Remote ischemic preconditioning in humans has two phases of protection against endothelial IR injury; an early (short) and late (prolonged) phase, both of which are neuronally mediated. The potential for late phase RIPC to provide prolonged protection during clinical IR syndromes merits investigation.

Background— Transient limb ischemia administered before a prolonged ischemic insult has systemic protective effects against ischemia-reperfusion (IR) injury (remote ischemic preconditioning [RIPC]). It has been demonstrated that protection from IR can be achieved by brief periods of ischemia applied at a remote site during an injurious ischemic event (remote postconditioning [RPostC]). Using an in vivo model of endothelial IR injury, we sought to determine whether RPostC occurred in humans and whether it shared mechanistic similarities with RIPC. Methods and Results— Endothelial function was assessed by flow-mediated dilation before and after IR (20 minutes of arm ischemia followed by reperfusion). RIPC was induced by conditioning cycles of 5 minutes of ischemia and reperfusion on the contralateral arm or leg before IR. For RPostC induction, conditioning cycles were administered during the ischemic phase of IR. Oral glibenclamide was used to determine the dependence of RIPC and RPostC on K ATP channels. IR caused a significant reduction in flow-mediated dilation in healthy volunteers (baseline, 9.3±1.2% versus post-IR, 3.3±0.7%; P <0.0001) and patients with atherosclerosis (baseline, 5.5±0.6% versus post-IR, 2.3±0.5%; P <0.01). This reduction was prevented by RIPC (post-IR+RIPC: healthy volunteers, 7.2±0.5% [ P <0.0001 versus post-IR]; patients, 4.5±0.3% [ P <0.01 versus post-IR]) and RPostC (post-IR+RPostC: 8.0±0.5%; P <0.0001 versus post-IR). The protective effects of RIPC and RPostC were blocked by glibenclamide. Conclusions— This study demonstrates for the first time in humans that RPostC can be induced by transient limb ischemia and is as effective as RIPC in preventing endothelial IR injury. RIPC and RPostC share mechanistic similarities, with protection being dependent on K ATP channel activation. These results suggest that remote conditioning stimuli could be protective in patients with acute ischemia about to undergo therapeutic reperfusion.

et al. Circulation 2007;116(suppl I):I-98-105. Conclusion: Remote ischemic preconditioning (RIPC) reduces postoperative myocardial injury, myocardial infarction, and renal impairment in patients undergoing elective open abdominal aortic aneurysm (AAA) repair.Summary: Remote ischemic preconditioning is a phenomenon where brief periods of ischemia, followed by reperfusion, can provide systemic protection from prolonged ischemia. The authors sought to investigate whether RIPC could reduce the incidence of myocardial and renal injury in patients undergoing elective AAA repair. This was a randomized trial, and 82 patients were randomized to undergo AAA repair with RIPC or AAA repair without RIPC. Remote ischemic preconditioning was performed using two cycles of intermittent cross-clamping of the common iliac arteries with 10 minutes of ischemia, followed by 10 minutes of reperfusion. Cardiac troponin levels were used to assess postoperative myocardial injury and myocardial infarction. Renal injury was assessed by serum creatinine level. Baseline characteristics were well matched in both groups.The incidence of myocardial injury was reduced 27% by RIPC (39% vs 12%; 95% confidence interval [CI], 8.8%-45%; P ϭ .005). Also reduced in the RIPC patients were myocardial infarction (27% vs 5%; 95% CI, 7.3%-38%; P ϭ .006) and renal impairment (30% vs 7%; 95% CI, 6.4%-39%; P ϭ .009. The effect of covariables was assessed with multivariable analysis. The protective effect of RIPC on myocardial injury (odds ratio, 0.22; 95% CI, 0.07-0.67; P ϭ .008), myocardial infarction (odds ratio, 0.18; 95% CI, 0.04-0.75; P ϭ .006) was independent of the covariables.Comment: Studies suggest that ischemia at a site distal from the heart can confer ischemic protection at remote sites. This must occur through some sort of neural mechanism or a circulating humoral mechanism. It is intriguing to think that a simple maneuver that is feasible in most AAA open repairs could reduce cardiac and renal impairment after open AAA repair.

Background-Hypoxic cell death follows interruption of blood supply to tissues. Although successful restoration of blood flow is mandatory for salvage of ischemic tissues, reperfusion can paradoxically place tissues at risk of further injury. Brief periods of ischemia applied at the onset of reperfusion have been shown to reduce ischemia-reperfusion (IR) injury, a phenomenon called postconditioning. The aim of this study was to determine whether postconditioning protects against endothelial IR injury in humans, in vivo. Methods and Results-Brachial artery endothelial function was assessed by vascular ultrasound to measure flow-mediated dilation (FMD) in response to forearm reactive hyperemia. FMD was measured before and after IR (20 minutes of arm ischemia followed by 20 minutes of reperfusion) in healthy volunteers. To test the protective effects of postconditioning, 3 cycles of reperfusion followed by ischemia (each lasting 10 or 30 seconds) were applied immediately after 20 minutes of arm ischemia. To determine whether postconditioning needs to be applied at the onset of reperfusion, a 1-minute period of arm reperfusion was allowed before the application of the 10-second postconditioning stimulus. IR caused endothelial dysfunction (FMD 9.1Ϯ1.2% pre-IR, 3.6Ϯ0.7% post-IR, PϽ0.001; nϭ11), which was prevented by postconditioning applied as 10-second cycles of reperfusion/ischemia (FMD 9.9Ϯ1.7% pre-IR, 8.3Ϯ1.4% post-IR, PϭNS; nϭ11) and 30-second cycles of reperfusion/ischemia (FMD 10.8Ϯ1.7% pre-IR, 9.5Ϯ1.5% post-IR, PϭNS; nϭ10) immediately at the onset of reperfusion. No protection was observed when the application of the 10-second postconditioning stimulus was delayed for 1 minute after the onset of reperfusion (FMD 9.8Ϯ1.2% pre-IR, 4.0Ϯ0.9% post-IR, PϽ0.001; nϭ8). Key Words: endothelium Ⅲ ischemia Ⅲ reperfusion Ⅲ reperfusion injury Ⅲ postconditioning T he prerequisite for salvage of viable myocardium and limitation of infarct size after an acute ischemic event is timely reperfusion. 1,2 However, restoration of coronary blood flow carries with it the risk of further myocardial injury (reperfusion injury). 3 Events occurring during reperfusion have been shown to be responsible in part for reversible (stunning) and, more important, lethal (necrosis/apoptosis) injury in animal models. 4 -7 Although the contribution of reperfusion injury to infarct size in humans is unknown, it is possible that minimizing reperfusion injury might reduce infarct size in humans. Conclusions-This Clinical Perspective p 1019Modulating blood flow on reperfusion (through gradual or intermittent reperfusion) has been shown to reduce experimental infarct size. 8,9 In particular, Vinten-Johansen et al 10 have shown that a schedule of intermittent reperfusion (termed "postconditioning") applied at the onset of reperfusion reduces infarct size in animal models of myocardial ischemia-reperfusion (IR) injury. The protective effect of postconditioning is of a similar magnitude to that seen with ischemic preconditioning. 11 However, unlike precondi...

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