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| AATS/NHLBI: Cardiothoracic Surgery Exploring Collaborative Clinical Research Opportunities |
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Title and Author Ischemia-Reperfusion Injury: A Conundrum to Prevent and TreatRobert M. Mentzer, Jr., M.D. Abstract
An unmet clinical need in heart surgery is the prevention of ischemia-reperfusion injury that results in postoperative myocardial stunning and necrosis. Depending upon the type of surgery, the incidence of stunning requiring inotropic support ranges between 60% and 90%. In high-risk patients with marginal cardiac reserve, it is often a cause of prolonged critical care and increased mortality. The incidence of myocardial necrosis after heart surgery is less appreciated, often underestimated, and the consequences more subtle. Outcomes may not be apparent for months to years. There is considerable evidence that new myonecrosis after CABG surgery ranges between 40% and 60%, and the incidence of Q wave or non-Q-wave MI ranges between 12% and 19%. Enzyme elevations after surgery are an independent predictor of increased risk of intermediate and late death—the risk may be as high as 40% to 50%. It now appears that even modest enzyme elevations in CK-MB levels within the first 24 hours after surgery are associated with increased risk of death at 5 years.1
The failure to develop more effective interventions is multifactorial. A major reason, however, has been the failure of phase II myocardial protection trials to predict successful phase III trials whether it is in the setting of patients undergoing cardiac surgery or reperfusion therapy for acute MI. This has resulted in lack of enthusiasm among cardiac surgeons and the pharmaceutical industry to develop new techniques or drugs for this indication. The use of more robust surrogate endpoints in future phase II trials would address this problem. This could be accomplished by directly measuring myocardial contractility and the incidence of MI before and after surgery using cine-CMR and delayed-enhancement cardiac magnetic resonance (DE CMR).2 Since the incidence of new myonecrosis (MI) after CABG surgery assessed by DE-CMR ranges between 30% and 40%,3 the use of this imaging modality would allow for the determination of efficacy in less than 600 patients and no more than 10 to 12 participating sites. Candidate strategies include preconditioning, postconditioning, and remote conditioning. Candidate drugs include chloramphenicol, adenosine, ivabradine, and cyclosporine A. In summary, an unmet clinical need in cardiac surgery is to identify more effective cardioprotective strategies. A major gap is the lack of a robust means to test the effectiveness of novel pretreatment or reperfusion therapies. The incorporation of DE-CMR into surgical phase II myocardial protection trials would address this gap. Key Research Gap Requiring NHLBI Leadership
A major gap is the lack of a robust means to test the effectiveness of novel cardioprotective pretreatment or reperfusion therapies in phase II cardiac surgical trials. Key Citations
1: Domanski MJ, Mahaffey K, Hasselblad V, et al. Association of myocardial enzyme elevation and survival following coronary artery bypass graft surgery. JAMA. Feb 9 2011;305(6):585-591.2: Kim HW, Farzaneh-Far A, Kim RJ. Cardiovascular magnetic resonance in patients with myocardial infarction: current and emerging applications. J Am Coll Cardiol. Dec 29 2009;55(1):1-16. 3: Selvanayagam JB, Petersen SE, Francis JM, et al. Effects of off-pump versus on-pump coronary surgery on reversible and irreversible myocardial injury: a randomized trial using cardiovascular magnetic resonance imaging and biochemical markers. Circulation. Jan 27 2004;109(3):345-350. |
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Copyright © 2012 American Association for Thoracic Surgery
All rights reserved. IMPORTANT REMINDER: The preceding information is intended only to provide
general guidance and not as a definitive basis for diagnosis or treatment in any particular case.
It is very important that you consult a doctor about any specific medical problem or question.
All rights reserved. IMPORTANT REMINDER: The preceding information is intended only to provide
general guidance and not as a definitive basis for diagnosis or treatment in any particular case.
It is very important that you consult a doctor about any specific medical problem or question.