Journal
CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY
Volume 4, Issue 3, Pages 362-372Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCEP.110.961615
Keywords
arrhythmia; gene therapy; calcium; heart failure; SERCA2a
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Funding
- UK Medical Research Council
- Fondation Leducq
- British Heart Foundation [BHF RG/05/009]
- British Heart Foundation [SP/09/007/27920, RG/10/11/28457] Funding Source: researchfish
- Medical Research Council [G0500373] Funding Source: researchfish
- MRC [G0500373] Funding Source: UKRI
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Background-Sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) gene therapy improves mechanical function in heart failure and is under evaluation in a clinical trial. A critical question is whether SERCA2a gene therapy predisposes to increased sarcoplasmic reticulum calcium (SR Ca2+) leak, cellular triggered activity, and ventricular arrhythmias in the failing heart. Methods and Results-We studied the influence of SERCA2a gene therapy on ventricular arrhythmogenesis in a rat chronic heart failure model. ECG telemetry studies revealed a significant antiarrhythmic effect of SERCA2a gene therapy with reduction of both spontaneous and catecholamine-induced arrhythmias in vivo. SERCA2a gene therapy also reduced susceptibility to reentry arrhythmias in ex vivo programmed electrical stimulation studies. Subcellular Ca2+ homeostasis and spontaneous SR Ca2+ leak characteristics were measured in failing cardiomyocytes transfected in vivo with a novel AAV9.SERCA2a vector. SR Ca2+ leak was reduced after SERCA2a gene therapy, with reversal of the greater spark mass observed in the failing myocytes, despite normalization of SR Ca2+ load. SERCA2a reduced ryanodine receptor phosphorylation, thereby resetting SR Ca2+ leak threshold, leading to reduced triggered activity in vitro. Both indirect effects of reverse remodeling and direct SERCA2a effects appear to underlie the antiarrhythmic action. Conclusions-SERCA2a gene therapy stabilizes SR Ca2+ load, reduces ryanodine receptor phosphorylation and decreases SR Ca2+ leak, and reduces cellular triggered activity in vitro and spontaneous and catecholamine-induced ventricular arrhythmias in vivo in failing hearts. SERCA2a gene therapy did not therefore predispose to arrhythmias and may represent a novel antiarrhythmic strategy in heart failure. (Circ Arrhythm Electrophysiol. 2011;4:362-372.)
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