Abstract
Introduction: Cardiac pacing can be created by myocardial delivery of TBX18. However, evidence for overt fibrosis at the injection site and the use of viral vectors impede clinical translation of this concept. We hypothesized that non-viral gene transfer of TBX18 combined with prevention of fibrosis with a Tgfβ inhibitor enables durable ventricular pacing in the porcine model of CAVB. Methods: All pigs underwent transvenous RF ablation of the AV node to achieve complete heart block on day-1. The pigs were implanted with a backup pacemaker (VVI=50 bpm) and with osmotic pumps designed to release A83-01, an inhibitor of Tgfβ receptors. Synthetic mRNA encoding either TBX18 (n=7) or GFP (n=2) in saline was injected in the high interventricular septum with a NOGA-MYOSTAR™ catheter. Continuous and ambulatory ECG, blood pressure (BP) and activity were recorded for the 4-week study period with telemetry. Results: The control pigs were dependent on backup pacing throughout 4 weeks with retrograde conduction from the RV apex. In contrast, TBX18 injected pigs showed higher heart rate (HR) compared to control (4-week mean HR of 58±7 vs 52±7, p <0.05), exhibiting antegrade conduction from the high septum with narrow QRS complexes. Max. HR was higher in TBX18 pigs compared to control with a 4-week average of 70±9 vs 55±11 bpm ( p <0.05). TBX18 pigs exhibited diurnal HR oscillations that directly correlated with their physical activity, indicating chronotropic competence. Likewise, mean BP correlated tightly with mean HR in TBX18 injected pigs ( p <0.01) but not in control ( p =0.164), indicating superior hemodynamic measures. Radiopaque agent-enabled, real-time fluoroscopic visualization revealed that the injected biologic spread beyond the intended delivery site in 2 of 7 TBX18 pigs. The mean and max. HR of the 2 pigs were slower than the other five TBX18 pigs, suggesting that conventional imaging can be leveraged to identify redosing criteria, and minimize non-responders. No increase in spontaneous or induced arrhythmias was observed in TBX18 pigs compared to control. Conclusions: mRNA delivery of TBX18 combined with Tgfβ inhibition achieved durable septal pacing for 4 weeks in a porcine model chronic heart block, demonstrating therapeutic efficacy with greater safety profiles.
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