• Je něco špatně v tomto záznamu ?

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

DR. King, M. Demirtas, M. Tarasov, HL. Struckman, X. Meng, D. Nassal, N. Moise, A. Miller, D. Min, AM. Soltisz, MNK. Anne, PA. Alves Dias, JL. Wagnon, SH. Weinberg, TJ. Hund, R. Veeraraghavan, PB. Radwański

. 2024 ; 10 (5) : 829-842. [pub] 20240228

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc24014142

Grantová podpora
R01 HL155378 NHLBI NIH HHS - United States
R01 NS121234 NINDS NIH HHS - United States

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, NaV 1.1, and is associated with particularly high SUDEP risk. Evidence is mounting that NaVs 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 NaV 1.1 functional expression in DS, pathogenic late sodium current (INa,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 Ca2+ -handling machinery, including NaV 1.6 and Na+/Ca2+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 Ca2+ imaging, and in vivo electrocardiography studies in Scn1a haploinsufficient murine model of DS. RESULTS: DS promotes INa,L in T-tubular nanodomains, but not in other subcellular regions. Consistent with increased NaV activity in these regions, super-resolution microscopy revealed increased NaV 1.6 density near Ca2+release channels, the ryanodine receptors (RyR2) and NCX in DS relative to WT hearts. The resulting INa,L in these regions promoted aberrant Ca2+ release, leading to ventricular arrhythmias in vivo. Cardiac-specific deletion of NaV 1.6 protects adult DS mice from increased T-tubular late NaV activity and the resulting arrhythmias, as well as sudden death. CONCLUSIONS: These data demonstrate that NaV 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.

Citace poskytuje Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc24014142
003      
CZ-PrNML
005      
20240905134324.0
007      
ta
008      
240725s2024 xxu f 000 0|eng||
009      
AR
024    7_
$a 10.1016/j.jacep.2024.01.003 $2 doi
035    __
$a (PubMed)38430092
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxu
100    1_
$a King, D Ryan $u 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
245    10
$a Cardiac-Specific Deletion of Scn8a Mitigates Dravet Syndrome-Associated Sudden Death in Adults / $c DR. King, M. Demirtas, M. Tarasov, HL. Struckman, X. Meng, D. Nassal, N. Moise, A. Miller, D. Min, AM. Soltisz, MNK. Anne, PA. Alves Dias, JL. Wagnon, SH. Weinberg, TJ. Hund, R. Veeraraghavan, PB. Radwański
520    9_
$a 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, NaV 1.1, and is associated with particularly high SUDEP risk. Evidence is mounting that NaVs 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 NaV 1.1 functional expression in DS, pathogenic late sodium current (INa,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 Ca2+ -handling machinery, including NaV 1.6 and Na+/Ca2+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 Ca2+ imaging, and in vivo electrocardiography studies in Scn1a haploinsufficient murine model of DS. RESULTS: DS promotes INa,L in T-tubular nanodomains, but not in other subcellular regions. Consistent with increased NaV activity in these regions, super-resolution microscopy revealed increased NaV 1.6 density near Ca2+release channels, the ryanodine receptors (RyR2) and NCX in DS relative to WT hearts. The resulting INa,L in these regions promoted aberrant Ca2+ release, leading to ventricular arrhythmias in vivo. Cardiac-specific deletion of NaV 1.6 protects adult DS mice from increased T-tubular late NaV activity and the resulting arrhythmias, as well as sudden death. CONCLUSIONS: These data demonstrate that NaV 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.
650    _2
$a zvířata $7 D000818
650    _2
$a ženské pohlaví $7 D005260
650    _2
$a lidé $7 D006801
650    _2
$a mužské pohlaví $7 D008297
650    _2
$a myši $7 D051379
650    _2
$a srdeční arytmie $x genetika $7 D001145
650    _2
$a vápník $x metabolismus $7 D002118
650    12
$a epilepsie myoklonické $x genetika $7 D004831
650    _2
$a myši knockoutované $7 D018345
650    _2
$a kardiomyocyty $x metabolismus $7 D032383
650    12
$a napěťově řízený sodíkový kanál, typ 6 $x genetika $x metabolismus $7 D062557
650    _2
$a pumpa pro výměnu sodíku a vápníku $x genetika $x metabolismus $7 D019831
650    _2
$a náhlá neočekávaná smrt při epilepsii $7 D000080485
655    _2
$a časopisecké články $7 D016428
700    1_
$a Demirtas, Mustafa $u 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
700    1_
$a Tarasov, Mikhail $u 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
700    1_
$a Struckman, Heather L $u 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
700    1_
$a Meng, Xiaolei $u 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
700    1_
$a Nassal, Drew $u 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
700    1_
$a Moise, Nicolae $u 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
700    1_
$a Miller, Alec $u 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
700    1_
$a Min, Dennison $u 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
700    1_
$a Soltisz, Andrew M $u 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
700    1_
$a Anne, Midhun N K $u 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
700    1_
$a Alves Dias, Patrícia A $u 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
700    1_
$a Wagnon, Jacy L $u 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
700    1_
$a Weinberg, Seth H $u 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
700    1_
$a Hund, Thomas J $u 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
700    1_
$a Veeraraghavan, Rengasayee $u 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
700    1_
$a Radwański, Przemysław B $u 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
773    0_
$w MED00193518 $t JACC. Clinical electrophysiology $x 2405-5018 $g Roč. 10, č. 5 (2024), s. 829-842
856    41
$u https://pubmed.ncbi.nlm.nih.gov/38430092 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y - $z 0
990    __
$a 20240725 $b ABA008
991    __
$a 20240905134318 $b ABA008
999    __
$a ok $b bmc $g 2143743 $s 1226008
BAS    __
$a 3
BAS    __
$a PreBMC-MEDLINE
BMC    __
$a 2024 $b 10 $c 5 $d 829-842 $e 20240228 $i 2405-5018 $m JACC. Clinical electrophysiology $n JACC Clin Electrophysiol $x MED00193518
GRA    __
$a R01 HL155378 $p NHLBI NIH HHS $2 United States
GRA    __
$a R01 NS121234 $p NINDS NIH HHS $2 United States
LZP    __
$a Pubmed-20240725

Najít záznam

Citační ukazatele

Možnosti archivace