There are limited epidemiologic data on ARVD. Its prevalence in the general population is between 1/2000 and 1/5000, with males being affected more often than females (3:1). Its incidence ranges between 1/1000 and 1/50 000, with considerable geographic variability.3–5

In most cases (80%) ARVD is diagnosed before the age of 40. Worldwide, it is identified as the cause of sudden cardiac death in young adults in 5-11% of cases. In a study in northern Italy it was the leading cause (22.4%) of sudden death in young athletes.6

ARVD should therefore be considered if previously healthy young individuals present with arrhythmia, syncope or cardiac arrest. An initial episode at older ages is unusual, and diagnosis of late-onset ARVD is made more difficult by possible confounding factors such as concomitant coronary artery disease.7

Electron microscope studies8 reveal alterations in desmosomal proteins to be the main ultrastructural factor that triggers failure of myocytes to adhere, resulting in cell death and progressive replacement by fibrofatty tissue, which is the typical pathologic substrate of ARVD. These structural changes increase mechanical stress on the ventricular myocardium with focal dilatation of the chamber, initially in the thinner parts of the right ventricle (apex, inflow tract and outflow tract, known as the triangle of dysplasia), and subsequently affecting the entire ventricle. This may explain why the right ventricle, which is more distensible than the left ventricle because of its thinner wall and asymmetric shape, is more often involved in ARVD, especially in the earlier stages.9

However, LV involvement is common (>50%) and increasingly prevalent at older ages as the disease advances. In some forms of presentation LV involvement predominates, and the final expression of the disease can resemble dilated cardiomyopathy.10–12

In the initial stages, structural changes are confined to the ‘triangle of dysplasia’ and the patient will be asymptomatic, but even so may be at risk for sudden death, particularly during physical exertion. Later, the myocardial fibers in areas undergoing fibrofatty transformation are the substrate for the development of symptomatic ventricular arrhythmias, and changes in RV function become evident. The disease progresses from epicardium to endocardium and eventually spreads to the entire right ventricle, leading to marked dilatation and dysfunction.10

In the case presented, the initial episode of syncope in a previously asymptomatic 67-year-old with marked structural and functional abnormalities (severe RV dilatation with regional hypokinesia/akinesia and EF of 21%), is a good example of how ARVD can be silent even in its advanced stages.

Estimates of the proportion of hereditary cases of ARVD vary widely, from 30% to over 50%.3,13

The main desmosomal proteins altered in ARVD are plakoglobin, desmoplakin, plakophilin-2, desmoglein-2 and desmocollin-2. Mutations in other genes have been identified, such as TMEM43 (which is associated with a high-risk form of ARVD and appears to be related to a PPAR-γ-regulated lipogenesis pathway), TGF-β3 and RYR2, the gene coding for the cardiac ryanodine receptor. The pathogenic mechanisms leading to ARVD associated with these genes are still under investigation, as are other mutations that may also be involved.1,14,15

Two forms of transmission have so far been identified, autosomal dominant (more common and with incomplete penetrance) and autosomal recessive, in which ARVD is part of a syndrome that includes palmoplantar keratoderma and woolly hair (Naxos and Carvajal syndromes, associated with mutations in the genes for plakoglobin and desmoplakin, respectively).16,17

The pattern of incomplete penetrance means that the age at which symptoms and clinical manifestations first appear varies between individuals with the same mutation and that asymptomatic carriers are at risk of developing the disease at any time.9,18

The natural history of ARVD depends on the rate of progression of RV dysfunction and development of symptoms.

The form of initial presentation varies widely, from palpitations, dizziness, general malaise, chest pain and dyspnea to syncope and occasionally sudden death. Symptoms usually appear between the first and fifth decades of life; mean age at diagnosis is 30 years, rarely before the age of 12 or after the age of 60.

Overall mortality is 4-20% in both sexes, peaking in the fourth decade of life, while the annual rate of sudden death is 1%. The high mortality from ARVD described in some studies, together with its progressive nature, mean that it is extremely important to identify the condition and to begin treatment promptly.3,9,15,19

A study in which hearts were examined macroscopically and microscopically after autopsy revealed that out of 1930 cases of unexpected sudden cardiac death, around 10% showed evidence of ARVD; most of these 200 deaths occurred at home, at work or in the street and only 3.5% during physical exercise.20 However, it has been demonstrated that in certain populations, exercise is an important cause of sudden death in athletes.

