| Autor: |
Shemer Y; Department of Physiology, Biophysics and Systems Biology, Rappaport Faculty of Medicine and Rappaport Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel., Mekies LN; Department of Physiology, Biophysics and Systems Biology, Rappaport Faculty of Medicine and Rappaport Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel., Ben Jehuda R; Department of Physiology, Biophysics and Systems Biology, Rappaport Faculty of Medicine and Rappaport Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel.; Department of Biotechnology, Technion-Israel Institute of Technology, Haifa 3200003, Israel., Baskin P; Department of Physiology, Biophysics and Systems Biology, Rappaport Faculty of Medicine and Rappaport Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel., Shulman R; Department of Physiology, Biophysics and Systems Biology, Rappaport Faculty of Medicine and Rappaport Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel., Eisen B; Department of Physiology, Biophysics and Systems Biology, Rappaport Faculty of Medicine and Rappaport Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel., Regev D; Department of Physiology, Biophysics and Systems Biology, Rappaport Faculty of Medicine and Rappaport Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel., Arbustini E; Centre for Inherited Cardiovascular Diseases, IRCCS Foundation, Policlinico San Matteo, 27100 Pavia, Italy., Gerull B; Comprehensive Heart Failure Center and Department of Internal Medicine I, University Hospital Würzburg, 97080 Würzburg, Germany., Gherghiceanu M; Victor Babes National Institute of Pathology, 050096 Bucharest, Romania., Gottlieb E; Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel., Arad M; Leviev Heart Center, Sheba Medical Center, Ramat Gan 52621, Israel.; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel., Binah O; Department of Physiology, Biophysics and Systems Biology, Rappaport Faculty of Medicine and Rappaport Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel. |
| Abstrakt: |
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 (I f ) density; (2) prolonged action potential duration and increased L-type Ca 2+ 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, 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 + /Ca 2+ exchanger, blocked the DADs in LMNA -mutated iPSC-CMs. Our findings demonstrate cellular electrophysiological mechanisms underlying the arrhythmias in LMNA -related dilated cardiomyopathy. |
