New Horizons in Cardioprotection
The National Heart, Lung, and Blood Institute (NHLBI) convened a Workshop on September 20-21, 2010 in Rockville, MD to provide recommendations to the NHLBI that would guide informed decisions on research priorities and directions in the field of myocardial protection against ischemia /reperfusion injury. The participants included national and international experts in basic and translational science as well as experts involved in clinical trials in the field of cardioprotection. These experts were asked to:
- Identify the highest priority knowledge gaps and barriers that prevented implementation of effective clinical studies on promising cardioprotective technologies.
- Consider approaches that capitalize on current scientific opportunities.
- Focus on areas which require unique NHLBI leadership to promote progress toward translation.
- Develop recommendations that would provide a strategy to facilitate the translation of experimentally successful cardioprotective therapies developed in basic science studies to patients at risk for myocardial ischemic heart disease.
Nearly 500,000 people die each year in the United States as a result of ischemic heart disease. In addition to the immediate consequences of acute myocardial infarction, acute ischemic insult may lead to congestive heart failure, arrhythmias, and sudden cardiac death. Age, obesity, and diabetes each increase the risk for myocardial ischemia. Thus, as the U.S. population continues to age and the prevalence of risk factors such as obesity and diabetes increases, the public health burden of ischemic heart disease may be expected to increase. Past basic science research has vastly improved our understanding of the process of reversible and irreversible myocardial cell injury that occurs with ischemia and reperfusion and the mechanisms of action of cardioprotective agents. Although there is still a need to improve our understanding of the fundamental bases of ischemia/reperfusion injury, there is also a need to translate past basic science findings into new therapies to protect the hearts of patients from ischemia/ reperfusion injury and improve both short-and long-term clinical outcomes.
The Workshop was focused on progress made since the 2003 NHLBI Working Group (WG) convened on this topic entitled, “Translation of Therapies for Protecting the Heart from Ischemia,” with recommendations reported in Circulation Research 2004, 95:125-134. One outcome of the 2003 WG was the recent NHBLI support of a multicenter Consortium for preclinicAl assESsment of cARdioprotective therapies (CAESAR), to perform systematic preclinical testing of cardioprotective therapies using standardized protocols performed by blinded investigators and analyzed by a single statistical core as done for randomized, multicenter clinical trials. The Workshop participants expressed considerable enthusiasm for the potential of this consortium as a means to move the field of cardioprotection forward and identify therapies that are truly efficacious in more than one animal model of human disease and more than one laboratory. Although the present Workshop participants strongly supported clinical trials of new and potentially selective receptor agonists over trials with adenosine, the other key recommendation from the 2003 WG, they recognized a need for studies to further test the clinical benefits of adenosine. This assessment was based on the final results of AMISTAD 2 which were reported after 2003 and showed a significant reduction in myocardial infarct size at a high dose of adenosine. Further, a post hoc analysis showed that patients reperfused early (<3.2 hours) had a reduction in clinical events with adenosine compared to placebo, indicating that adenosine itself could prove to be an appropriate therapeutic strategy in patients with acute anterior myocardial infarction.
The Workshop participants reviewed the current state-of-the-art in cardioprotection against myocardial ischemia / reperfusion injury that has been achieved through studies ranging from molecular studies to clinical trials and identified the most urgent knowledge gaps. These gaps include:
- The time course and mechanism of post-reperfusion cell death.
- The mechanism and potential long-term impact of no-reflow.
- Clinical situations when cardioprotective strategies can be effective, including understanding the role of age, gender, co-morbidities, or co-medications on infarct size.
- Pharmacological strategies that mimic, synergize, or add to the protection exerted by reperfusion and mechanical postconditioning.
- Protective mechanisms triggered by remote conditioning.
- Molecular and subcellular mechanisms of cardioprotection.
- Long-term consequences of myocardial salvage using a therapeutic intervention.
- How best to measure myocardial area-at-risk in patients with myocardial ischemia, whether by coronary angiography, ventriculography, MRI, or SPECT sestamibi.
The participants recommended four basic science priorities and one clinical science strategy that address these knowledge gaps and were identified as key to establishing progress toward improved fundamental understanding of ischemia/reperfusion injury and clinical implementation of cardioprotective therapies. The order of presentation does not imply relative priority or recommended sequence.
Basic Science Priorities
- Define effective cardioprotective interventions and the appropriate timing of their administration
- Define interventions that are efficacious at different time windows of the ischemia and reperfusion injury sequence. Clarify the biology and timecourse of reperfusion injury, especially in large animal models, and establish how the determinants of ischemic injury, including the duration and severity of the ischemic episode, affect reperfusion injury.
- Determine if microvascular and capillary structure and function can be preserved to prevent or reduce the no reflow phenomenon, and if so, identify the long term effects.
- Identify the mechanisms of anti-ischemia/reperfusion injury therapies, including remote preconditioning, preconditioning, postconditioning, and hypothermia.
- Evaluate the effectiveness of combination therapies compared to single therapies and determine the optimal timing of administration of the components of combination therapy.
