Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
DZHK (German Center for Cardiovascular Research), Partner site Heidelberg/Mannheim, University of Heidelberg, Im Neuenheimer Feld 669, 69120, Heidelberg, Germany.
Basic Res Cardiol. 2024 Feb;119(1):93-112. doi: 10.1007/s00395-023-01022-0. Epub 2024 Jan 3.
In recent years, SGLT2 inhibitors have become an integral part of heart failure therapy, and several mechanisms contributing to cardiorenal protection have been identified. In this study, we place special emphasis on the atria and investigate acute electrophysiological effects of dapagliflozin to assess the antiarrhythmic potential of SGLT2 inhibitors. Direct electrophysiological effects of dapagliflozin were investigated in patch clamp experiments on isolated atrial cardiomyocytes. Acute treatment with elevated-dose dapagliflozin caused a significant reduction of the action potential inducibility, the amplitude and maximum upstroke velocity. The inhibitory effects were reproduced in human induced pluripotent stem cell-derived cardiomyocytes, and were more pronounced in atrial compared to ventricular cells. Hypothesizing that dapagliflozin directly affects the depolarization phase of atrial action potentials, we examined fast inward sodium currents in human atrial cardiomyocytes and found a significant decrease of peak sodium current densities by dapagliflozin, accompanied by a moderate inhibition of the transient outward potassium current. Translating these findings into a porcine large animal model, acute elevated-dose dapagliflozin treatment caused an atrial-dominant reduction of myocardial conduction velocity in vivo. This could be utilized for both, acute cardioversion of paroxysmal atrial fibrillation episodes and rhythm control of persistent atrial fibrillation. In this study, we show that dapagliflozin alters the excitability of atrial cardiomyocytes by direct inhibition of peak sodium currents. In vivo, dapagliflozin exerts antiarrhythmic effects, revealing a potential new additional role of SGLT2 inhibitors in the treatment of atrial arrhythmias.
近年来，SGLT2 抑制剂已成为心力衰竭治疗不可或缺的一部分，并且已经确定了几种有助于心脏和肾脏保护的机制。在这项研究中，我们特别关注心房，并研究达格列净的急性电生理效应，以评估 SGLT2 抑制剂的抗心律失常潜力。我们在分离的心房心肌细胞的膜片钳实验中研究了达格列净的直接电生理效应。急性高剂量达格列净处理导致动作电位可诱导性、幅度和最大上升速度显著降低。该抑制作用在人诱导多能干细胞衍生的心肌细胞中重现，并且在心房细胞中比心室细胞更为明显。假设达格列净直接影响心房动作电位的去极化相，我们在人心房心肌细胞中检查了快速内向钠电流，发现达格列净显著降低了峰值钠电流密度，同时中度抑制了瞬时外向钾电流。将这些发现转化为猪大型动物模型，急性高剂量达格列净处理导致体内心房主导的心肌传导速度降低。这可用于阵发性心房颤动发作的急性电复律和持续性心房颤动的节律控制。在这项研究中，我们表明达格列净通过直接抑制峰值钠电流来改变心房心肌细胞的兴奋性。在体内，达格列净具有抗心律失常作用，揭示了 SGLT2 抑制剂在治疗心房性心律失常方面的潜在新作用。
