<i>Trpm4</i> Gene Invalidation Leads to Cardiac Hypertrophy and Electrophysiological Alterations

<div><p>Rationale</p><p>TRPM4 is a non-selective Ca²⁺-activated cation channel expressed in the heart, particularly in the atria or conduction tissue. Mutations in the <i>Trpm4</i> gene were recently associated with several human conduction disorders such as Brugada syndrome. TRPM4 channel has also been implicated at the ventricular level, in inotropism or in arrhythmia genesis due to stresses such as ß-adrenergic stimulation, ischemia-reperfusion, and hypoxia re-oxygenation. However, the physiological role of the TRPM4 channel in the healthy heart remains unclear.</p><p>Objectives</p><p>We aimed to investigate the role of the TRPM4 channel on whole cardiac function with a <i>Trpm4</i> gene knock-out mouse (<i>Trpm4</i>^-/-) model.</p><p>Methods and Results</p><p>Morpho-functional analysis revealed left ventricular (LV) eccentric hypertrophy in <i>Trpm4</i>^-/- mice, with an increase in both wall thickness and chamber size in the adult mouse (aged 32 weeks) when compared to <i>Trpm4^+/+</i> littermate controls. Immunofluorescence on frozen heart cryosections and qPCR analysis showed no fibrosis or cellular hypertrophy. Instead, cardiomyocytes in <i>Trpm4^-/-</i> mice were smaller than <i>Trpm4^+/+</i>with a higher density. Immunofluorescent labeling for phospho-histone H3, a mitosis marker, showed that the number of mitotic myocytes was increased 3-fold in the <i>Trpm4^-/-</i>neonatal stage, suggesting hyperplasia. Adult <i>Trpm4</i>^-/- mice presented multilevel conduction blocks, as attested by PR and QRS lengthening in surface ECGs and confirmed by intracardiac exploration. <i>Trpm4^-/-</i>mice also exhibited Luciani-Wenckebach atrioventricular blocks, which were reduced following atropine infusion, suggesting paroxysmal parasympathetic overdrive. In addition, <i>Trpm4</i>^-/- mice exhibited shorter action potentials in atrial cells. This shortening was unrelated to modifications of the voltage-gated Ca²⁺ or K⁺ currents involved in the repolarizing phase.</p><p>Conclusions</p><p>TRPM4 has pleiotropic roles in the heart, including the regulation of conduction and cellular electrical activity which impact heart development.</p>