Arrhythmogenic Left Ventricular Cardiomyopathy: Genotype-Phenotype Correlations and New Diagnostic Criteria
Abstract
:1. Introduction
2. Left Ventricular Involvement in Arrhythmogenic Cardiomyopathy
3. Genetic Basis of Arrhythmogenic Cardiomyopathy
3.1. Genotype-Phenotype Correlations in Left Arrhythmogenic Cardiomyopathy
3.1.1. Desmosomal Mutations
3.1.2. Non Desmosomal-Mutations
4. New Diagnostic Criteria for Arrhythmogenic Cardiomyopathy
- (1)
- As for RV forms, the diagnosis of LV variants is multiparametric, and comprises functional and structural ventricular alterations, tissue characterzation results, electrocardiographic (ECG) anomalies, VAs, and familial/genetic factors.
- (2)
- Structural abnormalities can be diagnosed by LGE at contrast enhanced CMR and represents a non-invasive imaging modality for the detection of fibro-fatty scar.
- (3)
- The diagnostic power of phenotypic criteria for left ventricular variants varies in accordance with the disease phenotype, whether biventricular or left-dominant.
- (4)
- When the criteria to diagnose the RV phenotype are met, “phenotypic criteria” such as morpho-functional and structural LV anomalies allows the diagnosis of biventricular variants.
- (5)
- When the RV is not involved, “phenotypic criteria” do not afford sufficient disease-specificity.
4.1. Cardiac Magnetic Resonance Imaging
4.2. Differential Diagnosis
5. Prognostic Role of LV Involvement and Genetic Mutations
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Corrado, D.; Cristina, B.; Judge, D.P. Arrhythmogenic cardiomyopathy. Circ. Res. 2017, 121, 784–802. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Corrado, D.; Basso, C.; Thiene, G. Essay: Sudden Death in Young Athletes. Lancet Lond. Engl. 2005, 366 (Suppl. 1), S47–S48. [Google Scholar] [CrossRef]
- Corrado, D.; Migliore, F.; Basso, C.; Thiene, G. Exercise and the Risk of Sudden Cardiac Death. Herz 2006, 31, 553–558. [Google Scholar] [CrossRef]
- Marcus, F.I.; McKenna, W.J.; Sherrill, D.; Basso, C.; Bauce, B.; Bluemke, D.A.; Calkins, H.; Corrado, D.; Cox, M.G.P.J.; Daubert, J.P.; et al. Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia: Proposed Modification of the Task Force Criteria. Circulation 2010, 121, 1533–1541. [Google Scholar] [CrossRef] [PubMed]
- Thiene, G.; Nava, A.; Corrado, D.; Rossi, L.; Pennelli, N. Right Ventricular Cardiomyopathy and Sudden Death in Young People. N. Engl. J. Med. 1988, 318, 129–133. [Google Scholar] [CrossRef] [PubMed]
- Sen-Chowdhry, S.; Syrris, P.; Ward, D.; Asimaki, A.; Sevdalis, E.; McKenna, W.J. Clinical and Genetic Characterization of Families with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Provides Novel Insights into Patterns of Disease Expression. Circulation 2007, 115, 1710–1720. [Google Scholar] [CrossRef] [Green Version]
- Sen-Chowdhry, S.; Syrris, P.; Prasad, S.K.; Hughes, S.E.; Merrifield, R.; Ward, D.; Pennell, D.J.; McKenna, W.J. Left-Dominant Arrhythmogenic Cardiomyopathy: An under-Recognized Clinical Entity. J. Am. Coll. Cardiol. 2008, 52, 2175–2187. [Google Scholar] [CrossRef] [Green Version]
- Pelliccia, A.; Caselli, S.; Sharma, S.; Basso, C.; Bax, J.J.; Corrado, D.; D’Andrea, A.; D’Ascenzi, F.; Di Paolo, F.M.; Edvardsen, T.; et al. European Association of Preventive Cardiology (EAPC) and European Association of Cardiovascular Imaging (EACVI) Joint Position Statement: Recommendations for the Indication and Interpretation of Cardiovascular Imaging in the Evaluation of the Athlete’s Heart. Eur. Heart J. 2018, 39, 1949–1969. [Google Scholar] [CrossRef] [PubMed]
- Corrado, D.; van Tintelen, P.J.; McKenna, W.J.; Hauer, R.N.W.; Anastastakis, A.; Asimaki, A.; Basso, C.; Bauce, B.; Brunckhorst, C.; Bucciarelli-Ducci, C.; et al. Arrhythmogenic Right Ventricular Cardiomyopathy: Evaluation of the Current Diagnostic Criteria and Differential Diagnosis. Eur. Heart J. 2020, 41, 1414–1429. [Google Scholar] [CrossRef] [Green Version]
