Abstract 2101: Genetic Ablation of Atrial Fibrillation in Pigs With Atrial Fibrillation
Introduction: Atrial fibrillation (AF) is the most common cardiac arrhythmia causing high morbidity and mortality. AF continues to be a challenge for both pharmacological and non pharmacological approaches. AF is associated with atrial conduction disturbances caused by electrical and/or structural remodeling. We just recently demonstrated downregulation of Connexin (Cx) 40 and 43 in both atria. We hypothesized that targeted gene transfer of the gap junction protein Cx43 to both atria could prevent persistent atrial fibrillation (pAF).
Methods: Domestic pigs were subjected to implantation of a pacemaker and atrial fibrillation was induced via right atrial burst pacing. In 10 pigs adenoviruses encoding for green fluorescent protein (AdGFP, n=5) or for Cx43 (AdCx43, n=5) were injected into both atria. To ensure homogeneous and efficient gene transfer injection of adenoviruses was followed by electroporation (EPO) (5 times 20 V/100 ms) applied to the epicardial surface of both atria. 2 weeks later pigs were euthanized and hearts were obtained for further histological examinations. ECG recordings were performed on a daily basis. Echocardiographic exams were performed on the day of pacemaker implantation and 14 days thereafter.
Results: Combining injection of adenoviruses into the atrial wall with EPO resulted in homogeneous and efficient gene transfer to both atria (50,8 ± 7,9 % vs. 9,8 ± 7,4 %, p<0.05). Successful overexpression of atrial Cx43 in AdCx43 treated pigs was confirmed by western blot and immunohistochemical analysis (94,3% vs. 40,1% in control pigs). Ad Cx43 treated animals did not develop pAF at all. In contrast control animals (AdGFP) developed pAF within 7 ± 1 days after initation of the burst pacing protocol. Fast ventricular heart rates during AF led to a tachycardiomyopathy in control pigs (30 ± 9 % left ventricular ejection fraction), but not in pigs treated with Ad Cx43 (54 ± 10 %, p<0.05).
Conclusions: Our study demonstrates a new method of homogeneous gene transfer to both atria. Overexpression of Cx 43 in both atria successfully suppressed development of persistent atrial fibrillation in an AF/heart failure model. Inhibition of AF further prevented heart failure in the verum group. Gene therapy might be potential alternative to treat AF.