Version May 2024
INTRODUCTION — Arrhythmogenic cardiomyopathy (ACM) is defined by a clinical presentation with documented or symptomatic arrhythmia and myocardial structural and functional abnormalities [1]. Arrhythmogenic right ventricular cardiomyopathy (ARVC), formerly called "arrhythmogenic right ventricular dysplasia" (ARVD), is the best characterized of the ACMs in relation to diagnosis, treatment, and outcomes. It is an underrecognized clinical entity characterized by ventricular arrhythmias of RV origin and a characteristic ventricular pathology [2-4]. ARVC is characterized macroscopically by fibrofatty replacement of the right ventricle (RV) myocardium, which initially produces regional wall motion abnormalities that later become global, producing RV dilation. The tissue replacement can also involve areas of the left ventricle (LV), but there is usually relative sparing of the septum [5].
The prevalence in the general population is estimated to be 1:1000 to 1:5000 [6,7]. ARVC is an important cause of sudden cardiac death (SCD) in young adults, and in one study, systematic data collection suggests that it accounts for approximately 11 percent of cases overall and 22 percent in athletes [3,8].
The anatomy, histology, genetics, and pathogenesis of ARVC will be reviewed here. The clinical manifestations, diagnostic criteria (including the potential role of genetic testing), evaluation, treatment, and prognosis of ARVC are discussed separately. (See "Arrhythmogenic right ventricular cardiomyopathy: Treatment and prognosis" and "Arrhythmogenic right ventricular cardiomyopathy: Anatomy, histology, and clinical manifestations".)
PATHOGENESIS — Five established disease-causing genes in ARVC encode desmosomal proteins (plakoglobin, desmoplakin, plakophilin-2, desmoglein, and desmocollin in autosomal dominant disease and plakoglobin and desmoplakin in autosomal recessive disease) and support a new model for the pathogenesis of ARVC [9]. Impaired desmosome function when subjected to mechanical stress causes myocyte detachment and cell death. The myocardial injury may be accompanied by inflammation. The presence of autoantibodies directed against elements of the intercalated disk is consistent with immune/autoimmune involvement [10-12]. This raises the question as to whether inflammation contributes to disease progression or represents the initial phase of the repair process, which ultimately results in fibrofatty replacement of damaged myocytes [13].
The impaired cell adhesion hypothesis is consistent with a number of the hallmark features of ARVC, including its anatomical progression:
●Early ARVC shows a predilection for certain areas of the right and left ventricle (the triangle of dysplasia, which is comprised of the RV inflow tract, the RV outflow tract, and the posterolateral LV). The heterogeneous distribution of mechanical stress within the ventricle accounts for regional disease expression and aneurysm formation. Athletes often have structurally severe disease, possibly resulting from the intense and prolonged mechanical stress on the heart during physical training.
●Cutaneous disease caused by desmosomal dysfunction is confined to areas exposed to pressure, stress, or abrasion, and the palmar and plantar surfaces.
●The penetrance of ARVC is often incomplete and is closely related to exercise level [14-18].
This observation suggests that mutant desmosomal proteins can maintain tissue integrity unless exposed to excessive mechanical stress. ARVC can occur at any age, but when seen below the age of 31 years it is almost always associated with extreme levels of competitive exercise [18].
The impact of exercise on the development of ARVC has been demonstrated in a mouse model [19]. Among heterozygous plakoglobin-deficient mice, the phenotypic expression of ARVC (RV dysfunction and arrhythmias) was accelerated by endurance training. Human data also reveal that exercise is associated with disease expression and arrhythmia risk [18]. Of particular note is a study that examined the degree of exercise required for development of ARVC in patients who do and do not harbor a pathogenic mutation [17]. This study revealed that patients who have a desmosomal mutation require significantly less exercise exposure to develop the disease than patients who are apparently mutation free.
