Optimizing feasibility and reproducibility of pacing-induced heart failure model in pigs

Heart failure (HF) is a major health problem worldwide, where gene therapy could provide promising new approaches for effective treatments. Pacing-induced tachycardiomyopathy in large animals is a well-established HF model but it suffers from poor tolerability and variable outcomes. In this study, we developed a reproducible, feasible, and tolerable pacing protocol for HF gene therapy studies. Single-chamber pacemakers were implanted in pigs. HF development was monitored with trans-thoracic echocardiography (TTE), invasive left-ventricular (LV) pressure measurements, and a treadmill exercise stress test. Four weeks of rapid right-ventricular pacing at over 200 bpm produced a significant impairment of cardiac function (LV stroke volume index 11.8 ± 1.22 (mL/m²) at day 28 vs 18.1 ± 0.99 (mL/m²) at day 0, p < 0.01, mean ± SEM, paired t-test), and reduced exercise capacity (- 14 ± 3.19% change in 15-min treadmill exercise stress test at day 28 compared to day 0, p = 0.02, mean ± SEM, paired t-test). Further pacing at 150 bpm was a well-tolerated way to prevent functional recovery. Good tolerability and reproducibility of the pacing were achieved by a gradual increase in the pacing rate, no higher than 200 bpm. Global left ventricular adenoviral (Ad) gene transfer via cardiac veins was performed after three weeks of rapid pacing and found well-tolerated and feasible. In this study, the protocols of pacemaker implantation and TTE in pigs were also optimized. In conclusion, the optimized pacing protocol considerably increases the feasibility and reproducibility of the pacing-induced HF for testing of new therapeutic applications.