The protective effect of remote ischemic conditioning is lost in patients with hypercholesterolemia

Abstract

Remote ischemic conditioning (RIC), brief repetitive cycles of ischemia and reperfusion in remote tissues, is known to induce robust protection against myocardial ischemia-reperfusion injury in preclinical studies. However, translation of the beneficial effects to the clinical setting has been challenging. A possibility is that co-morbidities, including hypercholesterolemia, interferes with the protective mechanisms of RIC. The aim of this study was to test if hypercholesterolemia attenuates the efficacy of RIC in patients with hypercholesterolemia. Patients with familial hypercholesterolemia (FH) with high (≥5.5 mmol/L) low-density lipoprotein cholesterol (LDL-C), FH with low (≤2.5 mmol/L) and healthy control subjects (n=12 in each group) were included. Flow-mediated vasodilatation (FMD) of the brachial artery was evaluated, before and after a 20 min period of forearm ischemia and 20 min reperfusion (IR) as a measure of endothelial function. Study subjects were randomized to a RIC protocol consisting of 4 cycles of 5 min of leg ischemia or sham using a cross-over protocol. Forearm IR induced significant reduction in FMD in all three groups during the sham procedure. RIC protected from endothelial dysfunction induced by forearm ischemia-reperfusion in healthy controls (FMD baseline 2.8±2.3% vs. FMD after IR+RIC 4.5±4.0; mean and SD) and in patients with FH with low LDL-C (4.5±3.5 vs. 4.4±4.2%). By contrast, RIC fail to protect against IR-induced endothelial dysfunction in patients with FH and high LDL-C (3.9±3.0 vs. 1.1±1.5%; P<0.01). These findings provide the first evidence in humans that the protective effect of RIC is lost in patients with elevated cholesterol.

Remote Ischemic Conditioning to Reduce Perihematoma Edema in Patients with Intracerebral Hemorrhage (RICOCHET): A Randomized Control Trial

“…In contrast, another study consisting of 24 patients observed that RIC protected from endothelial dysfunction induced by forearm ischemia-reperfusion in healthy controls (flow-mediated vasodilation (FMD) baseline 2.8 ± 2.3 vs. FMD after I/R + RIC 4.5 ± 4.0%; means SD) and in patients with familial hypercholesterolemia (FH) with low LDL-C (4.5 ± 3.5 vs. 4.4 ± 4.2%). However, RIC was ineffective in patients with FH and high LDL-C (FMD 3.9 ± 3.0 vs. 1.1 ± 1.5%; p < 0.01) [33]. In addition, statins are also known to blunt the effect of RIC, and this may have further attenuated the effects in the intervention arm [34].…”

Dyslipidemia and Efficacy of Remote Ischemic Conditioning in Acute Moderate Ischemic Stroke: A Post Hoc Analysis of the RICAMIS Study

“… 8 A recent study did not find the protective effect of RIC on ischemia–reperfusion injury‐induced endothelial dysfunction in patients with familial hypercholesterolemia with elevated LDL‐C. 9 Two small clinical studies reported that the cardioprotective effect of ischemic postconditioning was lost in the patients with coronary artery disease with higher cholesterol. 10 , 11 In addition, numerous animal experiments have revealed that hypercholesterolemia may interfere with the cardioprotective potential of ischemic conditioning.…”