates.

    View details for DOI 10.1016/j.athoracsur.2014.12.076

    View details for Web of Science ID 000357521600028

    View details for PubMedID 25865766

  • A "Repair-All" Strategy for Degenerative Mitral Valve Disease Safely Minimizes Unnecessary Replacement. Annals of thoracic surgery Goldstone, A. B., Cohen, J. E., Howard, J. L., Edwards, B. B., Acker, A. L., Hiesinger, W., Macarthur, J. W., Atluri, P., Woo, Y. J. 2015; 99 (6): 1983-1990

    Abstract

    We examined the feasibility and efficacy of a "repair-all" strategy applied in all patients with degenerative mitral regurgitation, regardless of valve complexity, risk profile, and surgical approach.Between 2002 and 2011, 4,241 patients underwent mitral operations at our institution. Analysis was limited to 525 consecutive patients with mitral regurgitation due to leaflet prolapse (posterior, 75%; anterior, 5%; bileaflet, 20%) who underwent isolated mitral operations. A right minithoracotomy was used in 46% of procedures. Propensity scores identified 153 well-matched patient pairs for evaluation of the effect of surgical approach on valve reparability.Mitral repair was successful in 99% (520 of 525) of patients. The location of the leaflet prolapse did not significantly influence the repair rate or the need for intraoperative revision of the initial repair. The repair rate and the need for intraoperative repair revision also did not significantly differ by surgical approach. Intraoperative revision did not confer a greater risk of perioperative morbidity or longer length of stay. At 8 years, freedom from severe mitral regurgitation was 97% ± 2%. Development of residual mitral regurgitation did not differ by location of the leaflet prolapse, need for repair revision, or surgical approach. After discharge, the survival trend did not differ between patients who did and did not require intraoperative repair revision.In experienced centers, a "repair-all" strategy for degenerative mitral regurgitation can be used with nearly 100% repair rates and excellent outcomes, regardless of valve complexity. When necessary, intraoperative revision of the initial repair may be performed in most patients without a significant incremental risk, thereby further enhancing repair rates.

    View details for DOI 10.1016/j.athoracsur.2014.12.076

    View details for PubMedID 25865766

  • Ventricular assist device implantation in the elderly. Annals of cardiothoracic surgery Hiesinger, W., Boyd, J. H., Woo, Y. J. 2014; 3 (6): 570-572

    Abstract

    Dramatic advances in ventricular assist device (VAD) design and patient management have made mechanical circulatory support an attractive therapeutic option for the growing pool of elderly heart failure patients.A literature review of all relevant studies was performed. No time or language restrictions were imposed, and references of the selected studies were checked for additional relevant citations.In concordance with the universal trend in mechanical circulatory support, continuous flow devices appear to have particular benefits in the elderly. In addition, the literature suggests that early intervention before the development of cardiogenic shock, important in all patients, is particularly paramount in older patients.The ongoing refinement of patient selection, surgical technique, and post-operative care will continue to improve surgical outcomes, and absolute age may become a less pivotal criterion for mechanical circulatory support. However, clear guidelines for the use of mechanical circulatory support in the elderly remain undefined.

    View details for DOI 10.3978/j.issn.2225-319X.2014.09.07

    View details for PubMedID 25512896

  • Bioengineered Stromal Cell- Derived Factor-1 alpha Analogue Delivered as an Angiogenic Therapy Significantly Restores Viscoelastic Material Properties of Infarcted Cardiac Muscle JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME Trubelja, A., MacArthur, J. W., Sarver, J. J., Cohen, J. E., Hung, G., Shudo, Y., Fairman, A. S., Patel, J., Edwards, B. B., Damrauer, S. M., Hiesinger, W., Atluri, P., Woo, Y. J. 2014; 136 (8)

    Abstract

    Ischemic heart disease is a major health problem worldwide, and current therapies fail to address microrevascularization. Previously, our group demonstrated that the sustained release of novel engineered stromal cell-derived factor 1-a analogue (ESA) limits infarct spreading, collagen deposition, improves cardiac function by promoting angiogenesis in the region surrounding the infarct, and restores the tensile properties of infarcted myocardium. In this study, using a well-established rat model of ischemic cardiomyopathy, we describe a novel and innovative method for analyzing the viscoelastic properties of infarcted myocardium. Our results demonstrate that, compared with a saline control group, animals treated with ESA have significantly improved myocardial relaxation rates, while reducing the transition strain, leading to restoration of left ventricular mechanics.

