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(Circulation. 2006;114:1000-1011.)
© 2006 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Bioartificial Sinus Node Constructed via In Vivo Gene Transfer of an Engineered Pacemaker HCN Channel Reduces the Dependence on Electronic Pacemaker in a Sick-Sinus Syndrome Model

Hung-Fat Tse, MD; Tian Xue, PhD; Chu-Pak Lau, MD; Chung-Wah Siu, MBBS; Kai Wang, BS; Qing-Yong Zhang, MD; Gordon F. Tomaselli, MD; Fadi G. Akar, PhD; Ronald A. Li, PhD

From the Department of Medicine, Queen Mary Hospital (H.-F.T., C.-P.L., C.-W.S., K.W., Q.-Y.Z., R.A.L.), University of Hong Kong, Hong Kong; Department of Medicine, Johns Hopkins University (G.F.T., F.G.A.), Baltimore, Md; Department of Cell Biology and Human Anatomy (T.X., C.-W.S., R.A.L.) and Stem Cell Program (T.X., R.A.L.), University of California, Davis, Calif; and Institute of Pediatric Regenerative Medicine, Shriners Hospital for Children of North America (R.A.L.), Sacramento, Calif.

Correspondence to Ronald Li, PhD, Associate Professor, Stem Cell Program, University of California, Room 650, Shriners Hospital, 2425 Stockton Blvd, Sacramento, CA 95817. E-mail ronaldli{at}ucdavis.edu

Received January 19, 2006; revision received June 20, 2006; accepted June 30, 2006.

Background— The normal cardiac rhythm originates in the sinoatrial (SA) node that anatomically resides in the right atrium. Malfunction of the SA node leads to various forms of arrhythmias that necessitate the implantation of electronic pacemakers. We hypothesized that overexpression of an engineered HCN construct via somatic gene transfer offers a flexible approach for fine-tuning cardiac pacing in vivo.

Methods and Results— Using various electrophysiological and mapping techniques, we examined the effects of in situ focal expression of HCN1-, the S3-S4 linker of which has been shortened to favor channel opening, on impulse generation and conduction. Single left ventricular cardiomyocytes isolated from guinea pig hearts preinjected with the recombinant adenovirus Ad-CMV-GFP-IRES-HCN1- in vivo uniquely exhibited automaticity with a normal firing rate (237±12 bpm). High-resolution ex vivo optical mapping of Ad-CGI-HCN1-–injected Langendorff-perfused hearts revealed the generation of spontaneous action potentials from the transduced region in the left ventricle. To evaluate the efficacy of our approach for reliable atrial pacing, we generated a porcine model of sick-sinus syndrome by guided radiofrequency ablation of the native SA node, followed by implantation of a dual-chamber electronic pacemaker to prevent bradycardia-induced hemodynamic collapse. Interestingly, focal transduction of Ad-CGI-HCN1- in the left atrium of animals with sick-sinus syndrome reproducibly induced a stable, catecholamine-responsive in vivo "bioartificial node" that exhibited a physiological heart rate and was capable of reliably pacing the myocardium, substantially reducing electronic pacing.

Conclusions— The results of the present study provide important functional and mechanistic insights into cardiac automaticity and have further refined an HCN gene–based therapy for correcting defects in cardiac impulse generation.

Key Words: sinoatrial node • pacemakers • therapyengineering • ion channels

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