Date of Award
8-19-2024
Degree Type
Thesis
Degree Name
Master of Science (MS)
Department
Physiology
First Advisor
David Barefield
Abstract
Dilated cardiomyopathy (DCM) is a common cause of heart failure with a strong hereditary component. Mutations in the myosin-binding protein H-like (MYBPHL) gene are linked to hereditary DCM, atrial fibrillation, and atrioventricular arrhythmias. MyBP-HL is a sarcomeric protein that is highly expressed in the atria with only scarce, distinct clusters of MyBP-HL positive cells in the ventricles, mostly in or surrounding the ventricular conduction system (VCS). Constitutive knock-out of MyBP-HL in mice causes atrial dilation, ventricular dysfunction, arrhythmia, and DCM. Whether MyBP-HL plays a developmental role, or if knock-down in adulthood will recapitulate a similar phenotype has yet to be examined. Moreover, the significance of the MyBP-HL expressing cells in the VCS is currently unknown. To further elucidate the role of MyBP-HL, we developed genetic mouse lines. The first is a ROSA26-Cre(ERT2) LoxP mouse that undergoes conditional Mybphl knock-down after tamoxifen (TAM) treatment. Echocardiography was used to measure cardiac contractile function, and conscious telemetry allowed for monitoring of heart rhythm. We demonstrate that mice with conditional decrease of MyBP-HL in adulthood develop a hypertrophic cardiomyopathy phenotype, along with atrial contractile changes, increased total heart weight compared to body weight, and increased heart rate variability. To better study the role of MyBP-HL in the cardiac conduction system, we used a Contactin-2-Cre mouse that deletes Mybphl solely in the cardiac conduction system from birth. The expression pattern of MyBP-HL in specific puncta associated with the ventricular conduction system, including some Purkinje cells, is distinctive. The functional need for differential thick filament regulation in cells related to the ventricular conduction system is unclear. Conscious telemetry was used to evaluate arrhythmias and electrical signal conduction changes in response to physiological stressors. Echocardiography shows that deletion of Mybphl solely within the cardiac conduction system trends toward mild hypercontractility. Mybphl deletion is associated with overall lower heart rates and increased interventricular septal thickness. In conclusion, we determined that the MyBP-HL protein is essential for proper cardiac function, and even minor alteration in protein levels within the heart cause a diseased phenotype.
Recommended Citation
Burnham, Hope Victoria, "The Effects of Conditional Loss of Myosin Binding Protein H-Like on Cardiac Function" (2024). Master's Theses. 4552.
https://ecommons.luc.edu/luc_theses/4552
