Historical Summary

In 1977, Fontaine et al reported six cases of sustained ventricular tachycardia (VT) in patients with enlarged right ventricles and hypothesized that this was a specific cardiomyopathy limited to the right ventricle.¹ In 1982, Marcus et al coined the term arrhythmogenic right ventricular dysplasia (ARVD) in a report of 24 cases characterized by left bundle branch block (LBBB) pattern VT, wall motion abnormalities of the right ventricle (RV), and replacement of the RV myocardium by adipose and fibrous tissue.² In 1994, the first diagnostic criteria were proposed. These were based on the identification of structural abnormalities, fibro-fatty replacement of the RV myocardium, particular electrocardiographic changes, arrhythmias of RV origin, and familial disease.³ This led to ARVC being recognized as a separate entity in the reclassification of cardiomyopathies by the World Health Organization/International Society and Federation of Cardiology Task Force on the definition and classification of cardiomyopathies.^4–6 Over the following decade, various groups mapped familial forms of ARVC to a number of genetic loci.^7–14 Molecular studies in a recessive, syndromic variant of ARVC, known as Naxos disease, led to identification of the first disease-causing mutation in the gene encoding plakoglobin, a major constituent of cell-to-cell junctions.¹⁵ This paved the way for the discovery of disease-causing mutations in other genes encoding desmosomal proteins in the more common autosomal dominant forms of ARVC.

Epidemiology

The prevalence of ARVC in the general population is difficult to determine because of the challenging nature of the diagnosis.¹⁶ Various studies in Europe reported a prevalence of between 0.6 and 4.4 per 1000, but it is unclear whether these represent local interest and expertise in the disease. ARVC is reported as a cause of SCD in 11% to 27% of individuals 35 years old and younger.^17–19 The prevalence in one Italian cohort was found to be higher in athletes (22.4%) compared with nonathletes (8.2%).¹⁷

Pathology

In the original descriptions of ARVC, the RV cavity was described as typically dilated, and the RV wall was characterized by dome-shaped aneurysms, occurring particularly on the anterior surface of the pulmonary infundibulum, at the RV apex, and on the inferior wall of the RV (subsequently called the triangle of dysplasia). These macroscopic changes were accompanied by abundant subepicardial fat and endocardial thickening (Figure 59-1). Microscopically, a marked decrease was seen in myocardial fibers, with replacement of the myocardium with fatty tissue and fibrosis (Figure 59-2).² Later, pathologic descriptions divided ARVC into two morphologic patterns: the fatty and the fibro-fatty forms, but fatty infiltration alone can be a normal phenomenon, particularly in older women.²⁰

FIGURE 59-1 Dilated right ventricle with partial replacement of free wall by a mixture of fat and white fibrous tissue. The patient, aged 31 years, died suddenly while exercising.

(Courtesy Dr. Margaret Burke, Consultant Pathologist, Royal Brompton and Harefield Trust, UK.)

FIGURE 59-2 Histologic specimen of the right ventricle showing fatty infiltration and fibrosis within the myocardium.

(Courtesy Dr. Antonis Pantazis, Consultant Cardiologist, University College London Hospitals, UK.)

In a small series of studies on deaths due to ARVC, apoptosis was reported in 75% of patients.²¹ These apoptotic myocardial cells were frequently found in the myocardium not affected by fibro-fatty replacement, which suggests that this could account for the progressive loss of myocardial cells in the disease.²² Endomyocardial biopsy in 20 patients with ARVC revealed apoptosis in 35%. This was significantly associated with acute symptoms and signs and with a shorter (<6 months) clinical history, indicating that apoptosis is present in an early symptomatic stage of the disease.²³

A number of postmortem reports described inflammatory infiltrates, and endomyocardial biopsies from some ARVC cases have been found to contain enteroviral ribonucleic acid (RNA) with homology to Coxsackie virus type B.^21,24–26 In one study, the frequency of viral deoxyribonucleic acid (DNA) was similar to that observed in patients with myocarditis or dilated cardiomyopathy (DCM), but subsequent reports have failed to confirm these findings, perhaps reflecting patient selection and differences among inherited, sporadic, and nonfamilial forms of ARVC.²⁷

