Biological pacemakers in canines exhibit positive chronotropic response to emotional arousal

Heart Rhythm. 2010 Dec;7(12):1835-40. doi: 10.1016/j.hrthm.2010.08.004. Epub 2010 Aug 11.


Background: Biological pacemakers based on the HCN2 channel isoform respond to beta-adrenergic and muscarinic stimulation, suggesting a capacity to respond to autonomic input.

Objective: The purpose of this study was to investigate autonomic response to emotional arousal in canines implanted with murine HCN2-based biological pacemakers using gene therapy.

Methods: An electronic pacemaker was implanted with its lead in the right ventricular apical endocardium (VVI 35 bpm). An adenoviral HCN2/GFP construct (Ad-HCN2, n = 7) or saline (control, n = 5) was injected into the left bundle branch on day 2 after radiofrequency ablation of the atrioventricular node to induce complete atrioventricular block. Emotional arousal was achieved by presenting food following an overnight fast. Autonomic control was evaluated with Poincaré plots of R-R(N) against R-R(N+1) intervals to characterize heart rate variability (HRV) and with continuous RR interval assessment via 24-hour ambulatory ECG. The 24-hour ECG and Poincaré plot shape were analyzed.

Results: During day 1 after biological pacemaker implantation, Poincaré HRV parameters and RR intervals were unchanged with food presentation. However, on day 7, food presentation was accompanied by an increase in HRV (SD1, p < 0.07, and SD2, p < 0.05) and shortening of RR interval (P < .05) in dogs with Ad-HCN2 but not in controls.

Conclusion: This is the first demonstration that biological pacemakers are capable of responding to natural arousal stimuli to elicit appropriate chronotropic responses, a potential advantage over electronic pacemakers.

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Arousal / physiology*
  • Atrioventricular Block / physiopathology
  • Atrioventricular Block / therapy
  • Biological Clocks / physiology*
  • Dogs
  • Electrocardiography
  • Emotions / physiology*
  • Genetic Therapy
  • Green Fluorescent Proteins
  • Heart Rate / physiology
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Ion Channels / physiology
  • Luminescent Agents
  • Pacemaker, Artificial


  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Ion Channels
  • Luminescent Agents
  • Green Fluorescent Proteins