Abstract
Rationale: TRPM4 is a Ca 2+ -activated non-selective cation channel that is abundantly expressed in the heart. Mutations in the Trpm4 gene are associated with human cardiac conduction disorders, including Progressive Familial Heart Block type I (PFHBI) and Brugada Syndrome. However, the mechanistic role and in vivo significance of TRPM4 in the triggering of cardiac arrhythmias is still completely unclear. Objective: To investigate the role of TRPM4 during pathological Ca 2+ handling in the heart. Methods and results: Using three in vivo pro-arrhythmic assays, we found that Trpm4 -/- mice show a reduced arrhythmic burden compared to control mice. First, aconitine intoxication resulted in severe cardiac arrhythmias, both in WT and Trpm4 -/- animals, but Trpm4 -/- mice developed significantly less ventricular ectopic beats (VEBs) and showed a lower arrhythmic score. Second, during ischemia-reperfusion, induced by 30 min of LAD ligation, significantly more WT animals developed arrhythmias compared to Trpm4 -/- mice. Third, catecholaminergic polymorphic ventricular tachycardia (CPVT) mice, carrying mutations in RyR2, were subjected to a stress test. Significantly more RyR +/R2474S -Trpm4 +/+ animals developed arrhythmias compared to RyR +/R2474S -Trpm4 -/- mice. Conclusion: Our data establish that TRPM4 represents a novel target in the prevention and treatment of cardiac arrhythmias.
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