- Corrado, D.; Perazzolo Marra, M.; Zorzi, A.; Beffagna, G.; Cipriani, A.; Lazzari, M.D.; Migliore, F.; Pilichou, K.; Rampazzo, A.; Rigato, I.; et al. Diagnosis of Arrhythmogenic Cardiomyopathy: The Padua Criteria. Int. J. Cardiol. 2020, 319, 106–114. [Google Scholar] [CrossRef]
- Cipriani, A.; Perazzolo Marra, M.; Bariani, R.; Mattesi, G.; Vio, R.; Bettella, N.; De Lazzari, M.; Motta, R.; Bauce, B.; Zorzi, A.; et al. Differential Diagnosis of Arrhythmogenic Cardiomyopathy: Phenocopies vs Disease Variants. Minerva Med. 2020. [Google Scholar] [CrossRef]
- Miles, C.; Finocchiaro, G.; Papadakis, M.; Gray, B.; Westaby, J.; Ensam, B.; Basu, J.; Parry-Williams, G.; Papatheodorou, E.; Paterson, C.; et al. Sudden Death and Left Ventricular Involvement in Arrhythmogenic Cardiomyopathy. Circulation 2019, 139, 1786–1797. [Google Scholar] [CrossRef] [PubMed]
- Kirchhof, P.; Fabritz, L.; Zwiener, M.; Witt, H.; Schäfers, M.; Zellerhoff, S.; Paul, M.; Athai, T.; Hiller, K.-H.; Baba, H.A.; et al. Age- and Training-Dependent Development of Arrhythmogenic Right Ventricular Cardiomyopathy in Heterozygous Plakoglobin-Deficient Mice. Circulation 2006, 114, 1799–1806. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Garcia-Gras, E.; Lombardi, R.; Giocondo, M.J.; Willerson, J.T.; Schneider, M.D.; Khoury, D.S.; Marian, A.J. Suppression of Canonical Wnt/Beta-Catenin Signaling by Nuclear Plakoglobin Recapitulates Phenotype of Arrhythmogenic Right Ventricular Cardiomyopathy. J. Clin. Investig. 2006, 116, 2012–2021. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yang, Z.; Bowles, N.E.; Scherer, S.E.; Taylor, M.D.; Kearney, D.L.; Ge, S.; Nadvoretskiy, V.V.; DeFreitas, G.; Carabello, B.; Brandon, L.I.; et al. Desmosomal Dysfunction Due to Mutations in Desmoplakin Causes Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. Circ. Res. 2006, 99, 646–655. [Google Scholar] [CrossRef] [Green Version]
- Pilichou, K.; Remme, C.A.; Basso, C.; Campian, M.E.; Rizzo, S.; Barnett, P.; Scicluna, B.P.; Bauce, B.; van den Hoff, M.J.B.; de Bakker, J.M.T.; et al. Myocyte Necrosis Underlies Progressive Myocardial Dystrophy in Mouse Dsg2-Related Arrhythmogenic Right Ventricular Cardiomyopathy. J. Exp. Med. 2009, 206, 1787–1802. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rampazzo, A.; Nava, A.; Danieli, G.A.; Buja, G.; Daliento, L.; Fasoli, G.; Scognamiglio, R.; Corrado, D.; Thlene, G. The Gene for Arrhythmogenic Right Ventricular Cardiomyopathy Maps to Chromosome 14q23–Q24. Hum. Mol. Genet. 1994, 3, 959–962. [Google Scholar] [CrossRef]
- McKoy, G.; Protonotarios, N.; Crosby, A.; Tsatsopoulou, A.; Anastasakis, A.; Coonar, A.; Norman, M.; Baboonian, C.; Jeffery, S.; McKenna, W.J. Identification of a Deletion in Plakoglobin in Arrhythmogenic Right Ventricular Cardiomyopathy with Palmoplantar Keratoderma and Woolly Hair (Naxos Disease). Lancet Lond. Engl. 2000, 355, 2119–2124. [Google Scholar] [CrossRef]
- Norgett, E.E.; Hatsell, S.J.; Carvajal-Huerta, L.; Cabezas, J.C.; Common, J.; Purkis, P.E.; Whittock, N.; Leigh, I.M.; Stevens, H.P.; Kelsell, D.P. Recessive Mutation in Desmoplakin Disrupts Desmoplakin-Intermediate Filament Interactions and Causes Dilated Cardiomyopathy, Woolly Hair and Keratoderma. Hum. Mol. Genet. 2000, 9, 2761–2766. [Google Scholar] [CrossRef] [Green Version]
- Gerull, B.; Heuser, A.; Wichter, T.; Paul, M.; Basson, C.T.; McDermott, D.A.; Lerman, B.B.; Markowitz, S.M.; Ellinor, P.T.; MacRae, C.A.; et al. Mutations in the Desmosomal Protein Plakophilin-2 Are Common in Arrhythmogenic Right Ventricular Cardiomyopathy. Nat. Genet. 2004, 36, 1162–1164. [Google Scholar] [CrossRef]
