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Coronary heart disease is the largest major killer of American men and women and accounted for 1 of every 6 deaths in the United States in 2007.1 The annual incidence of myocardial infarction in the United States is estimated to be 935 000, with 610 000 new cases and 325 000 recurrent attacks. Survivors have a much higher chance of suffering from congestive heart failure, arrhythmias, and sudden cardiac death.
Prognosis after an acute myocardial ischemic injury is primarily dependent on the amount of myocardium that undergoes irreversible injury.2–4 Large transmural infarcts yield a higher probability of cardiogenic shock, arrhythmias, adverse remodeling, and development of late chronic heart failure. Although it has been known since the early 1970s that the size of a myocardial infarction can be modified by various therapeutic interventions,5 early coronary artery reperfusion by fibrinolysis or percutaneous coronary intervention, including balloon angioplasty with or without stenting, remains the only established intervention capable of consistently reducing infarct size in humans. Although reperfusion has led to significant advances in patient care and reduction in hospital mortality, delays in seeking medical attention and inherent limitations in initiating fibrinolysis or percutaneous coronary intervention dictate that additional substantive improvements in morbidity and mortality can be achieved only with the development of new adjunctive therapies coupled with reperfusion. In addition, reperfusion therapy itself may induce reperfusion injury, a phenomenon that may encompass stunned myocardium, no-reflow phenomenon, and lethal myocardial cell death. If this injury could be prevented or minimized by administration of adjunctive therapy, then the net benefit of reperfusion could be enhanced.
The problem of acute ischemic injury and myocardial infarction is not limited to patients with acute coronary artery syndrome. It remains a major problem in cardiac surgery as well. It is well documented that the incidence of myocardial necrosis after surgery, as determined by creatine kinase MB enzyme release and troponin levels, ranges somewhere between 40% and 60%, and, depending on its clinical definition, the incidence of myocardial infarction after coronary artery bypass graft surgery may be as high as 19%. The intermediate and long-term implications are considerable. In a recent retrospective analysis of 18 908 patients who underwent coronary artery bypass graft surgery and in whom long-term follow-up was available, it was shown that myocardial enzyme elevation within the first 24 hours of surgery was associated with increasing mortality over the course of months to years. This study confirms earlier reports that even small enzyme elevations after surgery are associated with worse long-term outcomes.4
To expedite progress in cardioprotection against ischemia/reperfusion injury and facilitate translation of promising therapies from preclinical to clinical use, the National Heart, Lung, and Blood Institute (NHLBI) within the National Institutes of Health convened an invitational workshop of leading national and international experts in fundamental, translational, and clinical science on September 20 to 21, 2010, in Rockville, MD. The objectives of the workshop were to (1) identify the highest-priority knowledge gaps and barriers that have prevented the implementation of effective clinical studies on promising cardioprotective technologies; (2) consider approaches that capitalize on current scientific opportunities; (3) focus on areas that require unique NHLBI leadership to promote progress toward translation; and (4) 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 acute ischemic myocardial damage. The recommendations generated would be used to guide informed decisions on research priorities and directions in the field of myocardial protection against ischemia/reperfusion injury. Detailed summaries of individual presentations will be published in a focused issue of the Journal of Cardiovascular Pharmacology and Therapeutics. The present article focuses on the gaps in knowledge identified at the workshop and presents the recommendations for clinical and basic studies provided by the workshop participants.
The workshop was focused on progress made since the 2003 NHLBI Working Group convened on this topic entitled, “Translation of Therapies for Protecting the Heart From Ischemia.”6 Consistent with the recommendations of the 2003 Working Group was the recent NHBLI support of a multicenter Consortium for Preclinical Assessment of Cardioprotective Therapies (CAESAR) to perform systematic preclinical testing of cardioprotective therapies with the use of standardized and randomized protocols in multiple species, performed by blinded investigators, and analyzed by blinded data analysis cores and a single statistical core, as is done for randomized, multicenter clinical trials. Furthermore, the consortium offers unique opportunities for productive collaborations with industrial partners who, along with investigators in academia, will have the opportunity to propose therapies for testing in the consortium. The workshop participants expressed 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 1 animal model of human disease and more than 1 laboratory.
