Review| Volume 31, ISSUE 11, P1313-1324, November 2015

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Pathogenesis of Arrhythmogenic Cardiomyopathy

Published:April 23, 2015DOI:


      Arrhythmogenic cardiomyopathy (ACM) is a primary myocardial disease. It is characterized by frequent ventricular arrhythmias and increased risk of sudden cardiac death typically arising as an early manifestation before the onset of significant myocardial remodelling. Myocardial degeneration, often confined to the right ventricular free wall, with replacement by fibrofatty scar tissue, develops in many patients. ACM is a familial disease but genetic penetrance can be low and disease expression is highly variable. Inflammation might promote disease progression. It also appears that exercise increases disease penetrance and accelerates its development. More than 60% of probands harbour mutations in genes that encode desmosomal proteins, which has raised the possibility that defective cell-cell adhesion might play a role in disease pathogenesis. Recent advances have implicated changes in the canonical wingless-type mouse mammary tumour virus integration site (Wnt)/β-catenin and Hippo signalling pathways and defects in forwarding trafficking of ion channels and other proteins to the intercalated disk in cardiac myocytes. In this review we summarize the current understanding of the pathogenesis of ACM and highlight future research directions.


      La cardiomyopathie arythmogène (CMA) est une maladie myocardique primitive. Elle est caractérisée par de fréquentes arythmies ventriculaires et l’augmentation du risque de mort cardiaque subite se manifestant typiquement de manière précoce avant l’apparition d’un remodelage myocardique significatif. La dégénération myocardique, souvent limitée à la paroi libre du ventricule droit, avec le remplacement du tissu cicatriciel fibro-adipeux, se développe chez plusieurs patients. La MCA est une maladie familiale, mais la pénétrance peut être faible et l’expressivité de la maladie est très variable. L’inflammation favoriserait la progression de la maladie. Il semble également que l’exercice augmente la pénétrance de la maladie et accélère son développement. Plus de 60 % des proposants portent des mutations dans les gènes qui encodent les protéines desmosomales, ce qui soulève la possibilité que l’adhérence cellule-cellule défectueuse puisse jouer un rôle dans la pathogenèse de la maladie. De récentes avancées ont impliqué des changements dans les voies de signalisation Wnt/ β-caténine (voie canonique) et Hippo et des anomalies en transférant le trafic des canaux ioniques et les autres protéines au disque intercalé dans les myocytes cardiaques. Dans cette revue, nous résumons les connaissances actuelles sur la pathogenèse de la MCA et dégageons les orientations futures de la recherche.
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        • Marcus F.I.
        • Fontaine G.H.
        • Guiraudon G.
        • et al.
        Right ventricular dysplasia: a report of 24 adult cases.
        Circulation. 1982; 65: 384-398
        • McKenna W.J.
        • Thiene G.
        • Nava A.
        • et al.
        Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Task Force of the Working Group Myocardial and Pericardial Disease of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the International Society and Federation of Cardiology.
        Br Heart J. 1994; 71: 215-218
        • Sen-Chowdhry S.
        • Morgan R.D.
        • Chambers J.C.
        • McKenna W.J.
        Arrhythmogenic cardiomyopathy: etiology, diagnosis and treatment.
        Ann Rev Med. 2010; 61: 233-253
        • Quartaa G.
        • Elliott P.M.
        Diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy.
        Rev Esp Cardiol. 2012; 65: 599-605
        • Saffitz J.E.
        • Asimaki A.
        • Huang H.
        Arrhythmogenic right ventricular cardiomyopathy: new insights into mechanisms of disease.
        Cardiovasc Pathol. 2010; 19: 166-170
        • Basso C.
        • Thiene G.
        Adipositas cordis, fatty infiltration of the right ventricle, and arrhythmogenic right ventricular cardiomyopathy. Just a matter of fat?.
        Cardiovasc Pathol. 2005; 14: 37-41
        • Basso C.
        • Thiene G.
        • Corrado D.
        • et al.
        Arrhythmogenic right ventricular cardiomyopathy. Dysplasia, dystrophy, or myocarditis?.
        Circulation. 1996; 94: 983-991
        • Marcus F.I.
