TY  - JOUR
A1  - Gerull, Brenda
A1  - Brodehl, Andreas
T1  - Insights Into Genetics and Pathophysiology of Arrhythmogenic Cardiomyopathy
JF  - Current Heart Failure Reports
N2  - Purpose of Review
Arrhythmogenic cardiomyopathy (ACM) is a genetic disease characterized by life-threatening ventricular arrhythmias and sudden cardiac death (SCD) in apparently healthy young adults. Mutations in genes encoding for cellular junctions can be found in about half of the patients. However, disease onset and severity, risk of arrhythmias, and outcome are highly variable and drug-targeted treatment is currently unavailable.
Recent Findings
This review focuses on advances in clinical risk stratification, genetic etiology, and pathophysiological concepts. The desmosome is the central part of the disease, but other intercalated disc and associated structural proteins not only broaden the genetic spectrum but also provide novel molecular and cellular insights into the pathogenesis of ACM. Signaling pathways and the role of inflammation will be discussed and targets for novel therapeutic approaches outlined. 
Summary
Genetic discoveries and experimental-driven preclinical research contributed significantly to the understanding of ACM towards mutation- and pathway-specific personalized medicine.
KW  - dilated cardiomyopathy
KW  - arrhythmogenic cardiomyopathy
KW  - junctions
KW  - sudden cardiac death
KW  - cardiovascular genetics
KW  - desmosomes
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-269916
SN  - 1546-9549
VL  - 18
IS  - 6
ER  - 
TY  - JOUR
A1  - Shemer, Yuval
A1  - Mekies, Lucy N.
A1  - Ben Jehuda, Ronen
A1  - Baskin, Polina
A1  - Shulman, Rita
A1  - Eisen, Binyamin
A1  - Regev, Danielle
A1  - Arbustini, Eloisa
A1  - Gerull, Brenda
A1  - Gherghiceanu, Mihaela
A1  - Gottlieb, Eyal
A1  - Arad, Michael
A1  - Binah, Ofer
T1  - Investigating LMNA-related dilated cardiomyopathy using human induced Pluripotent Stem Cell-derived cardiomyocytes
JF  - International Journal of Molecular Sciences
N2  - 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.
KW  - LMNA
KW  - dilated cardiomyopathy
KW  - iPSC-CMs
KW  - electrophysiology
KW  - arrhythmia
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285673
SN  - 1422-0067
VL  - 22
IS  - 15
ER  -