In 1952 Dr Henry Uhl described a case of “almost total absence of the myocardium of the right ventricle” in an 8-month-old girl.¹ The case was characterized by complete heart block and right ventricular failure. At post mortem the myocardium of the left ventricle was normal and there was a sharp demarcation line between this and the very abnormal right ventricle in which there was virtually complete loss of the myocardium. There was no evidence of ischemic change or inflammation and the cause was assumed to be a maldevelopment or dysplastic process.

The first description of an ARVC was in 1978, when detailed electrocardiography readings of four French patients with right ventricular dysplasia associated with arrhythmia were reported.² In the same journal there was a report of two French patients in their sixth decade of life presenting with recurrent ventricular tachycardia of left bundle branch bock (LBBB) morphology resistant to medical therapy. Clinical examination, angiography and ultimately post-mortem examination identified what was described as “the parchment right ventricle syndrome of the adult.”³

A case series of 24 patients published 4 years later identi-fied the characteristics of the typical patient with what is now called arrhythmogenic right ventricular cardiomyopa-thy. The mean age at presentation (in those who had symptoms) was 39 years, and the male/female ratio was 2.7:1. Almost 90% of the patients had T-wave inversion in the right precordial leads. Ventricular postexcitation waves (epsilon waves) were present in one-third of patients. All but one of the patients had spontaneously occurring ventricular tachycardia with a LBBB configuration. In those who underwent echocardiography, the ratio of right to left ventricular size was increased, and wall motion abnormality of the right ventricle was seen in the majority. One patient had a wall motion abnormality of the posterior wall of the left ventricle. Morphologic findings were confirmed in 13 patients during surgical intervention. The right ventricle was invariably enlarged and there were discrete areas of segmental dilation associated with dyskinetic wall motion and aneurysms. The authors reported the most common location of these right ventricular aneurysms to be the anterior surface of the right ventricular outflow tract, apex and inferior wall, and coined the term “the triangle of dysplasia.” There was frequently an increase in subepi-cardial fat over these areas and depletion in the numbers of muscle fibers. The amount of fibrosis was variable. On microscopy some hypertrophy of the remaining myofibers was noted, and there was a varying degree of lymphocytic infiltration.⁴ One of the patients came from a family reported 4 years earlier in a description of seven cases of familial ventricular tachycardia.⁵

The first gene mutation to be associated with ARVC was identified in patients with a recessive cardiocutaneous syndrome characterized by wooly hair, palmoplantar kerato-derma and ARVC common on the Greek island of Naxos.⁶ The locus for Naxos disease was mapped to chromosome 17 (17q21), and subsequently a deletion in the gene encoding plakoglobin was identified as the disease-causing mutation.^7,8 Plakoglobin is a constituent protein in both adherens and desmosomal cell–cell junctions. Subsequent evaluation of other related desmosomal genes in ARVC patients with more typical autosomal dominant disease has identified disease-causing mutations in a further four genes encoding other desmosomal proteins.

The structure of the right ventricle renders it inherently more difficult to image than the left ventricle, but improvements in imaging techniques over the past decade have broadened the clinical spectrum of the disease by identifying patients at an earlier, often asymptomatic stage. Cardiac magnetic resonance imaging in particular has demonstrated a high prevalence of left ventricular involvement in many patients, illustrating the heterogeneity in disease expression.^9–13

In most populations the prevalence of ARVC is unknown. An apparent cluster of disease is reported in the Veneto region of Italy, with a frequency of 1 per 5000, but it is unclear whether this is a true clustering or a reflection of local interest and expertise in the disease. Nevertheless, the limited information available suggests that ARVC is an important cause of premature sudden cardiac death. A retrospective review of a French post-mortem series identified ARVC as a likely cause of death in 10% of the population aged 1–65 years.¹⁴ Prospective studies of an Italian cohort aged 12–35 years found evidence of ARVC in 12% of those who suffered a sudden cardiac death.¹⁵ A population-based study from the USA identified pathologic changes of ARVC in 17% of sudden death victims under 40 years of age.¹⁶ Other authors report that up to 25% of sudden deaths in athletes are due to ARVC.¹⁷

In the early stages, abnormal pathologic findings are localized to the apical, inflow and infundibular areas of the right ventricle.⁴ With disease progression, the left ventricle, particularly the posterolateral wall, is often involved, with relative sparing of the interventricular septum. In some cases, the pathologic abnormalities may be confined to the left ventricle.^18,19

Macroscopic examination of the heart shows diffuse or focal thinning of the right ventricular wall, affecting the subepicardium more than the subendocardium, with aneu-rysm formation in up to 50% of cases.^18,20 Histologically, there is myocardial atrophy and fibro-fatty replacement. Islands or strands of surviving myocytes exhibit a combination of degenerative change with myocyte vacuolation, often associated with focal mononuclear inflammatory cell infiltrates.^21–24 In some cases, typical histologic findings may be present in the absence of any macroscopic features.²⁵ A second histologic pattern, characterized by trans-mural infiltration of adipose tissue without fibrous replacement or wall thinning, has been considered to be an earlier stage of the condition^22,26 but this can be a normal finding, particularly in older women.²⁰

A number of studies have reported evidence of apoptosis in ARVC which is not found in normal controls, patients undergoing post-transplant surveillance or in patients with structurally normal hearts and VT arising from the RV outflow tract.^27–30 Apoptosis is more common in patients with a short (less than 6 months) clinical history and acute symptoms and signs.²⁷ Apoptosis is present to an equivalent degree in children and adults with ARVC.²⁸

Endomyocardial biopsies from some ARVC patients have been found to contain enteroviral RNA with homol-ogy to Coxsackie virus type B. In one study similar proportions of patients with myocarditis or dilated cardiomyopathy were positive for viral RNA but none of the control patients with non-inflammatory cardiac disorders.³¹ Other studies have failed to confirm these findings, which may reflect patient selection and differences between inherited and sporadic, non-familial forms of ARVC.^32–37

The natural history of ARVC can be divided into four phases.³⁸ In phase one (the “concealed” phase) patients are asymptomatic with few if any morphologic abnormalities. In the absence of systematic post-mortem evaluation of the right ventricle, the diagnosis may be missed at this stage and so the incidence of sudden death in this phase may be underestimated. In the second (electrical) phase, symptoms of arrhythmia occur and morphologic structural and functional abnormalities are easier to identify. The third phase is marked 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 associated with the development of biven-tricular systolic impairment. Although a useful disease paradigm, it is not inevitable that affected persons will progress through all phases as described. Moreover, multiple (mostly unknown) factors influence the clinical manifestations and natural history of the condition. It is generally thought that physical training and exercise both increase the risk of arrhythmic events in affected individuals and result in more aggressive disease progression.^{17,49,55–57} Some patients demonstrate left ventricular involvement early in the disease, and may have predominant left ventricular disease.^58–60

The first presentation of the disease is often sudden cardiac death in previously asymptomatic individuals, including young children and teenagers.^14,55,61,62 Occasionally, patients will have experienced syncope in the months preceding their death.^14,56,63 An imbalance of adrenergic activity has been suggested as a possible factor in the genesis of lethal ventricular arrhythmias; thus exposure to catecholamines (particularly during exercise) may increase the risk of sudden death.⁶⁴

Patients usually present with symptoms between the second and fifth decades of life. Syncope, palpitations and chest pain are common, but family studies have shown that most affected individuals are asymptomatic, particularly in the early stages.^65,66 With disease progression, features of right and later biventricular failure may be present.