Another key recommendation from the 2003 Working Group was a need for further studies to test the clinical benefit of adenosine. Since 2003, the final results of the Acute Myocardial Infarction Study of Adenosine (AMISTAD) 2 have been reported.7 In this study, >2100 ST-segment elevation myocardial infarction patients receiving reperfusion therapy were randomized to a 3-hour infusion of either intravenous adenosine (50 or 70 μg/kg per minute) or placebo. There was no difference in the primary end point (congestive heart failure or death within 6 months) between placebo and adenosine. In a prospective substudy, the median infarct size assessed by single photon emission computed tomography (SPECT) was 27% of the left ventricle for the placebo group; it was 11% in the 70-μg/kg per minute adenosine group (P=0.023) and 23% in the 50-μg/kg per minute (P=NS) group. The reduction of infarct size at the higher dose of adenosine confirmed the previous AMISTAD 1 study.8 The authors of AMISTAD 2 stated that “a likely explanation for failure for the trial to demonstrate a clinical benefit was that it was underpowered, since sample size calculation was based on a reduction of events in the pooled adenosine group by 25%. The reduction observed was only 11%.”7 In a subsequent analysis of patients reperfused in a timely fashion, adenosine therapy was associated with lower rates of death compared with placebo.9
The participants acknowledged promising small clinical trials that suggested the benefit of certain agents and mechanical interventions, sometimes within specific subpopulations, including postconditioning,10 cyclosporine,11 remote conditioning,12 hypothermia,13 hyperoxemia,14 and others. The present workshop participants strongly supported clinical trials of new and potentially selective adenosine receptor agonists in addition to adenosine.
The workshop focused on prevention of injury associated with acute myocardial infarction and reperfusion and did not address regeneration of the myocardium. Thus, the use of stem cells even as combination adjunctive therapies with other agents was considered to be beyond the purview of the discussions, although the participants suggested that this could be a future consideration.
Although a host of adjunctive therapies have failed, recently published clinical trials utilizing conditioning techniques have shown progress with positive benefit on myocardial salvage.10–12 In addition, basic science studies of cardioprotection have provided important knowledge that has improved our understanding of the physiology, pathology, and molecular biology of myocardial ischemia/reperfusion injury and furthered our understanding of the mechanisms of action of cardioprotective agents. Table 1 lists several of the major trials testing cardioprotective strategies published since the 2003 NHLBI Working Group convened on this topic.7,10,15–24 Although several of these studies have been negative, others have shown evidence that adjunctive therapy can salvage ischemic myocardium in the clinical setting. There have been significant advances in understanding the biochemical and molecular mechanisms involved in conditioning that have been derived from basic science studies, as summarized in Table 2. From these investigations, new pharmacological agents may be developed that mimic the benefits of conditioning without needing to induce the brief ischemic episodes of conditioning.
The workshop participants reviewed the current state of knowledge about the mechanisms that provide protection against myocardial ischemia/reperfusion injury and noted key areas for future development. Their aim was to provide basic science understanding as well as to facilitate or enhance translation of cardioprotective strategies to the bedside.
Myocardium exposed to a shorter period of ischemia is still viable but is reversibly injured and can be salvaged by reperfusion alone. With a sufficiently sustained period of severe ischemia, myocardium has the potential to become irreversibly injured and cannot be salvaged by restoration of flow alone. On reperfusion, some of this tissue rapidly undergoes contraction band necrosis and is subsequently replaced by fibrous tissue. The changes that lead to the development of the state of irreversible injury are not fully understood. In 2003, Zhao et al25 were the first to recognize that treatment of hearts with intermittent periods of ischemia, an intervention called postconditioning, is capable of salvaging myocardium previously made ischemic; these findings supported the concept of a reperfusion-induced component of lethal tissue injury. Postconditioning has been shown to be effective only when applied within the first minute of reperfusion,26 and there is evidence that its protection may be limited to mild or moderate injury.27 In contrast, a study by Manintveld at al28 suggests that postconditioning is deleterious when the duration of ischemia is short and that higher benefit is expected when occlusion is prolonged.
