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(Circulation. 2006;114:1682-1686.)
© 2006 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Gene Transfer of a Synthetic Pacemaker Channel Into the Heart

A Novel Strategy for Biological Pacing

Yuji Kashiwakura, MD, PhD; Hee Cheol Cho, PhD; Andreas S. Barth, MD; Ezana Azene, PhD; Eduardo Marbán, MD, PhD

From the Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Md.

Correspondence to Eduardo Marbán, MD, PhD, Division of Cardiology, Johns Hopkins University School of Medicine, 858 Ross Bldg, 720 Rutland Ave, Baltimore, MD 21205. E-mail marban{at}jhmi.edu

Received April 19, 2006; revision received July 15, 2006; accepted August 7, 2006.

Background— One key element of natural pacemakers is the pacemaker current encoded by the hyperpolarization-activated nucleotide-gated channel (HCN) gene family. Although HCN gene transfer has been used to engineer biological pacemakers, this strategy may be confounded by unpredictable consequences of heteromultimerization with endogenous HCN family members and limited flexibility with regard to frequency tuning of the engineered pacemaker.

Methods and Results— To circumvent these limitations, we converted a depolarization-activated potassium-selective channel, Kv1.4, into a hyperpolarization-activated nonselective channel by site-directed mutagenesis (R447N, L448A, and R453I in S4 and G528S in the pore). Gene transfer into ventricular myocardium demonstrated the ability of this construct to induce pacemaker activity with spontaneous action potential oscillations in adult ventricular myocytes and idioventricular rhythms by in vivo electrocardiography.

Conclusions— Given the sparse expression of Kv1 family channels in the human ventricle, gene transfer of a synthetic pacemaker channel based on the Kv1 family has novel therapeutic potential as a biological alternative to electronic pacemakers.

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