    View details for DOI 10.1115/1.4027731

    View details for Web of Science ID 000338507000012

  • A bioengineered hydrogel system enables targeted and sustained intramyocardial delivery of neuregulin, activating the cardiomyocyte cell cycle and enhancing ventricular function in a murine model of ischemic cardiomyopathy. Circulation. Heart failure Cohen, J. E., Purcell, B. P., Macarthur, J. W., Mu, A., Shudo, Y., Patel, J. B., Brusalis, C. M., Trubelja, A., Fairman, A. S., Edwards, B. B., Davis, M. S., Hung, G., Hiesinger, W., Atluri, P., Margulies, K. B., Burdick, J. A., Woo, Y. J. 2014; 7 (4): 619-626

    Abstract

    Neuregulin-1β (NRG) is a member of the epidermal growth factor family possessing a critical role in cardiomyocyte development and proliferation. Systemic administration of NRG demonstrated efficacy in cardiomyopathy animal models, leading to clinical trials using daily NRG infusions. This approach is hindered by requiring daily infusions and off-target exposure. Therefore, this study aimed to encapsulate NRG in a hydrogel to be directly delivered to the myocardium, accomplishing sustained localized NRG delivery.NRG was encapsulated in hydrogel, and release over 14 days was confirmed by ELISA in vitro. Sprague-Dawley rats were used for cardiomyocyte isolation. Cells were stimulated by PBS, NRG, hydrogel, or NRG-hydrogel (NRG-HG) and evaluated for proliferation. Cardiomyocytes demonstrated EdU (5-ethynyl-2'-deoxyuridine) and phosphorylated histone H3 positivity in the NRG-HG group only. For in vivo studies, 2-month-old mice (n=60) underwent left anterior descending coronary artery ligation and were randomized to the 4 treatment groups mentioned. Only NRG-HG-treated mice demonstrated phosphorylated histone H3 and Ki67 positivity along with decreased caspase-3 activity compared with all controls. NRG was detected in myocardium 6 days after injection without evidence of off-target exposure in NRG-HG animals. At 2 weeks, the NRG-HG group exhibited enhanced left ventricular ejection fraction, decreased left ventricular area, and augmented borderzone thickness.Targeted and sustained delivery of NRG directly to the myocardial borderzone augments cardiomyocyte mitotic activity, decreases apoptosis, and greatly enhances left ventricular function in a model of ischemic cardiomyopathy. This novel approach to NRG administration avoids off-target exposure and represents a clinically translatable strategy in myocardial regenerative therapeutics.

    View details for DOI 10.1161/CIRCHEARTFAILURE.113.001273

    View details for PubMedID 24902740

  • Preclinical evaluation of the engineered stem cell chemokine stromal cell-derived factor 1a analog in a translational ovine myocardial infarction model. Circulation research Macarthur, J. W., Cohen, J. E., McGarvey, J. R., Shudo, Y., Patel, J. B., Trubelja, A., Fairman, A. S., Edwards, B. B., Hung, G., Hiesinger, W., Goldstone, A. B., Atluri, P., Wilensky, R. L., Pilla, J. J., Gorman, J. H., Gorman, R. C., Woo, Y. J. 2014; 114 (4): 650-659

    Abstract

    After myocardial infarction, there is an inadequate blood supply to the myocardium, and the surrounding borderzone becomes hypocontractile.To develop a clinically translatable therapy, we hypothesized that in a preclinical ovine model of myocardial infarction, the modified endothelial progenitor stem cell chemokine, engineered stromal cell-derived factor 1α analog (ESA), would induce endothelial progenitor stem cell chemotaxis, limit adverse ventricular remodeling, and preserve borderzone contractility.Thirty-six adult male Dorset sheep underwent permanent ligation of the left anterior descending coronary artery, inducing an anteroapical infarction, and were randomized to borderzone injection of saline (n=18) or ESA (n=18). Ventricular function, geometry, and regional strain were assessed using cardiac MRI and pressure-volume catheter transduction. Bone marrow was harvested for in vitro analysis, and myocardial biopsies were taken for mRNA, protein, and immunohistochemical analysis. ESA induced greater chemotaxis of endothelial progenitor stem cells compared with saline (P<0.01) and was equivalent to recombinant stromal cell-derived factor 1α (P=0.27). Analysis of mRNA expression and protein levels in ESA-treated animals revealed reduced matrix metalloproteinase 2 in the borderzone (P<0.05), with elevated levels of tissue inhibitor of matrix metalloproteinase 1 and elastin in the infarct (P<0.05), whereas immunohistochemical analysis of borderzone myocardium showed increased capillary and arteriolar density in the ESA group (P<0.01). Animals in the ESA treatment group also had significant reductions in infarct size (P<0.01), increased maximal principle strain in the borderzone (P<0.01), and a steeper slope of the end-systolic pressure-volume relationship (P=0.01).The novel, biomolecularly designed peptide ESA induces chemotaxis of endothelial progenitor stem cells, stimulates neovasculogenesis, limits infarct expansion, and preserves contractility in an ovine model of myocardial infarction.

    View details for DOI 10.1161/CIRCRESAHA.114.302884

    View details for PubMedID 24366171

  • Therapeutic potential of Rb phosphorylation in atherosclerosis CELL CYCLE Hiesinger, W., Cohen, J. E., Atluri, P. 2014; 13 (3): 352

    View details for DOI 10.4161/cc.27551

    View details for Web of Science ID 000332833400010

    View details for PubMedID 24346501

    View details for PubMedCentralID PMC3956530

  • Sustained release of engineered stromal cell-derived factor 1-a from injectable hydrogels effectively recruits endothelial progenitor cells and preserves ventricular function after myocardial infarction. Circulation Macarthur, J. W., Purcell, B. P., Shudo, Y., Cohen, J. E., Fairman, A., Trubelja, A., Patel, J., Hsiao, P., Yang, E., Lloyd, K., Hiesinger, W., Atluri, P., Burdick, J. A., Woo, Y. J. 2013; 128 (11): S79-86

