Neuronal Na+ channel blockade suppresses arrhythmogenic diastolic Ca2+ release

Przemyslaw B. Radwański, Lucia Brunello, Rengasayee Veeraraghavan, Hsiang Ting Ho, Qing Lou, Michael A. Makara, Andriy E. Belevych, Mircea Anghelescu, Silvia G. Priori, Pompeo Volpe, Thomas J. Hund, Paul M L Janssen, Peter J. Mohler, John Bridg, Steven Poelzing, Sandor Györke

Research output: Contribution to journalArticlepeer-review

Abstract

Aims Sudden death resulting from cardiac arrhythmias is the most common consequence of cardiac disease. Certain arrhythmias caused by abnormal impulse formation including catecholaminergic polymorphic ventricular tachycardia (CPVT) are associated with delayed afterdepolarizations resulting from diastolic Ca2+ release (DCR) from the sarcoplasmic reticulum (SR). Despite high response of CPVT to agents directly affecting Ca2+ cycling, the incidence of refractory cases is still significant. Surprisingly, these patients often respond to treatment with Na+ channel blockers. However, the relationship between Na+ influx and disturbances in Ca2+ handling immediately preceding arrhythmias in CPVT remains poorly understood and is the object of this study. Methods and results We performed optical Ca2+ and membrane potential imaging in ventricular myocytes and intact cardiac muscles as well as surface ECGs on a CPVT mouse model with a mutation in cardiac calsequestrin. We demonstrate that a subpopulation of Na+ channels (neuronal Na+ channels; nNav) colocalize with ryanodine receptor Ca2+ release channels (RyR2). Disruption of the crosstalk between nNav and RyR2 by nNav blockade with riluzole reduced and also desynchronized DCR in isolated cardiomyocytes and in intact cardiac tissue. Such desynchronization of DCR on cellular and tissue level translated into decreased arrhythmias in CPVT mice. Conclusions Thus, our study offers the first evidence that nNav contribute to arrhythmogenic DCR, thereby providing a conceptual basis for mechanism-based antiarrhythmic therapy.

Original languageEnglish
Pages (from-to)143-152
Number of pages10
JournalCardiovascular Research
Volume106
Issue number1
DOIs
Publication statusPublished - Apr 1 2015

Keywords

  • Diastolic Ca<sup>2+</sup> release
  • Neuronal Na+ channels
  • Ventricular arrhythmias

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

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