Abstract 18147: AAV1-HCN4-mediated Biological Pacemaker Paces the Canine Heart with AV Block over 7 Months and Responds Well to Autonomic Challenges
Background: Implantation of an electronic pacemaker is necessary for patients with severe bradycardia, but such therapy has several limitations including hardware complications, limited battery life and lack of response to autonomic and physiologic demands on the heart. Compared to its counterpart, a biological pacemaker is conceptually an attractive alternative, but is still at a research stage.
Objective: This study was to test whether using adeno-associate virus-1 (AAV1) with truncated human HCN4 (hHCN4tr) would create a long-term (>6 months) and consistent (nearly 100% biologically induced pacing) biological pacemaker in the left ventricle (LV) of canines with atrioventricular (AV) nodal block.
Methods: Canines (n=3) with neutralizing anti-AAV1 antibodies (NAb) at a titer ≤ 1:40 serum dilution were selected. After complete AV block, the AAV1-hHCN4tr vectors were epicardially injected into the LV apex. An electrical pacemaker was implanted for backup pacing (VVI 50 bpm) and automatic electrogram recording every two hours. During the follow-up monitoring, drug and exercise challenges were performed. Twenty-four hour Holter monitoring and pacemaker log checks were also performed.
Results: All canines demonstrated biological pacemaker activities 5 days after AAV1-hHCN4tr injection. The biological pacemaker in two canines with NAb at a titer of 1:40 diminished 3 weeks after the gene transfer presumably due to the pre-existing immunity to AAV1. However, the canine with NAb at a titer of 1:20 has exhibited sustained biological pacing at a range of 60–150 bpm over 7 months and is presently being followed. The electrical pacemaker provided support pacing when biologically induced pacing rate fell below 50 bpm, but accounted for <2% of the beats. The biological pacemaker responded to isoproterenol and metoprolol, and also showed physiological diurnal variations and responses to exercise.
Conclusions: LV myocardial injection with AAV1-hHCN4tr creates long-term (>7 months) and consistent (>98% biologically induced pacing) biological pacemaker activity in a complete AV block canine model. Interestingly, such biological pacemaker responds well to autonomic challenges and physiological exercise.
- © 2010 by American Heart Association, Inc.