Aetiology

As far as aetiology is concerned, a number of theories to explain this condition have been proposed which include dysontogenetic, degenerative, inflammatory, transdifferentiation, apoptogenic and infective.4 ,5 But the exact mechanism remains still unknown.

Incidence and prevalence

True incidence of this disease is not known but the prevalence is approximately 0.02–0.1% in the general population.4 There is a wide variation seen geographically; in the USA, ARVC causes 5% of sudden cardiac deaths (SCDs) in individuals under the age of 65 years and at least 3–4% of deaths in young athletes. On the other hand, in the Veneto region of Italy, ARVC is the most common cause of sudden arrhythmic deaths in individuals under the age of 35 years and the main cause of sudden death in young athletes in Italy.6 Men are more commonly affected. The diagnosis of ARVC is made in 80% of cases in patients below the age of 40 years. Hence, it should be suspected in young patients presenting with unprecedented history of syncope, cardiac arrest or arrhythmias.

Clinical presentation

Patients with ARVC may have a wide range of presenting symptoms, varying from fatigue, atypical chest pain, syncope or acute coronary syndrome. Main presenting features include:

1. Arrhythmias: Generally with left bundle branch block morphology, as they are originating from the RV.

2. SCD: ARVC is responsible for SCD for approximately 5% of patients under the age of 65 years and for 3–4% deaths in young athletes. The annual mortality rate varies from 3% in the untreated to 1% in those with pharmacological medical treatment (not including ICD treatment).6 The cause of SCD is commonly VT degenerating into ventricular fibrillation (VF). The fibrofatty deposits form the substrate required to trigger these events induced by adrenergic stimulation.

3. Heart Failure: Patients may develop isolated RV failure or left-sided failure. This is generally seen in the fourth or the fifth decades7 and is due to dilatation and thinning of the RV.

4. In addition, patients may present with frequent ventricular ectopics >1000 beats/day.

Natural history

The natural history of ARVC depends on the rate of progression of RV dysfunction and the symptoms/presentation. The mortality rate has been reported to be in the range of 4–20%. It seems to be equal in men and women, though peaking in the fourth decade. It is stated to account for 5% of deaths in young adults and 25% deaths in athletes.4 Bi-and RV heart failure is known to occur in a period of 4–8 years after the development of complete right bundle branch block (RBBB). This has also been linked with cardiovascular mortality independently.4

In view of this, it is of great importance that this condition is identified and the treatment commenced.

Diagnosis

A definitive diagnosis of ARVC requires histological demonstration of fibrofatty, this in turn requires myocardial biopsy which may be difficult because of the patchy nature of the deposits, also interventricular septum is the most common site of biopsy and in ARVC the septum may be involved quite late, a diagnostic criterion was described in 1994 in a Task Force report,8 based on major and minor criteria involving structural, genetic, ECG, arrhythmia and histological factors (some of which are described below). In 2002, it was modified for first-degree relatives.9 More recently, studies have been conducted to determine screening interval and testing for strategy at-risk relatives of patients with ARVC.10

The only criticism of the diagnostic criteria was that though very specific, it was not very sensitive for early and familial diseases. This has been further modified in the Task Force recommendations in 201011 (box 1).

ECG characteristics

Approximately 90% of patients present with ECG abnormalities. The important ones include T wave inversions in leads V1–V3, which are seen in about 54% of the patients (in the absence of RBBB).12 It is important to remember that this can be a normal variant in children and in young, trained athletes and is therefore useful only in patients over the age of 12 years. In addition, complete RBBB is seen in 15% and incomplete in 18% of patients with ARVD13 and with the presence of QRS (complexes of >50 ms) in leads V1–V3 as compared with V6 forms a major criterion.14 Epsilon waves, which are postexcitation electrical potentials that occur at the end of QRS complex are seen in 30% of all cases of ARVD. They are very specific of ARVD and are due to delayed RV activation. In addition, presence of prolonged QRS duration of >110 ms in precordial leads and presence of RBBB with QRS precordial dispersion of >50 ms is a predictor of arrhythmic events.6 Late action potentials on signal averaged ECG, especially on the left precordial leads are a minor criterion for diagnosis of ARVD. Several studies have also shown a relation between ARVC and Brugada syndrome.4

Echocardiography

The major echocardiographic findings include RV dilation, localised aneurysms, enlarged left atria (LA), dilated RV outflow tract, increased reflectivity of moderator band, prominent trabeculations of RV apex and inferobasal dyskinesis. Other important parameters include RV end-systolic and end-diastolic diameters and ratio of RV to LV end-diastolic diameters. A ratio of >0.5 has a sensitivity of 86%, specificity of 93% and a positive predictive value of 86% in confirming the diagnosis of ARVC.13

RV angiography

RV ventricular angiography is still considered to be important for diagnosing ARVC by many but because it is invasive and associated with complications such as arrhythmias it is no longer used as a primary diagnostic tool and is largely superseded by magnetic resonance imaging (MRI). The findings include infundibular aneurysms, apical aneurysms, prominent moderator band, diastolic bulging of inferior wall, thick trabeculations, and in some tricuspid valve prolapse.12

Computerised tomography (CT)

CT scan is helpful in visualising the RV and the LV because of its high resolution and is also of use in patients with ICDs. It helps to identify the presence of epicardial fat, intramyocardial fat deposits, trabeculations and dilated hypokinetic RV. However, high radiation burden limits its usefulness as an initial screening tool.4

MRI

MRI is considered to be the one of the important and accurate non-invasive tests available to diagnose ARVC. It helps to analyse RV anatomically, morphologically and functionally. It is useful in demonstrating intramyocardial fat deposits, wall thinning, hypertrophy, trabeculations, right ventricular outflow tract (RVOT) enlargement, presence of RV aneurysms, RV dilation, failure of systolic thickening and impaired global RV function.