    Abstract

    Exogenously delivered chemokines have enabled neovasculogenic myocardial repair in models of ischemic cardiomyopathy; however, these molecules have short half-lives in vivo. In this study, we hypothesized that the sustained delivery of a synthetic analog of stromal cell-derived factor 1-α (engineered stromal cell-derived factor analog [ESA]) induces continuous homing of endothelial progenitor cells and improves left ventricular function in a rat model of myocardial infarction.Our previously designed ESA peptide was synthesized by the addition of a fluorophore tag for tracking. Hyaluronic acid was chemically modified with hydroxyethyl methacrylate to form hydrolytically degradable hydrogels through free-radical-initiated crosslinking. ESA was encapsulated in hyaluronic acid hydrogels during gel formation, and then ESA release, along with gel degradation, was monitored for more than 4 weeks in vitro. Chemotactic properties of the eluted ESA were assessed at multiple time points using rat endothelial progenitor cells in a transwell migration assay. Finally, adult male Wistar rats (n=33) underwent permanent ligation of the left anterior descending (LAD) coronary artery, and 100 µL of saline, hydrogel alone, or hydrogel+25 µg ESA was injected into the borderzone. ESA fluorescence was monitored in animals for more than 4 weeks, after which vasculogenic, geometric, and functional parameters were assessed to determine the therapeutic benefit of each treatment group. ESA release was sustained for 4 weeks in vitro, remained active, and enhanced endothelial progenitor cell chemotaxis. In addition, ESA was detected in the rat heart >3 weeks when delivered within the hydrogels and significantly improved vascularity, ventricular geometry, ejection fraction, cardiac output, and contractility compared with controls.We have developed a hydrogel delivery system that sustains the release of a bioactive endothelial progenitor cell chemokine during a 4-week period that preserves ventricular function in a rat model of myocardial infarction.

    View details for DOI 10.1161/CIRCULATIONAHA.112.000343

    View details for PubMedID 24030424

  • Predicting Right Ventricular Failure in the Modern, Continuous Flow Left Ventricular Assist Device Era 59th Annual Meeting of the Southern-Thoracic-Surgical-Association (STSA) Atluri, P., Goldstone, A. B., Fairman, A. S., MacArthur, J. W., Shudo, Y., Cohen, J. E., Acker, A. L., Hiesinger, W., Howard, J. L., Acker, M. A., Woo, Y. J. ELSEVIER SCIENCE INC. 2013: 857–64

    Abstract

    In the era of destination continuous flow left ventricular assist devices (LVAD), the decision of whether a patient will tolerate isolated LVAD support or will need biventricular support (BIVAD) can be challenging. Incorrect decision making with delayed right ventricular (RV) assist device implantation results in increased morbidity and mortality. Continuous flow LVADs have been shown to decrease pulmonary hypertension and improve RV function. We undertook this study to determine predictors in the continuous flow LVAD era that identify patients who are candidates for isolated LVAD therapy as opposed to biventricular support.We reviewed demographic, hemodynamic, laboratory, and echocardiographic variables for 218 patients who underwent VAD implant from 2003 through 2011 (LVAD=167, BIVAD=51), during the era of continuous flow LVADs.Fifty preoperative risk factors were compared between patients who were successfully managed with an LVAD and those who required a BIVAD. Seventeen variables demonstrated statistical significance by univariate analysis. Multivariable logistic regression analysis identified central venous pressure>15 mmHg (OR 2.0, "C"), severe RV dysfunction (OR 3.7, "R"), preoperative intubation (OR 4.3, "I"), severe tricuspid regurgitation (OR 4.1, "T"), heart rate>100 (OR 2.0, Tachycardia-"T")-CRITT as the major criteria predictive of the need for biventricular support. Utilizing these data, a highly sensitive and easy to use risk score for determining RV failure was generated that outperformed other established risk stratification tools.We present a preoperative risk calculator to determine suitability of a patient for isolated LVAD support in the current continuous flow ventricular assist device era.

    View details for DOI 10.1016/j.athoracsur.2013.03.099

    View details for Web of Science ID 000323940200026

    View details for PubMedID 23791165

  • Rapid onset of fulminant myocarditis portends a favourable prognosis and the ability to bridge mechanical circulatory support to recovery EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY Atluri, P., Ullery, B. W., MacArthur, J. W., Goldstone, A. B., Fairman, A. S., Hiesinger, W., Acker, M. A., Woo, Y. J. 2013; 43 (2): 379-382

