Bioartificial sinus node constructed via in vivo gene transfer of an engineered pacemaker HCN Channel reduces the dependence on electronic pacemaker in a sick-sinus syndrome model

Circulation. 2006 Sep 5;114(10):1000-11. doi: 10.1161/CIRCULATIONAHA.106.615385. Epub 2006 Aug 21.

Abstract

Background: The normal cardiac rhythm originates in the sinoatrial (SA) node that anatomically resides in the right atrium. Malfunction of the SA node leads to various forms of arrhythmias that necessitate the implantation of electronic pacemakers. We hypothesized that overexpression of an engineered HCN construct via somatic gene transfer offers a flexible approach for fine-tuning cardiac pacing in vivo.

Methods and results: Using various electrophysiological and mapping techniques, we examined the effects of in situ focal expression of HCN1-DeltaDeltaDelta, the S3-S4 linker of which has been shortened to favor channel opening, on impulse generation and conduction. Single left ventricular cardiomyocytes isolated from guinea pig hearts preinjected with the recombinant adenovirus Ad-CMV-GFP-IRES-HCN1-DeltaDeltaDelta in vivo uniquely exhibited automaticity with a normal firing rate (237+/-12 bpm). High-resolution ex vivo optical mapping of Ad-CGI-HCN1-DeltaDeltaDelta-injected Langendorff-perfused hearts revealed the generation of spontaneous action potentials from the transduced region in the left ventricle. To evaluate the efficacy of our approach for reliable atrial pacing, we generated a porcine model of sick-sinus syndrome by guided radiofrequency ablation of the native SA node, followed by implantation of a dual-chamber electronic pacemaker to prevent bradycardia-induced hemodynamic collapse. Interestingly, focal transduction of Ad-CGI-HCN1-DeltaDeltaDelta in the left atrium of animals with sick-sinus syndrome reproducibly induced a stable, catecholamine-responsive in vivo "bioartificial node" that exhibited a physiological heart rate and was capable of reliably pacing the myocardium, substantially reducing electronic pacing.

Conclusions: The results of the present study provide important functional and mechanistic insights into cardiac automaticity and have further refined an HCN gene-based therapy for correcting defects in cardiac impulse generation.

Publication types

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

MeSH terms

  • Animals
  • Arrhythmias, Cardiac / physiopathology
  • Arrhythmias, Cardiac / surgery*
  • Bioartificial Organs*
  • Cyclic Nucleotide-Gated Cation Channels
  • Disease Models, Animal
  • Electrophysiology
  • Gene Transfer Techniques
  • Guinea Pigs
  • Heart Rate
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Ion Channels / genetics*
  • Mice
  • Pacemaker, Artificial*
  • Potassium Channels
  • Sick Sinus Syndrome / physiopathology
  • Sick Sinus Syndrome / surgery*
  • Sinoatrial Node / physiology
  • Swine
  • Swine, Miniature

Substances

  • Cyclic Nucleotide-Gated Cation Channels
  • Hcn1 protein, mouse
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Ion Channels
  • Potassium Channels