Mitochondria have been identified as a common end effector of conditioning.29 Specifically, the mitochondrial permeability transition pore has emerged as having an important role in cell death during reperfusion and may be inhibited by preconditioning30 and postconditioning,31 although details of the structure and function of the pore are not fully understood.32 The pore may also participate in apoptotic cell death and may play a physiological role in autophagy.33
Uncertainty that exists regarding the magnitude, time course, and nature of lethal reperfusion injury and how it can be modulated represents an important gap of knowledge that may hinder the appropriate design of clinical trials.
Capillary endothelium swells markedly in the center of an ischemic focus and may impede reflow to the area when reperfusion therapy is applied. In this situation, the phenomenon of no-reflow occurs, and the tissue remains permanently ischemic. Large areas of no-reflow may result in more infarct expansion and adverse left ventricular remodeling in both experimental and clinical studies.34 Recent clinical studies have shown no-reflow to be an independent risk factor for poor prognosis for any infarct size.35 The mechanism of this phenomenon and its potential long-term impact represent a key knowledge gap.
The effectiveness of preconditioning,36 postconditioning,25 remote preconditioning,37 and perconditioning38 (the conditioning protocol of brief episodes of ischemia/reperfusion in a remote organ concurrent with the prolonged ischemic event in the target organ) to salvage additional myocardium when combined with reperfusion has been demonstrated in a variety of animal models of ischemia/reperfusion injury. Many molecular and biochemical pathways responsible for the actions of preconditioning have been elucidated39–42 and have provided targets for pharmacological interventions and therapeutic strategies.29 The molecular and subcellular mechanisms responsible for postconditioning, remote conditioning, and perconditioning are less well defined. Optimization of all conditioning strategies could benefit from integration of genomic, metabolomic, and proteomic information together with data denoting phenotypic function to elevate this understanding to the level of systems medicine. There is also a need to determine whether the protective mechanism triggered by remote conditioning is humoral, neural, or both. If it is humoral, then the substance or substances responsible for the benefit need to be defined so that therapies can be developed on the basis of the mechanism. Elucidation of these mechanisms would not only provide additional therapeutic targets but may enable optimization of therapeutic benefit through combined therapies.
Age, obesity, and diabetes mellitus may attenuate the beneficial effects of cardioprotective strategies such as ischemic or pharmacological preconditioning.43–46 There may also be gender differences in mechanisms of cardioprotection.47 The impact of concurrent medications on therapeutic strategies can also confound interpretation of the results of clinical trials. The mechanisms by which comorbidities and other factors (eg, medications, gender) can interfere with cardioprotective strategies, as well as development of maneuvers to overcome this interference, remain important knowledge gaps.
There is a wealth of preclinical data supporting a large number of drugs and interventions that have been reported to limit infarct size in animals. Some have been tested only in isolated hearts or cells, whereas others have been studied extensively in an in vivo model with supporting dose and schedule information. The workshop participants identified key criteria that define the minimum requirements for progression from preclinical studies to testing for therapeutic benefit in clinical studies. These include safety, availability of pharmaceutical-grade agent or technique, efficacy as verified in multiple species from multiple laboratories and confirmed in vivo and in large-animal models, and robustness of response. Preclinical studies should be conducted in a randomized, blinded fashion when possible, data should be obtained in acceptable models and reproduced from one laboratory to another and across species, and the effectiveness of treatments should be verified in models of comorbidities.