    Abstract

    Fulminant myocarditis with cardiogenic shock is fatal without mechanical circulatory support. Once haemodynamic stability has been established with a ventricular assist device (VAD), the decision to wait for myocardial recovery as opposed to listing for an orthotopic heart transplant (OHT) can be difficult. We have undertaken this study to establish the criteria for determining the need for heart transplantation following VAD implant for fulminant myocarditis.A total of 442 VADs were implanted between 1993 and 2011. Twenty-four VADs were implanted for fulminant myocarditis with refractory cardiogenic shock. We retrospectively analysed the variables and the pathology for this cohort. Patients who had a full recovery of myocardial function and subsequent VAD explant (Explant) were compared with those bridged to OHT. There was one acute death.There was no difference in the past medical history between the groups. Explant patients had a more acute onset of heart failure with a median of 7 days between the onset of symptoms and VAD implant, when compared with 22 days for OHT (P = 0.01). A rapid recovery in myocardial function was seen in the Explant group, with recovery of myocardial function (ejection fraction = 53 ± 24%) in 14 ± 7 days. Myocardial function was sustained for 5 years following the VAD explant. The female gender favoured myocardial recovery and VAD explantability. Two patients had giant cell myocarditis, neither of whom had a recovery of function, and they were bridged to heart transplant with a VAD.Fulminant myocarditis is a fatal condition without mechanical support. The rapid onset of symptoms is associated with a complete recovery of myocardial function and VAD explant. The absence of rapid recovery of myocardial function should prompt listing for a heart transplant.

    View details for DOI 10.1093/ejcts/ezs242

    View details for Web of Science ID 000313829300031

    View details for PubMedID 22564805

  • Mathematically engineered stromal cell-derived factor-1 alpha stem cell cytokine analog enhances mechanical properties of infarcted myocardium JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY MacArthur, J. W., Trubelja, A., Shudo, Y., Hsiao, P., Fairman, A. S., Yang, E., Hiesinger, W., Sarver, J. J., Atluri, P., Woo, Y. J. 2013; 145 (1): 278-284

    Abstract

    The biomechanical response to a myocardial infarction consists of ventricular remodeling that leads to dilatation, loss of contractile function, abnormal stress patterns, and ultimately heart failure. We hypothesized that intramyocardial injection of our previously designed pro-angiogenic chemokine, an engineered stromal cell-derived factor-1α analog (ESA), improves mechanical properties of the heart after infarction.Male rats (n = 54) underwent either sham surgery (n = 17) with no coronary artery ligation or ligation of the left anterior descending artery (n = 37). The rats in the myocardial infarction group were then randomized to receive either saline (0.1 mL, n = 18) or ESA (6 μg/kg, n = 19) injected into the myocardium at 4 predetermined spots around the border zone. Echocardiograms were performed preoperatively and before the terminal surgery. After 4 weeks, the hearts were explanted and longitudinally sectioned. Uniaxial tensile testing was completed using an Instron 5543 Microtester. Optical strain was evaluated using custom image acquisition software, Digi-Velpo, and analyzed in MATLAB.Compared with the saline control group at 4 weeks, the ESA-injected hearts had a greater ejection fraction (71.8% ± 9.0% vs 55.3% ± 12.6%, P = .0004), smaller end-diastolic left ventricular internal dimension (0.686 ± 0.110 cm vs 0.763 ± 0.160 cm, P = .04), greater cardiac output (36 ± 11.6 mL/min vs 26.9 ± 7.3 mL/min, P = .05), and a lower tensile modulus (251 ± 56 kPa vs 301 ± 81 kPa, P = .04). The tensile modulus for the sham group was 195 ± 56 kPa, indicating ESA injection results in a less stiff ventricle.Direct injection of ESA alters the biomechanical response to myocardial infarction, improving the mechanical properties in the postinfarct heart.

    View details for DOI 10.1016/j.jtcvs.2012.09.080

    View details for Web of Science ID 000312386300047

    View details for PubMedID 23244259

  • Re-Engineered Stromal Cell-Derived Factor-1 alpha and the Future of Translatable Angiogenic Polypeptide Design TRENDS IN CARDIOVASCULAR MEDICINE Hiesinger, W., Goldstone, A. B., Woo, Y. J. 2012; 22 (6): 139-144

    Abstract

    Smaller engineered analogs of angiogenic cytokines may provide translational advantages, including enhanced stability and function, ease of synthesis, lower cost, and, most important, the potential for modulated delivery via engineered biomaterials. In order to create such a peptide, computational molecular modeling and design was employed to engineer a minimized, highly efficient polypeptide analog of the stromal cell-derived factor-1α (SDF) molecule. After removal of the large, central β-sheet region, a designed diproline linker connected the native N-terminus (responsible for receptor activation and binding) and C-terminus (responsible for extracellular stabilization). This yielded energetic and conformational advantages resulting in a small, low-molecular-weight engineered SDF polypeptide analog (ESA) that was shown to have angiogenic activity comparable to or better than that of recombinant human SDF both in vitro and in a murine model of ischemic heart failure.

