Trampel, K. A. | bioRxiv Science

bioRxiv2024

Coordinated Tbx3 / Tbx5 transcriptional control of the adult ventricular conduction system

The cardiac conduction system (CCS) orchestrates the electrical impulses that enable coordinated contraction of the cardiac chambers. The T-box transcription factors TBX3 and TBX5 are required for cardiac conduction system development and associated with overlapping and distinct human cardiac conduction system diseases. We evaluated the coordinated role of Tbx3 and Tbx5 in the murine ventricular conduction system (VCS). We engineered a compound Tbx3:Tbx5 conditional knockout allele for both genes located in cis on mouse chromosome 5. Conditional deletion of both T-box transcriptional factors in the ventricular conduction system, using the VCS-specific MinK:Cre, caused loss of VCS function and molecular identity. Combined Tbx3 and Tbx5 deficiency in the adult VCS led to conduction defects, including prolonged PR and QRS intervals and elevated susceptibility to ventricular tachycardia. These electrophysiological defects occurred prior to detectable alterations in cardiac contractility or histologic morphology, indicative of a primary conduction system defect. Tbx3:Tbx5 double knockout VCS cardiomyocytes revealed a transcriptional shift towards non-CCS-specialized working myocardium, indicating a change to their cellular identity. Furthermore, optical mapping revealed a loss of VCS-specific conduction system propagation. Collectively, these findings indicate that Tbx3 and Tbx5 coordinate to control VCS molecular fate and function, with implications for understanding cardiac conduction disorders in humans.

developmental biology↗

bioRxiv2023

Moderate Endurance Exercise Increases Arrhythmia Susceptibility and modulates Cardiac Structure and Function in a Sexually Dimorphic manner.

BackgroundWhile moderate endurance exercise has been reported to improve cardiovascular health, its effects on cardiac structure and function are not fully characterized, especially with respect to sexual dimorphism. We aimed to assess the effects of moderate endurance exercise on cardiac physiology in male versus female mice. MethodsC57BL/6J mice of both sexes were run on a treadmill for six weeks. ECG and echocardiography were performed every two weeks. After six weeks of exercise, mice were euthanized, and triple parametric optical mapping was performed on Langendorff perfused hearts to assess cardiac electrophysiology. Arrhythmia inducibility was tested by programmed electrical stimulation. Left ventricular (LV) tissue was fixed, and RNA sequencing was performed to determine exercise-induced transcriptional changes. ResultsExercise-induced LV dilatation was observed in female mice alone, as evidenced by increased LV diameter and reduced LV wall thickness. Increased cardiac output was also observed in female exercised mice but not males. Optical mapping revealed further sexual dimorphism in exercise-induced modulation of cardiac electrophysiology. In female mice, exercise prolonged action potential duration and reduced voltage-calcium influx delay. In male mice, exercise reduced the calcium decay constant, suggesting faster calcium reuptake. Exercise increased arrhythmia inducibility in both male and female mice, however, arrhythmia duration was increased only in females. Lastly, exercise-induced transcriptional changes were sex-dependent: females and males exhibited the most significant changes in contractile versus metabolism-related genes, respectively. ConclusionsOur data suggest that moderate endurance exercise can significantly alter multiple aspects of cardiac physiology in a sex-dependent manner. While some of these effects are beneficial, like improved cardiac mechanical function, others are potentially pro-arrhythmic.

physiology↗