Division of Cardiovascular Diseases Strategic Plan

Goals in Cardiovascular Clinical Problems or Disease States

2.4f. Improve outcomes for all cardiac transplant patients and make transplantation available to a larger number of heart failure patients

Table of Contents

• Overview
• Strategies to Accomplish This Goal May Entail
  • Basic Research
  • Translational Research
  • Clinical Research
• Contributing Sources

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Overview

Heart transplantation remains the only successful treatment for end-stage heart failure. As of 2004, there were more than 17,000 patients of all ages living with a transplanted heart. Although one-year survival after heart transplantation is excellent at 88 percent, the long-term attrition rate (approximately 3.4 percent per year, due primarily to chronic rejection and infections) is discouraging. Several hundred patients die every year on the waiting list. Newer immunosuppressive drugs have reduced complication rates and improved quality of life, but continue to be associated with serious side effects, such as infections, malignancies, and kidney damage. The development of a successful protocol to induce donor-specific tolerance could eliminate much of the morbidity and mortality associated with the use of immunosuppressive drugs. Another major hurdle in heart transplantation is the scarcity of human organ donors of all ages. If the immunological hurdles associated with xenotransplantation could be overcome, transplantation would be available to a much larger number of patients. This could either eliminate the waiting list or at least greatly shorten the time spent on a waiting list, and thus eliminate a significant component of mortality for end-stage HF.

Strategies to Accomplish this Goal May Entail:

Basic Research:

• Determine the role of ischemia/reperfusion injury in early graft failure and acute rejection.
• Define the role of natural killer cells in acute and chronic rejection.
• Identify and overcome immunological and physiological hurdles to xenotransplantation.
• Develop a strategy to induce donor-specific tolerance for heart transplants in a large animal model of xenotransplantation.
• Produce transgenic animals that would be suitable organ donors for clinical transplantation.
• Develop assays to determine successful tolerance induction in humans.
• Elucidate developmental aspects of immunology as a means of identifying potential targets to modify for future tolerance induction.
• Determine optimal methods for donor myocardial preservation, including pre-harvest and optimal preservation strategies during transport.
• Investigate the role of lymphatic vessel disruption in allograft failure, myocardial fibrosis, reduction in ventricular function, and cardiac allograft vasculopathy.

Translational Research:

• Develop and test new strategies for inducing tolerance to transplanted hearts in nonhuman primates.
• Identify and validate biomarkers to show when tolerance has been induced and when it has been lost.
• Study the development of the immune system in infants and children to learn how they may respond differently to immunosuppression.
• Refine noninvasive methods to detect rejection, particularly before myocardial damage occurs.

Clinical Research:

• Identify genetic profiles that influence the risk of rejection so that immunosuppression can be adjusted accordingly.
• Evaluate newly identified strategies to induce donor-specific cardiac tolerance, e.g., mixed chimerism, blockade of co-stimulatory molecules, and induction of T regulatory cells.
• Identify additional risk factors for cardiac allograft vasculopathy, e.g., insulin resistance and metabolic syndrome, and ischemia/reperfusion injury.
• Increase the number of hearts available for transplantation by improving donor myocardial function after the treatment of autonomic storm during brain death.

Contributing Sources:

• NHLBI Strategic Plan Goals 1 and 2.
• Recommendations from the NHLBI Strategic Plan Level One Final Reports:
  • Regenerative and Reparative Medicine
• NHLBI Workshops and Working Groups:
  • NHLBI Heart and Lung Xenotransplantation Working Group, July 30, 2001.
  • Platt J, DiSesa V, Gail D, Massicot-Fisher J: Recommendations of the National Heart, Lung, and Blood Institute Heart and Lung Xenotransplantation Working Group. Circulation. 2002 Aug 27;106(9):1043-7.
  • NHLBI Heart and Lung Tolerance Working Group, December 4, 2000.
  • Massicot-Fisher J, Noel P, Madsen JC: Recommendations of the National Heart, Lung, and Blood Institute Heart and Lung Tolerance Working Group. Transplantation 2001 Oct 27;72(8):1467-70.

September 2008