Left Ventricular Involvement

By definition, the right ventricle must be affected to make a clinical diagnosis of ARVC, but it is well recognized that left ventricular involvement is common in patients fulfilling current diagnostic criteria. Pathologic examination of heart specimens at autopsy or cardiac transplantation revealed macroscopic and microscopic evidence of left ventricular involvement in up to 76% of cases.²⁸ More recently, a study of 200 patients with ARVC undergoing cardiac magnetic resonance imaging (MRI) reported biventricular involvement in 56% of cases and predominant left-sided disease in 5%.²⁹

Genetics

Systematic family studies have shown that ARVC is inherited in up to 50% of cases. Numerous genetic loci have been identified in linkage studies (Table 59-1). The mode of transmission is usually autosomal dominant, with a male predominance of 3 : 1 and variable penetrance, but autosomal recessive forms are well recognized and have provided the first insights into the genetic basis of ARVC.¹⁶

The first disease causing mutation was identified in an autosomal recessive syndromic form of ARVC, characterized by diffuse palmo-plantar keratoderma, woolly hair, and cardiomyopathy (Naxos disease).³⁰ A homozygous mutation was identified in the gene encoding plakoglobin, a member of the armadillo protein family found in the adherens and desmosomal junctions between cardiac myocytes.¹⁵ Mutations in another desmosomal protein, desmoplakin, were subsequently identified in similar autosomal recessive syndromic forms of ARVC in South American and Arab families.^31,32 Since then, heterozygous mutations in genes encoding these and other desmosomal proteins have been identified in patients with nonsyndromic autosomal dominant forms of ARVC.

The Intercellular Junction

Intercalated discs are specialized structures that provide mechanical and electrical coupling between adjacent cardiomyocytes. The intercalated disc is made up of three distinct structures: (1) gap junctions, (2) adherens junctions, and (3) desmosomes. The gap junction mediates the transfer of ions between cells, whereas the adherens junction (composed of cadherins, β-catenin, and γ-catenin [plakoglobin]) mediates the transmission of force between cells. The desmosome also mediates mechanical attachment between cells by linking the desmosomal cadherins, desmocollin, and desmoglein with the intermediate filament cytoskeleton.^33,34 The intracellular components of the desmosomal cadherins interact with plakoglobin and plakophilin, which, in turn, bind to the N-terminal domain of desmoplakin, a plakin protein. The C-terminal of desmoplakin anchors desmin intermediate filaments to the cell surface.³⁵ Another protein of the plakin family, plectin, is also present in desmosomes and contributes to the mechanical strength of cells.^36,37 As well as providing cells with mechanical strength, the desmosome also plays an important role in tissue morphogenesis and differentiation.³⁸ A simplified schematic representation of the organization of the cardiac desmosome is shown in Figure 59-3.

FIGURE 59-3 A schematic representation of the molecular desmosome.

(Data adapted from Green KJ, Gaudry CA: Are desmosomes more than tethers for intermediate filaments? Nat Rev Mol Cell Biol 1:208–216, 2000.)

In 2002, the first mutation in the autosomal dominant form of ARVC was reported. This was found in the plakoglobin-binding domain of desmoplakin, and mutations in this gene have been reported in 6% to 16% of probands.^14,39,40 Since then, heterozygous mutations have also been reported in plakoglobin, plakophilin-2 (PKP2), desmocollin-2 (DSC2), and desmoglein-2 (DSG2). PKP2 mutations are the most frequently found in patients with ARVC, with a reported prevalence between 27% and 43% of patents fulfilling diagnostic criteria.⁴¹ Over 50 individual mutations have been identified to date, but studies have not as yet revealed consistent genotype-phenotype correlations. The mechanism by which mutations result in disease is also unclear. It is suggested that mutations increase the susceptibility of the myocardium to the damaging effects of mechanical stress, thereby predisposing to cardiomyocyte detachment, death, and eventual replacement by fibro-fatty tissue.⁴² The predilection for the right ventricle has been explained by its thin wall and greater distensibility, but this is unlikely to be the sole explanation for disease in either ventricle.⁴³ As desmosomal proteins interact with many other proteins, including key components of the cellular cytoskeleton and intermediate filaments, it is possible that ventricular dysfunction occurs as the result of reduced cytoskeletal integrity and impaired force transduction.³⁷ Some desmosomal proteins (in particular plakoglobin) are also important signaling molecules that regulate the transcription of many other genes.⁴⁴ Finally, a reduction in the number and size of gap junctions may result in an electrical coupling defect, thus increasing the propensity to arrhythmia, and could explain the occurrence of sudden death in patients without significant morphologic changes Figure 59-4.⁴²

