钠-葡萄糖共转运蛋白2(SGLT2)抑制剂的主要药理作用是抑制葡萄糖和钠离子从肾脏近端小管的重吸收,并促进尿葡萄糖排泄。值得注意的是,一些临床试验最近证明了SGLT2抑制剂对心力衰竭(HF)或慢性肾病(CKD)患者的有效保护作用。无论是否存在糖尿病。然而,SGLT2抑制剂对心源性猝死(SCD)或致命性室性心律失常(VAs)的影响,其病理生理学部分类似于HF和CKD,仍然不确定。据报道,SGLT2抑制剂的心肾保护作用包括改善血液动力学,衰竭心脏的逆向重塑,改善交感神经过度活动,纠正贫血和铁代谢受损,抗氧化作用,纠正血清电解质异常,和抗纤维化作用,这可能导致防止SCD和/或VAs。最近,SGLT2抑制剂可能的直接心脏作用,不仅抑制Na+/H+交换剂(NHE)活性,而且后期Na+电流的抑制也一直是重点。除了SGLT2抑制剂的间接心脏保护机制外,抑制异常增加的晚期Na+电流可能有助于通过恢复衰竭心脏中延长的复极化阶段来预防SCD和/或VAs。这篇综述总结了SGLT2抑制剂预防SCD的临床试验结果。它们对心电图指标的影响,及其抗心律失常作用的可能分子机制。
The primary pharmacological action of sodium-glucose co-transporter 2 (SGLT2) inhibitors is to inhibit the reabsorption of glucose and sodium ions from the proximal tubules of the kidney and to promote urinary glucose excretion. Notably, several clinical trials have recently demonstrated potent protective effects of SGLT2 inhibitors in patients with heart failure (HF) or chronic kidney disease (CKD), regardless of the presence or absence of diabetes. However, the impact of SGLT2 inhibitors on sudden cardiac death (SCD) or fatal ventricular arrhythmias (VAs), the pathophysiology of which is partly similar to that of HF and CKD, remains undetermined. The cardiorenal protective effects of SGLT2 inhibitors have been reported to include hemodynamic improvement, reverse remodeling of the failing heart, amelioration of sympathetic hyperactivity, correction of anemia and impaired iron metabolism, antioxidative effects, correction of serum electrolyte abnormalities, and antifibrotic effects, which may lead to prevent SCD and/or VAs. Recently, as possible direct cardiac effects of SGLT2 inhibitors, not only inhibition of Na+/H+ exchanger (NHE) activity, but also suppression of late Na+ current have been focused on. In addition to the indirect cardioprotective mechanisms of SGLT2 inhibitors, suppression of aberrantly increased late Na+ current may contribute to preventing SCD and/or VAs via restoration of the prolonged repolarization phase in the failing heart. This review summarizes the results of previous clinical trials of SGLT2 inhibitors for prevention of SCD, their impact on the indices of electrocardiogram, and the possible molecular mechanisms of their anti-arrhythmic effects.