Investigating <i>LMNA</i>-Related Dilated Cardiomyopathy Using Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

• Main Authors: Yuval Shemer, Lucy N. Mekies, Ronen Ben Jehuda, Polina Baskin, Rita Shulman, Binyamin Eisen, Danielle Regev, Eloisa Arbustini, Brenda Gerull, Mihaela Gherghiceanu, Eyal Gottlieb, Michael Arad, Ofer Binah
• Format: Article
• Language: English
• Published: MDPI AG 2021-07-01
• Series: International Journal of Molecular Sciences
• Subjects: <i>LMNA</i>; dilated cardiomyopathy; iPSC-CMs; electrophysiology; arrhythmia
• Online Access: https://www.mdpi.com/1422-0067/22/15/7874
• ISSN: 1661-6596; 1422-0067

<i>LMNA</i>-related dilated cardiomyopathy is an inherited heart disease caused by mutations in the <i>LMNA</i> gene encoding for lamin A/C. The disease is characterized by left ventricular enlargement and impaired systolic function associated with conduction defects and ventricular arrhythmias. We hypothesized that <i>LMNA</i>-mutated patients’ induced Pluripotent Stem Cell-derived cardiomyocytes (iPSC-CMs) display electrophysiological abnormalities, thus constituting a suitable tool for deciphering the arrhythmogenic mechanisms of the disease, and possibly for developing novel therapeutic modalities. iPSC-CMs were generated from two related patients (father and son) carrying the same E342K mutation in the <i>LMNA</i> gene. Compared to control iPSC-CMs, <i>LMNA</i>-mutated iPSC-CMs exhibited the following electrophysiological abnormalities: (1) decreased spontaneous action potential beat rate and decreased pacemaker current (I_f) density; (2) prolonged action potential duration and increased L-type Ca²⁺ current (I_Ca,L) density; (3) delayed afterdepolarizations (DADs), arrhythmias and increased beat rate variability; (4) DADs, arrhythmias and cessation of spontaneous firing in response to β-adrenergic stimulation and rapid pacing. Additionally, compared to healthy control, <i>LMNA</i>-mutated iPSC-CMs displayed nuclear morphological irregularities and gene expression alterations. Notably, KB-R7943, a selective inhibitor of the reverse-mode of the Na⁺/Ca²⁺ exchanger, blocked the DADs in <i>LMNA</i>-mutated iPSC-CMs. Our findings demonstrate cellular electrophysiological mechanisms underlying the arrhythmias in <i>LMNA</i>-related dilated cardiomyopathy.