Electrophysiological Abnormalities in Patient-Specific LMNA-Mutated Induced Pluripotent Stem Cells-Derived Cardiomyocytes

Yuval Shemer Ruth and Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel Shelly Naor Ruth and Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel Lubna Willi Ruth and Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel Ronen Ben Jehuda Ruth and Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel Department of Biotechnology, Technion – Israel Institute of Technology, Haifa, Israel Revital Schick Ruth and Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel Binyamin Eisen Ruth and Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel Eloisa Arbustini Center for Inherited Cardiovascular Diseases, IRCCS Foundation Policlinico San Matteo, Pavia, Italy Dov Freimark Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel Michael Arad Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel Ofer Binah Ruth and Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel

Introduction

Lamins are type V intermediate filament proteins that form the nuclear lamina, a scaffolding structure underlying the inner nuclear membrane. Lamins A and C are encoded by the LMNA gene and are involved in a variety of cellular pathways including chromatin organization, nucleoskeleton-cytoskeleton connection, gene expression and signal transduction. Mutations in the LMNA gene cause a diverse group of diseases known as laminopathies. LMNA-related dilated cardiomyopathy (DCM) accounts for about 5%-8% of familial DCM and 30% of DCM with conduction disease. The disease is characterized by early conduction defects and malignant ventricular arrhythmias associated with ventricular chamber dilation and impaired systolic function. However, the mechanisms whereby LMNA mutations cause DCM with electrophysiological abnormalities remain unknown.

Purpose

To investigate the electrophysiological abnormalities underlying LMNA-related DCM using patient-specific induced Pluripotent Stem Cells-derived cardiomyocytes (iPSC-CMs).

Results

iPSC-CMs were generated from 2 related carriers of the E342K missense mutation in LMNA gene: a 63-year-old end-stage DCM patient and his 35-year-old son who was asymptomatic at time of biopsy, but since then developed ECG abnormalities. The LMNA-mutated iPSC-CMs exhibited the following aberrations compared to healthy iPSC-CMs: (1) lower spontaneous beat rates; (2) abnormalities in action potential parameters such as: prolongation of action potential duration at 50% and 90% repolarization (APD₅₀ and APD₉₀, respectively) and decreased maximal upstroke velocity of phase 0 depolarization (dV/dt_max); (3) prominent arrhythmias represented by afterdepolarizations and triggered activity; (4) increased beat rate variability.

Conclusions

LMNA-mutated iPSC-CMs showed electrophysiological abnormalities and arrhythmias, suggesting that this cellular model recapitulates key aspects of the clinical course of LMNA-related DCM.