Remote Ischemic Conditioning

Abstract

This editorial describes benefits and limitations of remote ischemic conditioning. Remote ischemic conditioning was shown to reduce myocardial intact size in at least 4 sizeable clinical trials of acute myocardial infarction. It was not effective in recent studies of cardiac surgery. Reasons for these differences are discussed.

There are relatively few therapies that have consistently shown benefits of protecting the heart during periods of ischemia or hypoxia followed by reperfusion. Ischemic preconditioning ¹ is one of them, but the problem with this approach is that the organ that is to become ischemic must be treated before the test ischemia. Another approach is remote ischemic preconditioning (RIPC), whereby a limb or limbs are made briefly and transiently ischemic, ^{2 –4} usually with a blood pressure cuff inflated to above systolic levels for a few minutes, followed by deflation, with repetition of this protocol a few times prior to test ischemia of a remote organ (such as coronary occlusion). When the ischemic conditioning protocol commences during the same time as the test occlusion, the term perconditioning has been used. Remote ischemic conditioning has been shown to reduce myocardial infarct size in numerous experimental studies. One suggested mechanism of action involves transfer of a humoral substance from one organ to another. There are several clinical trials of remote conditioning that have shown improved myocardial salvage in humans in the setting of acute ST-segment elevation myocardial infarction or elective percutaneous coronary interventions (PCIs). The data on using this form of therapy to protect hearts undergoing cardiac surgery have largely been mixed. Two large studies recently published in the New England Journal of Medicine showed no benefit of RIPC on clinical outcomes following cardiac surgery. Meybohm et al ⁵ reported results of a randomized controlled trial of 1385 patients who underwent RIPC using 4 cycles of 5 minutes of arm blood pressure cuff inflation to > or = 200 mm Hg followed by 5 minutes of cuff deflation or sham RIPC after propofol anesthesia and prior to cardiac surgery. The primary end points were death, nonfatal myocardial infarction, stroke, and acute renal failure up to 14 days. The primary end points were reached in 14.3% of the RIPC patients and 14.6% of the sham RIPC patients (P = not significant [NS]). There were no differences in any of the components of the primary outcome between the groups. In addition, there was no difference in the amount of troponin released between the groups. A second negative study was reported by Hausenloy et al. ⁶ This study involved 1612 patients at increased surgical risk subjected to coronary artery bypass surgery with or without valve replacement, who after anesthesia underwent randomization to RIPC induced by four 5-minute cycles of blood pressure cuff inflations and deflations on the upper arm or sham. The primary end point was the composite of death from cardiovascular causes, nonfatal myocardial infarction, coronary revascularization, or stroke at 12 months. The primary end point occurred in 26.5% of the RIPC patients and in 27.7% of the control patients (P = NS). There were no differences in components of the composite outcome between groups. Like the previous study, there was no evidence that RIPC reduced biomarker of myocardial necrosis. These 2 studies will likely end attempts to study the effect of RIPC as an adjunctive therapy for cardiac surgery. However, I was not surprised by the outcomes of these 2 studies. In a previous article, we reviewed the concept that there has been much variability in outcomes when RIPC is applied to cardiac surgery. ⁷ It is important to remember that in this situation, the cardiac surgeons already have been protecting the hearts during decades of surgical practice with cardioplegia, hypothermia, anesthetic agents, and analgesic agents that themselves may be cardioprotective, such as propofol and opoids, as well as unloading the ventricles during the procedure. There is even some evidence that a skin incision itself may through nociception mechanisms protect remote organs. If the heart is already protected, then it will be difficult to show that RIPC has an additive effect on top of other cardioprotective therapies that are already present. Does this spell the end of RIPC? I do not think so. The RIPC may not work for protecting hearts undergoing cardiac surgery, but there are at least 4 sizable clinical trials in patients with ST-segment elevation myocardial infarction showing that remote conditioning (actually perconditioning as the conditioning was started during the same time the coronary artery was presumed occluded) improves salvage of ischemic myocardium and in 1 study improved long-term outcome.

