Diabetes and Complications Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, United States of America.
Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX, United States of America.
Int J Cardiol. 2022 Sep 15;363:138-148. doi: 10.1016/j.ijcard.2022.06.054. Epub 2022 Jun 23.
Sodium glucose co-transporter 2 inhibitors (SGLT2i) demonstrate cardioprotective benefits independent of a glucose lowering effect including preservation of cardiac function during a myocardial ischemia. Sodium‑hydrogen exchanger-1 (NHE-1), has been hypothesized to contribute to the cardiac effects of SGLT2i. We characterized the beneficial effects of acute pre-ischemia exposure to SGLT2i and explored the possibility that these effects are explained by NHE-1 inhibition.
Swine were anesthetized and instrumented for invasive hemodynamic measurements. After baseline data collection, swine received a 15-30 min intravenous infusion of vehicle (DMSO), the SGLT2i canagliflozin (1 mg/kg), or the NHE-1 inhibitor cariporide (0.03 mg/kg) ending immediately prior to occlusion of the left circumflex artery. Measurements were obtained at baseline, during a 60-min complete occlusion of the circumflex coronary artery, and during a 2-h reperfusion period. Blood pressure, heart rate, left anterior descending artery flow, and associated myocardial oxygen consumption were unaffected by acute pre-treatment with canagliflozin or cariporide during ischemia and reperfusion. Acute pre-ischemic treatment with canagliflozin significantly increased diastolic filling and stroke work, producing a rightward shift in the Frank-Starling relationship, and also improved cardiac work efficiency relative to untreated control hearts during ischemia. Effects of NHE-1 inhibition with cariporide were modest and dissimilar. Examination of AP-1 cells transfected with wild-type NHE-1 and iPSC-derived cardiomyocytes confirmed dose-dependent-inhibition of NHE-1 activity by cariporide, while canagliflozin had no significant effect on NHE-1 activity.
Acute pre-treatment with SGLT2i produces cardioprotective effects during ischemia, including improved work efficiency. These effects are not explained by NHE-1 inhibition.
SGLT2 inhibitors have been shown to improve cardiac outcomes in patient including reducing myocardial infarction incidence and mortality. The mechanism(s) explaining this effect are not clear. This manuscript demonstrates a protective effect from acute SGLT2i exposure, as short as 15 min, prior to experimental infarction in swine. These effects were independent of NHE1 inhibition. These observations suggest that SGLT2 inhibitors can confer cardioprotective effects on a very short time scale. It is possible that such effects provide an ongoing contribution to ischemic protection even in the setting of chronic treatment.
钠-葡萄糖共转运蛋白 2 抑制剂（SGLT2i）具有心脏保护作用，其作用独立于降低血糖，包括在心肌缺血期间保留心脏功能。钠-氢交换体-1（NHE-1）被认为有助于 SGLT2i 的心脏作用。我们描述了急性缺血前暴露于 SGLT2i 的有益作用，并探讨了这些作用是否可以通过抑制 NHE-1 来解释。
猪被麻醉并进行了侵入性血流动力学测量。在基线数据采集后，猪接受了 15-30 分钟的静脉输液载体（DMSO）、SGLT2i 卡格列净（1mg/kg）或 NHE-1 抑制剂 cariporide（0.03mg/kg），输液结束时间为左旋支动脉闭塞前即刻。在基线、左回旋支动脉完全闭塞 60 分钟和再灌注 2 小时期间进行测量。在缺血和再灌注期间，急性预治疗卡格列净或 cariporide 对血压、心率、前降支动脉血流和相关心肌耗氧量没有影响。急性缺血前用卡格列净治疗可显著增加舒张充盈和射血功，使法兰克-斯塔林关系向右移位，并在缺血期间提高心脏工作效率与未经治疗的对照心脏相比。cariporide 抑制 NHE-1 的作用较小且不同。用野生型 NHE-1 转染的 AP-1 细胞和 iPSC 衍生的心肌细胞进行检查证实，cariporide 对 NHE-1 活性有剂量依赖性抑制作用，而卡格列净对 NHE-1 活性无显著影响。
急性 SGLT2i 预处理可在缺血期间产生心脏保护作用，包括提高工作效率。这些作用不能用 NHE-1 抑制来解释。
SGLT2 抑制剂已被证明可改善患者的心脏预后，包括降低心肌梗死发生率和死亡率。其作用机制尚不清楚。本研究在猪的实验性梗死前 15 分钟进行了 SGLT2i 的急性暴露，证明了其具有保护作用。这些影响与 NHE1 抑制无关。这些观察结果表明，SGLT2 抑制剂可以在非常短的时间内提供心脏保护作用。即使在慢性治疗的情况下，这种作用也可能对缺血保护产生持续贡献。
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