As stated above, even though in many patients AVRD can remain clinically silent for decades, the risk of sudden cardiac death, although relatively low, must be borne in mind, and so the diagnostic process must be undertaken without delay. However, this is not always the case, especially in sporadic cases with no known family history.21

No single diagnostic method is conclusive, particularly in the early stages of the disease. When ARVD is suspected, the essential diagnostic exams are the ECG and TTE.22

TTE is the most common method for detecting functional and structural abnormalities in the heart. It is non-invasive and readily available in most hospitals.3,4,18 However, the retrosternal position and complex geometry of the right ventricle mean it cannot be used as the only imaging method in AVRD.24

The alterations most often identified are RV dilatation, particularly of the outflow tract (there may also be regional aneurysms and atrial enlargement), morphological irregularity (found in up to 62% of cases and including trabecular derangement and hyper-reflective moderator band), and reduced right ventricular fractional area change (RVFAC), which correlates with EF. Regional wall motion abnormalities are observed in up to 80% of cases.25

The echocardiographic measures in the 2010 Task Force criteria (Figure 3) are less sensitive and hence less reliable than those of MRI, mainly due to difficulty in assessing regional ventricular wall motion abnormalities. New three-dimensional techniques look set to overcome these limitations. Studies have shown that besides its diagnostic capacity, echocardiography also has prognostic value in ARVD, demonstrating that reduced TAPSE and RVFAC are associated with major cardiac events. However, as pointed out above, major arrhythmic events can occur before the development of systolic dysfunction, and so risk stratification is hampered by the considerable variability in phenotypic expression of the disease.24

As stated above, echocardiography is not always sufficient for a diagnosis of ARVD, and MRI overcomes some of its limitations. It is a non-invasive method of detecting fibrofatty replacement of myocardium, wall thinning and regional wall motion abnormalities. The most important MRI findings for a diagnosis of ARVD are high signal intensity in the ventricular wall, which indicates fatty deposits, dilatation of the RV outflow tract, and hypokinesia, akinesia or dyskinesia and dilatation of the right ventricle and atrium.26

One MRI technique that correlates well with histopathologic findings, degree of RV dysfunction and inducibility of VT on EPS is late enhancement following injection of paramagnetic contrast to detect fibrous tissue, which was positive in 67% of patients with ARVD.27

Some studies show that MRI has greater diagnostic value than conventional echocardiography in ARVD.22,28 However, it also produces false positives, particularly if the criteria used are based solely on fibrofatty alterations and ventricular wall thickness.18,24,29

In addition to false positives, other limitations of MRI are interobserver variability in interpretation of its findings, artefacts caused by arrhythmias, restrictions to its use in the presence of intracardiac devices, cost, and lack of availability in less specialized centers.30

Several studies have demonstrated the value of Holter ECG monitoring in AVRD, to detect both ventricular extrasystoles and potentially life-threatening ventricular arrhythmias, since a correlation has been shown between the two.31–33

There are conflicting data concerning programmed ventricular stimulation and VT induction for risk stratification in ARVD. Nevertheless, although induction of VT does not predict future arrhythmic events, it does identify patients at greater risk for disease progression and sudden death.34

In a study of 62 patients diagnosed with ARVD according to the 2010 Task Force criteria, 55% presented inducible monomorphic VT, and after 10 years of follow-up cardiac death, heart transplantation, and VT with hemodynamic compromise were more frequent in these patients.18,35

The 2015 update of the Task Force consensus document recommends that EPS should be considered in the diagnosis and/or evaluation of patients with suspected ARVD.36

Genetic testing is not recommended for all patients with suspected AVRD. In particular, while it can be useful for patients satisfying Task Force diagnostic criteria for AVRD if clinical, ECG and imaging findings are doubtful but the diagnosis is possible, it is not considered necessary (class IIb recommendation).37

Discovery of the role of TMEM43, mentioned above, has opened up new avenues for the use of genetic testing in risk stratification, since mutations in this gene have been reported to be associated with 50% mortality in males by the age of 39.38

The main causes of failure to diagnose ARVD are misinterpretation of MRI findings and unawareness of the 2010 Task Force criteria. In the case presented, diagnosis was based on these criteria, which update those of the 1994 document and include alterations in RV structure and function, histopathology, repolarization and depolarization abnormalities on the ECG, arrhythmias, and family history.1 The case under discussion presented two major criteria (by MRI, RV akinesia and RV ejection fraction ≤40%; and by ECG, inverted T waves in right precordial leads [V1-V3]) and one minor criterion (>500 ventricular extrasystoles per 24 hours by Holter ECG), leading to a definitive diagnosis.

