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

Abstract

BackgroundIt 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 ResultsThirty 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, ΔFMD: −4.4±0.7%; celecoxib, ΔFMD: −5.0±0.5%). One‐day IPC completely prevented this effect (placebo, ΔFMD: −1.1±0.6%; celecoxib, ΔFMD: 0.0±0.7%; P<0.0001). Similarly, 7‐day IPC demonstrated persistent endothelial protection post‐IR (placebo, ΔFMD: −0.9±0.9%; celecoxib, ΔFMD: 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.ConclusionsDaily episodes of IPC provide sustained protection from IR‐induced endothelial dysfunction in humans through a mechanism that appears cyclooxygenase‐2‐independent.

The effect of 1 week of repeated ischaemic leg preconditioning on simulated Keirin cycling performance: a randomised trial

“…One recent study repeated IPC over nine consecutive days but failed to see any improvement in aerobic capacity. 7 Repeated IPC has been investigated in clinical studies, with local and remote improvements in endothelial function, brachial artery flowmediated dilation and resting skin microcirculation being observed, [8][9][10] although the physiological basis of this 'hyperconditioning' is still to be fully elucidated. 11 Oxidative stress is an integral component of ischaemia/reperfusion, 12 while vasodilation improved tissue oxygenation, 13 14 and inflammatory system modulation 15 is regulated through single or repetitive ischaemic treatment.…”

Repeated ischaemic preconditioning: a novel therapeutic intervention and potential underlying mechanisms

“…They provided evidence that repeated RIPC enhanced resistance artery endothelial function via increases in nitric oxide production, whereas daily repeated RIPC augmented both circulating endothelial progenitor cells and plasma concentrations of vascular endothelial growth factor. Luca et al (2013) followed this work by exploring whether repeated (daily) IPC alters the efficacy of a single IPC against endothelial ischaemia-reperfusion injury. They also found that 7 days of daily IPC provided sustained protection against ischaemia-reperfusion injury of the endothelium of peripheral arteries.…”

Impact of eight weeks of repeated ischaemic preconditioning on brachial artery and cutaneous microcirculatory function in healthy males

“…1,2 Recent studies have examined daily exposure of IPC episodes as a therapeutic intervention and found enhanced brachial artery endothelial function 3 , skin perfusion 3 , resistance 4 artery function and protection from conduit artery induced IRI 5 . Therefore, daily IPC may potentially be a useful intervention to improve vascular function.…”