- Awad, M.M.; Dalal, D.; Cho, E.; Amat-Alarcon, N.; James, C.; Tichnell, C.; Tucker, A.; Russell, S.D.; Bluemke, D.A.; Dietz, H.C.; et al. DSG2 Mutations Contribute to Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. Am. J. Hum. Genet. 2006, 79, 136–142. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Syrris, P.; Ward, D.; Evans, A.; Asimaki, A.; Gandjbakhch, E.; Sen-Chowdhry, S.; McKenna, W.J. Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Associated with Mutations in the Desmosomal Gene Desmocollin-2. Am. J. Hum. Genet. 2006, 79, 978–984. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Merner, N.D.; Hodgkinson, K.A.; Haywood, A.F.M.; Connors, S.; French, V.M.; Drenckhahn, J.-D.; Kupprion, C.; Ramadanova, K.; Thierfelder, L.; McKenna, W.; 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. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Quarta, G.; Syrris, P.; Ashworth, M.; Jenkins, S.; Zuborne Alapi, K.; Morgan, J.; Muir, A.; Pantazis, A.; McKenna, W.J.; Elliott, P.M. Mutations in the Lamin A/C Gene Mimic Arrhythmogenic Right Ventricular Cardiomyopathy. Eur. Heart J. 2012, 33, 1128–1136. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hedberg, C.; Melberg, A.; Kuhl, A.; Jenne, D.; Oldfors, A. Autosomal Dominant Myofibrillar Myopathy with Arrhythmogenic Right Ventricular Cardiomyopathy 7 Is Caused by a DES Mutation. Eur. J. Hum. Genet. EJHG 2012, 20, 984–985. [Google Scholar] [CrossRef] [PubMed]
- van Hengel, J.; Calore, M.; Bauce, B.; Dazzo, E.; Mazzotti, E.; De Bortoli, M.; Lorenzon, A.; Li Mura, I.E.A.; Beffagna, G.; Rigato, I.; et al. Mutations in the Area Composita Protein AT-Catenin Are Associated with Arrhythmogenic Right Ventricular Cardiomyopathy. Eur. Heart J. 2013, 34, 201–210. [Google Scholar] [CrossRef] [Green Version]
- van der Zwaag, P.A.; van Rijsingen, I.A.W.; Asimaki, A.; Jongbloed, J.D.H.; van Veldhuisen, D.J.; Wiesfeld, A.C.P.; Cox, M.G.P.J.; van Lochem, L.T.; de Boer, R.A.; Hofstra, R.M.W.; 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. [Google Scholar] [CrossRef]
- Beffagna, G.; Occhi, G.; Nava, A.; Vitiello, L.; Ditadi, A.; Basso, C.; Bauce, B.; Carraro, G.; Thiene, G.; Towbin, J.A.; et al. Regulatory Mutations in Transforming Growth Factor-Beta3 Gene Cause Arrhythmogenic Right Ventricular Cardiomyopathy Type 1. Cardiovasc. Res. 2005, 65, 366–373. [Google Scholar] [CrossRef] [Green Version]
- Taylor, M.; Graw, S.; Sinagra, G.; Barnes, C.; Slavov, D.; Brun, F.; Pinamonti, B.; Salcedo, E.E.; Sauer, W.; Pyxaras, S.; et al. Genetic Variation in Titin in Arrhythmogenic Right Ventricular Cardiomyopathy-Overlap Syndromes. Circulation 2011, 124, 876–885. [Google Scholar] [CrossRef] [Green Version]
- Cerrone, M.; Delmar, M. Desmosomes and the Sodium Channel Complex: Implications for Arrhythmogenic Cardiomyopathy and Brugada Syndrome. Trends Cardiovasc. Med. 2014, 24, 184–190. [Google Scholar] [CrossRef] [Green Version]
- Mayosi, B.M.; Fish, M.; Shaboodien, G.; Mastantuono, E.; Kraus, S.; Wieland, T.; Kotta, M.-C.; Chin, A.; Laing, N.; Ntusi, N.B.A.; et al. Identification of Cadherin 2 (CDH2) Mutations in Arrhythmogenic Right Ventricular Cardiomyopathy. Circ. Cardiovasc. Genet. 2017, 10. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- McKenna, W.J.; Thiene, G.; Nava, A.; Fontaliran, F.; Blomstrom-Lundqvist, C.; Fontaine, G.; Camerini, F. 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. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Angelini, A.; Basso, C.; Nava, A.; Thiene, G. Endomyocardial Biopsy in Arrhythmogenic Right Ventricular Cardiomyopathy. Am. Heart J. 1996, 132, 203–206. [Google Scholar] [CrossRef]
