Aims Cardiac arrhythmias are a major factor in the occurrence of morbidity and sudden death in patients with cardiovascular disease. Disturbances of Ca2+ homeostasis in the heart contribute to the initiation and maintenance of cardiac arrhythmias. Extrasystolic increases in intracellular Ca2+ lead to delayed afterdepolarizations and triggered activity, which can result in heart rhythm abnormalities. It is being suggested that the Ca2+-activated nonselective cation channel TRPM4 is involved in the aetiology of triggered activity, but the exact contribution and in vivo significance are still unclear. Methods and results In vitro electrophysiological and calcium imaging technique as well as in vivo intracardiac and telemetric electrocardiogram measurements in physiological and pathophysiological conditions were performed. In two distinct Ca2+-dependent proarrhythmic models, freely moving Trpm4−/− mice displayed a reduced burden of cardiac arrhythmias. Looking further into the specific contribution of TRPM4 to the cellular mechanism of arrhythmias, TRPM4 was found to contribute to a long-lasting Ca2+ overload-induced background current, thereby regulating cell excitability in Ca2+ overload conditions. To expand these results, a compound screening revealed meclofenamate as a potent antagonist of TRPM4. In line with the findings from Trpm4−/− mice, 10 µM meclofenamate inhibited the Ca2+ overload-induced background current in ventricular cardiomyocytes and 15 mg/kg meclofenamate suppressed catecholaminergic polymorphic ventricular tachycardia-associated arrhythmias in a TRPM4-dependent manner. Conclusion The presented data establish that TRPM4 represents a novel target in the prevention and treatment of Ca2+-dependent triggered arrhythmias.

中文翻译：

---

氯芬酸对 TRPM4 的抑制可抑制 Ca2+ 依赖性触发的心律失常

目的 心律失常是心血管疾病患者发病和猝死的主要因素。心脏中 Ca2+ 稳态的紊乱有助于引发和维持心律失常。细胞内 Ca2+ 的收缩期增加导致延迟的后去极化和触发的活动，这可能导致心律异常。有人认为 Ca2+ 激活的非选择性阳离子通道 TRPM4 参与了触发活动的病因，但确切的贡献和体内意义仍不清楚。方法和结果 在生理和病理生理条件下进行体外电生理和钙成像技术以及体内心内和遥测心电图测量。在两种不同的 Ca2+ 依赖性促心律失常模型中，自由移动的 Trpm4-/- 小鼠的心律失常负担减轻。进一步研究 TRPM4 对心律失常细胞机制的具体贡献，发现 TRPM4 有助于长期 Ca2+ 过载诱导的背景电流，从而调节 Ca2+ 过载条件下的细胞兴奋性。为了扩大这些结果，化合物筛选显示甲氯芬酸是 TRPM4 的有效拮抗剂。与 Trpm4-/- 小鼠的研究结果一致，10 µM 甲氯芬酸抑制了心室心肌细胞中 Ca2+ 过载诱导的背景电流，15 mg/kg 甲氯芬酸以 TRPM4 依赖性方式抑制了儿茶酚胺能多形性室性心动过速相关心律失常。