TRPM4 inhibition by meclofenamate suppresses Ca2+-dependent triggered arrhythmias . (13th July 2022)

• Record Type: Journal Article
• Authors: Vandewiele, Frone; Pironet, Andy; Jacobs, Griet; Kecskés, Miklos; Wegener, Jörg; Kerselaers, Sara; Hendrikx, Lio; Verelst, Joren; Philippaert, Koenraad; Oosterlinck, Wouter; Segal, Andrei; Van Den Broeck, Evy; Pinto, Silvia; Priori, Silvia G; Lehnart, Stephan E; Nilius, Bernd; Voets, Thomas; Vennekens, Rudi
• Is Part Of: European heart journal. Volume 43:Number 40(2022)
• Page Start: 4195
• Page End: 4207
• Publication Date: 2022-07-13
• Subjects: TRPM4 -- Arrhythmias -- Ca2+ overload -- Triggered activity -- Meclofenamate; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; 616.12005
• DOI: 10.1093/eurheartj/ehac354
• Languages: English
• ISSNs: 0195-668X

Abstract

Abstract: Aims: Cardiac arrhythmias are a major factor in the occurrence of morbidity and sudden death in patients with cardiovascular disease. Disturbances of Ca 2+ homeostasis in the heart contribute to the initiation and maintenance of cardiac arrhythmias. Extrasystolic increases in intracellular Ca 2+ lead to delayed afterdepolarizations and triggered activity, which can result in heart rhythm abnormalities. It is being suggested that the Ca 2+ -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 Ca 2+ -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 Ca 2+ overload-induced background current, thereby regulating cell excitability in Ca 2+ 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 Ca 2+ 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 Ca 2+ -dependent triggered arrhythmias. Structural Graphical Abstract: Structural graphical abstract Proposed mechanism of the specific contribution of TRPM4 to the cellular mechanism of Ca 2+ -dependent triggered arrhythmias associated with, for example, acute ischaemia or catecholaminergic polymorphic ventricular tachycardia (CPVT). Typically for these conditions, aberrant Ca 2+ release events induce a transient inward current ( I ti ) on top of a background current ( I background ) in ventricular myocytes, which underlies delayed afterdepolarizations that trigger ectopic action potentials when the threshold potential is reached. The TRPM4 specifically contributes to the Ca 2+ overload-induced background current that augments cellular excitability, and inhibition of TRPM4 with meclofenamate efficiently suppresses CPVT-associated arrhythmias in living mice. AP, action potential; CPVT, catecholaminergic polymorphic ventricular tachycardia; DAD, delayed afterdepolarization; Vm, membrane potential; V threshold, threshold potential.