Studies have suggested, that a proton leak into the cardiomyocyte through the NaV1.5 channel, or increased Na+ influx caused by gain-of-function variants, may lead to compensatory activation of the N+/H+ or the Na+/Ca2+ exchanger, thus leading to intracellular acidification or Ca2+ overload, respectively, and consequent impaired excitation–contraction coupling and/or myocardial damage with subsequent heart failure [22,24]. This evidence concerns the gene SCN5A and heart failure.