Abstract 21428: Ventricular Biological Pacemaker Successfully Created in Canine Model by Human HCN4 Gene Transfer
Introduction: Introduction: Electronic pacemakers provide palliation of symptoms of a variety of rhythm disorders. Biological pacemakers may provide a curative solution and overcome limitations of electronic devices such as limited battery life and lack of autonomic responsiveness. We examined the feasibility of local delivery of truncated human HCN4 (hHCN4tr) to produce a stable biological pacemaker and characterized the dose dependence of the approach.
Methods: In 6 canines, complete heart block was induced by ablation. Adenovirus containing green fluorescent protein (GFP)-fused hHCN4tr gene (Ad-GFP-hHCN4tr) was injected intramyocardially at the left ventricular apex using an epicardial approach. We delivered one dose in the range of 6.6×107 to 1.3×1010 pfu to each animal. A modified electronic pacemaker provided backup pacing and periodic EGM recordings. Challenges with metoprolol and isoproterenol were conducted to assess autonomic responsiveness. One week post-injection, electrical mapping was performed and tissues harvested to analyze hHCN4tr expression.
Results: Functional expression of a biological pacemaker at a rate of 164 ± 16.2 bpm was exhibited in those canines receiving at least 4.4×108 pfu (high dose, n=3). Origin of electrical activation was mapped to the injection site in the high-dose animals. With isoproterenol administration, stable but transient biopacemaking activity was elicited in 2/3 low-dose animals, and biopacer rate increased 44-67% in 2/3 high-dose animals. Immunohistochemistry staining and western blot analysis revealed notably greater hHCN4tr expression in high- vs. low-dose animals. Patch clamp showed HCN4 currents in isolated GFP+ myocytes.
Conclusions: Using Ad-GFP-hHCN4tr, we demonstrated the feasibility of creating a biological pacemaker with responsiveness to autonomic drug challenges. Efficacy was exhibited beyond a threshold dose, and gene modifications may be needed to produce a more physiological rate.
- © 2010 by American Heart Association, Inc.