1. Investigating LMNA-Related Dilated Cardiomyopathy Using Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes
- Author
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Polina Baskin, Eloisa Arbustini, Ofer Binah, Mihaela Gherghiceanu, Binyamin Eisen, Michael Arad, Yuval Shemer, Lucy N. Mekies, Rita Shulman, Brenda Gerull, Danielle Regev, Eyal Gottlieb, and Ronen Ben Jehuda
- Subjects
0301 basic medicine ,Male ,Heart disease ,Action Potentials ,Stimulation ,030204 cardiovascular system & hematology ,LMNA ,Pacemaker potential ,0302 clinical medicine ,Myocytes, Cardiac ,Biology (General) ,Induced pluripotent stem cell ,Spectroscopy ,health care economics and organizations ,integumentary system ,Dilated cardiomyopathy ,Cell Differentiation ,General Medicine ,Middle Aged ,Lamin Type A ,Computer Science Applications ,Pedigree ,Chemistry ,embryonic structures ,Cardiology ,Female ,Adult ,Cardiomyopathy, Dilated ,medicine.medical_specialty ,congenital, hereditary, and neonatal diseases and abnormalities ,QH301-705.5 ,Induced Pluripotent Stem Cells ,arrhythmia ,Catalysis ,Article ,Inorganic Chemistry ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,ddc:610 ,Physical and Theoretical Chemistry ,Molecular Biology ,QD1-999 ,business.industry ,Organic Chemistry ,Arrhythmias, Cardiac ,medicine.disease ,electrophysiology ,Electrophysiological Phenomena ,dilated cardiomyopathy ,Electrophysiology ,030104 developmental biology ,Mutation ,Calcium ,iPSC-CMs ,business ,Lamin - 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.
- Published
- 2021