Download The pathology and management of arrhythmogenic right ventricular

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"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.
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Paweł Rubiś
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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