title: Ca(2+)-stimulated adenylyl cyclase AC1 generates efficient biological pacing as single gene therapy and in combination with HCN2.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  AC1 or HCN2/AC1 overexpression in left bundle branches provides highly efficient biological pacing and greater sensitivity to autonomic modulation than HCN2 alone.
authors: Department of Pharmacology, Center for Molecular Therapeutics, Columbia University, New York, NY 10032, USA.
authors: Gerard J J
authors: GJ
authors: Boink
authors: Bruce D
authors: BD
authors: Nearing
authors: Iryna N
authors: IN
authors: Shlapakova
authors: Lian
authors: L
authors: Duan
authors: Yelena
authors: Y
authors: Kryukova
authors: Yevgeniy
authors: Y
authors: Bobkov
authors: Hanno L
authors: HL
authors: Tan
authors: Ira S
authors: IS
authors: Cohen
authors: Peter
authors: P
authors: Danilo
authors: Richard B
authors: RB
authors: Robinson
authors: Richard L
authors: RL
authors: Verrier
authors: Michael R
authors: MR
authors: Rosen
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000262:Adenylyl Cyclases / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D054537:Atrioventricular Block / Q000209:etiology / Q000628:therapy*; D001552:Benzazepines / Q000494:pharmacology; D017115:Catheter Ablation / Q000009:adverse effects; D002940:Circadian Rhythm / Q000502:physiology; D004285:Dogs; D004562:Electrocardiography; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006329:Heart Conduction System / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels / Q000235:genetics* / Q000502:physiology*; D000077550:Ivabradine; D023421:Models, Animal; D026902:Potassium Channel Blockers / Q000494:pharmacology
chemical_list: D001552:Benzazepines; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D026902:Potassium Channel Blockers; D000077550:Ivabradine; D000262:Adenylyl Cyclases; C106670:adenylyl cyclase 1