Electrophysiological basis of cardiac arrhythmia in a mouse model of myotonic dystrophy type 1

Frontiers in Physiology

Physiology

Yvonne Sleiman¹  Jean-Baptiste Reisqs¹  Michael Cupelli²  Nabil El-Sherif²  Vamsi Krishna Murthy Ginjupalli³  Mohamed Boutjdir⁴  Genevieve Gourdon⁵  Mohamed Chahine⁶  Jack Puymirat⁷ 

[1] Cardiovascular Research Program, VA New York Harbor Health care System, Brooklyn, NY, United States;Cardiovascular Research Program, VA New York Harbor Health care System, Brooklyn, NY, United States;Departments of Medicine, Cell Biology and Pharmacology, SUNY Downstate Health Sciences University, Brooklyn, NY, United States;Cardiovascular Research Program, VA New York Harbor Health care System, Brooklyn, NY, United States;Departments of Medicine, Cell Biology and Pharmacology, SUNY Downstate Health Sciences University, Brooklyn, NY, United States;Department of Medicine, Faculty of Medicine, Université Laval, Quebec City, QC, Canada;Cardiovascular Research Program, VA New York Harbor Health care System, Brooklyn, NY, United States;Departments of Medicine, Cell Biology and Pharmacology, SUNY Downstate Health Sciences University, Brooklyn, NY, United States;Department of Medicine, New York University, Grossman School of Medicine, New York, NY, United States;Centre de recherche en Myologie, Inserm, Institut de Myologie, Sorbonne Université, Paris, France;Department of Medicine, Faculty of Medicine, Université Laval, Quebec City, QC, Canada;CERVO Research Center, Institut Universitaire en Santé Mentale de Québec, Quebec City, QC, Canada;LOEX, CHU de Québec-Université Laval Research Center, Quebec City, QC, Canada;

关键词: myotonic dystrophy type 1;    electrophysiology;    ECG;    arrhythmia;    ion channels;    conduction defects;   

DOI  :  10.3389/fphys.2023.1257682

 received in 2023-07-12, accepted in 2023-09-06,  发布年份 2023

来源: Frontiers

【 摘 要 】

Introduction: Myotonic dystrophy type 1 (DM1) is a multisystemic genetic disorder caused by the increased number of CTG repeats in 3′ UTR of Dystrophia Myotonia Protein Kinase (DMPK) gene. DM1 patients experience conduction abnormalities as well as atrial and ventricular arrhythmias with increased susceptibility to sudden cardiac death. The ionic basis of these electrical abnormalities is poorly understood.Methods: We evaluated the surface electrocardiogram (ECG) and key ion currents underlying the action potential (AP) in a mouse model of DM1, DMSXL, which express over 1000 CTG repeats. Sodium current (INa), L-type calcium current (ICaL), transient outward potassium current (Ito), and APs were recorded using the patch-clamp technique.Results: Arrhythmic events on the ECG including sinus bradycardia, conduction defects, and premature ventricular and atrial arrhythmias were observed in DMSXL homozygous mice but not in WT mice. PR interval shortening was observed in homozygous mice while ECG parameters such as QRS duration, and QTc did not change. Further, flecainide prolonged PR, QRS, and QTc visually in DMSXL homozygous mice. At the single ventricular myocyte level, we observed a reduced current density for Ito and ICaL with a positive shift in steady state activation of L-type calcium channels carrying ICaL in DMSXL homozygous mice compared with WT mice. INa densities and action potential duration did not change between DMSXL and WT mice.Conclusion: The reduced current densities of Ito, and ICaL and alterations in gating properties in L-type calcium channels may contribute to the ECG abnormalities in the DMSXL mouse model of DM1. These findings open new avenues for novel targeted therapeutics.

【 授权许可】

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Copyright © 2023 Ginjupalli, Cupelli, Reisqs, Sleiman, El-Sherif, Gourdon, Puymirat, Chahine and Boutjdir.