        • McKenna W.J.
        • Sherrill D.
        • et al.
        Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria.
        Circulation. 2010; 121: 1533-1541
        • Ren L.
        • Liu Z.
        • Jia Y.
        • et al.
        Electrocardiographic difference between ventricular arrhythmias from the right ventricular outflow tract and idiopathic right ventricular arrhythmias.
        Pacing Clin Electrophysiol. 2014; 37: 1658-1664
        • Agullo-Pascual E.
        • Cerrone M.
        • Delmar M.
        Arrhythmogenic cardiomyopathy and Brugada syndrome: diseases of the connexome.
        FEBS Lett. 2014; 588: 1322-1330
        • Viskin S.
        • Rosso R.
        • Rogowski O.
        • Belhassen B.
        The “short-coupled” variant of right ventricular outflow ventricular tachycardia: a not-so-benign form of benign ventricular tachycardia?.
        J Cardiovasc Electrophysiol. 2005; 16: 912-916
        • Catalano O.
        • Antonaci S.
        • Moro G.
        • et al.
        Magnetic resonance investigations in Brugada syndrome reveal unexpectedly high rate of structural abnormalities.
        Eur Heart J. 2009; 30: 2241-2248
        • Ellinor P.T.
        • MacRae C.A.
        • Thierfelder L.
        Arrhythmogenic right ventricular cardiomyopathy.
        Heart Fail Clin. 2010; 6: 161-177
        • Ott P.
        • Marcus F.I.
        • Sobonya R.E.
        • et al.
        Cardiac sarcoidosis masquerading as right ventricular dysplasia.
        Pacing Clin Electrophysiol. 2003; 26: 1498-1503
        • Rojas A.
        • Calkins H.
        Present understanding of the relationship between exercise and arrhythmogenic right ventricular dysplasia/cardiomyopathy.
        Trends Cardiovasc Med. 2015; 25: 181-188
        • Marcus F.I.
        • Fontaine G.
        Arrhythmogenic right ventricular dysplasia/cardiomyopathy: a review.
        Pacing Clin Electrophysiol. 1995; 18: 1298-1314
        • Marcus F.I.
        • Zareba W.
        • Calkins H.
        • et al.
        Arrhythmogenic right ventricular cardiomyopathy/dysplasia, clinical presentation and diagnostic evaluation: results from the North American multidisciplinary study.
        Heart Rhythm. 2009; 6: 984-992
        • Dalal D.
        • Nasir K.
        • Bomma C.
        • et al.
        Arrhythmogenic right ventricular dysplasia: a United States experience.
        Circulation. 2005; 112: 3823-3832
        • den Haan A.D.
        • Tan B.Y.
        • Zikusoka M.N.
        • et al.
        Comprehensive desmosome mutation analysis in North Americans with Arrhythmogenic right ventricular dysplasia/cardiomyopathy.
        Circ Cardiovasc Genet. 2009; 2: 428-435
        • James C.A.
        • Bhonsale A.
        • Tichnell C.
        • et al.
        Exercise increases age-related penetrance and arrhythmic risk in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated desmosomal mutation carriers.
        J Am Coll Cardiol. 2013; 62: 1290-1297
        • Sen-Chowdhry S.
        • McKenna W.J.
        Sudden death from genetic and acquired cardiomyopathies.
        Circulation. 2012; 125: 1563-1576
        • Green K.J.
        • Gaudry C.A.
        Are desmosomes more than tethers for intermediate filaments.
        Nat Rev Mol Cell Biol. 2000; 1: 208-216
        • Li J.
        • Radice G.L.
        A new perspective on intercalated disk organization: implications for heart disease.
        Dermatol Res Pract. 2010; 2010: 207835
        • Coonar A.S.
        • Protonotarios N.
        • Tsatsopoulou A.
        • et al.
        Gene for arrhythmogenic right ventricular cardiomyopathy with diffuse nonepidermolytic palmoplantar keratoderma and woolly hair (Naxos disease) maps to 17q21.
        Circulation. 1998; 97: 2049-2058
        • McKoy G.
        • Protonotarios N.
        • Crosby A.
        • et al.
        Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease).
