Ca2+-Stimulated Adenylyl Cyclase AC1 Generates Efficient Biological Pacing as Single Gene Therapy and in Combination With HCN2

Article

关键词: HEART-RATE-VARIABILITY;    VENTRICULAR CARDIOMYOCYTES;    PACEMAKER CHANNELS;    STEM-CELLS;    QT;    OVEREXPRESSION;    INTEGRATION;    ENHANCEMENT;   

DOI  :  10.1161/CIRCULATIONAHA.111.083584

来源: SCIE

【 摘 要 】

Background-Biological pacing performed solely via HCN2 gene transfer in vivo results in relatively slow idioventricular rates and only moderate autonomic responsiveness. We induced biological pacing using the Ca2+-stimulated adenylyl cyclase AC1 gene expressed alone or in combination with HCN2 and compared outcomes with those with single-gene HCN2 transfer. Methods and Results-We implanted adenoviral HCN2, AC1, or HCN2/AC1 constructs into the left bundle branches of atrioventricular-blocked dogs. During steady-state gene expression (days 5-7), differences between AC1, HCN2/AC1, and HCN2 alone were evident in basal beating rate, escape time, and dependence on electronic backup pacing. In HCN2, AC1, and HCN2/AC1, these parameters were as follows: basal beating rate: 50 +/- 1.5, 60 +/- 5.0, and 129 +/- 28.9 bpm (P<0.05 for HCN2/AC1 versus HCN2 or AC1 alone), respectively; escape time: 2.4 +/- 0.2, 1.3 +/- 0.2, and 1.1 +/-.0.4 seconds (P<0.05 for AC1 and HCN2/AC1 versus HCN2); and percent electronic beats: 34 +/- 8%, 2 +/- 1%, and 6 +/- 2% (P<0.05 for AC1 and HCN2/AC1 versus HCN2). Instantaneous (SD1) and long-term (SD2) heart rate variability and circadian rhythm analyzed via 24-hour Holter recordings showed a shift toward greater sensitivity to parasympathetic modulation in animals injected with AC1 and a high degree of sympathetic modulation in animals injected with HCN2/AC1. Conclusion-AC1 or HCN2/AC1 overexpression in left bundle branches provides highly efficient biological pacing and greater sensitivity to autonomic modulation than HCN2 alone. (Circulation. 2012;126:528-536.)

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