Abrogation of ventricular arrhythmias in a model of ischemia and reperfusion by targeting myocardial calcium cycling

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Abstract
Abnormal intracellular Ca(2+) cycling plays an important role in cardiac dysfunction and ventricular arrhythmias in the setting of heart failure and transient cardiac ischemia followed by reperfusion (I/R). We hypothesized that overexpression of the sarcoplasmic reticulum Ca(2+) ATPase pump (SERCA2a) may improve both contractile dysfunction and ventricular arrhythmias. Continuous ECG recordings were obtained in 46 conscious rats after adenoviral gene transfer of either SERCA2a or the reporter gene beta-galactosidase (beta gal) or parvalbumin (PV), as early as 48 h before and 48 h after 30 min ligation of the left anterior descending artery by using an implantable telemetry system. Sham-operated animals were used for comparison for hemodynamic measurements, whereas within-animal baseline was used for electrocardiographic and echocardiographic parameters. All episodes of nonsustained ventricular tachycardia (VT) and ventricular fibrillation (VF) were counted, and their durations were summed by telemetry. I/R decreased regional cardiac wall thickening as well as the maximal rate of left ventricular pressure rise (+dP/dt) and ventricular pressure fall (-dP/dt). SERCA2a restored regional wall thickening and +dP/dt and -dP/dt to levels seen preoperatively. Regional-wall motion and anterior-wall thickening were improved in the SERCA2a animals, as assessed by echocardiography and piezoelectric crystals. To assess whether these effects are SERCA2a specific, we overexpressed a skeletal-muscle protein, PV, to examine whether Ca(2+) buffering alone can mitigate ventricular arrhythmias. During the first hour after I/R, the rate of nonsustained VT plus VF was 16 +/- 5 episodes per h (n = 6) in the Ad.beta gal group, 22 +/- 6 in the Ad.PV group, and 4 +/- 2(n = 6, P < 0.01) in the Ad.SERCA2a group. The decrease in VT plus VF in the Ad.SERCA2a group was consistent throughout the 48 h of monitoring. These results show that improving intracellular Ca(2+) handling by overexpression of SERCA2a restores contractile function and reduces ventricular arrhythmias during I/R.