- Igual, B.; Zorio, E.; Maceira, A.; Estornell, J.; Lopez-Lereu, M.P.; Monmeneu, J.V.; Quesada, A.; Navarro, J.; Mas, F.; Salvador, A. Arrhythmogenic cardiomyopathy. Patterns of ventricular involvement using cardiac magnetic resonance. Rev. Esp. Cardiol. 2011, 64, 1114–1122. [Google Scholar] [CrossRef] [PubMed]
- Rademakers, F.E.; Rogers, W.J.; Guier, W.H.; Hutchins, G.M.; Siu, C.O.; Weisfeldt, M.L.; Weiss, J.L.; Shapiro, E.P. Relation of Regional Cross-Fiber Shortening to Wall Thickening in the Intact Heart. Three-Dimensional Strain Analysis by NMR Tagging. Circulation 1994, 89, 1174–1182. [Google Scholar] [CrossRef] [Green Version]
- De Lazzari, M.; Zorzi, A.; Cipriani, A.; Susana, A.; Mastella, G.; Rizzo, A.; Rigato, I.; Bauce, B.; Giorgi, B.; Lacognata, C.; et al. Relationship Between Electrocardiographic Findings and Cardiac Magnetic Resonance Phenotypes in Arrhythmogenic Cardiomyopathy. J. Am. Heart Assoc. 2018, 7, e009855. [Google Scholar] [CrossRef] [Green Version]
- Bhonsale, A.; Groeneweg, J.A.; James, C.A.; Dooijes, D.; Tichnell, C.; Jongbloed, J.D.H.; Murray, B.; te Riele, A.S.J.M.; van den Berg, M.P.; Bikker, H.; et al. Impact of Genotype on Clinical Course in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy-Associated Mutation Carriers. Eur. Heart J. 2015, 36, 847–855. [Google Scholar] [CrossRef]
- Lodder, E.M.; Bezzina, C.R. Arrhythmogenic Right Ventricular Cardiomyopathy: Growing Evidence for Complex Inheritance. Circ. Cardiovasc. Genet. 2013, 6, 525–527. [Google Scholar] [CrossRef] [Green Version]
- Rigato, I.; Bauce, B.; Rampazzo, A.; Zorzi, A.; Pilichou, K.; Mazzotti, E.; Migliore, F.; Marra, M.P.; Lorenzon, A.; De Bortoli, M.; et al. Compound and Digenic Heterozygosity Predicts Lifetime Arrhythmic Outcome and Sudden Cardiac Death in Desmosomal Gene-Related Arrhythmogenic Right Ventricular Cardiomyopathy. Circ. Cardiovasc. Genet. 2013, 6, 533–542. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lorenzon, A.; Pilichou, K.; Rigato, I.; Vazza, G.; De Bortoli, M.; Calore, M.; Occhi, G.; Carturan, E.; Lazzarini, E.; Cason, M.; et al. Homozygous Desmocollin-2 Mutations and Arrhythmogenic Cardiomyopathy. Am. J. Cardiol. 2015, 116, 1245–1251. [Google Scholar] [CrossRef]
- Bauce, B.; Basso, C.; Rampazzo, A.; Beffagna, G.; Daliento, L.; Frigo, G.; Malacrida, S.; Settimo, L.; Danieli, G.; Thiene, G.; et al. Clinical Profile of Four Families with Arrhythmogenic Right Ventricular Cardiomyopathy Caused by Dominant Desmoplakin Mutations. Eur. Heart J. 2005, 26, 1666–1675. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pilichou, K.; Nava, A.; Basso, C.; Beffagna, G.; Bauce, B.; Lorenzon, A.; Frigo, G.; Vettori, A.; Valente, M.; Towbin, J.; et al. Mutations in Desmoglein-2 Gene Are Associated with Arrhythmogenic Right Ventricular Cardiomyopathy. Circulation 2006, 113, 1171–1179. [Google Scholar] [CrossRef] [Green Version]
- Rampazzo, A.; Nava, A.; Malacrida, S.; Beffagna, G.; Bauce, B.; Rossi, V.; Zimbello, R.; Simionati, B.; Basso, C.; Thiene, G.; et al. Mutation in Human Desmoplakin Domain Binding to Plakoglobin Causes a Dominant Form of Arrhythmogenic Right Ventricular Cardiomyopathy. Am. J. Hum. Genet. 2002, 71, 1200–1206. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sen-Chowdhry, S.; Syrris, P.; McKenna, W.J. Desmoplakin Disease in Arrhythmogenic Right Ventricular Cardiomyopathy: Early Genotype-Phenotype Studies. Eur. Heart J. 2005, 26, 1582–1584. [Google Scholar] [CrossRef] [PubMed]
- van Tintelen, J.P.; Van Gelder, I.C.; Asimaki, A.; Suurmeijer, A.J.H.; Wiesfeld, A.C.P.; Jongbloed, J.D.H.; van den Wijngaard, A.; Kuks, J.B.M.; van Spaendonck-Zwarts, K.Y.; Notermans, N.; et al. Severe Cardiac Phenotype with Right Ventricular Predominance in a Large Cohort of Patients with a Single Missense Mutation in the DES Gene. Heart Rhythm 2009, 6, 1574–1583. [Google Scholar] [CrossRef] [PubMed]