    View details for Web of Science ID 000311065900001

    View details for PubMedID 22902182

  • Myocardial tissue elastic properties determined by atomic force microscopy after stromal cell-derived factor 1 alpha angiogenic therapy for acute myocardial infarction in a murine model 37th Annual Meeting of the Western-Thoracic-Surgical-Association Hiesinger, W., Brukman, M. J., McCormick, R. C., Fitzpatrick, J. R., Frederick, J. R., Yang, E. C., Muenzer, J. R., Marotta, N. A., Berry, M. F., Atluri, P., Woo, Y. J. MOSBY-ELSEVIER. 2012: 962–66

    Abstract

    Ventricular remodeling after myocardial infarction begins with massive extracellular matrix deposition and resultant fibrosis. This loss of functional tissue and stiffening of myocardial elastic and contractile elements starts the vicious cycle of mechanical inefficiency, adverse remodeling, and eventual heart failure. We hypothesized that stromal cell-derived factor 1α (SDF-1α) therapy to microrevascularize ischemic myocardium would rescue salvageable peri-infarct tissue and subsequently improve myocardial elasticity.Immediately after left anterior descending coronary artery ligation, mice were randomly assigned to receive peri-infarct injection of either saline solution or SDF-1α. After 6 weeks, animals were killed and samples were taken from the peri-infarct border zone and the infarct scar, as well as from the left ventricle of noninfarcted control mice. Determination of tissues' elastic moduli was carried out by mechanical testing in an atomic force microscope.SDF-1α-treated peri-infarct tissue most closely approximated the elasticity of normal ventricle and was significantly more elastic than saline-treated peri-infarct myocardium (109 ± 22.9 kPa vs 295 ± 42.3 kPa; P < .0001). Myocardial scar, the strength of which depends on matrix deposition from vasculature at the peri-infarct edge, was stiffer in SDF-1α-treated animals than in controls (804 ± 102.2 kPa vs 144 ± 27.5 kPa; P < .0001).Direct quantification of myocardial elastic properties demonstrates the ability of SDF-1α to re-engineer evolving myocardial infarct and peri-infarct tissues. By increasing elasticity of the ischemic and dysfunctional peri-infarct border zone and bolstering the weak, aneurysm-prone scar, SDF-1α therapy may confer a mechanical advantage to resist adverse remodeling after infarction.

    View details for DOI 10.1016/j.jtcvs.2011.12.028

    View details for Web of Science ID 000301609200036

    View details for PubMedID 22264415

  • Oxygen-dependent quenching of phosphorescence used to characterize improved myocardial oxygenation resulting from vasculogenic cytokine therapy JOURNAL OF APPLIED PHYSIOLOGY Hiesinger, W., Vinogradov, S. A., Atluri, P., Fitzpatrick, J. R., Frederick, J. R., Levit, R. D., McCormick, R. C., Muenzer, J. R., Yang, E. C., Marotta, N. A., MacArthur, J. W., Wilson, D. F., Woo, Y. J. 2011; 110 (5): 1460-1465

    Abstract

    This study evaluates a therapy for infarct modulation and acute myocardial rescue and utilizes a novel technique to measure local myocardial oxygenation in vivo. Bone marrow-derived endothelial progenitor cells (EPCs) were targeted to the heart with peri-infarct intramyocardial injection of the potent EPC chemokine stromal cell-derived factor 1α (SDF). Myocardial oxygen pressure was assessed using a noninvasive, real-time optical technique for measuring oxygen pressures within microvasculature based on the oxygen-dependent quenching of the phosphorescence of Oxyphor G3. Myocardial infarction was induced in male Wistar rats (n = 15) through left anterior descending coronary artery ligation. At the time of infarction, animals were randomized into two groups: saline control (n = 8) and treatment with SDF (n = 7). After 48 h, the animals underwent repeat thoracotomy and 20 μl of the phosphor Oxyphor G3 was injected into three areas (peri-infarct myocardium, myocardial scar, and remote left hindlimb muscle). Measurements of the oxygen distribution within the tissue were then made in vivo by applying the end of a light guide to the beating heart. Compared with controls, animals in the SDF group exhibited a significantly decreased percentage of hypoxic (defined as oxygen pressure ≤ 15.0 Torr) peri-infarct myocardium (9.7 ± 6.7% vs. 21.8 ± 11.9%, P = 0.017). The peak oxygen pressures in the peri-infarct region of the animals in the SDF group were significantly higher than the saline controls (39.5 ± 36.7 vs. 9.2 ± 8.6 Torr, P = 0.02). This strategy for targeting EPCs to vulnerable peri-infarct myocardium via the potent chemokine SDF-1α significantly decreased the degree of hypoxia in peri-infarct myocardium as measured in vivo by phosphorescence quenching. This effect could potentially mitigate the vicious cycle of myocyte death, myocardial fibrosis, progressive ventricular dilatation, and eventual heart failure seen after acute myocardial infarction.

    View details for DOI 10.1152/japplphysiol.01138.2010

    View details for Web of Science ID 000290472400043

    View details for PubMedID 21292844

    View details for PubMedCentralID PMC3098666

  • Computational Protein Design to Re-Engineer Stromal Cell-Derived Factor-alpha (SDF) Generates a Supra-Efficient Angiogenic Polypeptide Analog Hiesinger, W., Perez-Aguilar, J., Atluri, P., Marotta, N. A., Frederick, J. R., Fitzpatrick, J. R., McCormick, R. C., Muenzer, J. R., Levit, R. D., Yuan, L., MacArthur, J. W., Saven, J. G., Woo, Y. J. LIPPINCOTT WILLIAMS & WILKINS. 2010
  • Acute Myocardial Rescue with Endogenous Endothelial Progenitor Cell Therapy HEART LUNG AND CIRCULATION Atluri, P., Panlilio, C. M., Liao, G. P., Hiesinger, W., Harris, D. A., McCormick, R. C., Cohen, J. E., Jin, T., Feng, W., Levit, R. D., Dong, N., Woo, Y. J. 2010; 19 (11): 644-654

