Reduced effect of ischemic preconditioning against endothelial ischemia-reperfusion injury with cardiovascular risk factors in humans.

The extent that clustered CVD risk factors interfere with ischemic preconditioning (IPC) to protect against microvascular endothelial dysfunction with ischemia-reperfusion (I/R) injury in humans is unclear. We hypothesized that adults with a clustered burden of ≥3 CVD risk factors would demonstrate a reduced capacity of IPC to protect endothelial function with I/R injury. Twenty-two (age: 45 ± 14 year) adults [12 healthy controls; 10 raised risk (10-year FRS risk score ~3%)] were studied using a 2 × 2 randomized cross-over design. Pulse arterial tonometry was used to assess microvascular endothelium-dependent vasodilation during reactive hyperemia in response to endothelial I/R injury (20 min brachial artery occlusion/45 min reperfusion) that was preceded by remote IPC (3 × 5 min ischemia/reperfusion) or mock IPC. In both groups, microvascular reactive hyperemia was reduced ~20% (both P < 0.01) after endothelial I/R injury without remote IPC. However, in control subjects remote IPC prevented endothelial I/R injury (from baseline reactive hyperemic ratio: 2.1 ± 0.4 AU to post I/R injury: 2.5 ± 0.5 AU; P = 0.09). In contrast, the reactive hyperemia ratio in raised risk subjects was significantly reduced from 2.2 ± 0.6 AU to 1.9 ± 0.5 AU (P = 0.0087) despite attempts to induce protection by remote IPC, with the magnitude of reduction similar to their mock IPC trial. The magnitude of remote IPC-mediated endothelial protection against I/R injury was inversely related to the number of risk factors. CVD risk factors diminish the effect of IPC to protect the microvasculature from I/R injury in humans. Translating IPC to clinical practice for vasculoprotection will continue to be challenging in patients with increased CVD risk.