Daily Ischemic Preconditioning Provides Sustained Protection From Ischemia-Reperfusion Induced Endothelial Dysfunction: A Human Study

Background-It is well established that acute ischemic preconditioning (IPC) protects against ischemia-reperfusion (IR) injury; however, the effectiveness of repeated IPC exposure has not been extensively investigated. We aimed to determine whether daily IPC episodes provide continued protection from IR injury in a human forearm model, and the role of cyclooxygenase-2 in these responses. Methods and Results-Thirty healthy volunteers were randomized to participate in 2 of 3 protocols (IR alone, 1-day IPC, 7-day IPC) in an operator-blinded, crossover design. Subjects in the IR alone protocol underwent flow-mediated dilation (FMD) measurements pre- and post-IR (15' upper-arm ischemia and 15' reperfusion). The 1-day IPC protocol involved FMD measurements before and after 1 episode of IPC (3 cycles of 5' upper-arm ischemia and 5' reperfusion) and IR. Day 7 of the 7-day IPC protocol was identical to the 1-day IPC protocol but was preceded by single daily episodes of IPC for 6 days prior. During each protocol, subjects received a 7-day treatment of either the cyclooxygenase-2 inhibitor celecoxib or placebo. Pre-IR FMD was similar between groups. IR alone reduced FMD post-IR (placebo, Delta FMD: -4.4 +/- 0.7%; celecoxib, Delta FMD: -5.0 +/- 0.5%). One-day IPC completely prevented this effect (placebo, Delta FMD: -1.1 +/- 0.6%; celecoxib, Delta FMD: 0.0 +/- 0.7%; P<0.0001). Similarly, 7-day IPC demonstrated persistent endothelial protection post-IR (placebo, Delta FMD: -0.9 +/- 0.9%; celecoxib, Delta FMD: 0.0 +/- 0.8%; P<0.0001, P<0.0001 for ANOVA effect of IPC protocol). Celecoxib did not alter responses to IR in any protocol. Conclusions-Daily episodes of IPC provide sustained protection from IR-induced endothelial dysfunction in humans through a mechanism that appears cyclooxygenase-2-independent.