Neuronal Na+ channel blockade suppresses arrhythmogenic diastolic Ca2+ release. (23rd December 2014)

• Record Type: Journal Article
• Authors: Radwański, Przemysław B.; Brunello, Lucia; Veeraraghavan, Rengasayee; Ho, Hsiang-Ting; Lou, Qing; Makara, Michael A.; Belevych, Andriy E.; Anghelescu, Mircea; Priori, Silvia G.; Volpe, Pompeo; Hund, Thomas J.; Janssen, Paul M. L.; Mohler, Peter J.; Bridge, John H. B.; Poelzing, Steven; Györke, Sándor
• Is Part Of: Cardiovascular research. Volume 106:Number 1(2015)
• Page Start: 143
• Page End: 152
• Publication Date: 2014-12-23
• Subjects: Ventricular arrhythmias -- Neuronal Na+ channels -- Diastolic Ca2+ release; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvu262
• Languages: English
• ISSNs: 0008-6363

Abstract

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 Ca 2+ release (DCR) from the sarcoplasmic reticulum (SR). Despite high response of CPVT to agents directly affecting Ca 2+ 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 Ca 2+ handling immediately preceding arrhythmias in CPVT remains poorly understood and is the object of this study. Methods and results: We performed optical Ca 2+ 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 Ca 2+ 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.