TBX18 overexpression enhances pacemaker function in a rat subsidiary atrial pacemaker model of sick sinus syndrome

• Published in: The Journal of physiology 2018-12, Vol.596 (24), p.6141-6155
• Main Authors: Choudhury, M., Black, N., Alghamdi, A., D'Souza, A., Wang, R., Yanni, J., Dobrzynski, H., Kingston, P. A., Zhang, H., Boyett, M. R., Morris, G. M.
• Format: Article
• Language: English
• Subjects: Animals; biopacemaking; Bradycardia; Calcium; Cardiovascular; Computer Simulation; Coronary artery disease; Electrophysiology; Gene expression; Gene Expression Regulation; gene therapy; Heart Atria; Heart Conduction System - metabolism; Heart diseases; Heart rate; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - genetics; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - metabolism; Ion channels (cyclic nucleotide-gated); Male; Models, Biological; Na+/Ca2+ exchanger; NCX1 protein; Pacemakers; Protein Isoforms - genetics; Protein Isoforms - metabolism; Rats; Research Paper; sick sinus syndrome; Sick Sinus Syndrome - therapy; Sinoatrial Node - physiology; Sodium-Calcium Exchanger - metabolism; Standard deviation; subsidiary atrial pacemaker tissue; Syncope; T-Box Domain Proteins - genetics; T-Box Domain Proteins - metabolism; TBX18; Tissue Culture Techniques; Transcription factors
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/JP276508

Key points The sinoatrial node (SAN) is the primary pacemaker of the heart. SAN dysfunction, or ‘sick sinus syndrome’, can cause excessively slow heart rates and pauses, leading to exercise limitation and syncope, currently treated by implantation of an electronic pacemaker. ‘Biopacemaking’ utilises gene therapy to restore pacemaker activity by manipulating gene expression. Overexpressing the HCN pacemaker ion channel has been widely used with limited success. We utilised bradycardic rat subsidiary atrial pacemaker tissue to evaluate alternative gene targets: the Na+/Ca2+ exchanger NCX1, and the transcription factors TBX3 and TBX18 known to be involved in SAN embryonic development. TBX18 overexpression restored normal SAN function, as assessed by increased rate, improved heart rate stability and restoration of isoprenaline response. TBX3 and NCX1 were not effective in accelerating the rate of subsidiary atrial pacemaker tissue. Gene therapy targeting TBX18 could therefore have the potential to restore pacemaker function in human sick sinus syndrome obviating electronic pacemakers. The sinoatrial node (SAN) is the primary pacemaker of the heart. Disease of the SAN, sick sinus syndrome, causes heart rate instability in the form of bradycardia and pauses, leading to exercise limitation and syncope. Biopacemaking aims to restore pacemaker activity by manipulating gene expression, and approaches utilising HCN channel overexpression have been widely used. We evaluated alternative gene targets for biopacemaking to restore normal SAN pacemaker physiology within bradycardic subsidiary atrial pacemaker (SAP) tissue, using the Na+/Ca2+ exchanger NCX1, and the transcription factors TBX3 and TBX18. TBX18 expression in SAP tissue restored normal SAN function, as assessed by increased rate (SAN 267.5 ± 13.6 bpm, SAP 144.1 ± 8.6 bpm, SAP‐TBX18 214.4 ± 14.4 bpm; P