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(Circulation. 2004;110:3115-3120.)
© 2004 American Heart Association, Inc.

Molecular Cardiology

Inhibitory G Protein Overexpression Provides Physiologically Relevant Heart Rate Control in Persistent Atrial Fibrillation

Alexander Bauer, MD; Amy D. McDonald, BS; Khurram Nasir, MD; Leah Peller, BS; Jeffrey J. Rade, MD; Julie M. Miller, MD; Alan W. Heldman, MD; J. Kevin Donahue, MD

From Johns Hopkins University, Baltimore, Md.

Correspondence to J. Kevin Donahue, MD, Johns Hopkins University, Ross 844, 720 Rutland Ave, Baltimore, MD 21205. E-mail kdonahue{at}jhmi.edu

Received April 20, 2004; revision received August 11, 2004; accepted August 18, 2004.

Background— The need for new treatment strategies for cardiac arrhythmias has motivated our continuing development of gene therapeutic options. Previously, we reported a decreased heart rate in an acute model of atrial fibrillation after atrioventricular nodal gene transfer. Here, we expand those observations to persistent atrial fibrillation and severe heart failure.

Methods and Results— After 3 weeks of atrial fibrillation, domestic swine received atrioventricular nodal gene transfer with adenoviruses encoding ß-galactosidase (ß-gal), wild-type G_i2 (wtGi), or constitutively active mutant (cGi). Heart rates in awake, alert animals were not altered by ß-gal or wtGi. cGi caused a sustained 15% to 25% decrease in heart rate. The wtGi effect became evident with sedation. A tachycardia-induced cardiomyopathy was present before gene transfer. In the ß-gal group, cardiomyopathy worsened over time. In the wtGi group, the condition improved slightly, and in the cGi group, ejection fraction was near normal at the end of the study. TUNEL staining results corroborated this finding.

Conclusions— cGi overexpression in the porcine atrioventricular node causes physiologically relevant heart rate control in persistent atrial fibrillation. These data advance the development of gene therapy as a potential treatment for common cardiac arrhythmias.

Key Words: arrhythmia • gene therapy • electrophysiology • atrioventricular node • fibrillation

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