Ca(2+)-stimulated adenylyl cyclase AC1 generates efficient biological pacing as single gene therapy and in combination with HCN2

Circulation. 2012 Jul 31;126(5):528-36. doi: 10.1161/CIRCULATIONAHA.111.083584. Epub 2012 Jun 29.


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 Ca(2+)-stimulated adenylyl cyclase AC1 gene expressed alone or in combination with HCN2 and compared outcomes with those with single-gene HCN2 transfer.

Methods and results: We implanted adenoviral HCN2, AC1, or HCN2/AC1 constructs into the left bundle branches 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 backup pacing. In HCN2, AC1, and HCN2/AC1, these parameters were as follows: basal beating rate: 50±1.5, 60±5.0, and 129±28.9 bpm (P<0.05 for HCN2/AC1 versus HCN2 or AC1 alone), respectively; escape time: 2.4±0.2, 1.3±0.2, and 1.1±.0.4 seconds (P<0.05 for AC1 and HCN2/AC1 versus HCN2); and percent electronic beats: 34±8%, 2±1%, and 6±2% (P<0.05 for AC1 and HCN2/AC1 versus HCN2). Instantaneous (SD1) and long-term (SD2) heart rate variability and circadian rhythm analyzed via 24-hour Holter recordings showed a shift toward greater sensitivity to parasympathetic modulation in animals injected with AC1 and a high degree of sympathetic modulation in animals injected with HCN2/AC1.

Conclusion: AC1 or HCN2/AC1 overexpression in left bundle branches provides highly efficient biological pacing and greater sensitivity to autonomic modulation than HCN2 alone.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Adenylyl Cyclases / genetics*
  • Adenylyl Cyclases / physiology*
  • Animals
  • Atrioventricular Block / etiology
  • Atrioventricular Block / therapy*
  • Benzazepines / pharmacology
  • Catheter Ablation / adverse effects
  • Circadian Rhythm / physiology
  • Dogs
  • Electrocardiography
  • Gene Transfer Techniques
  • Genetic Therapy*
  • Heart Conduction System / physiology*
  • Heart Rate / drug effects
  • Heart Rate / physiology
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Ion Channels / genetics*
  • Ion Channels / physiology*
  • Ivabradine
  • Models, Animal
  • Potassium Channel Blockers / pharmacology


  • Benzazepines
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Ion Channels
  • Potassium Channel Blockers
  • Ivabradine
  • Adenylyl Cyclases
  • adenylyl cyclase 1