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

Hung Fat Tse, Tian Xue, Chu Pak Lau, Chung Wah Siu, Kai Wang, Qing Yong Zhang, Gordon F. Tomaselli, Fadi G. Akar, Ronald A. Li

Research output: Contribution to journalArticlepeer-review

127 Scopus citations

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-ΔΔΔ, 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-ΔΔΔ in vivo uniquely exhibited automaticity with a normal firing rate (237±12 bpm). High-resolution ex vivo optical mapping of Ad-CGI-HCN1-ΔΔΔ- 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-ΔΔΔ 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.

Original languageEnglish (US)
Pages (from-to)1000-1011
Number of pages12
JournalCirculation
Volume114
Issue number10
DOIs
StatePublished - Sep 2006
Externally publishedYes

Keywords

  • Engineering
  • Ion channels
  • Pacemakers
  • Sinoatrial node
  • Therapy

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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