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Article* "Development of the European Network in Orphan Cardiovascular Diseases" „Rozszerzenie Europejskiej Sieci Współpracy ds Sierocych Chorób Kardiologicznych” Title: The pathology and management of arrhythmogenic right ventricular cardiomyopathy RCD code: III-4A (ICD-10 code I42.8) Author: Paweł Rubiś1,2, Affiliation: 1 Department of Cardiac and Vascular Diseases, John Paul II Hospital, Institute of Cardiology 2 Center for Rare Cardiovascular Diseases, John Paul II Hospital Date: 24/August/2014 Background John Paul II Hospital in Kraków Jagiellonian University, Institute of Cardiology 80 Prądnicka Str., 31-202 Kraków; tel. +48 (12) 614 33 99; 614 34 88; fax. +48 (12) 614 34 88 e-mail: [email protected] www.crcd.eu Epidemiology Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare myocardial disease, which results from the replacement of cardiomyocytes by fibrous and fatty tissue that leads to dilatation and impaired contraction of RV and electrical instability. ARVC is a disease of the desmosomes, which serve as a cell-to-cell junctions. The cardinal symptoms of ARVC are palpitations, dizziness, and syncope.The prevalence of ARVC is estimated to be 1 : 5000-10000 in the general adult population. Predominantly male gender is affected with the ratio of male to female approximately 3 : 1. ARVC is a frequent cause of unexplained SCD. According to two European registries from France and Italy, ARVC was confirmed as a cause of SCD in 10% and 11% of studied cases, respectively. Genetics In at least half of the cases, ARVC runs in families. Typically, ARVC is transmitted as a autosomal dominant pattern with variable penetrance. The majority of causative mutations affect genes encoding desmosomal proteins (junctions between myocytes), such as plakoglobin, desomplakin, plakofilin, desmoglein and desmokolin. Additionally, ARVC pathogenic mutations have been observed in genes for cardiac ryanodine receptor, which also accounts for catecholaminergic polymorphic ventricular tachycardia and transforming growth factor beta, with confirmed role in inflammation. So far several recessive syndromic variants of ARVC have been described, including Naxos syndrome, Carvajal syndrome, and Alcalai syndrome. The affected individuals come from small ethnic groups from isolated geographic areas and have associated palmoplantar keratoderma and wooly hair. Pathogenesis The accumulated data indicate that ARVC is a disease of the desmosomes, which serve as a cell-to-cell junctions. Desmosomes are particularly present in tissues that are prone to constant mechanical stress, such as epidermis and myocardium. They are build from three major protein families of plakins, armadillo proteins, and cadherins. The most important desmosomal proteins in the myocardium include desmoplakin, plakoglobin, plakophilin-2, desmoglein-2, and desmocollin-2. Fibro-fatty replacement of RV myocardium is a reparative mechanism for necrosis and apoptosis of myocytes. As the disease progress, the structural changes encompass the whole RV and in many cases LV. The tendency to ventricular arrhythmias is best explained by the micro- and macro-reentry electric circuits that form in the borders between normal and altered ventricular wall. Clinical manifestations The cardinal symptoms of ARVC are palpitations, dizziness, and syncope. In the contemporary registry of consecutive 130 ARVC patients two-third reported palpitations, one-third syncope, one-quarter atypical chest pain and 11% breathlessness. First manifestation of the disease could be symptomatic ventricular arrhythmia, syncope or sudden cardiac death (SCD) often in previously fit and well individuals. First manifestations of the disease occur in adolescence and young adults. When disease begins in more advanced age than RV failure predominates. In most cases ARVC is a progressive, three-staged disease, consisting of: latent phase – discrete morphological changes, ECG normal, arrhythmias absent/asymptomatic electrical instability phase – regional RV wall motion abnormalities, symptomatic ventricular arrhythmias dilatation phase – RV dilation and failure, frequent LV involvement Management As there is a strong and proven association between SCD and exercise, all ARVC patients should not be engaged in any professional sports. Furthermore, if during recreational activity appear symptoms such as palpitations, dizziness or presyncope, even that kind of exercise should not be continued. The prime target in the management of ARVC is to prevent SCD. The current recommendations for the management of ventricular arrhythmias in ARVC are based on the 2006 American Collage of Cardiology/American Heart Association/European Society of Cardiology (ACC/AHA/ESC). John Paul II Hospital in Kraków Jagiellonian University, Institute of Cardiology 80 Prądnicka Str., 31-202 Kraków; tel. +48 (12) 614 33 99; 614 34 88; fax. +48 (12) 614 34 88 e-mail: [email protected] www.crcd.eu Therefore, the single most effective and proven way to prevent SCD in ARVC is ICD. As for secondary SCD prevention, ICD is indicted for patients who experienced sustained ventricular arrhythmias. ICD is also recommended for primary prevention of SCD in high risk patients who are defined as those who have familial history of SCD, syncope, hemodynamic instability during VT, family history of SCD < 35 years of age, severe RV dilation and dysfunction, associated LV involvement, QT dispersion ≥ 40 ms, epsilon wave, particular ARVC types – ARVC-2 and 5, Naxos syndrome. Sotalol and Amiodarone are the most effective drugs in ARVC and are recommended by the 2006 ACC/AHA/ESC guidelines. Due to increased awareness of ARVC and improvement in treatment, particularly thanks to ICD, in the recent years it is observed a trend towards less SCDs but more severe or even end-stage RV-HF, which leads to death. References Maron BJ, Towbin JA, Thiene G, et al. Contemporary defintions and classsification of the cardiomyopathies. Circulation 2006; 113: 1807-16. Norman M, Simpson M, Mogensen J, Shaw A, Hughes S, Syrris P, Sen-Chowdhry S, Rowland E, Crosby A, McKenna WJ. Novel mutation in desmoplakin causes arrhythmogenic left ventricular cardiomyopathy. Circulation 2005; 112: 636-42. Elliot P, Andersson B, Arbustini E et al. Classification of the cardiomyopathies: a position statement from the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2007; 29: 270-7. Gemayel C, Pelliccia A, Thompson PD. Arrhythmogenic right ventricular cardiomyopathy. J Am Coll Cardiol 2001; 38: 1773. Tabib A, Loire R, Chalabreysse L, Meyronnet D, Miras A, Malicier D, Thivolet F, Chevalier P, Bouvagnet P. 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: 3000-5. Corrado D, Fontaine G, Marcus FI, et al. Arrhythmogenic right ventricular dysplasia/cardiomyopathy: need for an international registry. Study Group on Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy of the Working Groups on Myocardial and Pericardial Disease and Arrhythmias of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the World Heart Federation. Circulation 2000; 101: E101. Paweł Rubiś ………………………….. Author’s signature** [** Signing the article will mean an agreement for its publication] John Paul II Hospital in Kraków Jagiellonian University, Institute of Cardiology 80 Prądnicka Str., 31-202 Kraków; tel. +48 (12) 614 33 99; 614 34 88; fax. +48 (12) 614 34 88 e-mail: [email protected] www.crcd.eu