Published Online
on October 2, 2009

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Original Article

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

Michael J. Cutler¹; Xiaoping Wan¹; Kenneth R. Laurita¹; Roger J. Hajjar² and David S. Rosenbaum^1,3

¹ Case Western Reserve University, Cleveland, OH;
² Mount Sinai School of Medicine, New York, NY

^* Corresponding author; email: drosenbaum{at}metrohealth.org

Background—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 increasing SERCA2a gene expression will retard the development of cellular alternans.

Methods and Results—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 Ca²⁺ reuptake (p< 0.05) and were markedly resistant to Ca-ALT (p< 0.05) under repetitive constant action potential clamp conditions (i.e. when APD-ALT was prevented) proving that SR Ca²⁺ cycling is an important mechanism in the development of cellular alternans. Similarly, SERCA2a overexpression in the intact heart demonstrated significant resistance to APD-ALT when compared control hearts (HR threshold 484±25 bpm vs 396±11 bpm, p< 0.01), with no change in APD restitution slope. Importantly, SERCA2a overexpression produced a 4-fold reduction in susceptibility to alternans-mediated ventricular arrhythmias (p< 0.05).

Conclusions—These data provide new evidence that SR Ca²⁺ reuptake directly modulates susceptibility to cellular alternans. Moreover, SERCA2a overexpression suppresses cellular alternans, interrupting an important pathway to cardiac fibrillation in the intact heart.

Key Words: action potentials • arrhythmia • gene therapy • alternans • intracellular calcium • adenoviral gene transfer • repolarization