title: HCN2/SkM1 gene transfer into canine left bundle branch induces stable, autonomically responsive biological pacing at physiological heart rates.
abstract: OBJECTIVE
  This study sought to test the hypothesis that hyperpolarization-activated cyclic nucleotide-gated (HCN)-based biological pacing might be improved significantly by hyperpolarizing the action potential (AP) threshold via coexpression of the skeletal muscle sodium channel 1 (SkM1).
  
  
  BACKGROUND
  Gene-based biological pacemakers display effective in vivo pacemaker function. However, approaches used to date have failed to manifest optimal pacemaker properties, defined as basal beating rates of 60 to 90 beats/min, a brisk autonomic response achieving maximal rates of 130 to 160 beats/min, and low to absent electronic backup pacing.
  
  
  METHODS
  We implanted adenoviral SkM1, HCN2, or HCN2/SkM1 constructs into left bundle branches (LBB) or left ventricular (LV) epicardium of atrioventricular-blocked dogs.
  
  
  RESULTS
  During stable peak gene expression on days 5 to 7, HCN2/SkM1 LBB-injected dogs showed highly stable in vivo pacemaker activity superior to SkM1 or HCN2 alone and superior to LV-implanted dogs with regard to beating rates (resting approximately 80 beats/min; maximum approximately 130 beats/min), no dependence on electronic backup pacing, and enhanced modulation of pacemaker function during circadian rhythm or epinephrine infusion. In vitro isolated LV of dogs overexpressing SkM1 manifested a significantly more negative AP threshold.
  
  
  CONCLUSIONS
  LBB-injected HCN2/SkM1 potentially provides a more clinically suitable biological pacemaker strategy than other reported constructs. This superiority is attributable to the more negative AP threshold and injection into the LBB.
authors: Department of Pharmacology, Columbia University, New York, NY 10032, USA.
authors: Gerard J J
authors: GJ
authors: Boink
authors: Lian
authors: L
authors: Duan
authors: Bruce D
authors: BD
authors: Nearing
authors: Iryna N
authors: IN
authors: Shlapakova
authors: Eugene A
authors: EA
authors: Sosunov
authors: Evgeny P
authors: EP
authors: Anyukhovsky
authors: Eugene
authors: E
authors: Bobkov
authors: Yelena
authors: Y
authors: Kryukova
authors: Nazira
authors: N
authors: Ozgen
authors: Peter
authors: P
authors: Danilo
authors: Ira S
authors: IS
authors: Cohen
authors: Richard L
authors: RL
authors: Verrier
authors: Richard B
authors: RB
authors: Robinson
authors: Michael R
authors: MR
authors: Rosen
mesh_terms: D000818:Animals; D004285:Dogs; D018014:Gene Transfer Techniques; D006329:Heart Conduction System; D006339:Heart Rate / Q000502:physiology*; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels / Q000235:genetics*; D009124:Muscle Proteins / Q000235:genetics*
chemical_list: D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D009124:Muscle Proteins
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