The predominantly LV involvement in left-sided ARVC may be related to disrupted binding of the C-terminal end of desmoplakin to desmin filaments, analogous to the loss of cytoskeletal integrity that is considered the pathogenetic determinant of dilated cardiomyopathy [9]. Conversely, defects in the N-terminal of desmoplakin, which would be predicted to disrupt binding to plakoglobin, result in a primary dysfunction of cell adhesion and predominant right ventricular disease [20].
GENETICS — Data from clinical genetic studies suggest that 30 percent of cases of ARVC are familial [20-23]. However, this probably represents an underestimate since detailed pedigree evaluation is infrequently documented.
Two patterns of inheritance have been described in ARVC: an autosomal dominant form, which is most common, and an autosomal recessive form, in which ARVC is part of a cardiocutaneous syndrome, including hyperkeratosis of the palms and soles and woolly hair.
Although less common, autosomal recessive disease is of particular interest because it was the association of the cutaneous manifestations and cardiomyopathy that led to the identification of the first disease-causing genes (eg, plakoglobin in Naxos disease, desmoplakin in Carvajal syndrome).
Autosomal recessive disease and Naxos disease — Naxos disease, first recognized in the Cycladian island of Naxos, is an autosomal recessive cardiocutaneous disorder that is characterized by typical features of ARVC accompanied by nonepidermolytic palmoplantar keratosis, a disorder of the epidermis causing hyperkeratosis of the palms and soles, and woolly hair [23,24].
Plakoglobin gene — The cutaneous manifestations of Naxos disease, plus the almost 100 percent penetrance of cardiac disease by adolescence, facilitated recognition of affected patients and mapping of the genetic locus to chromosome 17q21 [25,26]. Affected individuals were then found to be homozygous for a two base pair deletion in the plakoglobin gene [27]. Plakoglobin is a key component of desmosomes and participates in maintaining tight cell-cell adhesion.
All patients who are homozygotes for Naxos disease have woolly hair in infancy and develop diffuse palmoplantar keratosis during early childhood; children usually have no cardiac symptoms, but may have electrocardiographic (ECG) abnormalities and nonsustained ventricular arrhythmias [28,29]. The cardiac disease is 100 percent penetrant by adolescence, being manifested by symptomatic arrhythmias, ECG abnormalities (92 percent), right ventricular structural alterations (100 percent), and LV involvement (27 percent). A minority of heterozygotes have minor ECG and echocardiographic changes, but clinically significant disease is not seen. (See "Arrhythmogenic right ventricular cardiomyopathy: Diagnostic evaluation and diagnosis", section on '12-lead ECG'.)
In one series of 26 patients followed for 10 years, 62 percent had structural progression of right ventricular abnormalities, and 27 percent developed heart failure due to LV involvement [28]. Twelve patients (46 percent) developed symptomatic arrhythmias and the annual cardiac and SCD mortality were 3 and 2.3 percent, respectively, which are marginally higher than seen in autosomal dominant forms of ARVC.
Desmoplakin gene — Carvajal syndrome is another autosomal recessive cardiocutaneous disorder with a similar phenotype in which a desmosomal mutation was identified. Like Naxos disease, it manifests with woolly hair, epidermolytic palmoplantar keratoderma, and cardiomyopathy [30]. The second gene for ARVC, a mutation in desmoplakin, was identified in an Ecuadorian family with Carvajal syndrome and subsequently in an Arab family with ARVC, woolly hair, and a pemphigus-like skin disorder [31].
Both of these mutations are located in exon 24 of the desmoplakin gene [30,31]. The cardiomyopathy of Carvajal syndrome was thought to have a predilection for the left ventricle, but subsequent evaluation of a deceased child revealed typical ARVC changes in both ventricles [32]. The cardiac phenotype in the Arab family appeared to be classic ARVC.
