Arrhythmogenic Cardiomyopathy
2018; Lippincott Williams & Wilkins; Volume: 137; Issue: 15 Linguagem: Galês
10.1161/circulationaha.118.033558
ISSN1524-4539
AutoresLuisa Mestroni, Orfeo Sbaizero,
Tópico(s)Cardiomyopathy and Myosin Studies
ResumoHomeCirculationVol. 137, No. 15Arrhythmogenic Cardiomyopathy Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBArrhythmogenic CardiomyopathyMechanotransduction Going Wrong Luisa Mestroni, MD and Orfeo Sbaizero, PhD Luisa MestroniLuisa Mestroni University of Colorado-Cardiovascular Institute, University of Colorado Anschutz Medical Campus, Aurora (L.M.). and Orfeo SbaizeroOrfeo Sbaizero Department of Engineering and Architecture, University of Trieste, Italy (O.S.). Originally published10 Apr 2018https://doi.org/10.1161/CIRCULATIONAHA.118.033558Circulation. 2018;137:1611–1613Article, see p 1595Arrhythmogenic cardiomyopathy (AC) is a genetic disorder characterized by high risk of life-threatening ventricular arrhythmias, sudden cardiac death, and progressive heart failure. Currently, there is evidence that AC includes a spectrum of cardiomyopathy phenotypes, ranging from the classical form of arrhythmogenic right ventricular cardiomyopathy (ARVC) to more recently identified forms of arrhythmogenic left ventricular cardiomyopathy.1,2ARVC is considered a disease of the desmosome, because in the majority of cases, it is caused by mutations in genes encoding proteins of the cardiac desmosomes.3 However, mutations in nondesmosomal genes have also been found in ARVC, such as the genes encoding the cardiac ryanodine receptor 2 (RYR2), the transforming growth factor β-3 (TGFB3), the nuclear transmembrane protein 43 (TMEM43), and desmin (DES). Mutations in LMNA, encoding the nuclear envelope protein lamin A/C, known to cause dilated cardiomyopathy with an arrhythmic phenotype, was reported to cause also an ARVC phenotype,3 even though the association between LMNA and ARVC is still questioned.In the left dominant form, which clinically presents as an arrhythmogenic dilated cardiomyopathy, the same desmosomal genes causing ARVC can be found,1 as well as LMNA and the more recently identified filamin C gene (FLNC), encoding an actin cross-linker, Z-line, and integrin-binding protein.4–6 These findings clearly show that the AC phenotype may involve both the right and left ventricle with variable expressivity, with mechanisms that are still not well understood and that extend beyond the desmosome to include several components of the cellular mechanotransduction machinery.In this issue of Circulation, Bermúdez-Jiménez et al describe a Spanish family in which ~30 affected family members with AC phenotype were found to carry a rare missense variant of DES gene (c.1203G>C; p.Glu401Asp).7DES mutations have been previously reported in myopathies, conduction disease, and cardiomyopathies, in particular cases of dilated cardiomyopathy 8 and ARVC.9 While truncation variants have a deleterious effect and therefore, in general, are considered to be pathogenic, missense variants are much more difficult to classify. In DES, missense mutations are frequent in controls;10 however, this study provides convincing evidence that the unique DES Glu401Asp variant causes the disease in this family, with 100% penetrance and variable expressivity. The mutation carriers presented an arrhythmogenic phenotype with high risk of sudden cardiac death and progressive heart failure. It should be noted that in this case of AC caused by DES mutation, as in the cases of other nondesmosomal AC genes, such as FLNC and LMNA, the phenotype is not typical of ARVC; it is unclear if any of the subjects fulfilled the ARVC 2010 Task Force Criteria, although 4 of 31 had right ventricular involvement and 2 had epsilon waves. In the cardiac tissue, the investigators found fibro-fatty infiltration predominantly in the left ventricle. Cardiomyocytes showed reduced cellular adhesion, reminiscent of the defect found in ARVC, and reduced expression of DES and cell-cell junction proteins.Indeed, one of the aspects that deserves more investigations in AC is the role of altered mechanotransduction. An essential necessity for cells is the capacity to adapt to their mechanical environment (mechanosensing and mechanotrasduction). To accomplish this task, cardiomyocytes can use members of the G-protein family, integrins, or strain-activated ion channels.11 Moreover, the cytoskeleton supplies a network through which the mechanical stresses can be transmitted by actin, microtubules, and intermediate filaments