- Establish the identity, physiologic function, and regulatory mechanism of the mitochondrial permeability transition pore, implicated as a central mediator of cell death during reperfusion, and define its overall relationship between mitochondrial health and ischemic/reperfusion injury.
- Identify molecular markers and/or biomarkers that indicate the presence of a cardioprotected state, indicate responsiveness to a protective agent, or indicate susceptibility to either injury or therapy. Identification of a predictive marker of success may include assessment of tissue by genomics, proteomics, metabolomics, or molecular imaging.
- Evaluate the impact and mechanisms of impact of co-morbidities (such as age, gender, diabetes, hypertension, dyslipidemia, atherosclerosis) and co-medications (statins, ACE inhibitors, aspirin, clopidogrel) on cardioprotection. Develop strategies to overcome potential interference of these co-morbidities and co-medications with protection.
Clinical Science Strategy
- Establish a cardioprotective clinical trial network concurrent with the existing and complementary preclinical network (CAESAR) to test promising cardioprotective agents and strategies in patients in the setting of both acute myocardial infarction and cardiac surgery. This would both enhance the likelihood of a successful clinical trial and validate the use of animal models for therapy development with the aim of improving outcomes for cardiovascular patients. Advantages of a clinical research network include the opportunity to conduct important proof-of-concept studies in a multi-center format not likely to be pursued by industry, fostering and maintaining collaboration between member laboratories, an accelerated pace of protocol development through an established infrastructure, reduced operational costs, streamlined training of personnel, and broad recruitment and consideration of protocols through an independent steering committee.
- Since large areas of ischemia are more likely to show beneficial or deleterious effects, utilize well-defined patient populations that include large infarcts (e.g. anterior infarcts), successfully reperfused in a timely manner, without complicating features such as previous Q-wave myocardial infarctions.
- Initially conduct Phase II trials with endpoints of infarct size reduction assessed by nuclear SPECT imaging or MRI as well as enzymatic measures, potentially including Phase III trials as appropriate.
- Include a surgical arm which provides the advantage of pre-treatment and determination of the optimal timing of administration of agents (before the procedure, during the procedure, or after). The current existence of the Cardiothoracic Surgical Trials Network (CTSN), supported by NHLBI, could facilitate this arm of a cardioprotection network through collaboration and shared or consolidated resources.
- Incorporate comparison of MRI and SPECT imaging at centers with these capabilities.
- Include a data coordinating center component and core laboratories to validate study sites for accuracy of imaging.
- Include a preclinical component to characterize biomarkers, delineate mechanisms, and optimize therapeutic agents and protocols. The concurrent and complementary NHLBI consortium, CAESAR, could be a useful resource for this optimization.
- Candidates for clinical trials might include those that have already been shown to have efficacy in multiple preclinical laboratories, especially in large animal models, or in smaller clinical trials (i.e. cyclosporine A, remote conditioning, postconditioning, perconditioning, preconditioning, hypothermia, sodium hydrogen exchange inhibitors, and possibly adenosine or adenosine agonists), and combinational therapies (cocktails). The concept of starting with multiple interventions simultaneously might be considered as a best first step to show that reducing infarct size is feasible, with subsequent studies to isolate which portion or portions of the cocktail are active. Workshop participants also expressed interest in newer agents that could be candidates for further testing (ivabridine, chloramphenicol, glucagon-like peptide, etc). The clinical trial network could consider interventions recommended by CAESAR.
The participants appreciate that there is substantial work in the field of cardioprotection in other countries and recognize the value of joint efforts in this area. They suggest that there be continued dialogue with groups outside the U.S. and consideration of future collaborative trials.
A report is planned for publication in a peer-reviewed journal. Concurrent peer review and publication of individual presentations is planned in a separate journal.
Lisa Schwartz Longacre, PhD
Division of Cardiovascular Sciences
Jerome Fleg, MD
Division of Cardiovascular Sciences
Isabella Liang, PhD
Division of Cardiovascular Sciences
Lynn Rundhaugen, MPH
Division of Cardiovascular Sciences
Robert A. Kloner, MD, PhD
Heart Institute, Good Samaritan Hospital
Keck School of Medicine, University of Southern California
- Andrew Arai, MD – NHBLI (intramural)
- Christopher Baines, PhD - University of Missouri
- Roberto Bolli, MD – University of Louisville
- Eugene Braunwald, MD – Harvard University
- James Downey, PhD – University of South Alabama
- Raymond Gibbons, MD – Mayo Clinic
- Roberta Gottlieb, MD - San Diego State University
- Gerd Heusch, MD, PhD – University of Essen
- Robert Jennings, MD – Duke University
- David Lefer, PhD – Emory University
- Robert Mentzer, MD – San Diego State University and Wayne State University
- Elizabeth Murphy, PhD – NHLBI (intramural)
- Michel Ovize, MD, PhD – University of Lyon
- Peipei Ping, PhD – University of California, Los Angeles
- Karin Przyklenk, PhD – Wayne State University
- Michael Sack, MD – NHLBI (intramural)
- Richard Vander Heide, MD, PhD – Louisiana State University
- Jakob Vinten-Johansen, PhD – Emory University
- Derek Yellon, DSc, PhD – University College London