Neuronal Na+ Channels Are Integral Components of Pro-arrhythmic Na+/Ca2+ Signaling Nanodomain That Promotes Cardiac Arrhythmias During β-adrenergic Stimulation

JACC Basic Transl Sci. 2016 Jun;1(4):251-266. doi: 10.1016/j.jacbts.2016.04.004.

Przemysław B Radwański ¹, Hsiang-Ting Ho ², Rengasayee Veeraraghavan ³, Lucia Brunello ², Bin Liu ², Andriy E Belevych ², Sathya D Unudurthi ⁴, Michael A Makara ², Silvia G Priori ⁵, Pompeo Volpe ⁶, Antonis A Armoundas ⁷, Wolfgang H Dillmann ⁸, Bjorn C Knollmann ⁹, Peter J Mohler ², Thomas J Hund ¹⁰, Sándor Györke ²

Affiliations

1 Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA ; Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, US ; Division of Pharmacy Practice and Sciences, College of Pharmacy, The Ohio State University, Columbus, OH, US.
2 Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA ; Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, US.
3 Center for Heart and Regenerative Medicine Research, Virginia Tech Carilion Research Institute, Virginia Polytechnic University, Roanoke, VA, USA.
4 Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA ; Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, OH, USA.
5 Division of Cardiology and Molecular Cardiology, Maugeri Foundation-University of Pavia, Pavia, Italy.
6 Department of Biomedical Sciences, University of Padova, Padova, Italy.
7 Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, USA.
8 Department of Medicine, University of California San Diego, La Jolla, CA, USA.
9 Division of Clinical Pharmacology, Vanderbilt University Medical School, Nashville, TN, USA.
10 Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA ; Center for Heart and Regenerative Medicine Research, Virginia Tech Carilion Research Institute, Virginia Polytechnic University, Roanoke, VA, USA.

PMID: 27747307 DOI: 10.1016/j.jacbts.2016.04.004

Abstract

Background: Cardiac arrhythmias are a leading cause of death in the US. Vast majority of these arrhythmias including catecholaminergic polymorphic ventricular tachycardia (CPVT) are associated with increased levels of circulating catecholamines and involve abnormal impulse formation secondary to aberrant Ca²⁺ and Na⁺ handling. However, the mechanistic link between β-AR stimulation and the subcellular/molecular arrhythmogenic trigger(s) remains elusive.

Methods and results: We performed functional and structural studies to assess Ca²⁺ and Na⁺ signaling in ventricular myocyte as well as surface electrocardiograms in mouse models of cardiac calsequestrin (CASQ2)-associated CPVT. We demonstrate that a subpopulation of Na⁺ channels (neuronal Na⁺ channels; nNa_v) that colocalize with RyR2 and Na⁺/Ca²⁺ exchanger (NCX) are a part of the β-AR-mediated arrhythmogenic process. Specifically, augmented Na⁺ entry via nNa_v in the settings of genetic defects within the RyR2 complex and enhanced sarcoplasmic reticulum (SR) Ca²⁺-ATPase (SERCA)-mediated SR Ca²⁺ refill is both an essential and a necessary factor for the arrhythmogenesis. Furthermore, we show that augmentation of Na⁺ entry involves β-AR-mediated activation of CAMKII subsequently leading to nNa_v augmentation. Importantly, selective pharmacological inhibition as well as silencing of Na_v1.6 inhibit myocyte arrhythmic potential and prevent arrhythmias in vivo.

Conclusion: These data suggest that the arrhythmogenic alteration in Na⁺/Ca²⁺ handling evidenced ruing β-AR stimulation results, at least in part, from enhanced Na⁺ influx through nNa_v. Therefore, selective inhibition of these channels and Na_v1.6 in particular can serve as a potential antiarrhythmic therapy.

Keywords

Diastolic Ca2+ release; Neuronal Na+ channels; Ventricular arrhythmias; β-adrenergic receptor.

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HY-15515

SEA0400

99.96%, Na+/Ca2+ Exchanger Inhibitor

Na+/Ca2+ Exchanger

Cardiovascular Disease

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