to the nucleus, inducing protein conformational changes and nuclear deformation that can alter biological activity.Among the cytoskeleton filaments, intermediate filaments are the most flexible and they are also highly stretchable. In cardiomyocytes, the main intermediate filaments are DES, which link myofibrils radially along Z-disks to the sarcomeres, longitudinally to the intercalated discs, and attach directly to the nuclear inner surface interacting with LMNA.12 DES filaments are strategically located to maintain sarcomere alignment and homogeneity, to act as a lateral mechanical link between Z-disks and to transmit force radially. These intermediate filaments are crucial for force transmission from the cell membrane to the nuclei and for its mechanical stability. Nuclei in healthy cells when stretched increased their aspect ratio in parallel with increased sarcomere length, while nuclei in DES-null cells deformed less.13 This lack of hard-wiring of the nucleus to the cytoskeleton results in a reduced degree of phosphorylation of the Jun N-terminal kinase (JNK). In fact, DES-null cells showed a near absence of stretch-induced signaling leading to JNK phosphorylation.13 Furthermore, DES is connected to the desmosome proteins via desmoplakin (Figure).14 In this way, DES filaments provide a link to desmosomes critical in cardiac mechanotransduction and long-range force transmission across cells. Therefore, it is not surprising that a mutation that affects the DES filaments network will also affect the distribution of desmoplakin at the junctional sites, eventually causing an AC phenotype. Taken together, these data show an essential role for DES being involved in both mechanical stress transmission and stress transduction in cardiac muscle cells.Download figureDownload PowerPointFigure 1. Desmosomal proteins, desmin and nuclear lamina provide a continuum structure for mechanotransduction and mechanosensing in cardiomyocytes, which explains their common role in arrhythmogenic cardiomyopathy.In conclusion, there are 3 important insights from the study of Bermúdez-Jiménez et al7 that have intriguing scientific and clinical implications: (1) Failure of the proper connection between the cell-cell junction with the intracellular structures (desmosome, nucleus) alters the cardiomyocyte mechanotransduction and mechanosensing, and eventually leads to an arrhythmogenic phenotype; (2) The AC phenotype is a spectrum, even in the same family, and can involve either the right or the left ventricle or both; and (3) In this disease, that overlaps with the dilated cardiomyopathy phenotype, there is a need of appropriate risk stratification as done in ARVC, which takes into account the risk of life-threatening arrhythmias (regardless of the left ventricular dysfunction),2 and should include genetic testing, ECG monitoring, and cardiac magnetic resonance with late gadolinium enhancement.Sources of FundingThis work is supported in part by the American Heart Association grant AHA17GRNT33670495 (to Dr Mestroni) and a Trans-Atlantic Network of Excellence grant from the Fondation Leducq (14-CVD 03) (to Drs Mestroni and Sbaizero).DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.http://circ.ahajournals.orgLuisa Mestroni, MD, University of Colorado Denver Anschutz Medical Campus, 12700 E 19th Ave # F442, Aurora, Colorado 80045–2507. 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Beffagna G, Sommariva E and Bellin M (2020) Mechanotransduction and Adrenergic Stimulation in Arrhythmogenic Cardiomyopathy: An Overview of in vitro and in vivo Models, Frontiers in Physiology, 10.3389/fphys.2020.568535, 11 Segura-Rodríguez D, Bermúdez-Jiménez F, Carriel V, López-Fernández S, González-Molina M, Oyonarte Ramírez J, Fernández-Navarro L, García-Roa M, Cabrerizo E, Durand-Herrera D, Alaminos M, Campos A, Macías R, Álvarez M, Tercedor L and Jiménez-Jáimez J (2019) Myocardial fibrosis in arrhythmogenic cardiomyopathy: a genotype–phenotype correlation study, European Heart Journal - Cardiovascular Imaging, 10.1093/ehjci/jez277, 21:4, (378-386), Online publication date: 1-Apr-2020. April 10, 2018Vol 137, Issue 15 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.118.033558PMID: 29632153 Originally publishedApril 10, 2018 KeywordsARVCsudden cardiac deathEditorialsdilated cardiomyopathymechanotransductiondesminarrhythmogenic cardiomyopathyPDF download Advertisement SubjectsCardiomyopathyCell Biology/Structural BiologyGeneticsSudden Cardiac Death
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