The Ca2+-Stimulated Adenylyl Cyclase AC1 Generates Efficient Biological Pacing as Single Gene Therapy and in Combination with HCN2
Background—Biological pacing performed solely via HCN2 gene transfer in vivo results in relatively slow idioventricular rates and only moderate autonomic responsiveness. We induced biological pacing using the Ca2+-stimulated adenylyl cyclase AC1 gene expressed alone or in combination with HCN2 and compared outcomes to those with single gene HCN2 transfer.
Methods and Results—We implanted adenoviral HCN2, AC1, or HCN2/AC1 constructs into the left bundle branches (LBB) of atrioventricular-blocked dogs. During steady-state gene expression (days 5-7), differences between AC1, HCN2/AC1 and HCN2 alone were evident in basal beating rate, escape time, and dependence on electronic back-up pacing. In HCN2, AC1, and HCN2/AC1, these parameters were, respectively: Basal beating rate: 50±1.5bpm, 60±5.0bpm, and 129±28.9bpm (P<0.05 for HCN2/AC1 vs. HCN2 or AC1 alone); Escape time: 2.4±0.2 sec, 1.3±0.2 sec, and 1.1±.0.4sec (P<0.05 for AC1 and HCN2/AC1 vs. HCN2); and % Electronic beats: 34±8%, 2±1%, and 6±2% (P<0.05 for AC1 and HCN2/AC1 vs. HCN2). Instantaneous (SD1) and long-term (SD2) heart rate variability (HRV) and circadian rhythm analyzed via 24h Holter recordings showed a shift toward greater sensitivity to parasympathetic modulation in animals injected with AC1 as well as a high degree of sympathetic modulation in animals injected with HCN2/AC1.
Conclusions—AC1 or HCN2/AC1 overexpression in LBB provides highly efficient biological pacing and greater sensitivity to autonomic modulation than HCN2 alone.
- Received December 1, 2011.
- Accepted June 8, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited