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Cardiac Transplantation Research in the Next Decade: A Goal to Evidence-Based Outcomes

Executive Summary

The National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group (WG) on August 5-6, 2010 in Bethesda, MD to discuss future directions of research in cardiac transplantation. The WG was composed of researchers with expertise in the basic science, clinical science, and epidemiological aspects of advanced heart failure and cardiac transplantation. These experts were asked to identify the highest priority research gaps in the field and make recommendations for future research strategies that would address those gaps. The WG was also asked to include approaches that capitalize on current scientific opportunities and focus on areas which required unique NHLBI leadership. Finally, the WG was charged with developing recommendations that were both visionary and practical, and that would have both short and long-term impact on the field of cardiac transplantation.

Discussion

Cardiac transplantation is considered the gold standard treatment for patients with advanced heart failure who are refractory to management with medical therapy and mechanical circulatory support. However, clinical care in cardiac transplantation is dominated by group consensus based on anecdotal experience rather than strong scientific evidence. Progress in the pharmacological and device-based management of heart failure has led to longer survival of patients with advanced heart failure, creating a potential recipient pool in the United States of greater than 50,000 patients annually. Yet, the number of cardiac transplants performed in this country has remained relatively fixed at 2200 per year, a number that has not changed for a decade. Also, advances in immunosuppression and a better understanding of how to treat cardiac allograft rejection have led to improved 1 year cardiac allograft survival. However, late outcomes in this population remain dismal with a median cardiac allograft survival of 11 years, a statistic that has also not improved in over a decade. Thus, there is an urgent need for innovative clinical and basic research to develop evidence-based therapies and standard approaches that will expand the donor pool and prolong the survival of cardiac transplant recipients.

The WG participants reviewed key areas in cardiac transplantation and identified the most urgent knowledge gaps. These gaps were then organized into the following four specific research directions: 1) Enhanced phenotypic characterization of the pre-transplant population – including the prediction and management of renal impairment and recovery, the impact of nutrition, pulmonary hypertension, and mechanical circulatory support on late allograft outcomes, and the characterization and management of sensitization; 2) Donor-recipient optimization strategies – including the evaluation of donor-recipient interactions, standards for utilizing donor hearts, and optimization of donor outcomes by limiting ischemia-reperfusion injury; 3) Individualized immunosuppression therapy – including the use of pharmacogenomics and pattern-integrated biosignatures; and, 4) Investigations of immune and non-immune factors affecting late cardiac allograft outcomes – including a better understanding of antibody mediated rejection, measures to predict and induce clinical allograft tolerance, and prevention and management of complications of the cardio-metabolic syndrome in the cardiac transplant recipient. Finally, because the cardiac transplant population is relatively small compared to other patient groups, the WG strongly urged concerted efforts to enroll every transplant recipient into a clinical study in order to optimize research in this field.

Recommendations

  • Enhanced phenotypic characterization of the pre-transplant population
    • Develop a funded database that would define pre-transplant risk factors and allow investigators to identify optimal candidates from the limited donor pool.  A network of funded centers would contribute to the database, with centers enrolling patients listed each year for cardiac transplantation.
    • Conduct randomized clinical trials (RCT) in various pre-transplant populations to evaluate specific management strategies. Proposed trials should address two key areas
      • The impact of LVAD versus inotropic therapy on pulmonary hypertension and post transplant outcomes
      • The impact of combined heart-kidney transplant versus other renal-sparing strategies in candidates with renal insufficiency
  • Donor-recipient optimization strategies
    • Conduct a RCT in elderly HF patients (>70 years) comparing outcomes of heart transplant with donors older than 60 years versus destination left ventricular assist devices. Studies would be designed to concurrently address fundamental questions about the senescent immune system and the balance between rejection and infection.
    • Pursue research to enhance donor utilization. Areas to address include preventing the deleterious effects of prolonged ischemia time, novel strategies of warm versus cold perfusion, and other methods to limit ischemia-reperfusion injury.
  • Individualizing immunosuppression therapies and addressing immune and non-immune factors affecting late allograft outcomes
    • Create an observational longitudinal database, which would include a bio-specimen bank and phenotype information. The purpose of this database would be to characterize the pathophysiology of antibody mediated rejection, create standardized definitions of this entity, and ascertain the impact of this form of rejection on long term outcomes.
    • Pursue a RCT to evaluate a calcineurin inhibitor (CNI) sparing approach on late outcomes, including major cardiac adverse events (MACE), solid cancers, renal failure, and graft and patient survival. Pharmacogenomic and systems biology investigations of individual responses to immunosuppression should be embedded in such a trial
    • Pursue a RCT to evaluate the impact of intensive metabolic risk factor modification on late allograft outcomes including graft and patient survival, MACE, and renal impairment.
    • Due to the synergy of immune and non-immune variables on late outcomes, factorial trial designs should be considered to answer both questions concurrently.
    • Investigate the mechanisms of cardiac allograft injury and repair, and the impact on graft outcomes using a focused basic science approach.

Publication Plans

A report is planned for publication in a peer-reviewed journal.

NHLBI Contacts

Monica R. Shah, MD, MHS, MSJ
Division of Cardiovascular Sciences
shahmr@nhlbi.nih.gov

Lisa Schwartz Longacre, PhD
Division of Cardiovascular Sciences
Schwartzlongal@nhlbi.nih.gov

Lynn Rundhaugen, MPH
Division of Cardiovascular Sciences
rundhaul@nhlbi.nih.gov

Working Group Members

Co-Chairs

  • Mandeep Mehra, MD, University of Maryland School of Medicine
  • Randall C. Starling, MD, MPH, The Cleveland Clinic Foundation

Members

  • Mark Barr, MD – University of Southern California and Children’s Hospital, Los Angeles
  • Howard Eisen, MD – Drexel University College of Medicine
  • Gary Francis, MD – University of Minnesota
  • John Fung, MD – The Cleveland Clinic Foundation
  • Kathleen Grady, PhD, APN – Northwestern University
  • Valluvan Jeevanandam, MD – University of Chicago Medical Center
  • Maryl Johnson, MD – University of Wisconsin
  • Abdallah Kfoury, MD – Intermountain Medical Center
  • James Kirklin, MD – University of Alabama at Birmingham
  • Jon Kobashigawa, MD – Cedars-Sinai Heart Institute
  • Robert Kormos, MD – University of Pittsburgh Medical Center
  • Joren Madsen, MD, DPhil – Massachusetts General Hospital
  • Donna Mancini, MD – Columbia University Medical Center
  • Bruce McManus, MD, PhD – University of British Columbia
  • Christopher O’Connor, MD – Duke University Medical Center
  • Marc Pfeffer, MD, PhD – Brigham and Women’s Hospital
  • Richard Pierson, III, MD – University of Maryland
  • Elaine Reed, PhD – University of California, Los Angeles
  • Daniel Salomon, MD – The Scripps Research Institute
  • Charles Steenbergen, MD, PhD – The Johns Hopkins Hospital
  • Lynne Stevenson, MD – Brigham and Women’s Hospital
  • Liewei Wang, MD, PhD – The Mayo Clinic

FDA Representative

  • LaRee Tracy, PhD

NIAID Representative

  • Jonah Odim, MD, PhD

NIDDK Representative

  • Michael Flessner, MD

Last Updated: September 2010

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