Heart failure (HF) presents high prevalence and mortality worldwide. In HF, the cardiac contractile machine is weakened, affecting the troponin complex. No treatment has yet convincingly shown to improve outcomes in patients with HF. The aim of my research is to examine whether the cyclic peptide Trop_L01, derived from a RaPID screen, improves the contractility of human cardiomyocytes by augmenting the interaction between intracellular cardiac troponin C and I.
Internalization studies using fluorescently tagged Trop_L01 demonstrated intracellular distribution throughout the cytoplasm of human-induced pluripotent stem cell-derived cardiomyocytes ( hiPSC-CMs). To assay the function of the peptide, videos were recorded after the cyclic peptide addition to hiPSC-CMs, and contractility parameters were analyzed. Trop_L01 significantly enhance contractility by reducing time to peak and relaxation time, and monolayers of cardiomyocytes treated with this peptide demonstrated increased force in a dose manner. Fluorescent imaging plate reader analysis revealed no significant effect on calcium transients compared to baseline values. We examined Trop_L01's effects on calcium sensitivity in pig ventricular tissue experiments indicating a decrease in myofilament sensitivity to calcium in the presence of Trop_L01. Furthermore, Trop_L01-induced changes in calcium binding to the human cardiac troponin complex suggested increased calcium sensitivity and contractility. In conclusion, Trop_L01 exhibits potential as a modulator of cardiomyocyte contractility.