- Ortiz-Genga, M.F.; Cuenca, S.; Dal Ferro, M.; Zorio, E.; Salgado-Aranda, R.; Climent, V.; Padrón-Barthe, L.; Duro-Aguado, I.; Jiménez-Jáimez, J.; Hidalgo-Olivares, V.M.; et al. Truncating FLNC Mutations Are Associated With High-Risk Dilated and Arrhythmogenic Cardiomyopathies. J. Am. Coll. Cardiol. 2016, 68, 2440–2451. [Google Scholar] [CrossRef]
- Yu, J.; Hu, J.; Dai, X.; Cao, Q.; Xiong, Q.; Liu, X.; Liu, X.; Shen, Y.; Chen, Q.; Hua, W.; et al. SCN5A Mutation in Chinese Patients with Arrhythmogenic Right Ventricular Dysplasia. Herz 2014, 39, 271–275. [Google Scholar] [CrossRef]
- Te Riele, A.S.J.M.; Agullo-Pascual, E.; James, C.A.; Leo-Macias, A.; Cerrone, M.; Zhang, M.; Lin, X.; Lin, B.; Sobreira, N.L.; Amat-Alarcon, N.; et al. Multilevel Analyses of SCN5A Mutations in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Suggest Non-Canonical Mechanisms for Disease Pathogenesis. Cardiovasc. Res. 2017, 113, 102–111. [Google Scholar] [CrossRef] [PubMed]
- Tiso, N.; Stephan, D.A.; Nava, A.; Bagattin, A.; Devaney, J.M.; Stanchi, F.; Larderet, G.; Brahmbhatt, B.; Brown, K.; Bauce, B.; 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. [Google Scholar] [CrossRef] [Green Version]
- Groeneweg, J.A.; Bhonsale, A.; James, C.A.; te Riele, A.S.; Dooijes, D.; Tichnell, C.; Murray, B.; Wiesfeld, A.C.P.; Sawant, A.C.; Kassamali, B.; et al. Clinical Presentation, Long-Term Follow-Up, and Outcomes of 1001 Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Patients and Family Members. Circ. Cardiovasc. Genet. 2015, 8, 437–446. [Google Scholar] [CrossRef]
- Te Riele, A.S.J.M.; Bhonsale, A.; Burt, J.R.; Zimmerman, S.L.; Tandri, H. Genotype-Specific Pattern of LV Involvement in ARVD/C. JACC Cardiovasc. Imaging 2012, 5, 849–851. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fressart, V.; Duthoit, G.; Donal, E.; Probst, V.; Deharo, J.-C.; Chevalier, P.; Klug, D.; Dubourg, O.; Delacretaz, E.; Cosnay, P.; et al. Desmosomal Gene Analysis in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy: Spectrum of Mutations and Clinical Impact in Practice. EP Eur. 2010, 12, 861–868. [Google Scholar] [CrossRef] [PubMed]
- Wong, J.A.; Duff, H.J.; Yuen, T.; Kolman, L.; Exner, D.V.; Weeks, S.G.; Gerull, B. Phenotypic Analysis of Arrhythmogenic Cardiomyopathy in the Hutterite Population: Role of Electrocardiogram in Identifying High-Risk Desmocollin-2 Carriers. J. Am. Heart Assoc. 2014, 3, e001407. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bariani, R.; Cipriani, A.; Rizzo, S.; Celeghin, R.; Bueno Marinas, M.; Giorgi, B.; De Gaspari, M.; Rigato, I.; Leoni, L.; Zorzi, A.; et al. “Hot Phase” Clinical Presentation in Arrhythmogenic Cardiomyopathy. EP Eur. 2020. [Google Scholar] [CrossRef]
- Smith, E.D.; Lakdawala, N.K.; Papoutsidakis, N.; Aubert, G.; Mazzanti, A.; McCanta, A.C.; Agarwal, P.P.; Arscott, P.; Dellefave-Castillo, L.M.; Vorovich, E.E.; et al. Desmoplakin Cardiomyopathy, a Fibrotic and Inflammatory Form of Cardiomyopathy Distinct From Typical Dilated or Arrhythmogenic Right Ventricular Cardiomyopathy. Circulation 2020, 141, 1872–1884. [Google Scholar] [CrossRef]
- Piriou, N.; Marteau, L.; Kyndt, F.; Serfaty, J.M.; Toquet, C.; Le Gloan, L.; Warin-Fresse, K.; Guijarro, D.; Le Tourneau, T.; Conan, E.; et al. Familial Screening in Case of Acute Myocarditis Reveals Inherited Arrhythmogenic Left Ventricular Cardiomyopathies. ESC Heart Fail. 2020, 7, 1520–1533. [Google Scholar] [CrossRef]
- Poller, W.; Haas, J.; Klingel, K.; Kühnisch, J.; Gast, M.; Kaya, Z.; Escher, F.; Kayvanpour, E.; Degener, F.; Opgen-Rhein, B.; et al. Familial Recurrent Myocarditis Triggered by Exercise in Patients With a Truncating Variant of the Desmoplakin Gene. J. Am. Heart Assoc. 2020, 9, e015289. [Google Scholar] [CrossRef]
