**4. DCM as a Manifestation of Pure NaV1.5 Dysfunction**

One theory is that DCM represents a direct consequence of NaV1.5 channel dysfunction, meaning that the structural phenotype is primarily driven by electrical abnormalities [23,24]. Studies have suggested, that a proton leak into the cardiomyocyte through the NaV1.5 channel, or increased Na<sup>+</sup> influx caused by gain-of-function variants, may lead to compensatory activation of the N+/H<sup>+</sup> or the Na+/Ca2<sup>+</sup> exchanger, thus leading to intracellular acidification or Ca2<sup>+</sup> overload, respectively, and consequent impaired excitation–contraction coupling and/or myocardial damage with subsequent heart failure [22,24]. The first mechanism has been demonstrated for *SCN5A*-R219H [25], while the second was indirectly assumed for the loss-of-function A1180V missense variant [26]. These hypotheses, however, do not explain why the majority of the variants causing significant NaV1.5 dysfunction do not result in left ventricular (LV) dysfunction. Thus, it is more likely that mechanisms other than direct modulation of NaV1.5 activity are involved, such as down-regulation of channel expression, or channel mislocalization due to altered cytoskeletal anchoring [14,19]. As such, an increasing body of literature suggests interactions between sodium channel alpha subunits to form dimers [27]. Variants at the interaction sites mediating dimerization and sodium channel macromolecular complex formation might be involved in the DCM pathogenesis.