    Abstract

    Post-myocardial infarction heart failure is a major health concern with limited therapy. Molecular revascularisation utilising granulocyte-macrophage colony stimulating factor (GMCSF) mediated endothelial progenitor cell (EPC) upregulation and stromal cell derived factor-1α (SDF) mediated myocardial EPC chemokinesis, may prevent myocardial loss and adverse remodelling. Vasculogenesis, viability, and haemodynamic improvements following therapy were investigated.Lewis rats (n=91) underwent LAD ligation and received either intramyocardial SDF and subcutaneous GMCSF or saline injections at the time of infarction. Molecular and haemodynamic assessments were performed at pre-determined time points following ligation.SDF/GMCSF therapy upregulated EPC density as shown by flow cytometry (0.12±0.02% vs. 0.06±0.01% circulating lymphocytes, p=0.005), 48hours following infarction. A marked increase in perfusion was evident eight weeks after therapy, utilising confocal angiography (5.02±1.7×10(-2)μm(3)blood/μm(3)myocardial tissue vs. 2.03±0.710(-2)μm(3)blood/μm(3)myocardial tissue, p=0.00004). Planimetric analysis demonstrated preservation of wall thickness (0.98±0.09mm vs. 0.67±0.06mm, p=0.003) and ventricular diameter (7.81±0.99mm vs. 9.41±1.1mm, p=0.03). Improved haemodynamic function was evidenced by echocardiography and PV analysis (ejection fraction: 56.4±18.1% vs. 25.3±15.6%, p=0.001; pre-load adjusted maximal power: 6.6±2.6mW/μl(2) vs. 2.7±1.4mW/μl(2), p=0.01).Neovasculogenic therapy with GMCSF-mediated EPC upregulation and SDF-mediated EPC chemokinesis maybe an effective therapy for infarct modulation and preservation of myocardial function following acute myocardial infarction.

    View details for DOI 10.1016/j.hlc.2010.06.1056

    View details for Web of Science ID 000283908600002

    View details for PubMedID 20719564

    View details for PubMedCentralID PMC3235678

  • Spliced stromal cell-derived factor-1 alpha analog stimulates endothelial progenitor cell migration and improves cardiac function in a dose-dependent manner after myocardial infarction JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Hiesinger, W., Frederick, J. R., Atluri, P., McCormick, R. C., Marotta, N., Muenzer, J. R., Woo, Y. J. 2010; 140 (5): 1174-1180

    Abstract

    Stromal cell-derived factor (SDF)-1α is a potent endogenous endothelial progenitor cell (EPC) chemokine and key angiogenic precursor. Recombinant SDF-1α has been demonstrated to improve neovasculogenesis and cardiac function after myocardial infarction (MI) but SDF-1α is a bulky protein with a short half-life. Small peptide analogs might provide translational advantages, including ease of synthesis, low manufacturing costs, and the potential to control delivery within tissues using engineered biomaterials. We hypothesized that a minimized peptide analog of SDF-1α, designed by splicing the N-terminus (activation and binding) and C-terminus (extracellular stabilization) with a truncated amino acid linker, would induce EPC migration and preserve ventricular function after MI.EPC migration was first determined in vitro using a Boyden chamber assay. For in vivo analysis, male rats (n = 48) underwent left anterior descending coronary artery ligation. At infarction, the rats were randomized into 4 groups and received peri-infarct intramyocardial injections of saline, 3 μg/kg of SDF-1α, 3 μg/kg of spliced SDF analog, or 6 μg/kg spliced SDF analog. After 4 weeks, the rats underwent closed chest pressure volume conductance catheter analysis.EPCs showed significantly increased migration when placed in both a recombinant SDF-1α and spliced SDF analog gradient. The rats treated with spliced SDF analog at MI demonstrated a significant dose-dependent improvement in end-diastolic pressure, stroke volume, ejection fraction, cardiac output, and stroke work compared with the control rats.A spliced peptide analog of SDF-1α containing both the N- and C- termini of the native protein induced EPC migration, improved ventricular function after acute MI, and provided translational advantages compared with recombinant human SDF-1α.

    View details for DOI 10.1016/j.jtcvs.2010.08.012

    View details for Web of Science ID 000283057600043

    View details for PubMedID 20951261

  • Stromal Cell-Derived Factor-1 alpha Activation of Tissue-Engineered Endothelial Progenitor Cell Matrix Enhances Ventricular Function After Myocardial Infarction by Inducing Neovasculogenesis 82nd National Conference and Exhibitions and Annual Scientific Session of the American-Heart-Association Frederick, J. R., Fitzpatrick, J. R., McCormick, R. C., Harris, D. A., Kim, A., Muenzer, J. R., Marotta, N., Smith, M. J., Cohen, J. E., Hiesinger, W., Atluri, P., Woo, Y. J. LIPPINCOTT WILLIAMS & WILKINS. 2010: S107–S117