- Dominguez, F.; Zorio, E.; Jimenez-Jaimez, J.; Salguero-Bodes, R.; Zwart, R.; Gonzalez-Lopez, E.; Molina, P.; Bermúdez-Jiménez, F.; Delgado, J.F.; Braza-Boïls, A.; et al. Clinical Characteristics and Determinants of the Phenotype in TMEM43 Arrhythmogenic Right Ventricular Cardiomyopathy Type 5. Heart Rhythm 2020, 17, 945–954. [Google Scholar] [CrossRef]
- Begay, R.L.; Graw, S.L.; Sinagra, G.; Asimaki, A.; Rowland, T.J.; Slavov, D.B.; Gowan, K.; Jones, K.L.; Brun, F.; Merlo, M.; et al. Filamin C Truncation Mutations Are Associated With Arrhythmogenic Dilated Cardiomyopathy and Changes in the Cell-Cell Adhesion Structures. JACC Clin. Electrophysiol. 2018, 4, 504–514. [Google Scholar] [CrossRef]
- Augusto, J.B.; Eiros, R.; Nakou, E.; Moura-Ferreira, S.; Treibel, T.A.; Captur, G.; Akhtar, M.M.; Protonotarios, A.; Gossios, T.D.; Savvatis, K.; et al. Dilated Cardiomyopathy and Arrhythmogenic Left Ventricular Cardiomyopathy: A Comprehensive Genotype-Imaging Phenotype Study. Eur. Heart J. Cardiovasc. Imaging 2020, 21, 326–336. [Google Scholar] [CrossRef]
- Segura-Rodríguez, D.; Bermúdez-Jiménez, F.J.; Carriel, V.; López-Fernández, S.; González-Molina, M.; Oyonarte Ramírez, J.M.; Fernández-Navarro, L.; García-Roa, M.D.; Cabrerizo, E.M.; Durand-Herrera, D.; et al. Myocardial Fibrosis in Arrhythmogenic Cardiomyopathy: A Genotype-Phenotype Correlation Study. Eur. Heart J. Cardiovasc. Imaging 2020, 21, 378–386. [Google Scholar] [CrossRef] [PubMed]
- Sepehrkhouy, S.; Gho, J.M.I.H.; van Es, R.; Harakalova, M.; de Jonge, N.; Dooijes, D.; van der Smagt, J.J.; Buijsrogge, M.P.; Hauer, R.N.W.; Goldschmeding, R.; et al. Distinct Fibrosis Pattern in Desmosomal and Phospholamban Mutation Carriers in Hereditary Cardiomyopathies. Heart Rhythm 2017, 14, 1024–1032. [Google Scholar] [CrossRef] [PubMed]
- te Riele, A.S.J.M.; Bhonsale, A.; James, C.A.; Rastegar, N.; Murray, B.; Burt, J.R.; Tichnell, C.; Madhavan, S.; Judge, D.P.; Bluemke, D.A.; et al. Incremental Value of Cardiac Magnetic Resonance Imaging in Arrhythmic Risk Stratification of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy-Associated Desmosomal Mutation Carriers. J. Am. Coll. Cardiol. 2013, 62, 1761–1769. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zorzi, A.; Perazzolo Marra, M.; Rigato, I.; De Lazzari, M.; Susana, A.; Niero, A.; Pilichou, K.; Migliore, F.; Rizzo, S.; Giorgi, B.; et al. Nonischemic Left Ventricular Scar as a Substrate of Life-Threatening Ventricular Arrhythmias and Sudden Cardiac Death in Competitive Athletes. Circ. Arrhythm. Electrophysiol. 2016, 9. [Google Scholar] [CrossRef]
- Mattesi, G.; Zorzi, A.; Corrado, D.; Cipriani, A. Natural History of Arrhythmogenic Cardiomyopathy. J. Clin. Med. 2020, 9, 878. [Google Scholar] [CrossRef] [Green Version]
- Caforio, A.L.P.; Pankuweit, S.; Arbustini, E.; Basso, C.; Gimeno-Blanes, J.; Felix, S.B.; Fu, M.; Helio, T.; Heymans, S.; Jahns, R.; et al. Current State of Knowledge on Aetiology, Diagnosis, Management, and Therapy of Myocarditis: A Position Statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur. Heart J. 2013, 34, 2636–2648. [Google Scholar] [CrossRef]
- Scheel, P.J.; Murray, B.; Tichnell, C.; James, C.A.; Tandri, H.; Calkins, H.; Chelko, S.P.; Gilotra, N.A. Arrhythmogenic Right Ventricular Cardiomyopathy Presenting as Clinical Myocarditis in Women. Am. J. Cardiol. 2021. [Google Scholar] [CrossRef]
- Sen-Chowdhry, S.; Morgan, R.D.; Chambers, J.C.; McKenna, W.J. Arrhythmogenic Cardiomyopathy: Etiology, Diagnosis, and Treatment. Annu. Rev. Med. 2010, 61, 233–253. [Google Scholar] [CrossRef]
