NHLBI Working Group
Translation of Therapies for Protecting the Heart from Ischemia

Executive Summary

The National Heart, Lung, and Blood Institute convened a Working Group of investigators on June 23-24, 2003, in Bethesda, Maryland to review the reasons for the failure to effectively translate potential therapies for protecting the heart from ischemia and reperfusion and to make recommendations for future approaches that would help to accomplish this task. Working Group members included basic scientists and physicians whose work has focused on the need for new therapies to protect the heart from ischemic and reperfusion injury.

The major goals for the Working Group were to: (1) evaluate the gaps and barriers in basic research which have delayed the clinical implementation of cardioprotective therapies; (2) identify clinical settings in which cardioprotective therapies may be useful; (3) identify basic science findings that are ready for translation into clinical research; and (4) provide prioritized recommendations to facilitate the advancement of both basic and clinical research and identify approaches to applying therapies to protect the heart from ischemic injury.

The two-day Working Group meeting was organized into three sessions covering the following topics:

Session 1: Protection in Cardiac Interventions

• Adjuncts to Cardiac Surgery
• Mechanical vs. pharmacological approaches
• Alternative approaches to preconditioning

Session 2: Treatment of Stable Angina

• Pharmacological approaches to chronic protection
• Gene therapy for prolonged protection
• Identification of ‘High Risk' patient populations
  

Session 3: Acute Coronary Syndromes and Out-of-Hospital Arrest

• Predicting ischemia and preventing sudden death
• Preventing/reversing ischemia induced arrhythmias
• Strategies for limiting infarct size
• Nuclear and MR assessment of infarction
• Clinical Trials, lessons and opportunities

The Working Group concluded that the field of cardioprotection in the setting of acute myocardial ischemia, cardiac surgery, and cardiac arrest is at a crossroads. The process that has been used thus far to identify cardioprotective therapies at the basic research level is often inefficient, wasteful, and ultimately counterproductive. For three decades, pharmaceutical companies and federal funding agencies have invested significant resources in single-center studies of cardioprotection that have often yielded inconclusive results that have failed to be translated to clinical practice. The Working Group believed that opportunity presently exists for a new paradigm that can obviate many of the unreproducible, conflicting, contradictory, and unconfirmed results of single-center studies. As such, they indicated that the time has come to focus on translational research using clinically-relevant outcomes in addition to mechanisms of action. Their recommended approach was to establish a system for rigorous preclinical testing of promising cardioprotective agents using methods analogous to those used in clinical trials (i.e., blinded, randomized, multicenter, and adequately powered studies using standardized methods). In addition, they indicated that continued efforts are justified in pursuing the interventions that have been identified as promising in preclinical studies and, in some cases, in phase I and II clinical trials. A preclinical research consortium would advance the ability to rationally and progressively translate important findings from the basic science laboratory into eventual clinical use. In addition, such a consortium would increase opportunities for productive collaborations with industrial partners

Finally, the Working Group believed that the investment in cardioprotection made by the pharmaceutical industry and federal government during the past three decades could and should be developed into clinically effect therapies. They, therefore, recommended that the NIH proactively intervene to remedy the problems that have impeded the translation of cardioprotective therapies. Their specific recommendations include a short-term, low-risk project (preclinical consortium) and two medium-term, clinical studies with a high likelihood of demonstrating effectiveness (phase III clinical trials of adenosine in AMI and cardiac surgery). Among these recommendations, the Working Group assigned the highest priority to the preclinical consortium, because such an entity would serve as a source of potentially useful therapies to be tested in subsequent clinical trials. The Working Group believed that with these initiatives, the NIH could catalyze the translation of improved cardioprotection into clinical reality.

A summary of the meeting is available in the journal, Circulation Research:
Roberto Bolli R, Becker L, Gross G, Mentzer R, et al. Myocardial Protection at a Crossroads: The Need for Translation into Clinical Therapy. Circ Res. 2004;95:125-134. (The full article is available online)

Working Group Members

Chair: Roberto Bolli, MD, Department of Medicine, University of Louisville

Session Moderators:

• Lance Becker, MD, Emergency Resuscitation, University of Chicago

• Garrett Gross, PhD, Department of Pharmacology & Toxicology, Medical College of Wisconsin

• Robert M. Mentzer, Jr., MD, Department of Surgery, University of Kentucky

Participants:

• Christopher B. Granger, MD, Duke Clinical Research Institute
• Dara Kraitchman, VMD, PhD, Department of Radiology, Johns Hopkins University School of Medicine
• Rakesh Kukreja, PhD, Medical College of Virginia
• Robert J. Myerburg, MD, Department of Medicine, University of Miami
• Karin Przyklenk, PhD, Department of Emergency Medicine, University of Massachusetts Medical School
• Jakob Vinten-Johansen, PhD, Department of Surgery, Emory University
• Richard D. Weisel, MD, Toronto General Hospital, University Health Network

• James Weiss, MD, Department of Medicine, UCLA School of Medicine

• Sir Magdi Yacoub, MD, Harefield Heart Science Centre, Middlesex

NHLBI Staff:

• David M. Balshaw, PhD, Heart Research Program, Division of Heart and Vascular Diseases
• David A. Lathrop, PhD, Clinical and Molecular Medicine Program, Division of Heart and Vascular Diseases
• Jerome Fleg, MD, Clinical Trials Research Group, Division of Epidemiology and Clinical Application
• Ahmed Hasan, MD, Division of Blood Diseases and Resources