    Abstract

    Myocardial ischemia causes cardiomyocyte death, adverse ventricular remodeling, and ventricular dysfunction. Endothelial progenitor cells (EPCs) have been shown to ameliorate this process, particularly when activated with stromal cell-derived factor-1α (SDF), known to be the most potent EPC chemokine. We hypothesized that implantation of a tissue-engineered extracellular matrix (ECM) scaffold seeded with EPCs primed with SDF could induce borderzone neovasculogenesis, prevent adverse geometric remodeling, and preserve ventricular function after myocardial infarction.Lewis rats (n=82) underwent left anterior descending artery ligation to induce myocardial infarction. EPCs were isolated, characterized, and cultured on a vitronectin/collagen scaffold and primed with SDF to generate the activated EPC matrix (EPCM). EPCM was sutured to the anterolateral left ventricular wall, which included the region of ischemia. Control animals received sutures but no EPCM. Additional groups underwent application of the ECM alone, ECM primed with SDF (ECM+SDF), and ECM seeded with EPCs but not primed with SDF (ECM+SDF). At 4 weeks, borderzone myocardial tissue demonstrated increased levels of vascular endothelial growth factor in the EPCM group. When compared to controls, Vessel density as assessed by immunohistochemical microscopy was significantly increased in the EPCM group (4.1 versus 6.2 vessels/high-powered field; P<0.001), and microvascular perfusion measured by lectin microangiography was enhanced 4-fold (0.7% versus 2.7% vessel volume/section volume; P=0.04). Comparisons to additional groups also showed a significantly improved vasculogenic response in the EPCM group. Ventricular geometry and scar fraction assessed by digital planimetric analysis of sectioned hearts exhibited significantly preserved left ventricular internal diameter (9.7 mm versus 8.6 mm; P=0.005) and decreased infarct scar formation expressed as percent of total section area (16% versus 7%; P=0.002) when compared with all other groups. In addition, EPCM animals showed a significant preservation of function as measured by echocardiography, pressure-volume conductance, and Doppler flow.Extracellular matrix seeded with EPCs primed with SDF induces borderzone neovasculogenesis, attenuates adverse ventricular remodeling, and preserves ventricular function after myocardial infarction.

    View details for DOI 10.1161/C1RCULATIONAHA.109.930404

    View details for Web of Science ID 000282294800017

    View details for PubMedID 20837901

  • Rapid Onset of Fulminant Myocarditis Portends a Favorable Prognosis and Ability To Bridge Mechanical Support to Recovery Atluri, P., Ullery, B. W., Howard, J. L., Hiesinger, W., Filzpatrick, J., Jessup, M., Acker, M. A., Morris, R. J., Woo, Y. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2010: S51
  • Early planned institution of biventricular mechanical circulatory support results in improved outcomes compared with delayed conversion of a left ventricular assist device to a biventricular assist device JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Fitzpatrick, J. R., Frederick, J. R., Hiesinger, W., Hsu, V. M., McCormick, R. C., Kozin, E. D., Laporte, C. M., O'Hara, M. L., Howell, E., Dougherty, D., Cohen, J. E., Southerland, K. W., Howard, J. L., Paulson, C., Acker, M. A., Morris, R. J., Woo, Y. J. 2009; 137 (4): 971-977

    Abstract

    It is generally accepted that patients who require biventricular assist device support have poorer outcomes than those requiring isolated left ventricular assist device support. However, it is unknown how the timing of biventricular assist device insertion affects outcomes. We hypothesized that planned biventricular assist device insertion improves survival compared with delayed conversion of left ventricular assist device support to biventricular assist device support.We reviewed and compared outcomes of 266 patients undergoing left ventricular assist device or biventricular assist device placement at the University of Pennsylvania from April 1995 to June 2007. We subdivided patients receiving biventricular assist devices into planned biventricular assist device (P-BiVAD) and delayed biventricular assist device (D-BiVAD) groups based on the timing of right ventricular assist device insertion. We defined the D-BiVAD group as any failure of isolated left ventricular assist device support.Of 266 patients who received left ventricular assist devices, 99 (37%) required biventricular assist device support. We compared preoperative characteristics, successful bridging to transplantation, survival to hospital discharge, and Kaplan-Meier 1-year survival between the P-BiVAD (n = 71) and D-BiVAD (n = 28) groups. Preoperative comparison showed that patients who ultimately require biventricular support have similar preoperative status. Left ventricular assist device (n = 167) outcomes in all categories exceeded both P-BiVAD and D-BiVAD group outcomes. Furthermore, patients in the P-BiVAD group had superior survival to discharge than patients in the D-BiVAD group (51% vs 29%, P < .05). One-year and long-term Kaplan-Meier survival distribution confirmed this finding. There was also a trend toward improved bridging to transplantation in the P-BiVAD (n = 55) versus D-BiVAD (n = 22) groups (65% vs 45%, P = .10).When patients at high risk for failure of isolated left ventricular assist device support are identified, proceeding directly to biventricular assist device implantation is advised because early institution of biventricular support results in dramatic improvement in survival.

