Published Online
on October 9, 2006

A more recent version of this article appeared on October 17, 2006

This Article Full Text (PDF) Data Supplement All Versions of this Article: 114/16/1682    most recent CIRCULATIONAHA.106.634865v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kashiwakura, Y. Articles by Marbán, E. Search for Related Content PubMed PubMed Citation Articles by Kashiwakura, Y. Articles by Marbán, E. Related Collections Ion channels/membrane transport Gene therapy Related Article

Submitted on April 19, 2006
Revised on July 15, 2006
Accepted on August 7, 2006

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, and Eduardo Marbán MD, PhD^*

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

^* To whom correspondence should be addressed. E-mail: marban{at}jhmi.edu.

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.

Key words: gene therapy • ion channels • pacing

Related Article:

Issue Highlights
Circulation 2006 114: 1669. [Extract] [Full Text]

This article has been cited by other articles:

				M. R. Rosen, P. R. Brink, I. S. Cohen, and R. B. Robinson Cardiac Pacing: From Biological to Electronic ... to Biological? Circ Arrhythm Electrophysiol, April 1, 2008; 1(1): 54 - 61. [Abstract] [Full Text] [PDF]

				A. N. Plotnikov, I. Shlapakova, M. J. Szabolcs, P. Danilo Jr, B. H. Lorell, I. A. Potapova, Z. Lu, A. B. Rosen, R. T. Mathias, P. R. Brink, et al. Xenografted Adult Human Mesenchymal Stem Cells Provide a Platform for Sustained Biological Pacemaker Function in Canine Heart Circulation, August 14, 2007; 116(7): 706 - 713. [Abstract] [Full Text] [PDF]

				S. Kaab Tuning the Beat: Differential Expression of Ion Channels in the Sinus Node Circ. Res., December 8, 2006; 99(12): 1283 - 1284. [Full Text] [PDF]