Atrioventricular nodal gene transfer with constitutively active mutant Gα i2 caused a sustained 15% to 25% decrease in heart rate and normalized ejection fraction in swine with persistent AF.
Does atrioventricular nodal gene transfer with inhibitory G protein overexpression reduce heart rate and improve cardiomyopathy in a porcine model of persistent atrial fibrillation?
Constitutively active mutant Gα i2 gene transfer to the AV node effectively controls heart rate and improves tachycardia-induced cardiomyopathy in a porcine model of persistent atrial fibrillation.
Effect estimate: 15% to 25% decrease
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 β-galactosidase (β-gal), wild-type Gα i2 (wtGi), or constitutively active mutant (cGi). Heart rates in awake, alert animals were not altered by β-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 β-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.
Bauer et al. (Tue,) conducted a other in Persistent atrial fibrillation and severe heart failure. Atrioventricular nodal gene transfer with adenoviruses encoding wild-type Gα i2 (wtGi) or constitutively active mutant (cGi) vs. Adenoviruses encoding β-galactosidase (β-gal) was evaluated on Heart rate (15% to 25% decrease). Atrioventricular nodal gene transfer with constitutively active mutant Gα i2 caused a sustained 15% to 25% decrease in heart rate and normalized ejection fraction in swine with persistent AF.