Investigating LMNA-Related Dilated Cardiomyopathy Using Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

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 t...

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Published in:International journal of molecular sciences 2021-08, Vol.22 (15), p.7874
Main Authors: Shemer, Yuval, Mekies, Lucy N., Ben Jehuda, Ronen, Baskin, Polina, Shulman, Rita, Eisen, Binyamin, Regev, Danielle, Arbustini, Eloisa, Gerull, Brenda, Gherghiceanu, Mihaela, Gottlieb, Eyal, Arad, Michael, Binah, Ofer
Format: Article
Language:English
Subjects:
Abnormalities
Action potential
arrhythmia
Calcium channels (L-type)
Calcium currents
Calcium ions
Cardiac arrhythmia
Cardiomyocytes
Cardiomyopathy
Cloning
Coronary artery disease
Dilated cardiomyopathy
Disease
electrophysiology
Enlargement
Experiments
Gene expression
Heart diseases
Heart failure
iPSC-CMs
LMNA
Muscular dystrophy
Mutation
Na+/Ca2+ exchanger
Pacemakers
Pluripotency
Proteins
Stem cells
Ventricle
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Summary: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.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms22157874