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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

TRPM4 inhibition by meclofenamate suppresses Ca2+-dependent triggered arrhythmias

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  • Media type: E-Article
  • Title: TRPM4 inhibition by meclofenamate suppresses Ca2+-dependent triggered arrhythmias
  • Contributor: 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
  • imprint: Oxford University Press (OUP), 2022
  • Published in: European Heart Journal
  • Language: English
  • DOI: 10.1093/eurheartj/ehac354
  • ISSN: 0195-668X; 1522-9645
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title> <jats:sec> <jats:title>Aims</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods and results</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion</jats:title> <jats:p>The presented data establish that TRPM4 represents a novel target in the prevention and treatment of Ca2+-dependent triggered arrhythmias.</jats:p> </jats:sec>
  • Access State: Open Access