Abstract 251: Modeling LMNA Associated Cardiomyopathy Using Patient-Specific Human Induced Pluripotent Stem Cells
Mutations in LMNA are the most prevalent cause of dilated cardiomyopathy (DCM), accounting for up to 5-10% all the familial DCM. LMNA encodes the lamin A/C proteins which form filamentous structures that underline nuclear envelop. Sudden cardiac death and arrhythmia are common in patients with LMNA mutations. Despite recent advancement in the field, still the exact mechanism that link the mutation in LMNA to the formation of DCM and arrythmia is still largely unknown. In this study, we have generated an in vitro model of LMNA associated DCM using patient specific human induced pluripotent stem cells (hiPSCs). A family with pathogenic deletion in LMNA gene (c. 1142-1157 + 1del17) and history of DCM were selected. hiPSCs were generated from 4 affected individuals in the family and 5 healthy individuals. hiPSCs were then directly differentiated into cardiomyocytes and assessed at day 30 post differentiation. Cardiomyocytes derived from LMNA variant patients showed significantly higher level of nuclear deformation compared to control group. Moreover, after 2 days of mechanical stress cardiomyocytes derived from LMNA variant patients showed significantly higher level of nuclear dysmorphism while the control group were not affected. Field potential analysis of cardiomyocytes derived from LMNA patients compared to controls using multielectrode array revealed significantly higher beat rate irregularity in LMNA variant group which was consistent with the clinical symptoms of the patients. Furthermore, calcium transient of the cardiomyocytes derived from LMNA variant patients were significantly different from control group. Finally, patch clamp analysis also proved our previous findings and showed electrophysiological abnormalities in patients’ cells. In summary our finding thus far shows significant electrophysiological differences between cardiomyocytes derived from LMNA variant patients and control group which could help to unravel the cellular mechanism underlying formation of arrhythmia in LMNA variant patients.