P586Modeling hypertrophic cardiomyopathy with human induced pluripotent stem cells

Purpose: The two most predominant Finnish founder mutations for hypertrophic cardiomyopathy (HCM) are located in cardiac myosin binging protein C (cMYBPC, Q1061X) and in α-tropomyosin (TPM1, D175N). The functional consequences and the mechanisms by which mutations cause diverse phenotypes in HCM are still only partly understood. Here we have developed cell models for studying pathophysiological mechanisms of the Finnish HCM founder mutations by using human induced pluripotent stem cells (hiPSCs). Methods: We have established hiPSC lines from HCM patients carrying cMYBPC (Q1061X) and TMP1 (D175N) mutations. We have studied the morphology, Ca2+ cycling and electrophysiological properties of hiPSC-derived HCM cardiomyocytes. Results: We have observed dysregulated Ca2+ cycling and aberrant action potentials in hiPSC-derived HCM cardiomyocytes in single-cell level. The frequency of abnormalities in Ca2+ cycling increases during the maturation of cardiomyocytes. Conclusions: The electrophysiological properties of hiPSC-derived HCM cardiomyocytes differ from the properties of cardiomyocytes derived from healthy controls. Our HCM hiPSC models can be used to studying pathophysiological mechanisms of the HCM disease in humans and to drug screening regarding the two Finnish founder mutations in TPM1 and cMYBPC.