        Lancet. 2000; 355: 2119-2124
        • Lazzarini E.
        • Jongbloed J.D.
        • Pilichou K.
        • et al.
        The ARVD/C Genetic Variants Database: 2014 Update.
        Hum Mutat. 2015; 36: 403-410
        • Tiso N.
        • Stephan D.A.
        • Nava A.
        • et al.
        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: 189-194
        • George C.H.
        • Higgs G.V.
        • Lai F.A.
        Ryanodine receptor mutations associated with stress-induced ventricular tachycardia mediate increased calcium release in stimulated cardiomyocytes.
        Circ Res. 2003; 93: 531-540
        • Merner N.D.
        • Hodgkinson K.A.
        • Haywood A.F.
        • et al.
        Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene.
        Am J Hum Genet. 2008; 82: 809-821
        • Rajkumar R.
        • Sembrat J.C.
        • McDonough B.
        • et al.
        Functional effects of the TMEM43 Ser358Leu mutation in the pathogenesis of arrhythmogenic right ventricular cardiomyopathy.
        BMC Med Genet. 2012; 13: 21
        • van der Zwaag P.A.
        • van Rijsingen I.A.
        • Asimaki A.
        • et al.
        Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy.
        Eur J Heart Fail. 2012; 14: 1199-1207
        • Beffagna G.
        • Occhi G.
        • Nava A.
        • et al.
        Regulatory mutations in transforming growth factor-beta3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1.
        Cardiovasc Res. 2005; 65: 366-373
        • Lorenzon A.
        • Beffagna G.
        • Bauce B.
        • et al.
        Desmin mutations and arrhythmogenic right ventricular cardiomyopathy.
        Am J Cardiol. 2013; 111: 400-405
        • Lopez-Ayala J.M.
        • Ortiz-Genga M.
        • Gomez-Milanes I.
        A mutation in the Z-line Cypher/ZASP protein is associated with arrhythmogenic right ventricular cardiomyopathy.
        Clin Genet. 2015; 88: 172-176
        • Marcus F.I.
        • Edson S.
        • Towbin J.A.
        Genetics of arrhythmogenic right ventricular cardiomyopathy: a practical guide for physicians.
        J Am Coll Cardiol. 2013; 61: 1945-1948
        • Rizzo S.
        • Pilichou K.
        • Thiene G.
        • Basso C.
        The changing spectrum of arrhythmogenic (right ventricular) cardiomyopathy.
        Cell Tissue Res. 2012; 348: 319-323
        • Guiraudon C.M.
        Histological diagnosis of right ventricular dysplasia: a role for electron microscopy?.
        Eur Heart J. 1989; 10: 95-96
        • Basso C.
        • Czarnowska E.
        • Della Barbera M.
        • et al.
        Ultrastructural evidence of intercalated disc remodelling in arrhythmogenic right ventricular cardiomyopathy: an electron microscopy investigation on endomyocardial biopsies.
        Eur Heart J. 2006; 27: 1847-1854
        • Pilichou K.
        • Remme C.A.
        • Basso C.
        • et al.
        Myocyte necrosis underlies progressive myocardial dystrophy in mouse dsg2-related arrhythmogenic right ventricular cardiomyopathy.
        J Exp Med. 2009; 206: 1787-1802
        • Sato P.Y.
        • Coombs W.
        • Lin X.
        • et al.
        Interactions between ankyrin-G, plakophilin-2, and connexin43 at the cardiac intercalated disc.
        Circ Res. 2011; 109: 193-201
        • Hariharan V.
        • Asimaki A.
        • Michaelson J.E.
        • et al.
        Arrhythmogenic right ventricular cardiomyopathy mutations alter shear response without changes in cell-cell adhesion.
        Cardiovasc Res. 2014; 104: 280-289
        • Asimaki A.
        • Tandri H.
        • Huang H.
        • et al.
        A new diagnostic test for arrhythmogenic right ventricular cardiomyopathy.
        N Engl J Med. 2009; 360: 1075-1084
        • Munkholm J.
        • Andersen C.B.
        • Ottesen G.L.
        Plakoglobin: a diagnostic marker of arrhythmogenic right ventricular cardiomyopathy in forensic pathology?.
