SERCA2a gene transfer decreases sarcoplasmic reticulum @entity460 leak and reduces XXXX in a model of @entity712 .

@entity712 @entity35 @entity8452 @entity460 @entity2922 @entity141 @entity943
BACKGROUND: Sarcoplasmic reticulum @entity460 ATPase 2a (SERCA2a) gene therapy improves mechanical function in @entity712 and is under evaluation in a clinical trial. A critical question is whether SERCA2a gene therapy predisposes to increased sarcoplasmic reticulum @entity460 (SR @entity141 ) leak, cellular triggered activity, and @entity943 in the failing heart. METHODS AND RESULTS: We studied the influence of SERCA2a gene therapy on ventricular arrhythmogenesis in a @entity35 @entity712 model. ECG telemetry studies revealed a significant antiarrhythmic effect of SERCA2a gene therapy with reduction of both spontaneous and @entity2922 -induced @entity943 in vivo. SERCA2a gene therapy also reduced susceptibility to reentry @entity943 in ex vivo programmed electrical stimulation studies. Subcellular @entity141 homeostasis and spontaneous SR @entity141 leak characteristics were measured in failing cardiomyocytes transfected in vivo with a novel AAV9.SERCA2a vector. SR @entity141 leak was reduced after SERCA2a gene therapy, with reversal of the greater spark mass observed in the failing myocytes, despite normalization of SR @entity141 load. SERCA2a reduced @entity8452 receptor phosphorylation, thereby resetting SR @entity141 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 @entity141 load, reduces @entity8452 receptor phosphorylation and decreases SR @entity141 leak, and reduces cellular triggered activity in vitro and spontaneous and @entity2922 -induced @entity943 in vivo in failing hearts. SERCA2a gene therapy did not therefore predispose to @entity943 and may represent a novel antiarrhythmic strategy in @entity712 .
