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Percutaneous Atrial Delivery of TBX18 Creates a Stable Supraventricular Biological Pacemaker in Porcine Sick Sinus
James F Dawkins1, Thassio Mesquita1, Kevin Holm1
1Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Background:
Sick sinus syndrome (SSS) is caused primarily by sinoatrial node (SAN) dysfunction, often necessitating permanent pacemaker implantation. Although effective, electronic pacing has inherent limitations and hardware-related complications. Here, we developed a reproducible large-animal model of SSS to test the concept of "hardware-free" biological pacemaker therapy via percutaneous T-box transcription factor 18 (human) (TBX18) gene delivery.
Objectives:
This study sought to create a preclinical model of SSS and rescue the phenoytpe by percutaneous delivery of TBX18 biological pacemaker.
Methods:
Healthy pigs underwent high-resolution electroanatomical mapping followed by targeted radiofrequency ablation of the SAN to induce sinus arrest. A backup electronic pacemaker was implanted to provide hemodynamic support. Two weeks postablation, after verification of SSS, the animals received percutaneous endovascular injection of either phosphate-buffered saline (n = 9) or TBX18 adenovirus (n = 9) into the lower atrial septum. Continuous electrocardiographic telemetry was performed for 4 weeks postinjection.
Results:
By 2 weeks, TBX18-injected pigs exhibited higher intrinsic heart rates than controls (controls: 71.4 ± 4.0 beats/min vs TBX18: 96.3 ± 7.0 beats/min, P = 0.007) and reduced backup pacemaker use (P = 0.009). Heart rate variability analysis demonstrated improved rhythm stability in TBX18-injected animals (SD1/SD2, P = 0.0005), with fewer sinoatrial pauses and tachyarrhythmic episodes. Patch-clamp analysis of cells from the injection site revealed spontaneous action potentials and sinus node-like morphology, confirming the reprogramming of atrial myocytes into induced SAN-like cells.
Conclusions:
In this preclinical large-animal model of SSS, percutaneous TBX18 gene therapy successfully restored supraventricular pacemaker function, improved heart rate dynamics, and reduced reliance on electronic pacing. These findings support the use of biological pacemakers as a potential alternative to conventional device-based therapies for SSS.
