ABC | Volume 112, Nº1, January 2019

Elias Nero et al ARVC/D - Diagnosis and treatment Arq Bras Cardiol. 2019; 112(1):91-103 Review Article In the typical ARVC/D form, the LV is affected to a lesser degree than the RV; however, there are variants of the disease characterized by equivalent or even predominant involvement of the LV. 1,4,5 Genetic and molecular characteristics In most cases, ARVC/D is an inherited disease with an autosomal dominant pattern, with variable penetrance and expressivity. Among the probands diagnosed with the disease, a screening of first-degree relatives allows the identification of the presence of genetic mutations in approximately 50% of cases, regardless of gender. In a small number of cases, ARVC/D has an autosomal recessive pattern as part of a cardiocutaneous syndrome (Naxos disease or Carvajal syndrome), characterized by woolly hair and palmoplantar keratoderma. 4,6 As observed in other familial diseases, there is a high degree of heterogeneity in ARVC/D. To date, mutations in more than 12 genes have been identified as causing ARVC/D, although many of these genes are also responsible for other diseases. 9 Other patients with ARVC/Dmay have genetic abnormalities whose mutations have not been identified yet. These mutations may be inherited from family members or be the result of a new mutation. 9 An individual who has a ARVC/Dmutation may or may not develop signs and symptoms of the disease. Recent studies suggest the presence of one or more additional genetic abnormalities in a single gene class, such as plakophilin-2 (PKP2), for example, which may determine when a mutation- carrier individual may be clinically affected by the disease. 10-12 Mutations may be in desmosomal and non-desmosomal genes. These mutations can be found and registered at the electronic address: https://doi.org/10.1002/humu.22765 o. 13 Importance and Limitations of Genetic Testing Genetic testing can be useful to determine the diagnosis in an individual suspected of having ARVC/D, and to identify relatives who do not have signs and symptoms of ARVC/D but who are carriers of the genetic defect. If an abnormal gene is identified in a proband and not in family members, it is unlikely that these members will have the disease based on this genetic abnormality. 4,5,10,11 However, there are several observations that limit the analysis and the use of the genetic test in ARVC/D: • The proband may have a second unidentifiable genetic defect. • The gene most commonly related to the manifestation of signs and symptoms of ARVC/D is that of PKP2 . However, this genetic abnormality may require a second mutation in that same gene or in another desmosomal gene for the disease to manifest itself. That is, the simple identification of the gene cannot define whether it is the cause of the disease. • Not being able to identify all the genes associated with the pathology, as well as the existence of combined mutations, make ARVC/D a genetically complex disease, which makes family counseling difficult. 11 Periodic examinations should be performed on all individuals with genetic abnormalities for ARVC/D. It is recommended that cardiac evaluation be started between 10 and 12 years of age, because the manifestation of the disease before this age is rare. It is suggested that the tests include electrocardiogram, high resolution electrocardiogram (ECG-HR), echocardiogram and, if possible, CMR and 24-hour Holter. It is recommended that this evaluation is repeated every 2 years, between 10 and 20 years of age, and every 5 years after 20 years of age. The evaluation may be interrupted between 50 and 60 years of age because the presentation of the disease in this age group is uncommon. An additional advantage of the genetic test lies in the aid of the differential diagnosis, as in the case of cardiac sarcoidosis, which can mimic the signs and symptoms of ARVC/D. In addition, recent molecular biology studies have again put into perspective the debate about a possible pathogenic link between ARVC/D and Brugada syndrome (BS). 4,12,13 Clinical presentation and natural history Epidemiology ARVC/D has an age-dependent penetrance and is typically manifested between the 3 rd and 5 th decade of life in the form of episodes of ventricular arrhythmias that may progress to SAD. The estimated prevalence ranges from 1:2,000 to 1:5,000, with a predominance in the Caucasian population and in participants in strenuous exercise or competitive sports. 1,6,7 Despite its low prevalence, ARVC/D accounts for approximately 5% to 20% of SAD cases in young people. The occurrence of ARVC/D in individuals younger than 12 years of age, or older than 60 years is extremely rare. 7,14,15 The disease is more malignant in men than in women, a finding that can be explained by a direct influence of sex hormones on the mechanisms involved in the phenotypic expression of the disease, or by differences in the amount and intensity of physical effort. 5 Clinical and natural history The natural history of ARVC/D, in its classic form (dominant RV), can be classified into 4 distinct phases, according to the progression of structural alterations and clinical symptomatology: • Occult phase: this is the subclinical phase, in which the patient remains asymptomatic and with discrete structural abnormalities in the RV or without them. At this stage, SAD may be the first manifestation of the disease. • Arrhythmic phase: the patient has palpitations, syncope and, generally, symptomatic ventricular arrhythmias originating in the RV, triggered by physical effort. Arrhythmias may range from isolated ventricular ectopies (non-sustained ventricular tachycardia) (NSVT) with left bundle-branch block morphology (LBBB) until reaching SAD episodes due to ventricular fibrillation. • Right ventricular failure : The progressive replacement of myocardial tissue with fibro-fatty tissue leads to progressive impairment of RV function, which can lead to heart failure. 2