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(Circulation. 2003;107:1106.)
© 2003 American Heart Association, Inc.

Brief Rapid Communications

Expression and Function of a Biological Pacemaker in Canine Heart

Jihong Qu, PhD^*; Alexei N. Plotnikov, MD^*; Peter Danilo, Jr, PhD; Iryna Shlapakova, MD; Ira S. Cohen, MD, PhD; Richard B. Robinson, PhD; Michael R. Rosen, MD

From the Departments of Pharmacology and Pediatrics, Center for Molecular Therapeutics, College of Physicians & Surgeons of Columbia University, New York, NY.

Correspondence to Michael R. Rosen, MD (Gustavus A. Pfeiffer Professor of Pharmacology; Professor of Pediatrics; Director, Center for Molecular Therapeutics), College of Physicians & Surgeons of Columbia University, Department of Pharmacology, 630 West 168 St, PH7W-321, New York, NY 10032. E-mail mrr1{at}columbia.edu

Background— We hypothesized that localized overexpression of the hyperpolarization-activated, cyclic nucleotide-gated (HCN2) pacemaker current isoform in canine left atrium (LA) would constitute a novel biological pacemaker.

Methods and Results— Adenoviral constructs of mouse HCN2 and green fluorescent protein (GFP) or GFP alone were injected into LA, terminal studies performed 3 to 4 days later, hearts removed, and myocytes examined for native and expressed pacemaker current (I_f). Spontaneous LA rhythms occurred after vagal stimulation-induced sinus arrest in 4 of 4 HCN2+GFP dogs and 0 of 3 GFP dogs (P<0.05). Native I_f in nonexpressed atrial myocytes was 7±4 pA at -130 mV (n=5), whereas HCN2+GFP LA had expressed pacemaker current (I_HCN2) of 3823±713 pA at -125 mV (n=10) and 768±365 pA at -85 mV.

Conclusions— HCN2 overexpression provides an I_f-based pacemaker sufficient to drive the heart when injected into a localized region of atrium, offering a promising gene therapy for pacemaker disease.

Key Words: arrhythmia • pacemakers • electrophysiology

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