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Updated: Dec 12, 2025
Viral Transgene Expression in Rodent Hearts and the Assessment of Cardiac Arrhythmia Risk
Published on: July 27, 2022
Preclinical evidence for the therapeutic value of TBX5 normalization in arrhythmia control
Franziska S Rathjens1,2, Alica Blenkle1, Lavanya M Iyer1,2
1Institute of Pharmacology and Toxicology, University Medical Center, Goettingen, Germany.
Aims:
Arrhythmias and sudden cardiac death (SCD) occur commonly in patients with heart failure. We found T-box 5 (TBX5) dysregulated in ventricular myocardium from heart failure patients and thus we hypothesized that TBX5 reduction contributes to arrhythmia development in these patients. To understand the underlying mechanisms, we aimed to reveal the ventricular TBX5-dependent transcriptional network and further test the therapeutic potential of TBX5 level normalization in mice with documented arrhythmias.
Methods And Results:
We used a mouse model of TBX5 conditional deletion in ventricular cardiomyocytes. Ventricular (v) TBX5 loss in mice resulted in mild cardiac dysfunction and arrhythmias and was associated with a high mortality rate (60%) due to SCD. Upon angiotensin stimulation, vTbx5KO mice showed exacerbated cardiac remodelling and dysfunction suggesting a cardioprotective role of TBX5. RNA-sequencing of a ventricular-specific TBX5KO mouse and TBX5 chromatin immunoprecipitation was used to dissect TBX5 transcriptional network in cardiac ventricular tissue. Overall, we identified 47 transcripts expressed under the control of TBX5, which may have contributed to the fatal arrhythmias in vTbx5KO mice. These included transcripts encoding for proteins implicated in cardiac conduction and contraction (Gja1, Kcnj5, Kcng2, Cacna1g, Chrm2), in cytoskeleton organization (Fstl4, Pdlim4, Emilin2, Cmya5), and cardiac protection upon stress (Fhl2, Gpr22, Fgf16). Interestingly, after TBX5 loss and arrhythmia development in vTbx5KO mice, TBX5 protein-level normalization by systemic adeno-associated-virus (AAV) 9 application, re-established TBX5-dependent transcriptome. Consequently, cardiac dysfunction was ameliorated and the propensity of arrhythmia occurrence was reduced.
Conclusions:
This study uncovers a novel cardioprotective role of TBX5 in the adult heart and provides preclinical evidence for the therapeutic value of TBX5 protein normalization in the control of arrhythmia.
Insights
Reduced T-box 5 (TBX5) levels in heart failure contribute to arrhythmias. Restoring TBX5 levels in mice with arrhythmias ameliorated cardiac dysfunction and reduced arrhythmia occurrence, suggesting TBX5 normalization as a potential therapy.
Area of Science:
- Cardiology
- Molecular Biology
- Genetics
Background:
- Arrhythmias and sudden cardiac death (SCD) are common in heart failure patients.
- T-box 5 (TBX5) is found to be dysregulated in the ventricular myocardium of heart failure patients.
Purpose of the Study:
- To investigate the hypothesis that reduced TBX5 contributes to arrhythmia development in heart failure.
- To elucidate the ventricular TBX5-dependent transcriptional network.
- To assess the therapeutic potential of normalizing TBX5 levels in arrhythmias.
Main Methods:
- A mouse model with conditional deletion of TBX5 in ventricular cardiomyocytes was utilized.
- RNA-sequencing and chromatin immunoprecipitation were employed to identify the TBX5 transcriptional network.
- Adeno-associated virus (AAV) 9 was used for systemic TBX5 protein-level normalization.
Main Results:
- Ventricular TBX5 loss led to cardiac dysfunction, arrhythmias, and high mortality (60%) from SCD.
- TBX5 regulates transcripts involved in cardiac conduction, contraction, cytoskeleton organization, and stress protection.
- TBX5 protein normalization reduced cardiac dysfunction and arrhythmia propensity in mice.
Conclusions:
- TBX5 plays a novel cardioprotective role in the adult heart.
- Restoring TBX5 levels demonstrates preclinical therapeutic potential for controlling arrhythmias.
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