Cardiac-specific deletion of Scn8a mitigates dravet syndrome-associated sudden death in adults

Abstract

BACKGROUND 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 voltagegated sodium channel, Na V 1.1, and is associated with particularly high SUDEP risk. Evidence is mounting that Na V s 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. OBJECTIVES In this study, the authors sought to provide evidence implicating remodeling of Na (+ )- and Ca (2+) -handling machinery, including Na V 1.6 and Na + /Ca (2+) exchanger (NCX) within transverse (T) -tubules in DS -associated arrhythmias. METHODS The authors undertook scanning ion conductance microscopy (SICM)-guided patch clamp, super-resolution microscopy, confocal Ca 2+ imaging, and in vivo electrocardiography studies in Scn1a haploinsuf ficient murine model of DS. RESULTS 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 Ca (2+) release channels, the ryanodine receptors (RyR2) and NCX in DS relative to WT hearts. The resulting I (Na,L) in these regions promoted aberrant Ca (2+) release, leading to ventricular arrhythmias in vivo. Cardiac-speci fic 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. CONCLUSIONS These data demonstrate that Na V 1.6 undergoes remodeling within T -tubules of adult DS hearts serving as a substrate for Ca (2+) -mediated cardiac arrhythmias and may be a druggable target for the prevention of SUDEP in adult DS subjects. (J Am Coll Cardiol EP 2024;10:829 -842) (c) 2024 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY -NC -ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).