Arrhythmogenic Right Ventricular Cardiomyopathy is a Disease of Cardiac Stem Cells

Overview

Journal Curr Opin Cardiol

Specialty Cardiology & Vascular Diseases

Date 2010 Feb 4

PMID 20124997

Citations 19

Authors

Raffaella Lombardi

Ali J Marian

Affiliations

Soon will be listed here.

Abstract

Purpose: To review recent developments in clinical aspects, molecular genetics and pathogenesis of arrhythmogenic right ventricular cardiomyopathy (ARVC).

Recent Findings: ARVC is a primary disease of the myocardium characterized by fibro-adipocytic replacement of myocytes, predominantly in the right ventricle. Phenotypic expression of ARVC is variable and a significant number of patients may exhibit a subtle phenotype, particularly in the early stages of the disease. Mutations in DSP, JUP, PKP2, DSG2 and DSC2, encoding desmosomal proteins desmoplakin, plakoglobin, plakophilin 2 (PKP2), desmoglein 2 (DSG2), and desmocollin 2 (DSC2), respectively, cause ARVC. Thus, ARVC, at least in a subset, is a disease of desmosomes. In addition, mutations in TMEM43 and TGFB1 have been associated with ARVC. Mechanistic studies indicate that suppressed canonical Wnt signaling, imposed by nuclear plakoglobin, is the responsible mechanism for the pathogenesis of ARVC. It leads to the differentiation of a subset of second heart field cardiac progenitor cells at the epicardium to adipocytes due to enhanced expression of adipogenic factors. This mechanism explains the predominant involvement of the right ventricle in ARVC. Hence, ARVC is the first identified disease of disrupted differentiation of cardiac progenitor cells.

Summary: Advances in molecular genetics and the pathogenesis of ARVC could afford the opportunity for a genetic-based diagnosis and development of novel diagnostic markers and therapeutic targets aimed to prevent, attenuate and reverse the evolving phenotype.

Citing Articles

Using Zebrafish Animal Model to Study the Genetic Underpinning and Mechanism of Arrhythmogenic Cardiomyopathy.

Niu Y, Sun Y, Liu Y, Du K, Xu X, Ding Y Int J Mol Sci. 2023; 24(4).

PMID: 36835518 PMC: 9966228. DOI: 10.3390/ijms24044106.

Uncovering Inherited Cardiomyopathy With Human Induced Pluripotent Stem Cells.

Jiang X, Chen Y, Liu X, Ye L, Yu M, Shen Z Front Cell Dev Biol. 2021; 9:672039.

PMID: 34079803 PMC: 8166268. DOI: 10.3389/fcell.2021.672039.

Established and Emerging Mechanisms in the Pathogenesis of Arrhythmogenic Cardiomyopathy: A Multifaceted Disease.

Gao S, Puthenvedu D, Lombardi R, Chen S Int J Mol Sci. 2020; 21(17).

PMID: 32878278 PMC: 7503882. DOI: 10.3390/ijms21176320.

Arrhythmogenic Cardiomyopathy and Skeletal Muscle Dystrophies: Shared Histopathological Features and Pathogenic Mechanisms.

Gao S, Chen S, Di Nardo C, Lombardi R Front Physiol. 2020; 11:834.

PMID: 32848821 PMC: 7406798. DOI: 10.3389/fphys.2020.00834.

Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia: An Updated Review of Diagnosis and Management.

Sattar Y, Abdullah H, Neisani Samani E, Myla M, Ullah W Cureus. 2019; 11(8):e5381.

PMID: 31616612 PMC: 6786836. DOI: 10.7759/cureus.5381.

References

Klymkowsky M, Williams B, Barish G, Varmus H, Vourgourakis Y . Membrane-anchored plakoglobins have multiple mechanisms of action in Wnt signaling. Mol Biol Cell. 1999; 10(10):3151-69. PMC: 25571. DOI: 10.1091/mbc.10.10.3151. View

Zhurinsky J, Shtutman M, Ben-Zeev A . Differential mechanisms of LEF/TCF family-dependent transcriptional activation by beta-catenin and plakoglobin. Mol Cell Biol. 2000; 20(12):4238-52. PMC: 85792. DOI: 10.1128/MCB.20.12.4238-4252.2000. View

Ross S, Hemati N, Longo K, Bennett C, Lucas P, Erickson R . Inhibition of adipogenesis by Wnt signaling. Science. 2000; 289(5481):950-3. DOI: 10.1126/science.289.5481.950. View

Alcalai R, Metzger S, Rosenheck S, Meiner V, Chajek-Shaul T . A recessive mutation in desmoplakin causes arrhythmogenic right ventricular dysplasia, skin disorder, and woolly hair. J Am Coll Cardiol. 2003; 42(2):319-27. DOI: 10.1016/s0735-1097(03)00628-4. View

