Nav channel complex heterogeneity: new targets for the treatment of arrhythmia?

Abstract

Despite major breakthroughs in cardiovascular diagnostics and therapies over the past century, diseases of the heart remain a leading cause of death in the United States, nearing 600 000 deaths per year.1 Most of these deaths (200 000–400 000 per year)2 are due to cardiac arrhythmia in which syncope and sudden death are often the first manifestations of heart disease. Foundational work by Wang et al3 in the mid-1990s cemented the critical role of ion channel dysfunction in human arrhythmia. Today, we know that ≈35% of sudden unexplained death and ≈20% of sudden infant death syndrome cases may be explained by mutations in cardiac ion channels (cardiac channelopathies).4,5 Furthermore, defects in ion channel function have widely been observed in common forms of heart failure.6 This year marks the 25th anniversary of publication of the preliminary Cardiac Arrhythmia Suppression Trial (CAST) findings in the New England Journal of Medicine .7 Here, we discuss new findings reported by Shy et al8 on Nav channel macromolecular complexes reported in this issue of Circulation and reflect on lessons learned in the ensuing years after CAST that may help propel advances in treatment of cardiovascular disease over the next quarter-century. Article see p 147 Defects in voltage-gated sodium (Nav) channels are among the best characterized of the cardiac channelopathies. Nav channel complexes are composed of a large ≈260-kDa pore-forming α-subunit and an associated auxiliary β-subunit. In humans, Nav α-subunits are encoded by 9 genes, whereas 4 genes encode Nav β-subunits.9 Beyond heart, Nav channel gene defects are linked to a host of excitable cell phenotypes, including epilepsy and seizures, myotonia, and erythromelalgia.9 Although multiple Nav channel α-subunits are expressed in heart, Nav1.5 ( SCN5A ) is the …