Preconditioning36 is a powerful maneuver to reduce infarct size in experimental models, but its clinical application is limited to situations in which therapy is administered in advance of a scheduled ischemic event, such as cardiac surgery, planned angioplasty, and organ preservation protocols. Preconditioning is not really practical for treating acute myocardial infarction in patients, an event that is not predictable. However, recent small clinical trials have suggested that other types of conditioning may limit myocardial infarct size in humans, including postconditioning by brief angioplasty balloon reinflations and deflations after placement of an intracoronary stent,10 pharmacological postconditioning with cyclosporine,11 and remote perconditioning with brachial cuff inflations and deflations begun in the ambulance.12 There is a need to develop additional pharmacological strategies that mimic, synergize, or augment the protection exerted by conditioning protocols in conjunction with reperfusion. Moreover, the encouraging results of these recent clinical conditioning trials should be tempered by the fact that in general they were small and should be confirmed in larger trials.
Assessment of the effect of potentially confounding factors, such as diabetes mellitus, age, and concomitant medicine (such as the oral antidiabetic agents that block the protective KATP channels), might help to optimize the efficiency of protective interventions in subpopulations of poor responders or nonresponders and aid in the design of future studies that seek to examine protective interventions against lethal reperfusion injury. Clinical situations in which cardioprotective strategies can be effective, including understanding the role of gender, age, comorbidities, and comedications on infarct size, remain a critical knowledge gap.
Demonstration of an incremental treatment benefit with reperfusion therapy in acute myocardial infarction is a challenge that requires superior imaging resolution to assess both the infarct and the risk region. Infarct size in patients is highly variable and reflects known variability in confounding factors including myocardium at risk, time to reperfusion, and amount of residual flow to the infarct zone through collaterals or intermittent antegrade flow. Whenever possible, the size of the ischemic zone should be measured and used to stratify the risk in these patients. Sophistication in the measurement of risk zone over the past 10 years has markedly increased, but questions remain concerning the timing and how best to measure myocardial area at risk in patients with myocardial ischemia, whether by coronary angiography, ventriculography, technetium-99m sestamibi SPECT myocardial perfusion imaging, or magnetic resonance imaging (MRI).
MRI offers a new and intriguing alternative to SPECT with regard to imaging myocardial infarct size, area at risk, and myocardial salvage. Infarct size is often assessed by cardiac enzyme release or imaging modalities, such as MRI and SPECT.48–52 Myocardial perfusion imaging with technetium-99m sestamibi has been well validated as a technique for measurement of infarct size.49,50 There is a close association between infarct size determined by SPECT sestamibi and left ventricular function, fibrosis in human hearts, subsequent patient mortality, and response of abnormal segments to revascularization.53,54 Multiple single-center studies have employed paired imaging to measure both the myocardium at risk for infarction and infarct size. Limitations of SPECT include the intrinsic resolution of SPECT images, the logistical difficulty of performing paired imaging to measure myocardium at risk, the small absolute benefit from ancillary therapy in patients receiving successful reperfusion therapy with either fibrinolytic therapy or percutaneous coronary intervention, the potential confounding effect of late myocardial recovery, and the inability to distinguish poor blood flow from fibrosis. Infarct imaging by MRI, with the use of delayed contrast-enhanced imaging with a paramagnetic contrast agent such as gadolinium, has been validated in both animal and clinical studies. The higher-resolution images obtained with the use of cardiac MRI make MRI the first clinically available tool able to resolve the transmural extent of infarction.48,51 When the classic wavefront theory describing the progression from subendocardial to transmural infarction is considered,55,56 gadolinium-enhanced MRI is an excellent tool for determining the transmural extent of infarction. A multicenter, multivendor study showed that gadolinium-enhanced MRI is feasible, sensitive, specific, and accurate for detecting acute and chronic myocardial infarction.57
More recent developments in T2-weighted MRI and other methods suggest that MRI can detect the area at risk on the basis of regional myocardial edema.58 However, there may be some unresolved technical issues with this approach,59 and there is a theoretical concern that some cardioprotective therapies might limit reperfusion-induced edema, resulting in a falsely attenuated risk zone that could lead to an underestimation of myocardial salvage. MRI has the convenience that area at risk and infarct size can be measured in a single examination ≈2 to 7 days after acute myocardial infarction.58,60 T2-weighted MRI has been validated in humans and compared well with SPECT and invasive angiographic measures of area at risk.60–62 T2-weighted MRI has been used successfully in a clinical trial for detecting myocardial salvage with hypothermia protection,63 but there are relatively few such studies to date.
