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

Remote ischemic conditioning (RIC), brief repetitive cycles of ischemia and reperfusion in remote tissues, is known to induce robust protection against myocardial ischemia-reperfusion (I/R) injury in preclinical studies. However, translation of the beneficial effects to the clinical setting has been challenging. A possibility is that comorbidities, including hypercholesterolemia, interfere 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 (I/R) as a measure of endothelial function. Study subjects were randomized to a RIC protocol consisting of four cycles of 5 min of leg ischemia or sham using a crossover design. Forearm I/R 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 I/R + RIC 4.5 ± 4.0%; means (SD)] and in patients with FH with low LDL-C (4.5 ± 3.5 vs. 4.4 ± 4.2%). By contrast, RIC fails to protect against I/R-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.NEW & NOTEWORTHY We investigated the impact of hypercholesterolemia on the protective effect of RIC on ischemia-reperfusion injury in a well-characterized patient population with isolated hypercholesterolemia. The results show that the protective effect of RIC is absent in patients with hypercholesterolemia but is apparent in patients with hypercholesterolemic following treatment with lipid-lowering drugs. The results are of importance for the understanding of how comorbidities affect the therapeutic potential of RIC.

Long-term effect of remote ischemic conditioning on infarct size and clinical outcomes in patients with anterior ST-elevation myocardial infarction.

BACKGROUND: Conflicting evidence exists concerning the cardioprotective efficacy of remote ischemic conditioning as an adjunct to primary percutaneous intervention (PCI) in ST-elevation myocardial infarction (STEMI) and data on long-term outcomes are scarce. We evaluated final infarct size by cardiac magnetic resonance (CMR) performed 6 months after anterior STEMI treated with remote ischemic conditioning and clinical outcomes up to 3 years after the event. METHODS: One hundred and fifteen patients with anterior STEMI were randomized to remote ischemic per-postconditioning (RIperpostC) or sham procedure as adjunct to primary PCI. The primary outcome was myocardial salvage index (MSI) on CMR 6 months after the event. Secondary outcomes were absolute infarct size, left ventricular function, cardiac mortality, major adverse cardiac and cerebrovascular events (MACCE-composite of all-cause mortality, myocardial infarction, readmission for heart failure, ischemic stroke, and target lesion revascularization) and all the individual components of MACCE. RESULTS: There was no difference in MSI or left ventricular function between the RIperpostC and the control group after 6 months. Nor did clinical outcomes at 6 months or 3 years differ between the groups. CONCLUSIONS: RIperpostC as an adjunct to PCI in anterior STEMI did not result in better MSI or left ventricular function 6 months after the event. Furthermore, clinical outcomes at 6 months and 3 years were not altered.

Ticagrelor Does Not Protect Against Endothelial Ischemia-Reperfusion Injury in Patients With Coronary Artery Disease.

BACKGROUND: Ticagrelor is a recommended P2Y12 receptor inhibitor after acute coronary syndrome (ACS). Its superiority has been suggested to rely on pleiotropic effects beyond platelet inhibition. Experimental studies indicate that ticagrelor may protect from ischemia-reperfusion injury but no data are available from such studies on patients. This study aimed to determine if chronic ticagrelor treatment protects against endothelial ischemia-reperfusion injury in patients with a previous ACS. METHODS: Patients with a previous ACS were studied with flow mediated dilatation of the left brachial artery to determine the degree of endothelial ischemia-reperfusion injury before and after discontinuation of ticagrelor treatment, which had been continuous since 1 year. Each patient underwent 3 identical examinations. The first examination (Visit A) was at the end of ticagrelor treatment and the following 2 (Visit B and C) were after cessation of this treatment with an interval of 2 to 4 weeks. RESULTS: Ischemia and reperfusion induced significant impairment of endothelial function at all 3 occasions (absolute decline in flow mediated dilatation 3.0% ± 0.7 at Visit A (P < 0.001), 1.9% ± 0.9 at Visit B (P < 0.05) and 1.9% ± 0.4 at Visit C (P < 0.0001)). However, there was no difference in the degree of endothelial ischemia-reperfusion injury or baseline endothelial function between the visits. CONCLUSION: Chronic ticagrelor treatment in patients 1 year after an ACS does not protect against endothelial ischaemia-reperfusion injury. Nor is it associated with better basal endothelial function compared to after discontinuation of treatment.

L-arginine protects from ischemia-reperfusion-induced endothelial dysfunction in humans in vivo.

It has been shown that nitric oxide (NO) protects from myocardial ischemia-reperfusion injury in animal models. The present study investigated whether administration of the NO substrate l-arginine protects against ischemia-reperfusion-induced endothelial dysfunction in humans. Forearm blood flow was measured with venous occlusion plethysmography in 16 healthy male subjects who were investigated on two occasions. Forearm ischemia was induced for 20 min followed by 60-min reperfusion. With the use of a crossover protocol, the subject received a 15-min intrabrachial artery infusion of l-arginine (20 mg/min) and vehicle (saline, n = 12 or d-arginine, n = 4) starting at 15 min of ischemia on two separate occasions. Compared with preischemia, endothelium-dependent increase in forearm blood flow induced by intra-arterial acetylcholine (3-30 microg/min) was significantly impaired at 15 and 30 min of reperfusion when the subjects received saline (P < 0.001). When the subjects received l-arginine, the acetylcholine-induced increase in forearm blood flow was not significantly affected by ischemia-reperfusion. The recovery of endothelium-dependent vasodilatation at 15- and 30-min reperfusion was significantly greater after administration of l-arginine than after saline (P < 0.05). d-Arginine did not affect the response to acetylcholine. Endothelium-independent vasodilatation to nitroprusside was not affected during reperfusion. These results demonstrate that the NO substrate l-arginine significantly attenuates ischemia-reperfusion-induced endothelial dysfunction in humans in vivo. This suggests that l-arginine may be useful as a therapeutic agent in the treatment of ischemia-reperfusion injury in humans.