Author + information
- Received September 9, 2012
- Revision received December 7, 2012
- Accepted December 18, 2012
- Published online March 19, 2013.
- Gerard J.J. Boink, MSc⁎,†,‡,§,
- Lian Duan, MD⁎,†∥,¶,
- Bruce D. Nearing, PhD#,
- Iryna N. Shlapakova, MD⁎,†,
- Eugene A. Sosunov, PhD⁎,†,
- Evgeny P. Anyukhovsky, PhD⁎,†,
- Eugene Bobkov, BSC⁎,
- Yelena Kryukova, PhD⁎,†,
- Nazira Ozgen, MD, PhD⁎,†,
- Peter Danilo Jr, PhD⁎,†,
- Ira S. Cohen, MD, PhD⁎⁎,
- Richard L. Verrier, PhD∥,#,
- Richard B. Robinson, PhD⁎,† and
- Michael R. Rosen, MD⁎,†,⁎⁎,††,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Michael R. Rosen, Columbia University,
Department of Pharmacology and Pediatrics, 630 West 168th Street, PH 7W-321, New York, New York 10032-3702
Objectives 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.
This work was supported by U.S. Public Health Service National Heart, Lung, and Blood Institute grants HL-094410 and HL-12738 and by the American Heart Association. Gerard Boink received grant support from the Netherlands Foundation for Cardiovascular Excellence, the Netherlands Heart Foundation, the Dr. Saal van Zwanenberg Foundation, and the Interuniversity Cardiology Institute of the Netherlands. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received September 9, 2012.
- Revision received December 7, 2012.
- Accepted December 18, 2012.
- American College of Cardiology Foundation