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

Autor:	King DR; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Division of Outcomes and Translational Sciences, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA., Demirtas M; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Division of Outcomes and Translational Sciences, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA., Tarasov M; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Division of Outcomes and Translational Sciences, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA., Struckman HL; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, Ohio, USA., Meng X; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Division of Outcomes and Translational Sciences, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA., Nassal D; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, Ohio, USA., Moise N; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, Ohio, USA., Miller A; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Division of Outcomes and Translational Sciences, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA., Min D; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Division of Outcomes and Translational Sciences, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA., Soltisz AM; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, Ohio, USA., Anne MNK; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, Ohio, USA., Alves Dias PA; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Division of Outcomes and Translational Sciences, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Akademika Heyrovského Hradec Králové, Czech Republic., Wagnon JL; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, Ohio, USA., Weinberg SH; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, Ohio, USA., Hund TJ; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, Ohio, USA; Department of Internal Medicine, Division of Cardiovascular Medicine, College of Medicine, The Ohio State University, Columbus, Ohio, USA., Veeraraghavan R; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, Ohio, USA., Radwański PB; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Division of Outcomes and Translational Sciences, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA. Electronic address: radwanski.2@osu.edu.
Jazyk:	angličtina
Zdroj:	JACC. Clinical electrophysiology [JACC Clin Electrophysiol] 2024 May; Vol. 10 (5), pp. 829-842. Date of Electronic Publication: 2024 Feb 28.
DOI:	10.1016/j.jacep.2024.01.003
Abstrakt:	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 voltage-gated 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 haploinsufficient 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-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. 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. Competing Interests: Funding Support and Author Disclosures This work was supported by National Institutes of Health grants R01NS121234 and R01HL155378 (to Dr Radwański), R01HL148736 (to Dr Veeraraghavan), R01HL156652 (to Dr Hund), K99HL157684 (to Dr Nassal), and T32HL149637-02 and L40NS129034 (to Dr King); National Science Foundation Graduate Research Fellowship, NSF Fellow ID: 2019259354 (to Dr Struckman); and American Heart Association postdoctoral fellowships 915300 (to Dr Tarasov) and 908824 (to Dr Moise). The authors have reported that they have no relationships relevant to the contents of this paper to disclose. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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