LAUSR

Remote ischemic conditioning (RIC) is the intriguing phenomenon whereby brief, benign episodes of ischemia–reperfusion applied in one vascular bed render remote tissues and organs resistant to the stress of a sustained ischemic insult. The first report of RIC, published by our group in 1993, provided evidence of “intracardiac” protection: using the anesthetized canine model, we found that infarct size in the left anterior descending coronary artery bed was significantly reduced in subjects that received brief antecedent periods of circumflex ischemia when compared with time-matched controls. This initial observation was, perhaps not surprisingly, considered provocative, was received with skepticism, and was, at best, viewed as a laboratory curiosity. However, nearly a decade later, interest in RIC was piqued by evidence of “intraorgan” protection: data obtained in the swine model revealed that brief periods of skeletal muscle ischemia— achieved noninvasively by simple inflation of a blood pressure cuff on a hind limb—evoked a profound, infarct-sparing effect. In the ensuing years, interest in RIC has continued to grow, with the publication of >1000 papers (PubMed, April 12, 2017) seeking to characterize the phenomenon, elucidate the molecular mechanisms that underlie RIC-induced protection, and, most notably, establish whether RIC would transcend preclinical investigation and improve patient outcomes. Definitive proof of clinical relevance has, however, proven to be problematic. Despite the wealth of data obtained in multiple experimental models documenting infarct size reduction with RIC, and the promising results obtained in numerous small phase I and II trials, progress toward the clinical translation has been described as “ . . . somewhere between frustrating and disappointing . . . ”. Moreover, this sense of disenchantment has been exacerbated by the recent neutral outcomes of 2 highly anticipated phase III trials designed to evaluate the cardioprotective efficacy of RIC in patients undergoing cardiac surgery: both the Effect of Remote Ischemic Preconditioning on Clinical Outcomes in Patients Undergoing Coronary Artery Bypass Graft Surgery (ERICCA) and Remote Ischaemic Preconditioning for Heart Surgery (RIPHeart) trials found no evidence of benefit in patients randomized to receive RIC prior to surgery when compared with controls. The failures of both of ERICCA and RIPHeart have led to much speculation and editorial commentary. Moreover, the outcomes of ERICCA and RIPHeart have raised the pivotal question: Do these neutral findings herald the demise of all future investigation and interest in the clinical application of RIC? This question—the future of RIC in the wake of ERICCA and RIPHeart—is the overarching theme of this 2-part focused issue. Accordingly, part I, to be published in July 2017, begins with a balanced, state-of-the-art assessment of the current status of RIC in cardiovascular surgery and a reasoned perspective on how the disappointments from ERICCA and RIPHeart can be (and should be) leveraged in the design of future surgical trials. Evaluation of RIC has not been limited to cardiac surgery and, moreover, has not been limited to heart: The scope of RIC includes (but is not limited to) cardioprotection in the settings of acute myocardial infarction and elective percutaneous coronary intervention, better maintenance of renal function in acute kidney injury and kidney transplant, as well as organ protection in patients undergoing vascular surgery— facets of RIC that are all addressed by leaders in their respective fields. In addition, an intriguing hypothesis is presented to suggest that the salutary effects of RIC may extend beyond organ protection: RIC may serve as a novel strategy to maintain uterine quiescence during pregnancy and thus limit the incidence (and potentially devastating consequences) of preterm birth. Part II of the focused issue, scheduled for publication in September 2017, expands on novel aspects of RIC to include evidence that local and remote conditioning have a favorable, inhibitory effect on platelet-mediated thrombosis, that exercise may serve as a RIC-like stimulus and