Transient Limb Ischemia Induces Remote Ischemic Preconditioning In Vivo

Abstract

Background-Ischemic preconditioning reduces local tissue injury caused by subsequent ischemia-reperfusion (IR), but may also have a salutary effect on IR injury of tissues remote from those undergoing preconditioning. We tested the hypothesis that limb ischemia induces remote preconditioning, reduces endothelial IR injury in humans, and reduces experimental myocardial infarct size. Methods and Results-Endothelial IR injury of the human forearm was induced by 20 minutes of upper limb ischemia (inflation of a blood pressure cuff to 200 mm Hg) followed by reperfusion. Remote preconditioning was induced by three 5-minute cycles of ischemia of the contralateral limb. Venous occlusion plethysmography was used to assess forearm blood flow in response to acetylcholine at baseline and 15 minutes after reperfusion. Experimental myocardial infarction was achieved by 40 minutes of balloon occlusion of the left anterior descending artery in 15-kg pigs. Remote preconditioning was induced by four 5-minute cycles of lower limb ischemia. Triphenyltetrazolium staining was used to assess the extent of myocardial infarction. In the human study, the response to acetylcholine was significantly attenuated in the control group after 15 minutes' reperfusion, but remote preconditioning prevented this reduction. Limb ischemia caused a significant reduction in the extent of myocardial infarction relative to the area at risk compared with control (26Ϯ9% versus 53Ϯ8%, PϽ0.05). Key Words: endothelium Ⅲ ischemia Ⅲ reperfusion Ⅲ ischemic preconditioning, remote I schemia-reperfusion (IR) complicates myocardial infarction and stroke and contributes to the associated tissue injury and mortality; reducing IR injury may improve the outcome of reperfusion therapy for these conditions. 1 One successful approach in the experimental setting is ischemic preconditioning (IPC), whereby prior sublethal ischemia induces a state of protection against subsequent prolonged IR. 2 Although animal studies have shown that protection occurs locally in the tissue being preconditioned, systemic effects of localized IPC have been observed. 3 This raises the possibility that regional ischemia of accessible nonvital tissues might protect remote vital organs undergoing IR, and some data support this in humans. 4 In the present study we tested the hypothesis that short periods of limb ischemia induce remote preconditioning and reduce IR injury in vivo. We used a human model of endothelial IR injury to test whether remote limb ischemia induces systemic preconditioning in humans. Furthermore, we studied an experimental model of myocardial infarction to characterize whether limb ischemia reduced myocardial IR injury. Conclusion-Remote Methods Study 1: Remote Preconditioning of Human Endothelium by Contralateral Limb Ischemia Subjects and Study DesignFourteen healthy volunteers, with a mean age of 33 (range, 26 to 52) years, gave informed signed consent and were randomized to remote preconditioning and control groups. Studies were approved by the local Research Ethics Committ...

Hypoxia-inducible factor 1 is required for remote ischemic preconditioning of the heart

“…However, the discovery that an IPC stimulus applied to the circumflex coronary artery reduced the size of an MI arising from sustained occlusion of the left anterior descending artery (6) was subsequently extended by the demonstration that the heart could be protected by subjecting a remote organ or tissue, such as kidney, small intestine, liver, or limb, to short episodes of IR, a phenomenon known as remote IPC (7)(8)(9)(10). Application of a tourniquet to the hind limb before prolonged cardiac IR reduced arrhythmias in rats and IS in pigs (9,11). Most recently, a randomized clinical trial was conducted in which patients who received a remote IPC stimulus consisting of three cycles of I 5 and R 5 of the arm before coronary artery bypass graft surgery were found to have significantly reduced postoperative serum levels of cardiac troponin I, which is indicative of cardioprotection (12).…”

Preconditioning and postconditioning: from bench to bedside

“…(6) The discovery that myocardial infarct size could be limited by applying brief episodes of ischaemia and reperfusion to the lower limb (53) resulted in the development of a non-invasive strategy for eliciting RIPC in the clinical arena. (54,55) We and others have demonstrated that brief episodes of ischaemia and reperfusion applied to either the upper limb (non-invasively using a blood pressure cuff) or the lower limb (by invasive clamping of the iliac arteries) is capable of reducing myocardial injury in patients undergoing cardiac surgery (56,57) or surgical repair of an abdominal aortic aneurysm. (58) Interestingly, Ali and colleagues (58) were able to demonstrated renal protection using RIPC of the lower-limb in addition to myocardial protection.…”

The endothelial cell in health and disease: its function, dysfunction, measurement and therapy

“…[96][97][98] Ischemic preconditioning is a phenomenon in which brief periods of nonlethal ischemia, followed by reperfusion, protects local tissue against later episodes of prolonged ischemia and reperfusion. In remote ischemic preconditioning, protection is conveyed to distant tissues or organs.…”

“…More prolonged periods of ischemia (X20 min) and reperfusion cause local endothelial dysfunction and inhibit FMD and the vasodilatory response to acetylcholine. 97,98 In a series of studies, Kharbanda et al 97 and Loukogeorgakis et al 98 showed that a series of three 5-min cuff inflations preserved endothelial function in the contralateral brachial artery when exposed to acetylcholine or more prolonged ischemia (20 min) and reperfusion. In addition, using this remote ischemic preconditioning protocol before coronary artery bypass graft surgery in a randomized, placebo-controlled design, Hausenloy et al 96 showed cardiac protection by lower levels of troponin T postoperatively in the preconditioning group versus the control group.…”