Cardiac Sodium Channel Dysfunction and Dilated Cardiomyopathy: A Contemporary Reappraisal of Pathophysiological Concepts

A key emerging theme in translational cardiovascular medicine is the need to identify specific causes of arrhythmias and heart failure, defined by phenotype and/or genotype that will respond to a particular intervention. Unlike other genes implicated in hereditary arrhythmias and cardiomyopathies, pathogenic/likely pathogenic variants in the cardiac sodium channel alpha subunit gene (SCN5A) produce a remarkably diverse set of electrical and structural phenotypes, one of them being dilated cardiomyopathy. There has been debate about whether left ventricular remodeling is a bona fide phenotypic feature of cardiac sodium channel dysfunction, or a consequence of tachyarrhythmias or conduction disturbances. In light of recent findings, a critical digest of the available experimental and medical literature is necessary. This paper provides a critical appraisal of the evidence linking a dysfunctional cardiac sodium channel to ventricular dysfunction, and discusses the potential mechanisms involved in shaping this phenotype along with implications for precision therapy.