        Forensic Sci Med Pathol. 2015; 11: 47-52
        • Ermakov S.
        • Ursell P.C.
        • Johnson C.J.
        • et al.
        Plakoglobin immunolocalization as a diagnostic test for arrhythmogenic right ventricular cardiomyopathy.
        Pacing Clin Electrophysiol. 2014; 37: 1708-1716
        • Siragam V.
        • Cui X.
        • Masse S.
        • et al.
        TMEM43 mutation p.S358L alters intercalated disc protein expression and reduces conduction velocity in arrhythmogenic right ventricular cardiomyopathy.
        PLoS One. 2014; 9: e109128
        • Asimaki A.
        • Tandri H.
        • Duffy E.R.
        • et al.
        Altered desmosomal proteins in granulomatous myocarditis and potential pathogenic links to arrhythmogenic right ventricular cardiomyopathy.
        Circ Arrhythm Electrophysiol. 2011; 4: 743-752
        • Garcia-Gras E.
        • Lombardi R.
        • Giocondo M.J.
        • et al.
        Suppression of canonical Wnt/beta-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy.
        J Clin Invest. 2006; 116: 2012-2021
        • Swope D.
        • Li J.
        • Radice G.L.
        Beyond cell adhesion: the role of armadillo proteins in the heart.
        Cell Signal. 2013; 25: 93-100
        • Salomon D.
        • Sacco P.A.
        • Roy S.G.
        • et al.
        Regulation of beta-catenin levels and localization by overexpression of plakoglobin and inhibition of the ubiquitin-proteasome system.
        J Cell Biol. 1997; 139: 1325-1335
        • Ben-Ze’ev A.
        • Geiger B.
        Differential molecular interactions of beta-catenin and plakoglobin in adhesion, signaling and cancer.
        Curr Opin Cell Biol. 1998; 10: 629-639
        • Choi H.J.
        • Gross J.C.
        • Pokutta S.
        • et al.
        Interactions of plakoglobin and beta-catenin with desmosomal cadherins: basis of selective exclusion of alpha- and beta-catenin from desmosomes.
        J Biol Chem. 2009; 284: 31776-31788
        • Wahl 3rd, J.K.
        • Nieset J.E.
        • Sacco-Bubulya P.A.
        • et al.
        The amino- and carboxyl-terminal tails of (beta)-catenin reduce its affinity for desmoglein 2.
        J Cell Sci. 2000; 113: 1737-1745
        • Sadot E.
        • Simcha I.
        • Iwai K.
        • et al.
        Differential interaction of plakoglobin and beta-catenin with the ubiquitin-proteasome system.
        Oncogene. 2000; 19: 1992-2001
        • Zhurinsky J.
        • Shtutman M.
        • Ben-Ze’ev A.
        Plakoglobin and beta-catenin: protein interactions, regulation and biological roles.
        J Cell Sci. 2000; 113: 3127-3139
        • Williams B.O.
        • Barish G.D.
        • Klymkowsky M.W.
        • et al.
        A comparative evaluation of beta-catenin and plakoglobin signaling activity.
        Oncogene. 2000; 19: 5720-5728
        • Lombardi R.
        • da Graca Cabreira-Hansen M.
        • Bell A.
        • et al.
        Nuclear plakoglobin is essential for differentiation of cardiac progenitor cells to adipocytes in arrhythmogenic right ventricular cardiomyopathy.
        Circ Res. 2011; 109: 1342-1353
        • Saffitz J.E.
        Dependence of electrical coupling on mechanical coupling in cardiac myocytes – insights gained from cardiomyopathies caused by defects in cell-cell communication.
        Ann NY Acad Sci. 2005; 1047: 336-344
        • Asimaki A.
        • Kléber A.G.
        • MacRae C.A.
        • Saffitz J.E.
        Arrhythmogenic cardiomyopathy - new insights into disease mechanisms and drug discovery.
        Prog Pediatr Cardiol. 2014; 37: 3-7
        • Asimaki A.
        • Kapoor S.
        • Plovie E.
        • et al.
        Identification of a new modulator of the intercalated disc in a zebrafish model of arrhythmogenic cardiomyopathy.