A study of the diagnostic performance of imaging methods found that only 50% of patients diagnosed with ARVD by MRI fulfilled the echocardiographic criteria of the 2010 Task Force, highlighting the importance of MRI in the diagnosis of this disease.39

Of the indicators currently used for risk stratification, left and right ventricular dysfunction, mutations in TMEM43, T-wave inversion in leads V1-V3 and documented VT are the most convincing. Given the progressive nature of the disease, risk stratification should be considered a dynamic process that is subject to continual reassessment.34

Treatment should be directed primarily toward prevention of sudden cardiac death, but the best way to prevent this outcome has yet to be determined.

For reasons outlined above, patients with ARVD should avoid strenuous physical exercise and should therefore not usually participate in competitive sports (class Ic recommendation).36,40,41

Although there have been few specific studies on the use of beta-blockers in ARVD, their benefits in protecting against sudden cardiac death in other conditions are well known, and their use is a class Ic recommendation. In view of the effects of exercise on the myocardium in affected individuals, the mechanism of action of beta-blockers in ARVD is likely to be by inhibiting the harmful effects of the sympathetic nervous system in this disease.

One study demonstrated that amiodarone was more effective in preventing clinically significant ventricular arrhythmias and that sotalol was associated with increased risk of first clinically relevant ventricular arrhythmia.42 However, another study showed sotalol to be superior to amiodarone and that verapamil and beta-blockers could be effective.43 Further studies are needed to determine the efficacy of these and other drugs for primary prevention in carriers of ARVD-related mutations.

In view of the conflicting data in the literature, in the case presented we decided on a low-dose beta-blocker as an adjuvant to the ICD.36,42,43

Due to the regional and progressive character of ARVD, radiofrequency ablation is not a definitive treatment, and should not be used in isolation or as first-line treatment. Cases in which the arrhythmogenic focus is clearly localized may benefit from the technique.44

Current guidelines recommend an ICD for patients fulfilling the 2010 Task Force criteria, particularly those with a family history of sudden cardiac death, sustained VT or recent unexplained syncope. The number of ventricular extrasystoles, frequency of arrhythmic events, and inducibility of VT are indicators of suitability for ICD implantation.9,12

An ICD should be considered for primary prevention in high-risk patients, although there is no agreement concerning indications. Syncope predicts appropriate ICD therapies in such patients, particularly for prevention of potentially fatal events.45,46

There is unanimity concerning the use of ICDs in the presence of documented ventricular tachycardia or fibrillation.45,47,48

The main complications of ICDs are pocket hematoma, problems with lead placement, and pericardial effusion or infection. In patients with ARVD, the RV wall may be perforated, while structural changes may hamper lead placement, reduce the device's sensitivity or affect cardiac rhythm. In addition, in young recipients the ICD will eventually need to be replaced and the leads repositioned.49

In the case presented, given the patient's unexplained syncope and induction of monomorphic VT and subsequent hemodynamic collapse, it was decided to place an ICD in line with the class Ic recommendation.47

Genetic studies should be performed in asymptomatic relatives of AVRD patients to stratify risk, but the presence of a mutation merely indicates risk and does not necessarily mean that it will lead to clinical expression. The only formal indication for genetic testing of relatives is when a causative mutation is identified in an index case.

Studies have shown in cases of familial disease that 50% of relatives who initially show no signs of disease eventually develop it later in life.2,40,50

Diagnosis of ARVD in relatives of an affected patient is based on the presence of inverted T waves in leads V1-V3 in individuals >14 years of age (this finding may be observed in younger healthy children), late potentials on signal-averaged ECG, VT of LBBB morphology on Holter ECG monitoring or during exercise testing, >200 ventricular extrasystoles per 24 hours by Holter, and mild RV dilatation or reduced EF and regional hypokinesia.51

The authors declare that no experiments were performed on humans or animals for this study.

The authors declare that they have followed the protocols of their work center on the publication of patient data.

The authors have obtained the written informed consent of the patients or subjects mentioned in the article. The corresponding author is in possession of this document.