**11. Conclusions**

The aforementioned controversies suggest that neither of the living hypotheses provides an ultimate explanation according to today's knowledge, and that molecular mechanisms responsible for NaV1.5/*SCN5A*-related cardiomyopathy are rather multifaceted and yet to be explored. The era of next-generation sequencing gives the advantage of identifying genetic modifiers that may play a role in shaping the DCM phenotype. However, genetic substrates alone in the absence of post-translational and/or environmental influences are unlikely to give full and conclusive explanation for this controversy. Looking ahead, the growing experience with disease modeling based on human induced pluripotent stem cell-derived cardiomyocytes and transgenic animal models, will optimistically pave the way for better characterization of NaV1.5 role in cellular biological processes and help identify mechanisms by which genetic and/or environmental factors affect the ventricular contractility in carriers of *SCN5A* variants. Sound evidence on disease pathogenesis will also guide us on our path for disease modification and show whether gene therapy might be a viable option for treatment of patients with

*SCN5A-*mediated DCM in the near future. Before that expands our horizon, we need to adhere the conventional guidelines for management of arrhythmias and heart failure in these patients, and strictly limit our precision therapy with sodium channel blockers only as an alternative therapy to those with known gain-of-function *SCN5A* variants.

**Conflicts of Interest:** The authors declare no conflicts of interest.