- Pinto, Y.M.; Elliott, P.M.; Arbustini, E.; Adler, Y.; Anastasakis, A.; Böhm, M.; Duboc, D.; Gimeno, J.; de Groote, P.; Imazio, M.; et al. Proposal for a Revised Definition of Dilated Cardiomyopathy, Hypokinetic Non-Dilated Cardiomyopathy, and Its Implications for Clinical Practice: A Position Statement of the ESC Working Group on Myocardial and Pericardial Diseases. Eur. Heart J. 2016, 37, 1850–1858. [Google Scholar] [CrossRef] [Green Version]
- Cipriani, A.; Bauce, B.; De Lazzari, M.; Rigato, I.; Bariani, R.; Meneghin, S.; Pilichou, K.; Motta, R.; Aliberti, C.; Thiene, G.; et al. Arrhythmogenic Right Ventricular Cardiomyopathy: Characterization of Left Ventricular Phenotype and Differential Diagnosis with Dilated Cardiomyopathy. J. Am. Heart Assoc. 2020, 9, e014628. [Google Scholar] [CrossRef]
- Spezzacatene, A.; Sinagra, G.; Merlo, M.; Barbati, G.; Graw, S.L.; Brun, F.; Slavov, D.; Di Lenarda, A.; Salcedo, E.E.; Towbin, J.A.; et al. Arrhythmogenic Phenotype in Dilated Cardiomyopathy: Natural History and Predictors of Life-Threatening Arrhythmias. J. Am. Heart Assoc. 2015, 4, e002149. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Philips, B.; Madhavan, S.; James, C.A.; te Riele, A.S.J.M.; Murray, B.; Tichnell, C.; Bhonsale, A.; Nazarian, S.; Judge, D.P.; Calkins, H.; et al. Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and Cardiac Sarcoidosis: Distinguishing Features When the Diagnosis Is Unclear. Circ. Arrhythm. Electrophysiol. 2014, 7, 230–236. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yatsynovich, Y.; Dittoe, N.; Petrov, M.; Maroz, N. Cardiac Sarcoidosis: A Review of Contemporary Challenges in Diagnosis and Treatment. Am. J. Med. Sci. 2018, 355, 113–125. [Google Scholar] [CrossRef] [PubMed]
- Vita, T.; Okada, D.R.; Veillet-Chowdhury, M.; Bravo, P.E.; Mullins, E.; Hulten, E.; Agrawal, M.; Madan, R.; Taqueti, V.R.; Steigner, M.; et al. Complementary Value of Cardiac Magnetic Resonance Imaging and Positron Emission Tomography/Computed Tomography in the Assessment of Cardiac Sarcoidosis. Circ. Cardiovasc. Imaging 2018, 11, e007030. [Google Scholar] [CrossRef]
- Florian, A.; Ludwig, A.; Engelen, M.; Waltenberger, J.; Rösch, S.; Sechtem, U.; Yilmaz, A. Left Ventricular Systolic Function and the Pattern of Late-Gadolinium-Enhancement Independently and Additively Predict Adverse Cardiac Events in Muscular Dystrophy Patients. J. Cardiovasc. Magn. Reson. 2014, 16, 81. [Google Scholar] [CrossRef] [Green Version]
- van der Bijl, P.; Delgado, V.; Bootsma, M.; Bax, J.J. Risk Stratification of Genetic, Dilated Cardiomyopathies Associated With Neuromuscular Disorders: Role of Cardiac Imaging. Circulation 2018, 137, 2514–2527. [Google Scholar] [CrossRef]
- Hasselberg, N.E.; Haland, T.F.; Saberniak, J.; Brekke, P.H.; Berge, K.E.; Leren, T.P.; Edvardsen, T.; Haugaa, K.H. Lamin A/C Cardiomyopathy: Young Onset, High Penetrance, and Frequent Need for Heart Transplantation. Eur. Heart J. 2018, 39, 853–860. [Google Scholar] [CrossRef]
- Corrado, D.; Wichter, T.; Link, M.S.; Hauer, R.N.W.; Marchlinski, F.E.; Anastasakis, A.; Bauce, B.; Basso, C.; Brunckhorst, C.; Tsatsopoulou, A.; et al. Treatment of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia: An International Task Force Consensus Statement. Circulation 2015, 132, 441–453. [Google Scholar] [CrossRef]
- Hulot, J.-S.; Jouven, X.; Empana, J.-P.; Frank, R.; Fontaine, G. Natural History and Risk Stratification of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. Circulation 2004, 110, 1879–1884. [Google Scholar] [CrossRef] [Green Version]
- Lemola, K.; Brunckhorst, C.; Helfenstein, U.; Oechslin, E.; Jenni, R.; Duru, F. Predictors of Adverse Outcome in Patients with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy: Long Term Experience of a Tertiary Care Centre. Heart Br. Card. Soc. 2005, 91, 1167–1172. [Google Scholar] [CrossRef] [Green Version]