Autosomal dominant disease — Disease loci for the autosomal dominant disorder have been mapped to chromosomes 14q23-q24 (ARVC1) [33], 1q42-q43 (ARVC2) [34], 14q12-q22 (ARVC3) [35], 2q32 (ARVC4) [36], 3p25 (ARVC5) [37,38], 10p12-p14 (ARVC6) [39], 10q22, 6p24 (ARVC8) [20,40], and 12p11 (ARVC9) [41]. The relative frequency of several of these disorders was assessed in a review of 28 Italian families that underwent linkage analysis: six had ARVC1, four had ARVC2, and four had ARVC4 [42]. No linkage with known loci was found in four families (only ARVC1 through ARVC5 were tested) and uninformative results were obtained in 10.
The responsible gene has been identified in some of these disorders.
Desmoplakin gene — Desmoplakin was the first disease-causing gene identified in autosomal dominant ARVC; the affected family had a missense mutation linked to 6p24 (ARVC8) [20]. The mutation affected the N-terminal of desmoplakin, in the region of the plakoglobin-binding domain. The phenotype of this and four additional families with ARVC caused by desmoplakin mutations was of "classic ARVC" with a clinical presentation of arrhythmia, sudden death, and LV involvement as the disease progresses [20,43,44]. In one cohort of 541 patients with ARVC, carriers of a desmoplakin mutation were fourfold more likely to develop left ventricular dysfunction and heart failure compared with carriers of plakophilin-2 mutation [22].
Desmoplakin is a key component of desmosomes and adherens junctions that is important for maintaining the tight adhesion of many cell types, including those in the heart and skin. When these junctions are disrupted, cell death and fibrofatty replacement occur. (See 'Pathogenesis' above.)
Desmoplakin gene mutations have also been associated with left-sided ARVC, and as noted above, with autosomal recessive disease. (See 'Autosomal recessive disease and Naxos disease' above.)
Plakophilin-2 gene — The gene at locus 12p11 (ARVC9) encodes the desmosomal protein plakophilin-2. In a genetic analysis of 120 unrelated individuals with ARVC, 32 had 25 different mutations in the gene encoding plakophilin-2 [41]. Three additional series, enrolling between 56 and 100 unrelated index patients who fulfilled published task force diagnostic criteria for ARVC, evaluated the incidence and clinical significance of PKP2 mutations [45-47]. The following findings were noted:
●PKP2 mutations were found in 11 to 43 percent of the patients.
●In a Dutch study, 43 percent of ARVC probands had a mutation in PKP2. Haplotype analysis suggested founder mutations were responsible for 4 of the 14 different mutations identified. Among index patients with a positive family history of ARVC, 70 percent had a PKP2 mutation [47].
●Patients with PKP2 mutation presented at a younger age (28 versus 36 years), but had similar rates of appropriate ICD discharges compared with patients without PKP2 mutations [46].
Thus, PKP2 appears to be a relatively common mutation, particularly in cases with a documented family history. However, there does not appear to be a substantial phenotypic distinction from other mutations, and due to relatively small sample sizes and the potential for referral bias, the incidence of PKP2 mutations in a broader population may be lower [6,45].
Desmoglein-2 gene — Desmoglein is another component of the desmosome, and desmoglein-2 (DSG2) is the only isoform expressed in cardiac myocytes. Due to the known association of ARVC with defects in other desmosomal proteins, a series of patients with ARVC were screened for mutations in DSG2 [48]. Among 80 unrelated probands, 26 were known to have desmoplakin or plakophilin-2 mutations. Direct sequencing of DSG2 in the other 54 patients revealed nine distinct mutations in eight individuals. These individuals demonstrated typical clinical characteristics of ARVC, although four had some evidence of LV involvement.
An analogous study of 86 ARVC probands identified eight novel DSG2 mutations in nine probands. Clinical evaluation of family members with DSG2 mutations revealed penetrance of 58 percent using Task Force criteria and 75 percent using proposed modified criteria. Morphological abnormalities of the right ventricle were present in 66 percent of gene carriers, LV involvement in 25 percent, and classical right precordial T-wave inversion in only 26 percent. The authors noted that disease expression of DSG2 mutations was of variable severity, but that overall penetrance was high and LV involvement prominent [49].
