Targeted SERCA2a Gene Expression Identifies Molecular Mechanism and Therapeutic Target for Arrhythmogenic Cardiac Alternans

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Abstract
Beat-to-beat alternans of cellular repolarization is closely linked to ventricular arrhythmias in humans. We hypothesized that sarcoplasmic reticulum calcium reuptake by SERCA2a plays a central role in the mechanism of cellular alternans and that increasing SERCA2a gene expression will retard the development of cellular alternans. In vivo gene transfer of a recombinant adenoviral vector with the transgene for SERCA2a (Ad.SERCA2a) was performed in young guinea pigs. Isolated myocytes transduced with Ad.SERCA2a exhibited improved sarcoplasmic reticulum Ca(2+) reuptake (P<0.05) and were markedly resistant to cytosolic calcium alternans (P<0.05) under repetitive constant action potential clamp conditions (ie, when alternation of action potential duration was prevented), proving that sarcoplasmic reticulum Ca(2+) cycling is an important mechanism in the development of cellular alternans. Similarly, SERCA2a overexpression in the intact heart demonstrated significant resistance to alternation of action potential duration when compared with control hearts (heart rate threshold, 484+/-25 bpm versus 396+/-11 bpm, P<0.01), with no change in action potential duration restitution slope. Importantly, SERCA2a overexpression produced a 4-fold reduction in susceptibility to alternans-mediated ventricular arrhythmias (P<0.05). These data provide new evidence that sarcoplasmic reticulum Ca(2+) reuptake directly modulates susceptibility to cellular alternans. Moreover, SERCA2a overexpression suppresses cellular alternans, interrupting an important pathway to cardiac fibrillation in the intact heart.