    View details for DOI 10.1016/j.jtcvs.2008.09.021

    View details for Web of Science ID 000264562000028

    View details for PubMedID 19327526

    View details for PubMedCentralID PMC3232461

  • Off-pump, minimally invasive and robotic coronary revascularization yield improved outcomes over traditional on-pump CABG INTERNATIONAL JOURNAL OF MEDICAL ROBOTICS AND COMPUTER ASSISTED SURGERY Atluri, P., Kozin, E. D., Hiesinger, W., Woo, Y. J. 2009; 5 (1): 1-12

    Abstract

    Coronary artery disease is a global health concern, with increasing morbidity and mortality. Surgical coronary artery bypass grafting has been performed on cardiopulmonary bypass for nearly four decades, with excellent long-term durability. Beating-heart coronary surgery has been increasing in frequency in an attempt to decrease cardiopulmonary bypass-related morbidity. Furthermore, with increasing expertise and technology, minimally invasive and robotic techniques have been developed to enhance post-operative recovery, patient satisfaction and cosmesis. Several clinical trials have demonstrated decreased morbidity and more rapid recovery following off-pump, minimally invasive and robotic procedures when compared to on-pump coronary artery bypass grafts (CABGs). An equivalent extent of revascularization and medium-term anastomotic patency has been demonstrated among all approaches. Furthermore, for a large number of patients who do not have anatomy amenable to traditional coronary revascularization, adjunctive molecular therapies may provide alternative myocardial micro-revascularization.

    View details for DOI 10.1002/rcs.230

    View details for Web of Science ID 000263998300001

    View details for PubMedID 19117020

  • Cardiac retransplantation is an efficacious therapy for primary cardiac allograft failure JOURNAL OF CARDIOTHORACIC SURGERY Atluri, P., Hiesinger, W., Gorman, R. C., Pochettino, A., Jessup, M., Acker, M. A., Morris, R. J., Woo, Y. J. 2008; 3

    Abstract

    Although orthotopic heart transplantation has been an effective treatment for end-stage heart failure, the incidence of allograft failure has increased, necessitating treatment options. Cardiac retransplantation remains the only viable long-term solution for end-stage cardiac allograft failure. Given the limited number of available donor hearts, the long term results of this treatment option need to be evaluated.709 heart transplants were performed over a 20 year period at our institution. Repeat cardiac transplantation was performed in 15 patients (2.1%). A retrospective analysis was performed to determine the efficacy of cardiac retransplantation. Variables investigated included: 1 yr and 5 yr survival, length of hospitalization, post-operative complications, allograft failure, recipient and donor demographics, renal function, allograft ischemic time, UNOS listing status, blood group, allograft rejection, and hemodynamic function.Etiology of primary graft failure included transplant arteriopathy (n = 10), acute rejection (n = 3), hyperacute rejection (n = 1), and a post-transplant diagnosis of metastatic melanoma in the donor (n = 1). Mean age at retransplantation was 45.5 +/- 9.7 years. 1 and 5 year survival for retransplantation were 86.6% and 71.4% respectively, as compared to 90.9% and 79.1% for primary transplantation. Mean ejection fraction was 67.3 +/- 12.2% at a mean follow-up of 32.6 +/- 18.5 mos post-retransplant; follow-up biopsy demonstrated either ISHLT grade 1A or 0 rejection (77.5 +/- 95.7 mos post-transplant).Cardiac retransplantation is an efficacious treatment strategy for cardiac allograft failure.

    View details for DOI 10.1186/1749-8090-3-26

    View details for Web of Science ID 000262855000001

    View details for PubMedID 18462494

    View details for PubMedCentralID PMC2432055

  • Ischemic heart failure enhances endogenous myocardial apelin and APJ receptor expression CELLULAR & MOLECULAR BIOLOGY LETTERS Atluri, P., Morine, K. J., Liao, G. P., Panlilio, C. M., Berry, M. F., Hsu, V. M., Hiesinger, W., Cohen, J. E., Woo, Y. J. 2007; 12 (1): 127-138

    Abstract

    Apelin interacts with the APJ receptor to enhance inotropy. In heart failure, apelin-APJ coupling may provide a means of enhancing myocardial function. The alterations in apelin and APJ receptor concentrations with ischemic cardiomyopathy are poorly understood. We investigated the compensatory changes in endogenous apelin and APJ levels in the setting of ischemic cardiomyopathy.Male, Lewis rats underwent LAD ligation and progressed into heart failure over 6 weeks. Corresponding animals underwent sham thoracotomy as control. Six weeks after initial surgery, the animals underwent hemodynamic functional analysis in the presence of exogenous apelin-13 infusion and the hearts were explanted for western blot and enzyme immunoassay analysis. Western blot analysis of myocardial APJ concentration demonstrated increased APJ receptor protein levels with heart failure (1890750+/-133500 vs. 901600+/-143120 intensity units, n=8, p=0.00001). Total apelin protein levels increased with ischemic heart failure as demonstrated by enzyme immunoassay (12.0+/-4.6 vs. 1.0+/-1.2 ng/ml, n=5, p=0.006) and western blot (1579400+/-477733 vs. 943000+/-157600 intensity units, n=10, p=0.008). Infusion of apelin-13 significantly enhanced myocardial function in sham and failing hearts. We conclude that total myocardial apelin and APJ receptor levels increase in compensation for ischemic cardiomyopathy.

    View details for DOI 10.2478/s11658-006-0058-7

    View details for Web of Science ID 000244632300011

    View details for PubMedID 17119870