The participants recommended 4 basic science priorities and 1 comprehensive 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. Formal recommendations from this workshop for use in planning and prioritization in concert with the NHLBI mission are summarized as follows (order of presentation does not imply relative priority or recommended sequence):
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 in a multicenter format important proof-of-concept studies not likely to be pursued by industry, the opportunity to foster and maintain 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.
The participants appreciate that there is substantial work in the field of cardioprotection in other countries67,68 and recognize the value of joint efforts in this area. They suggest that there be continued dialogue with groups outside the United States and consideration of future collaborative trials.
Additional NHLBI staff participants included Dr Jerome Fleg, Dr Isabella Liang, and Lynn Rundhaugen. We thank Karen Schwartz, Christy Ezell, Kathleen Smith, and Ashley Lewis for their assistance in organizing the meeting.
Sources of Funding This study was supported by the Division of Cardiovascular Sciences, NHLBI, National Institutes of Health.
Disclosures Dr Schwartz Longacre is an employee of National Institutes of Health; Dr Kloner receives research support (>$10K) and honoraria (>$10K) from Gilead (formerly CV Therapeutics), receives research support from Stealth (>$10K), and consulted with Gilead and Stealth; Dr Arai is an employee of National Institutes of Health and receives research support through a US government Cooperative Research and Development Agreement with Siemens (>$10K); Dr Baines receives research support from National Institutes of Health (>$10K) and the American Heart Association (>$10K); Dr Bolli receives National Institutes of Health research support for CAESAR (U24 HL094373), which is a consortium to study cardioprotective therapies (>$10K); Dr Braunwald reports no disclosures; Dr Downey receives research support from National Institutes of Health (>$10K; R01 HL020648); Dr Gibbons receives research support from Ikaria (>$10K); Dr Gottlieb receives research support from National Institutes of Health (R01 HL060590, R01 HL092136, R01 AG033283, and P01 HL085577) (>$10K), receives honoraria for various academic visiting professorships (<$10K), and is a cofounder of Radical Therapeutix, Inc (>$10K invested); Dr Heusch receives research support from the German Research Foundation (>$10K) and honoraria for educational lectures (<$10K) and speakers bureau payments (<$10K) for Servier; Dr Jennings reports no disclosures; Dr Lefer receives research support from National Institutes of Health on nitrate-mediated cardioprotection and H2Smediated cardioprotection (>$10K); Dr Mentzer receives research support from National Institutes of Health for studies on autophagy, adenosine, and pyruvate protection during heart surgery (>$10K) and is a scientific advisor to the Board of Radical Therapeutix; Dr Murphy is an employee of National Institutes of Health, and a family member receives research support from National Institutes of Health (>$10K) and serves on the ACADESINE advisory board (<$10K); Dr Ovize is conducting the CIRCUS study supported by a program hospitalier de recherche cinique with study treatment (iCsA) provided by NeuroVive (<$10K); Dr Ping has no disclosures; Dr Przyklenk received honoraria for invited lectures on preconditioning and remote preconditioning (>$10K); Dr Sack is an employee of National Institutes of Health; Dr Vander Heide receives research support from National Institutes of Health (>$10K; R01 HL084405 and R21 HL098786); Dr Vinten-Johansen holds 2 patents on postconditioning (<$10K) and is a consultant for Reperfusion Therapeutics, Inc (<$10K); Dr Yellon receives research support from the British Heart Foundation Program (>$10K), British Heart Foundation Project on mitochondria (>$10K), British Heart Foundation Project on Akt Signaling (>$10K), British Heart Foundation Project on Preconditioning (>$10K), and National Institute for Health Research Clinical Trial (>$10K), drugs and research support from Fibrogen (>$10K), drugs and research support from Merck Sharp & Dohme (>$10K), payments for speakers bureau appointments to Pfizer, Bristol-Myers Squibb, and Glaxo (<$10K), honoraria from Roche (<$10K), and consultations for Roche (<$10K).