- Peters, S. Long-Term Follow-up and Risk Assessment of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy: Personal Experience from Different Primary and Tertiary Centres. J. Cardiovasc. Med. 2007, 8, 521–526. [Google Scholar] [CrossRef] [PubMed]
- Migliore, F.; Viani, S.; Bongiorni, M.G.; Zorzi, A.; Silvetti, M.S.; Francia, P.; D’Onofrio, A.; De Franceschi, P.; Sala, S.; Donzelli, S.; et al. Subcutaneous Implantable Cardioverter Defibrillator in Patients with Arrhythmogenic Right Ventricular Cardiomyopathy: Results from an Italian Multicenter Registry. Int. J. Cardiol. 2019, 280, 74–79. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Gene | Encoded Protein | Chromosomal Locus | Mode of Transmission | Reference | Predominately Affected Ventricle | Notes |
---|---|---|---|---|---|---|
Desmosomal | ||||||
JUP | Junction plakoglobin | 17q21.2 | AD/AR also reported | McKoy et al. [18] | RV, biventricular | AR form: Cardiocutaneous syndrome (Naxos) |
DSP | Desmoplakin | 6p24.3 | AD/AR also reported | Norgett et al. [19] | LV, biventricular | AR form: Cardiocutaneous syndrome (Carvajal) |
PKP2 | Plakophillin-2 | 12p11.21 | AD/AR also reported | Gerull et al. [20] | RV, biventricular | classic RV phenotype |
DSG2 | Desmoglein-2 | 18q12.1 | AD/AR also reported | Awad et al. [21] | classic RV phenotype, biventricular | frequent LV involvement |
DSC2 | Desmocollin-2 | 18q12.1 | AD/AR also reported | Syrris et al. [22] | RV, biventricular | AR Cardiocutaneous form |
Non desmosomal | ||||||
TMEM43 | Transmembrane protein 43 | 3p25.1 | AD | Merner et al. [23] | RV, biventricular | Newfoundland founder variant, SCD |
LMNA | Lamin A/C | 1q22 | AD | Quarta et al. [24] | LV, biventricular | Overlapping syndrome (DCM, Lipodystrophies, Myopathies) |
DES | Desmin | 2q35 | AD | Hedberg et al. [25] | LV, biventricular | Overlapping syndrome (DCM and HCM, early conduction disturbances) |
CTNNA3 | Alpha T-catenin | 10q21.3 | AD | Van Hengel et al. [26] | RV, biventricular | Low penetrance |
PLN | Phospholamban | 6q22.31 | AD | Van der Zwaag et al. [27] | LV, biventricular | Founder mutation in Netherlands. High SCD risk. |
TGFB3 | Transforming grow factor beta 3 | 14q24.3 | AD | Beffagna et al. [28] | RV | |
TTN | Titin | 2q31.2 | AD | Taylor et al. [29] | RV, LV, biventricular | Overlapping syndrome (early conduction disturbances, AF, DCM) |
SCN5A | Sodium voltage-gated channel alpha subunit 5 | AD | Cerrone et al. [30] | LV, biventricular | Overlap syndrome (BrS, LQTS Type 3, AF) | |
CDH2 | Cadherin C | AD | Mayosi et al. [31] | RV, biventricular |
Category | Right Ventricle | Left Ventricle |
---|---|---|
| By echocardiography, CMR or angiography: Major
| By echocardiography, CMR or angiography: Minor
|
| By CE-CMR: Major
Major
| By CE-CMR: Major
|
| Major
| Minor
|
| Minor
| Minor
|
| Major
| Minor
|
| Major
|
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Mattesi, G.; Cipriani, A.; Bauce, B.; Rigato, I.; Zorzi, A.; Corrado, D. Arrhythmogenic Left Ventricular Cardiomyopathy: Genotype-Phenotype Correlations and New Diagnostic Criteria. J. Clin. Med. 2021, 10, 2212. https://doi.org/10.3390/jcm10102212
Mattesi G, Cipriani A, Bauce B, Rigato I, Zorzi A, Corrado D. Arrhythmogenic Left Ventricular Cardiomyopathy: Genotype-Phenotype Correlations and New Diagnostic Criteria. Journal of Clinical Medicine. 2021; 10(10):2212. https://doi.org/10.3390/jcm10102212
Chicago/Turabian StyleMattesi, Giulia, Alberto Cipriani, Barbara Bauce, Ilaria Rigato, Alessandro Zorzi, and Domenico Corrado. 2021. "Arrhythmogenic Left Ventricular Cardiomyopathy: Genotype-Phenotype Correlations and New Diagnostic Criteria" Journal of Clinical Medicine 10, no. 10: 2212. https://doi.org/10.3390/jcm10102212