In addition, MRI has been used for diagnosing ARVC using anatomical, morphological and functional criteria including: presence of high intensity areas indicating fat deposits, RVOT ectasia, dyskinesia, RV dilatation and right atrial (RA) enlargement.15 However, this technique may be limited because of thin RV free wall resulting in difficulty in assessing RV thickness and in identifying intramyocardial fat in the presence of epicardial and pericardial fat deposits.16

Radioisotope techniques

These techniques though useful in diagnosing SCD in patients by demonstrating RV and LV involvement, are not the first-line diagnostic tools mainly because of their suboptimal spatial resolution and exposure to radiation.4

Genetic factors

ARVC has a strong family predilection; it is commonly inherited as autosomal dominant trait with various degrees of penetrance and polymorphic phenotypical expression. Several ARVC loci to chromosomes have been identified, this includes 14q23- q24(ARVD1),1q42-q43(ARVD2),14q12-q22(ARVD3), 2q32(ARVD4), 3p23(ARVD5), 10p12–14(ARVD6), 10q22,6p24(ARVD8) and 12p11(ARVD9).17 An autosomal recessive variant associated with palmoplantar keratosis has been mapped to 17q21 (Naxos disease). In addition, cardiac ryanodine receptor gene (RyR2) association with ARVC has also been recently described.4

Genetic screening therefore is very useful in detection and risk stratification, in family members with little or no symptoms, but genetic testing can only support a diagnosis of ARVC not make it. Having a mutation does not necessarily mean that the patient will present clinically, only that they are at risk. This is useful when considered along with other criteria to make the diagnosis of ARVD.18

Histology

The most characteristic histological feature of ARVC is replacement of myocytes with fibrofatty tissue and thinning of the RV wall. This begins at subepicardium and progresses to endocardium.7 Most frequently involved areas are RV inflow, the apex and the infundibulum. These three form the ‘triangle of dysplasia’,16 though interventricular septum and LV free wall may also be involved. Histology forms one of the major criteria for definitive diagnosis of this condition (box 1).

Management of patients with ARVC

The main treatment modalities for ARVC include

Pharmacological therapy

Despite the importance of antiarrhythmic drugs in ARVC there are no clinical trials focusing on their efficacy in these patients. β-blockers and amiodarone are considered useful for patients with asymptomatic ARVC to suppress adrenergically stimulated arrhythmias. Studies that have been carried out on sotalol prove it to be more effective than β-blockers and amiodarone for inducible and non-inducible VT19 during programmed stimulation in 68% but its efficacy in preventing sudden death is unknown. In some cases, verapamil can also be considered. In a recent study of patients with ICDS amiodarone proved to be more effective than β-blockers and sotalol. Antiarrhythmic drugs are useful in patients with ICDs and ventricular arrhythmias.20

Radiofrequency ablation

Radiofrequency ablation may be attempted in non-responders or those intolerant of medical treatment but it is not very effective and may need multiple procedures as there may be more than one foci due to the diffuse and progressive nature of the disease. The success rates have been reported to be 32%, 45% and 66% after first, second and third attempts, respectively.21 Epicardial VT ablation has also been reported to be useful especially in patients with limited endocardial substrate and in those with refractory VT to improve long-term clinical outcomes.22

Intracardiac defibrillators

The recommendations for ICD implantation for the prevention of SCD in patients with ARVD/ARVC include documented sustained VT or VF for those who are receiving optimal medical therapy and have a reasonable expectation of survival (Class I recommendation). For primary prevention of ICD implantation can be considered (Class IIa recommendation) in patients with extensive disease, including those with LV involvement, with one affected family member with SCD, or undiagnosed syncope when VT or VF has not been excluded as the cause of syncope, and who are receiving optimal medical therapy and have a reasonable expectation of survival.23

A recent study carried out to identify the predictors, characteristics and treatment of ventricular arrhythmias in patients with ARVC found that the incidence of VT was predicted by the presence of sustained ventricular arrhythmias prior to ICD implantations and T wave inversion in inferior leads and the only predictor for life-threatening arrhythmias was young age at enrolment. Antitachycardia pacing successfully terminated 92% of VT irrespective of VT cycle length. They have therefore recommended that all ICDs should be programmed for antitachycardia pacing, even for rapid VT.24 But it is important to remember that ICD implantation may not be entirely straightforward because of thin myocardium and difficulty in sensing because of fibrofatty deposits.

Once patients have developed RV or biventricular failure secondary to ARVC, therapy for heart failure management may be required.

In case of refractory disease, surgical therapies can be considered including (previously) total disconnection of RV free wall, RV exclusion surgery and heart transplantation. Total disconnection is associated with RV dilatation and failure, so RV exclusion surgery can be considered.25

As ARVC has been recognised an important cause of death in young athletes, mostly secondary to malignant ventricular arrhythmias caused by adrenergic stimulation, young patients with this condition are prohibited from vigorous athletic sports. This restriction applies even after ICD implantation, as most devices are programmed to deliver a maximum of six shocks only, which may not be enough to terminate malignant ventricular fibrillation26–28 (table 1).