Botker et al ⁸ studied 333 patients with first acute myocardial infarction who were randomized to receive remote conditioning (four 5-minute inflation/deflation cycles with an arm blood pressure cuff) during transport to the hospital and prior to primary PCI. The primary end point, the amount of myocardial salvage at 30 days measured by perfusion imaging, was improved in the conditioning group (salvage index = .75) versus the control group (0.55; P = .03). Sloth et al ⁹ reported the long-term clinical outcome from this study. Major adverse cardiovascular events were followed for a median of 3.8 years and were reduced in the conditioned patients (13.5%) compared to the control patients (25.6%), with a hazard ratio of 0.49 (P = .018). In addition, the hazard ratio for all-cause mortality also favored the group that had remote conditioning (0.32; P = .027). The authors concluded that remote ischemic conditioning prior to PCI improved long-term clinical outcomes in patients with myocardial infarction. A second study was reported in 2013 by Crimi et al. ¹⁰ They studied 100 patients with ST-segment elevation myocardial infarction with occluded left anterior descending coronary artery and randomized them to remote ischemic conditioning utilizing 3 cycles of 5 minutes of cuff inflation/deflation of the lower limb during primary PCI of the infarct artery. Median area under the curve for the biomarker of necrosis (in this case CK-MB) was 8814 Units in the conditioning group versus 10 065 in the control group, for a relative reduction of infarct size in the conditioned group by 20% (P = .04). There was more complete ST resolution in the conditioned group. In addition, magnetic resonance imaging demonstrated less edema in the conditioned group compared to the control patients. A third major study was reported by White et al ¹¹ who randomized 197 patients with ST-segment elevation myocardial infarction and Thrombolysis in Myocardial Infarction flow grade of 0 (total occlusion of the infarct artery) to remote ischemic conditioning (four 5-minute cycles of upper arm inflation/deflation using a blood pressure cuff) or sham control prior to primary PCI. Myocardial infarct size, measured by magnetic resonance imaging at days 3 to 6 after admission, was 24.5% in the control group and 18.0% in the conditioning group (P = .009), representing a 27% reduction in the size of the myocardial infarctions. High-sensitivity troponin T, a biomarker of myocardial necrosis, was also lower in the conditioned group as was myocardial edema by magnetic resonance imaging. When the authors used the coronary artery angiographic jeopardy score to estimate an ischemic risk zone, remote conditioning improved the myocardial salvage index from 0.28 in the control group to 0.42 in the treated group (P = .03). The authors concluded that remote ischemic conditioning instituted prior to PCI reduced myocardial infarct size and edema and improved myocardial salvage.

Besides reducing cardiac damage in the throes of an acute myocardial infarction, RIPC was shown to reduce release of biomarkers of myocardial necrosis associated with elective percutaneous coronary interventions. ¹² In the CRISP stent trial, a 6-year follow-up showed that RIPC was associated with reduced major adverse cardiovascular events compared to untreated patients. ¹³ A host of meta-analyses have also suggested that remote conditioning prior to percutaneous intervention reduces necrosis and may confer other benefits, ^{14 –16} although not all studies have shown reductions in mortality or major cardiac events, even when remote conditioning was shown to reduce periprocedural myocardial infarctions and release of necrotic biomarkers. ¹⁷

Although recent clinical studies examining the effect of remote ischemic conditioning on outcomes following cardiac surgery have been negative, this should not dissuade researchers from pursuing other potential applications of conditioning. Again, this therapy has now been shown to be successful in robust ST-segment elevation myocardial infarction studies and a host of elective PCI studies. The technique is simple, cost effective, and has little risk. It is equally effective to other conditioning therapies. In fact, in one recent study of ST-segment elevation myocardial infarction (fourth large study), adding postconditioning to RIPC just prior to reperfusion did not demonstrate added reduction in infarct size compared to RIPC alone. ¹⁸ Remote conditioning is also being studied for neuroprotective properties, for reducing contrast-induced nephropathy as well as to enhance athletic performance. ¹⁹ It likely will not work in all situations, such as that of cardiac surgery, where the test organ is already being protected by a host of other interventions such as cardioplegia, hypothermia, anesthetic agents, and opioids. However, it is clear that remote conditioning has been effective in several sizable ST-segment elevation myocardial infarction trials, and so this therapeutic approach is deserving of future study and exploration.