Abstract 740: Gene Therapeutic Prevention of Atrioventricular Conduction Delay in Pigs with Persistent Atrial Fibrillation and Heart Failure
Background: Heart failure (HF) is a common cause for the worldwide morbidity and mortality. In up to 30 % of these patients conduction disturbances are present which often worsen the prognosis. Both bundle branch- as well as AV-block may occur. The present study elucidates, whether downregulation of connexin 43, a subunit of cardiac Gap junctions, accounts for these conduction abnormalities. We further developed an AV-nodal gene-transfer approach to prevent conduction disturbances in pigs with persistent atrial fibrillation (AF) and heart failure.
Methods and Results: In 10 domestic pigs a pacemaker (PM) capable of 42 Hz bursting was implanted into the right atrium. After 5±1 days all pigs were in persistent AF. Fast ventricular rates during AF led to a significant decrease of left ventricular ejection fraction (69±3 vs. 33±3 % (p<0.05). On the day of pacemaker implantation recombinant adenoviruses encoding for β-galactosidase (Adβgal, control) or Connexin 43 (AdCX43) were injected into the AV-node artery. Twenty days after pacemaker implantation pigs receiving Adβgal revealed a significant increase of Wenckebach-cycle-length (208±6 ms vs. 272±10 ms, p<0.05) and PQ-interval (102 ± 22 ms vs. 164±26 ms, p<0.05). In contrast in those pigs with AV-nodal gene-transfer of AdCx43 neither Wenckebach-cycle-length (234±22 ms vs. 220±19 ms, p>0.05) nor PQ-interval (131±7 ms vs. 130±12 ms, p>0.05) changed. Western Blot analysis from AV-nodes demonstrate a significantly lower expression of Connexin 43 in pigs treated with Adβgal than in healthy pigs lacking AF and HF. In contrast pigs treated with AdCx43 had a similar AV-nodal expression of Connexin 43 compared with healthy pigs.
Conclusions: In pigs with persistent AF and HF early AV-conduction disturbances are evident, which are due to downregulation of gap-junction expression. Overexpression of AV-nodal Connexin 43 by adenoviral gene transfer successfully prevented worsening of AV-nodal conduction. This approach might be a potential alternative to pacemaker therapy in patients with heart failure and conduction disturbances.