February 11, 2020 415 Gerd Heusch, MD Bernard J. Gersh, MD, PhD Despite decades of preclinical and clinical proof-of-concept studies that have demonstrated that cardioprotection results in unequivocal infarct size reduction, translation into a benefit in clinical outcomes has been very disappointing. This is particularly frustrating given the clear relationship between infarct size and mortality as demonstrated in a recent meta-analysis of 10 trials.1 The concept of remote ischemic conditioning (RIC), which can be applied to an organ distant from the heart, such as by inducing ischemia and reperfusion by a cuff on the arm before, during, and after coronary occlusion, is particularly appealing from both a mechanistic and a logistical standpoint. Prior smaller studies had provided some encouragement with regard to infarct size reduction, and retrospective secondary analyses of some of these studies have also suggested an improvement in clinical end points, including cardiac death and hospitalization for heart failure. A single prospective randomized trial with >500 patients with ST-segment–elevation myocardial infarction has been completed demonstrating that RIC of the leg reduced the primary end point of cardiac mortality and hospitalization for heart failure.2 The observed clinical outcome was achieved despite the absence of infarct size reduction as measured by biomarkers that do not take into account the area at risk, depend on washout from the necrotic myocardium and the timing of blood sample withdrawal, and are therefore less robust to reflect infarct size reduction than imaging modalities.2 The expectations were that the CONDI2/ERIC-PPCI randomized trial (Effect of Remote Ischaemic Conditioning on Clinical Outcomes in STEMI Patients Undergoing PPCI)3 of >5000 patients would finally take us across one of the last frontiers of reperfusion therapy and that RIC in an ambulance or at hospital admission would become an integral component of reperfusion strategies in ST-segment–elevation myocardial infarction. Nonetheless, expectations were dashed by the results of this trial in which RIC of the upper arm did not reduce infarct size (as measured by troponin release over 48 hours, with a full troponin data set of 3 measurements only available for <15% of the recruited patients) or the primary end point of cardiac mortality and hospitalization for heart failure after 1 year.3 These neutral results in clinical outcomes with RIC are consistent with other encouraging proof-of-concept studies demonstrating reduced infarct size with ischemic postconditioning and many drugs, including cyclosporine and metoprolol, but failing to clear the hurdle of hard clinical end points in larger trials. How can the many positive preclinical and clinical proof-of-concept studies on reduced infarct size by ischemic conditioning interventions and cardioprotective drugs be reconciled with the mostly neutral results in regard to clinical outcomes? There are important differences between animal models and the clinical scenario of ST-segment–elevation myocardial infarction in humans with regard to comorbidities, the temporal pattern of coronary occlusion and reperfusion, the presence © 2020 American Heart Association, Inc. ON MY MIND
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