        Sci Transl Med. 2014; 6: 240ra74
        • Cerrone M.
        • Noorman M.
        • Lin X.
        • et al.
        Sodium current deficit and arrhythmogenesis in a murine model of plakophilin-2 haploinsufficiency.
        Cardiovasc Res. 2012; 95: 460-468
        • Kléber A.G.
        • Rudy Y.
        Basic mechanisms of cardiac impulse propagation and associated arrhythmias.
        Physiol Rev. 2004; 84: 431-488
        • Noorman M.
        • Hakim S.
        • Kessler E.
        • et al.
        Remodeling of the cardiac sodium channel, connexin43, and plakoglobin at the intercalated disk in patients with arrhythmogenic cardiomyopathy.
        Heart Rhythm. 2013; 10: 412-419
        • Shaw R.M.
        • Fay A.J.
        • Puthenveedu M.A.
        • et al.
        Microtubule plus-end-tracking proteins target gap junctions directly from the cell interior to adherens junctions.
        Cell. 2007; 128: 547-560
        • Smyth J.W.
        • et al.
        Actin cytoskeleton rest stops regulate anterograde traffic of connexin 43 vesicles to the plasma membrane.
        Circ Res. 2012; 110: 978-989
        • Smyth J.W.
        • Shaw R.M.
        Visualizing cardiac ion channel trafficking pathways.
        Methods Enzymol. 2012; 505: 187-202
        • Patel D.M.
        • Dubash A.D.
        • Kreitzer G.
        • Green K.J.
        Disease mutations in desmoplakin inhibit Cx43 membrane targeting mediated by desmoplakin-EB1 interactions.
        J Cell Biol. 2014; 206: 779-797
        • Zhang S.
        • Kuhn D.A.
        • Kessler E.
        • et al.
        Arrhythmogenic cardiomyopathy mutations cause disassembly of the Cx43 forward trafficking machinery which can be rescued by GSK-3β inhibition [abstract 15042].
        Circulation. 2014; 130: A15042
        • Petitprez S.
        • Zmoos A.F.
        • Ogrodnik J.
        • et al.
        SAP97 and dystrophin macromolecular complexes determine two pools of cardiac sodium channels Nav1.5 in cardiomyocytes.
        Circ Res. 2011; 108: 294-304
        • Milstein M.L.
        • Musa H.
        • Balbuena D.P.
        • et al.
        Dynamic reciprocity of sodium and potassium channel expression in a macromolecular complex controls cardiac excitability and arrhythmia.
        Proc Natl Acad Sci U S A. 2012; 109: E2134-E2143
        • Shy D.
        • Gillet L.
        • Ogrodnik J.
        • et al.
        PDZ domain-binding motif regulates cardiomyocyte compartment-specific Nav1.5 channel expression and function.
        Circulation. 2014; 130: 147-160
        • Gillet L.
        • Rougier J.S.
        • Shy D.
        • et al.
        Cardiac-specific ablation of synapse-associated protein SAP97 in mice decreases potassium currents but not sodium current.
        Heart Rhythm. 2015; 12: 181-192
        • Lombardi R.
        • Dong J.
        • Rodriguez G.
        • et al.
        Genetic fate mapping identifies second heart field progenitor cells as a source of adipocytes in arrhythmogenic right ventricular cardiomyopathy.
        Circ Res. 2009; 104: 1076-1084
        • Chen S.N.
        • Gurha P.
        • Lombardi R.
        • et al.
        The hippo pathway is activated and is a causal mechanism for adipogenesis in arrhythmogenic cardiomyopathy.
        Circ Res. 2014; 114: 454-468
        • Zhu Z.
        • Kremer P.
        • Tadmori I.
        • et al.
        Lithium suppresses astrogliogenesis by neural stem and progenitor cells by inhibiting STAT3 pathway independently of glycogen synthase kinase 3 beta.
        PLoS One. 2011; 6: e23341
        • Kim C.
        • Wong J.
        • Wen J.
        • et al.
        Studying arrhythmogenic right ventricular dysplasia with patient-specific iPSCs.
        Nature. 2013; 494: 105-110