Proteomic profiling of hiPSC-CMs harbouring hypertrophic cardiomyopathy-troponin T variants

Hypertrophic cardiomyopathy (HCM) is a genetic heart disease which typically results in asymmetric hypertrophy, myofibrillar disarray, hypercontractility, and impaired relaxation. It is inherited in an autosomal dominant pattern and is the most common heritable heart disease. HCM often results in an increased incidence of arrhythmogenesis which can lead to sudden cardiac arrest (SCA) and death. Its prevalence in the general population is about one in five hundred, making it the leading known cause for SCA in youth and young athletes. This study focuses on HCM inducing variants in the cardiac-troponin T protein, encoded by the TNNT2 gene, which account for five percent of total HCM cases. The two HCM-associated TNNT2 variants that were investigated are: I79N+/- and R278C+/-. The mechanisms underlying pathogenesis of these variants at the proteomic level remain poorly understood. There is a crucial need to utilize a model that represents human cardiac physiology better than animal models. Human-induced Pluripotent Stem Cell-derived Cardiomyocytes (hiPSC-CMs) have been increasingly used in cardiac research due to their ability to reflect disease manifestation on many different cellular levels, including but not limited to proteomic deviations. The effects of the TNNT2 variants on the thin-filament proteome quantity and quality in multiple hiPSC-CM lines were studied using bottom-up Mass Spectrometry (MS). Proteomic characterization using MS provided us with a novel perception regarding the intrinsic mechanisms and pathways responsible for the pathogenic cardiac remodelling seen in HCM patients. This presents a future opportunity to identify new therapeutic targets and broad-spectrum treatments for this genetically challenging disease.