Examining stress mediated profibrotic response in HCM associated TNNT2 variants

The heart beats 100,000 times a day, and cardiac contractile proteins are essential to facilitate oxygen-rich blood circulation. Hypertrophic cardiomyopathy (HCM) is an inherited heart disease that promotes enlargement of the heart and fibrotic scars, leading to arrhythmias and sudden cardiac death (SCD). In Canada, all age groups are affected by HCM, especially children and youth, including elite athletes. The cardiac troponin T (TNNT2) gene variants account for 15 to 20 percent of HCM in humans. TNNT2 mutations can cause increased cardiac contractility and impaired heart relaxation, leading to structural remodelling and triggering arrhythmias and SCD. Currently, no specific medication is available to treat HCM patients. Previously, mouse or rabbit heart muscle cells were used for studying these TNNT2 mutations, which is not closely relevant to human physiology. Therefore, I aim to test TNNT2 mutants in human induced pluripotent stem cell-derived heart muscle cells (hiPSC-CMs) with different physiological and pathological stress conditions compared to normal hiPSC-CMs. Our research outcome will help us refine the profibrotic mechanism behind arrhythmias and SCD in HCM patients and timely intervention to manage patient care better.