FIGURE 59-4 Electron micrographs of cardiac cells expressing wild-type and mutant plakoglobin. The arrows indicate adhesive junctions between cells (desmosomes). Mutant forms show fewer desmosomes per micrograph.

(From Asimaki A, Syrris P, Wichter T, et al: A novel dominant mutation in plakoglobin causes arrhythmogenic right ventricular cardiomyopathy, Am J Hum Genet 81:964–973, 2007.)

Clinical Features

The natural history of ARVC has been divided into four phases. In the earliest (“concealed”) phase, patients are asymptomatic and have few if any morphologic abnormalities in the right ventricle. In the second (“electrical”) phase, symptoms of arrhythmia occur, and structural and functional abnormalities are easier to identify. The third phase is typified by the classic right ventricular functional abnormalities that can progress to right ventricular failure with relatively preserved left ventricular function. The final or end stage is characterized by the development of biventricular systolic impairment. It is not inevitable that affected persons will progress through all these phases, but this can be a useful disease paradigm. Moreover, it is likely that many other genetic and environmental factors (e.g., exercise) influence the clinical manifestations and natural history of the condition in individual patients.

Symptoms and Physical Signs

Patients can present at any age with syncope, presyncope, or palpitations, In one case series, approximately one third of live probands gave a history of syncope, with over half reporting palpitations and presyncope.⁵⁸ Other symptoms include chest pain or dyspnea often precipitated by exercise.⁵⁹ In approximately 50% of cases, the first manifestation of ARVC is SCD, but in living patients, aborted SCD is the first manifestation in less than 10% of cases.^28,60 Heart failure as a first presentation is probably uncommon; it accounted for less than 10% of cases in one series.⁵⁸ Increasingly, patients are identified through family screening and are often asymptomatic. Cardiac examination in symptomatic and asymptomatic individuals is usually unremarkable.

Diagnosis

Because of the nonspecific nature of the clinical findings and the absence of a single diagnostic test, the diagnosis of ARVC is challenging. Recognition of these difficulties resulted in the formation of an International Task Force, which proposed standardized criteria for the diagnosis of ARVC in 1994.³ These criteria are based on the identification of structural, histologic, ECG, arrhythmic, and familial features, which are subdivided into major and minor criteria according to specificity. The presence of two major criteria, one major criterion plus two minor criteria, or four minor criteria from different categories is considered diagnostic (Table 59-2).³

Table 59-2 Task Force Criteria for the Diagnosis of Right Ventricular Dysplasia/Cardiomyopathy

RV, Right ventricle; LV, left ventricle; RBBB, right bundle branch block; SAECG, signal-averaged electrocardiogram.

From McKenna WJ, Thiene G, Nava A, et al: Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy, Br Heart J 71:215–218, 1994.

The main goal of these guidelines was to establish a definitive diagnosis in probands, but tertiary referral center experience suggests that while the criteria are highly specific, they lack sensitivity for early disease.⁵⁹ This led to the proposal of modified familial criteria for the diagnosis of ARVC in relatives of index cases. According to these criteria, the presence of a single disease feature (right precordial T-wave inversion, late potentials on signal averaged ECG, VT with LBBB morphology, or minor functional or structural abnormalities of the RV on imaging) in a relative of an index case should be considered diagnostic of ARVC (Table 59-3).⁵⁸

Table 59-3 Familial Criteria for the Diagnosis of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy