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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:
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
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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
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