Cardiac-Specific Deletion of Scn8a Mitigates Dravet Syndrome-Associated Sudden Death in Adults

Sudden unexpected death in epilepsy (SUDEP) is a fatal complication experienced by otherwise healthy epilepsy patients. Dravet syndrome (DS) is an inherited epileptic disorder resulting from loss of function of the voltage-gated sodium channel, Na_V 1.1, and is associated with particularly high SUDEP risk. Evidence is mounting that Na_Vs abundant in the brain also occur in the heart, suggesting that the very molecular mechanisms underlying epilepsy could also precipitate cardiac arrhythmias and sudden death. Despite marked reduction of Na_V 1.1 functional expression in DS, pathogenic late sodium current (I_Na,L) is paradoxically increased in DS hearts. However, the mechanisms by which DS directly impacts the heart to promote sudden death remain unclear.

In this study, the authors sought to provide evidence implicating remodeling of Na⁺ - and Ca²⁺ -handling machinery, including Na_V 1.6 and Na⁺/Ca²⁺exchanger (NCX) within transverse (T)-tubules in DS-associated arrhythmias.

The authors undertook scanning ion conductance microscopy (SICM)-guided patch clamp, super-resolution microscopy, confocal Ca²⁺ imaging, and in vivo electrocardiography studies in Scn1a haploinsufficient murine model of DS.

DS promotes I_Na,L in T-tubular nanodomains, but not in other subcellular regions. Consistent with increased Na_V activity in these regions, super-resolution microscopy revealed increased Na_V 1.6 density near Ca²⁺release channels, the ryanodine receptors (RyR2) and NCX in DS relative to WT hearts. The resulting I_Na,L in these regions promoted aberrant Ca²⁺ release, leading to ventricular arrhythmias in vivo. Cardiac-specific deletion of Na_V 1.6 protects adult DS mice from increased T-tubular late Na_V activity and the resulting arrhythmias, as well as sudden death.

These data demonstrate that Na_V 1.6 undergoes remodeling within T-tubules of adult DS hearts serving as a substrate for Ca²⁺ -mediated cardiac arrhythmias and may be a druggable target for the prevention of SUDEP in adult DS subjects.