1982Molecular mechanisms of arrhythmia upon TBX5 loss

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Introduction: Transcription factor T-box 5 (TBX5) is essential for cardiac development and conduction. Patients with a non-functional TBX5 allele present cardiac malformations and conduction disorders (Holt-Oram-Syndrome). Interestingly, we found TBX5 expression reduced in human dilated and ischemic cardiomyopathy samples, suggesting TBX5 loss as a link between cardiac disease and arrhythmia development beyond the context of congenital cardiomyopathy. Methods: To characterise the molecular mechanisms of TBX5 loss leading to ventricular arrhythmia, we generated a tamoxifen-inducible TBX5 Knock-Out (KO) line by crossing TBX5LDN/LDN and α-MHC-MerCreMer mice. ECGs were recorded using implantable telemetric ECG transmitters. TBX5LDN/LDN and α-MHC-MerCreMer mice injected with Tamoxifen served as control (CT). We performed RNA-Sequencing from KO and CT mouse ventricles. We performed chromatin immunoprecipitation (ChIP) against TBX5 in CT ventricular samples followed by next-generation sequencing. Downregulated transcripts were validated by quantitative PCR and immunoblot whereas putative binding regions were validated by Luciferase assays. Results: Telemetric ECG analysis of TBX5 KO mice showed first and second degree atrioventricular block (PR KO 48 ms vs. 34 ms CT, p<0.001, n>5). Additionally, KO mice had prolonged ventricular depolarization (QRS 17.5 ms vs. 13.5 ms, p<0.05, n>5) and repolarization (QT 47 ms vs. 37 ms, p<0.01, n>5).

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