Patient-derived Lamin A/C mutant cardiomyocytes demonstrate altered electrophysiological characteristics and responses to hypoxia induced stress

Dilated cardiomyopathy (DCM) is a severe cardiac disease associated with increased mortality rates. Prevalence of DCM is 1:2500 and approximately 20–48% of cases are of familial origin. Several mutations in lamin A/C gene ( LMNA ) have been shown to cause DCM, often leading to sudden cardiac death. Human induced pluripotent stem cell (hiPSC) -derived cardiomyocytes (CMs) provide valuable resources in further research of the condition and in the development of effective treatments. In this study hiPSC-CMs carrying the p.S143P mutation in LMNA gene were compared to healthy CMs. Our aim was to define electrophysiological responses of CMs to acute hypoxic stress. Upon acute hypoxia exposure, the LMNA mutant CMs altered their beat rate less than the control CMs. The LMNA CMs had significantly longer depolarization time compared to control CMs. In response to hypoxia the depolarization time prolonged more in the LMNA mutant CMs compared to control CMs. The conduction velocity was different between the cell lines, being significantly lower in the LMNA mutant CMs. This study demonstrates that cardiomyocytes carrying the p.S143P mutation in lamin A/C gene respond differently to acute hypoxic stress compared to healthy control CMs. These features suggest regulatory dysfunctions in LMNA mutant cells and may sensitize to cellular injury under acute hypoxia.