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Background Remote ischemic conditioning (RIC) is a noninvasive therapeutic strategy that uses brief cycles of blood pressure cuff inflation and deflation to protect the myocardium against ischemia-reperfusion injury. We sought to compare major adverse cardiovascular events (MACE) for patients who received RIC before PCI for ST-segment–elevation myocardial infarction (STEMI) compared with standard care. Methods We conducted a pre- and postimplementation study. In the preimplementation phase, STEMI patients were taken directly to the PCI lab. After implementation, STEMI patients received 4 cycles of RIC by paramedics or emergency department staff before PCI. The primary outcome was MACE at 90 days. Secondary outcomes included MACE at 30, 60, and 180 days. Inverse probability of treatment weighting using propensity scores estimated causal effects independent from baseline covariables. Results A total of 1667 (866 preimplementation, 801 postimplementation) patients were included. In the preimplementation phase, 13.4% had MACE at 90 days compared with 11.8% in the postimplementation phase (odds ratio [OR] 0.86, 95% CI 0.62-1.21). There were no significant differences in MACE at 30, 60, and 180 days. Patients presenting with cardiogenic shock or cardiac arrest before PCI were less likely to have MACE at 90 days (42.7% pre vs 27.8% post) if they received RIC before PCI (OR 0.52, 95% CI 0.27-0.98). Conclusions A strategy of RIC before PCI for STEMI did not reduce 90-day MACE. Future research should explore the impact of RIC before PCI for longer-term clinical outcomes and for patients presenting with cardiogenic shock or cardiac arrest.

GPR81, which exhibits a high degree of homology with GPR109a, has been recently identified as a lactate receptor. Similar to GPR109a, the activation of GPR81 by lactate suppresses lipolysis, suggesting that GPR81 may be a potential drug target for treating dyslipidemia. In addition, the fact that GPR81 is expressed only in adipocytes, whereas GPR109a is expressed in various tissues and cells, including Langerhans cells, which are considered responsible for flushing, indicates that targeting GPR81 could lead to the development of antidyslipidemia agents with a reduced risk of this side effect. However, the pharmacological role of GPR81 remains largely unclear, mainly because of the lack of potent and selective surrogate GPR81 agonists suitable for in vivo studies. In the present study, we showed that lactate-induced suppression of lipolysis in explants of white adipose tissue (WAT) depends on the presence of GPR81. We also performed high-throughput screening (HTS) and identified four novel chemical clusters as GPR81 agonists. Chemical optimization of aminothiazole derivatives led to the discovery of a lead compound with improved potency. The compound inhibited lipolysis in differentiated 3T3-L1 adipocytes. Finally, intraperitoneal administration of this compound suppressed lipolysis in mice at doses that did not cause cutaneous flushing. This is the first description of a 50nM GPR81 selective agonist with in vivo efficacy, without the side effect, i.e., flushing. These results suggest that GPR81 is an attractive drug target for treating dyslipidemia without the risk of flushing.