Arrhythmogenic Cardiomyopathy

Saffitz, Jeffrey E.

doi:10.1161/circulationaha.111.064022

Cited by 29 publications

(7 citation statements)

References 35 publications

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“…Desmosomes contain desmosomal cadherins (desmocollin, desmoglein), which bind to the armadillo family proteins (junctional plakoglobin, plakopilin), which, in turn, anchor to a plakin family member (for example, desmoplakin) that connects to the intermediate filament cytoskeleton [ 47 ]. Over-expression of N-cadherins in mouse models causes dilated cardiomyopathies, while desmosome mutations in human lead to arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) and impaired mechanical coupling between individual cells with possible impairment of electrical coupling [ 48 , 49 ]. Morphologically, ICDs are normally arranged at the ends of adult CMs, but in immature or diseased cells the adherens junctions and gap junctions can be located on the lateral sides of CMs.…”

Section: Heart Development and Physical Cuesmentioning

confidence: 99%

Physical developmental cues for the maturation of human pluripotent stem cell-derived cardiomyocytes

et al. 2014

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Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are the most promising source of cardiomyocytes (CMs) for experimental and clinical applications, but their use is largely limited by a structurally and functionally immature phenotype that most closely resembles embryonic or fetal heart cells. The application of physical stimuli to influence hPSC-CMs through mechanical and bioelectrical transduction offers a powerful strategy for promoting more developmentally mature CMs. Here we summarize the major events associated with in vivo heart maturation and structural development. We then review the developmental state of in vitro derived hPSC-CMs, while focusing on physical (electrical and mechanical) stimuli and contributory (metabolic and hypertrophic) factors that are actively involved in structural and functional adaptations of hPSC-CMs. Finally, we highlight areas for possible future investigation that should provide a better understanding of how physical stimuli may promote in vitro development and lead to mechanistic insights. Advances in the use of physical stimuli to promote developmental maturation will be required to overcome current limitations and significantly advance research of hPSC-CMs for cardiac disease modeling, in vitro drug screening, cardiotoxicity analysis and therapeutic applications.

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Section: Heart Development and Physical Cuesmentioning

confidence: 99%

Physical developmental cues for the maturation of human pluripotent stem cell-derived cardiomyocytes

et al. 2014

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“…4, 5, 6, 7 In ARVC, progressive fibrofatty replacement of the normal cardiac tissue predisposes to ventricular tachycardia and sudden death. 8, 9 The prevalence of these three cardiomyopathies in the general population has been estimated to be 1:500, 1:2500, and 1:5000, respectively. 3 …”

Section: Introductionmentioning

confidence: 99%

New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants

et al. 2013

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Cardiomyopathies are a heterogeneous group of diseases with various etiologies. We focused on three genetically determined cardiomyopathies: hypertrophic (HCM), dilated (DCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC). Eighty-four genes have so far been associated with these cardiomyopathies, but the disease-causing effect of reported variants is often dubious. In order to identify possible false-positive variants, we investigated the prevalence of previously reported cardiomyopathy-associated variants in recently published exome data. We searched for reported missense and nonsense variants in the NHLBI-Go Exome Sequencing Project (ESP) containing exome data from 6500 individuals. In ESP, we identified 94 variants out of 687 (14%) variants previously associated with HCM, 58 out of 337 (17%) variants associated with DCM, and 38 variants out of 209 (18%) associated with ARVC. These findings correspond to a genotype prevalence of 1:4 for HCM, 1:6 for DCM, and 1:5 for ARVC. PolyPhen-2 predictions were conducted on all previously published cardiomyopathy-associated missense variants. We found significant overrepresentation of variants predicted as being benign among those present in ESP compared with the ones not present. In order to validate our findings, seven variants associated with cardiomyopathy were genotyped in a control population and this revealed frequencies comparable with the ones found in ESP. In conclusion, we identified genotype prevalences up to more than one thousand times higher than expected from the phenotype prevalences in the general population (HCM 1:500, DCM 1:2500, and ARVC 1:5000) and our data suggest that a high number of these variants are not monogenic causes of cardiomyopathy.

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“…However, recent studies have identified non-classical left ventricular prominent forms of the disease (Sen-Chowdhry et al, 2007), leading to a revision of the criteria for diagnosis and included adoption of the broader term arrhythmogenic cardiomyopathy (AC) when describing the disease (Delmar and McKenna, 2010). Characteristic of ARVC is also fibrotic/fatty replacement of the ventricle as well as high frequency of ventricular arrhythmias leading to sudden cardiac death in seemingly healthy young people, including athletes (Saffitz, 2011). ARVC has been termed a desmosomal disease, since 40% of patients carry mutations in desmosomal cell junction components, key components of the intercalated disc involved in the mechanical integrity of the myocardium (Saffitz, 2011; Sheikh et al, 2009).…”

Section: Modeling Cardiac Disease Using Hipsc-derived Cardiomyocytes—mentioning

confidence: 99%

“…Characteristic of ARVC is also fibrotic/fatty replacement of the ventricle as well as high frequency of ventricular arrhythmias leading to sudden cardiac death in seemingly healthy young people, including athletes (Saffitz, 2011). ARVC has been termed a desmosomal disease, since 40% of patients carry mutations in desmosomal cell junction components, key components of the intercalated disc involved in the mechanical integrity of the myocardium (Saffitz, 2011; Sheikh et al, 2009). At present, two groups have modeled ARVC arising from mutations in the desmosomal component plakophilin-2 in patients with clinical diagnosis of ARVC (Kim et al, 2013; Ma et al, 2012).…”

Section: Modeling Cardiac Disease Using Hipsc-derived Cardiomyocytes—mentioning

confidence: 99%

Modeling heart disease in a dish: From somatic cells to disease-relevant cardiomyocytes

Zanella

Lyon

Sheikh

2014

Trends in Cardiovascular Medicine

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A scientific milestone that has tremendously impacted the cardiac research field has been the discovery and establishment of human-induced pluripotent stem cells (hiPSC). Key to this discovery has been uncovering a viable path in generating human patient and disease-specific cardiac cells to dynamically model and study human cardiac diseases in an in vitro setting. Recent studies have demonstrated that hiPSC-derived cardiomyocytes can be used to model and recapitulate various known disease features in hearts of patient donors harboring genetic-based cardiac diseases. Experimental drugs have also been tested in this setting and shown to alleviate disease phenotypes in hiPSC-derived cardiomyocytes, further paving the way for therapeutic interventions for cardiac disease. Here, we review state-of-the-art methods to generate high-quality hiPSC and differentiate them towards cardiomyocytes as well as the full range of genetic-based cardiac diseases, which have been modeled using hiPSC. We also provide future perspectives on exploiting the potential of hiPSC to compliment existing studies and gain new insights into the mechanisms underlying cardiac disease.

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Arrhythmogenic Cardiomyopathy

Cited by 29 publications

References 35 publications

Physical developmental cues for the maturation of human pluripotent stem cell-derived cardiomyocytes

Physical developmental cues for the maturation of human pluripotent stem cell-derived cardiomyocytes

New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants

Modeling heart disease in a dish: From somatic cells to disease-relevant cardiomyocytes

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