Desmocollin-2 gene — Desmocollin is an important desmosomal cadherin. Two heterozygous mutations (a deletion and an insertion) were identified in 4 of 77 probands with ARVC. Both DSC2 mutations resulted in frameshifts and premature truncation of the desmocollin-2 protein. The identification of the fifth desmosomal cell adhesion gene abnormality further supports the hypothesis that ARVC is a disease of cell adhesion [50]. Substitution mutations in the cadherin 2 gene CDH2 have also been reported [51].
TMEM43 gene — A missense mutation in the TMEM43 gene causes ARVC5, a fully penetrant, sex-influenced, high-risk form of ARVC [38,52]. The TMEM43 gene contains the response element for PPAR gamma, an adipogenic transcription factor. If the TMEM43 gene mutation causes dysregulation of an adipogenic pathway regulated by PPAR gamma, this dysregulation may explain the fibrofatty replacement of myocardium in ARVC patients.
Other genes
●The RyR2 gene, which encodes the cardiac ryanodine receptor RyR2, and the TGF-beta-3 gene, which encodes transforming growth factor-beta-3 (TGF-beta-3), had previously been associated with ARVC [53-55]. A recent evidence-based reappraisal of genes associated with ARVC using the Clinical Genome Resource Framework does not support either of these genes being causative in ARVC [56].
●CDH2 encoding cadherin-2, CTNNA3 encoding catenin alpha 3, and TJP1 encoding tight junction protein 1, all related to the area composita, have been associated with ARVC, but further evidence is required in each case to confirm causality [51,57,58].
Left-dominant arrhythmogenic cardiomyopathy — As mentioned above, the pathologic process in ARVC predominantly involves the right ventricle, although it may extend to the left ventricle [59-61]. In contrast, patients with left-dominant arrhythmogenic cardiomyopathy (LDAC, also known as left-sided ARVC or arrhythmogenic left ventricular cardiomyopathy) have typical pathological changes predominantly involving the LV [62,63].
Similar to ARVC, some patients with LDAC have desmosomal gene mutations. Genetic testing was performed in a series of 42 individuals diagnosed with LDAC with unexplained (infero) lateral T-wave inversion, arrhythmia of LV origin, and/or proven LDAC [64]. Disease causing mutations in known desmosomal genes were identified in 8 of 24 families (33 percent), a rate of desmosomal mutations similar to that observed in ARVC populations [65]. Six of the mutations involved the desmoplakin gene, one involved the plakophilin-2 gene, and one involved the desmoglein-2 gene. The clinical characteristics of LDAC are discussed separately. (See "Arrhythmogenic right ventricular cardiomyopathy: Anatomy, histology, and clinical manifestations", section on 'Left-dominant arrhythmogenic cardiomyopathy'.)
SUMMARY AND RECOMMENDATIONS
●Pathogenesis – The pathogenesis of arrhythmogenic right ventricular cardiomyopathy (ARVC) is most likely related to impaired desmosome function when subjected to mechanical stress, resulting in myocyte detachment and cell death. The myocardial injury may be accompanied by inflammation as the initial phase of the repair process, which ultimately results in fibrofatty replacement of damaged myocytes. (See 'Pathogenesis' above.)
A number of studies have made it very clear that exercise is an important and very potent environmental stimulus that plays a critical role in the development of this disease. (See 'Pathogenesis' above.)
●Genetics – Data from clinical genetic studies suggest that 30 percent of cases of ARVC are familial, although this probably represents an underestimate, since detailed pedigree evaluation is infrequently documented.
ARVC can be either autosomal dominant or autosomal recessive, with defects in a variety of genes (including plakoglobin, desmoplakin, plakophilin-2, desmoglein-2, desmocollin-2, and TMEM43, among others) resulting in the disease. (See 'Genetics' above.)
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