Inhibitory G protein overexpression provides physiologically relevant heart rate control in persistent atrial fibrillation

• Published in: Circulation (New York, N.Y.) N.Y.), 2004-11, Vol.110 (19), p.3115-3120
• Main Authors: Bauer, Alexander, McDonald, Amy D, Nasir, Khurram, Peller, Leah, Rade, Jeffrey J, Miller, Julie M, Heldman, Alan W, Donahue, J Kevin
• Format: Article
• Language: English
• Subjects: Acute Disease; Adenoviridae - genetics; Animals; Anti-Arrhythmia Agents - pharmacology; Anti-Arrhythmia Agents - therapeutic use; Atrial Fibrillation - diagnostic imaging; Atrial Fibrillation - genetics; Atrial Fibrillation - physiopathology; Atrial Fibrillation - therapy; Atrioventricular Node; Cardiac Pacing, Artificial; Digoxin - pharmacology; Digoxin - therapeutic use; Diltiazem - pharmacology; Diltiazem - therapeutic use; Gene Expression Regulation; Genetic Therapy; Genetic Vectors - therapeutic use; GTP-Binding Protein alpha Subunit, Gi2; GTP-Binding Protein alpha Subunits, Gi-Go - biosynthesis; GTP-Binding Protein alpha Subunits, Gi-Go - genetics; Heart Failure - diagnostic imaging; Heart Failure - genetics; Heart Failure - physiopathology; Heart Failure - therapy; Heart Rate; Propanolamines - pharmacology; Propanolamines - therapeutic use; Proto-Oncogene Proteins - biosynthesis; Proto-Oncogene Proteins - genetics; Recombinant Fusion Proteins - biosynthesis; Recombinant Fusion Proteins - genetics; Stroke Volume; Sus scrofa; Ultrasonography
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.cir.0000147185.31974.be

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. After 3 weeks of atrial fibrillation, domestic swine received atrioventricular nodal gene transfer with adenoviruses encoding beta-galactosidase (beta-gal), wild-type Galpha(i2) (wtGi), or constitutively active mutant (cGi). Heart rates in awake, alert animals were not altered by beta-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 beta-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. 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.