Norman M, Simpson M, Mogensen J, Shaw A, Hughes S, Syrris P . Novel mutation in desmoplakin causes arrhythmogenic left ventricular cardiomyopathy. Circulation. 2005; 112(5):636-42. DOI: 10.1161/CIRCULATIONAHA.104.532234. View

Lombardi R, Dong J, Rodriguez G, Bell A, Leung T, Schwartz R . Genetic fate mapping identifies second heart field progenitor cells as a source of adipocytes in arrhythmogenic right ventricular cardiomyopathy. Circ Res. 2009; 104(9):1076-84. PMC: 2767296. DOI: 10.1161/CIRCRESAHA.109.196899. View

Beffagna G, De Bortoli M, Nava A, Salamon M, Lorenzon A, Zaccolo M . Missense mutations in desmocollin-2 N-terminus, associated with arrhythmogenic right ventricular cardiomyopathy, affect intracellular localization of desmocollin-2 in vitro. BMC Med Genet. 2007; 8:65. PMC: 2190757. DOI: 10.1186/1471-2350-8-65. View

Tabib A, Loire R, Chalabreysse L, Meyronnet D, Miras A, Malicier D . Circumstances of death and gross and microscopic observations in a series of 200 cases of sudden death associated with arrhythmogenic right ventricular cardiomyopathy and/or dysplasia. Circulation. 2003; 108(24):3000-5. DOI: 10.1161/01.CIR.0000108396.65446.21. View

Finsterer J, Stollberger C . The heart in human dystrophinopathies. Cardiology. 2003; 99(1):1-19. DOI: 10.1159/000068446. View

10.

Ai D, Fu X, Wang J, Lu M, Chen L, Baldini A . Canonical Wnt signaling functions in second heart field to promote right ventricular growth. Proc Natl Acad Sci U S A. 2007; 104(22):9319-24. PMC: 1890492. DOI: 10.1073/pnas.0701212104. View

11.

Heuser A, Plovie E, Ellinor P, Grossmann K, Shin J, Wichter T . Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet. 2006; 79(6):1081-8. PMC: 1698714. DOI: 10.1086/509044. View

12.

Maron B, Shirani J, Poliac L, Mathenge R, Roberts W, Mueller F . Sudden death in young competitive athletes. Clinical, demographic, and pathological profiles. JAMA. 1996; 276(3):199-204. View

13.

Tandri H, Castillo E, Ferrari V, Nasir K, Dalal D, Bomma C . Magnetic resonance imaging of arrhythmogenic right ventricular dysplasia: sensitivity, specificity, and observer variability of fat detection versus functional analysis of the right ventricle. J Am Coll Cardiol. 2006; 48(11):2277-84. DOI: 10.1016/j.jacc.2006.07.051. View

14.

Maeda O, Usami N, Kondo M, Takahashi M, Goto H, Shimokata K . Plakoglobin (gamma-catenin) has TCF/LEF family-dependent transcriptional activity in beta-catenin-deficient cell line. Oncogene. 2003; 23(4):964-72. DOI: 10.1038/sj.onc.1207254. View

15.

Chen A, Ginty D, Fan C . Protein kinase A signalling via CREB controls myogenesis induced by Wnt proteins. Nature. 2004; 433(7023):317-22. DOI: 10.1038/nature03126. View

16.

van Tintelen J, Entius M, Bhuiyan Z, Jongbloed R, Wiesfeld A, Wilde A . Plakophilin-2 mutations are the major determinant of familial arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circulation. 2006; 113(13):1650-8. DOI: 10.1161/CIRCULATIONAHA.105.609719. View

17.

Tandri H, Asimaki A, Abraham T, Dalal D, Tops L, Jain R . Prolonged RV endocardial activation duration: a novel marker of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Heart Rhythm. 2009; 6(6):769-75. PMC: 2778730. DOI: 10.1016/j.hrthm.2009.02.031. View

18.

Tiso N, Stephan D, Nava A, Bagattin A, Devaney J, Stanchi F . Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Hum Mol Genet. 2001; 10(3):189-94. DOI: 10.1093/hmg/10.3.189. View

19.

Frank R, Fontaine G, Vedel J, Mialet G, Sol C, GUIRAUDON G . [Electrocardiology of 4 cases of right ventricular dysplasia inducing arrhythmia]. Arch Mal Coeur Vaiss. 1978; 71(9):963-72. View

20.

Polesskaya A, Seale P, Rudnicki M . Wnt signaling induces the myogenic specification of resident CD45+ adult stem cells during muscle regeneration. Cell. 2003; 113(7):841-52. DOI: 10.1016/s0092-8674(03)00437-9. View