Investigating LMNA-related dilated cardiomyopathy using human induced pluripotent stem cell-derived cardiomyocytes

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

LMNA-related dilated cardiomyopathy is an inherited heart disease caused by mutations in the LMNA 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 LMNA-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 LMNA gene. Compared to control iPSC-CMs, LMNA-mutated iPSC-CMs exhibited the following electrophysiological abnormalities: (1) decreased spontaneous action potential beat rate and decreased pacemaker current (If) density; (2) prolonged action potential duration and increased L-type Ca2+ current (ICa,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, LMNA-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 LMNA-mutated iPSC-CMs. Our findings demonstrate cellular electrophysiological mechanisms underlying the arrhythmias in LMNA-related dilated cardiomyopathy.

Original languageEnglish
Article number7874
JournalInternational Journal of Molecular Sciences
Volume22
Issue number15
DOIs
StatePublished - 1 Aug 2021

Funding

FundersFunder number
Niedersachsisches Ministerium: Medizinischen Hochschule Hannover
Rappaport Family Institute for Research in the Medical Science01012020RI
Technion?Israel Institute of Technology, Haifa, Israel
Maison Heinrich Heine76251-99-16/14
Israel Science FoundationISF 824/19
Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum WürzburgE-338

    Keywords

    • Arrhythmia
    • Dilated cardiomyopathy
    • Electrophysiology
    • IPSC-CMs
    • LMNA

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