Abstract 717: Biological Pacemaker Engineered by Non-viral Gene Delivery improves Survival in a Mouse Model of Complete Atrioventricular Block
We hypothesized that a non-viral gene transfer of the hyperpolarization-activated, cyclic nucleotide-gated HCN2 channel (Hcn2) combined with the β2-adrenergic receptor (Adrb2) would generate a functional ventricular pacemaker in a mouse model of complete atrioven-tricular block (cAVB). Plasmids encoding the mouse Hcn2 and Adrb2 genes mixed with tetronic 304, a poloxamine block copolymer, were injected at one site in the left ventricular myocardium of anesthetized open-chest mice (HCN2 mice). Sham mice were injected with non-coding plasmid. Catheter-mediated radiofrequency AV node ablation was performed 5 days after plasmid injection. Up to 5 days after AV node ablation, ventricular escape rhythms were similar in HCN2 and sham mice. After 5 days, differences in escape rhythms increased and persisted over time: 15 and 40 days after ablation, HCN2 mice had escape rhythms 47% and 35% faster respectively (RR of 361 ± 38 ms and 422 ± 32 ms) than sham mice (531 ± 30 ms and 569 ± 25 ms; p < 0.01 in both cases). HCN2 mice were characterized by abnormal QRS axes and longer QRS complexes than sham mice (18 ± 1 ms vs 15 ± 1 ms at day 15; p < 0.05) suggesting abnormal ventricular activation. In the mouse, cAVB induces progressive hypertrophy and heart failure leading to death after 3– 4 months. HCN2 mice survived longer than sham mice: median survival was 134 days in HCN2 mice versus only 110 days in sham group. Finally, the β-adrenergic agonist isoproterenol (40 μg/kg IP) increased ventricular escape rhythms significantly more in HCN2 mice (+40%) than in sham mice (+23%), suggesting that engineered pacemakers can be regulated by the sympathetic nervous system. In conclusion, we provide a proof of concept that non-viral gene transfer produces a functional cardiac biological pacemaker and improves life expectancy in a clinically-relevant model.