Arrhythmogenic Right Ventricular Cardiomyopathy and Variants

Patients may be asymptomatic, but those who are symptomatic often present first with syncope, sustained ventricular tachycardia (VT), ventricular fibrillation (VF), or sudden death (1). Ventricular tachyarrhythmias are particularly likely to occur during emotional or physical stress.

Patients may have palpitations or syncope.

Atrial fibrillation and signs of right and/or left ventricular systolic failure are usually manifestations of advanced disease.

• ECG

• Sometimes signal-averaged ECG

• Cardiac imaging (eg, echocardiography, cardiac CT, cardiac MRI, right ventricular angiography)

• Sometimes right ventricular biopsy

• Genetic testing

• Screening of first-degree relatives

Diagnosis of ARVC and its variants is difficult, leading to historic under-recognition of the disorders. ARVC or a variant should be suspected in patients, particularly young patients (often < 40 years old) (1), with palpitations, cardiac syncope, documented ventricular tachyarrhythmias, or resuscitation from unexplained cardiac arrest in the absence of clinically evident structural heart disease.

The diagnosis of ARVC is often first suspected when it is recognized that the patient's ventricular arrhythmias are of right ventricular origin, typically indicated by a left bundle branch block–shaped QRS complex with a superior frontal plane axis (the latter helping to differentiate ARVC from the more benign idiopathic right ventricular outflow tract ventricular tachycardia, which usually has an inferior frontal plane QRS axis). When monomorphic VT occurs, ECG morphology usually reflects the location of the ventricular scar, most commonly a left bundle branch block pattern indicating a right ventricular origin (2)

The initial evaluation of patients with suspected arrhythmogenic cardiomyopathy includes history, family history, ECG, echocardiography, and cardiac MRI. If no spontaneous ventricular arrhythmia has been demonstrated, exercise testing, ambulatory ECG monitoring, and/or electrophysiologic testing may be required. If the diagnosis remains in doubt, testing may include signal averaged ECG, electrophysiologic testing, and right ventricular endomyocardial biopsy (2, 3). Right ventricular angiography is not routine but, if performed, may reveal characteristic structural abnormalities and also allow biopsy of the right ventricle; however, biopsy findings are often nonspecific, and biopsy is rarely performed.

Fatty Infiltration of Myocardium

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NIGEL DOWNER/SCIENCE PHOTO LIBRARY

Because no single test is diagnostic, major and minor diagnostic criteria have been proposed by an international task force (4). Different combinations of major and minor criteria are required for the diagnosis of possible, borderline, or definite disease of the right, left, or both ventricles. The criteria include:

• Evidence of right and/or left ventricular disease on imaging studies (often fibrous or fatty infiltration or replacement of myocardial tissue)

• Ventricular biopsy showing replacement of myocytes by fibrous tissue, fatty tissue, or both

• ECG repolarization changes including right precordial T-wave inversion

• ECG depolarization changes including right precordial epsilon waves

• Signal-averaged ECG showing late potentials

• Documented ventricular arrhythmias originating from ventricular scar (most commonly from the right ventricle)

• Family history of ARVC or a variant,or of sudden death

• Identification of a gene mutation associated with ARVC or a variant

The key entities to consider in the differential diagnosis are cardiac sarcoidosis, athlete's heart, myocarditis, and idiopathic right ventricular outflow tract VT.

Genetic testing is recommended in patients suspected of having ARVC or one of its variants. The yield of testing is approximately 50 to 70% when diagnostic criteria are met (5, 6).

Clinical screening and genetic testing are also recommended in first-degree relatives if the patient has a causative mutation. Family members who do not carry the causative mutation can then be released from ongoing surveillance. Family members who share the causative genetic mutation and first-degree relatives with unknown genetic status should have clinical evaluation (ie, to detect symptoms suggestive of arrhythmia), ECG, ambulatory ECG monitoring, and echocardiography starting at age 10 to 12 years and every 1 to 3 years thereafter (3). Some experts suggest individualized family screening based upon age, symptoms, and degree of diagnostic certainty (7).

• Moderation of physical activity

• Often an implantable cardioverter-defibrillator (ICD)

• Usually a beta-blocker

• Sometimes antiarrhythmic medications (particularly sotalol or amiodarone)

• Heart failure therapy (including transplantation) as required

Treatment of ARVC and its variants focuses on prevention of sudden death and prevention of symptomatic ventricular tachyarrhythmias.

Patients should avoid competitive or frequent high-intensity endurance athletics because such activities lead to both disease progression and increased risk of life-threatening arrhythmias (1, 2). These risks are higher in males and in patients with more advanced disease (as evidenced by more task force criteria). However, even patients with genotype-positive, phenotype-negative disease are advised to limit competitive and endurance exercise as reduction has been associated with reduced development and progression of clinical disease.

The 5-year risk of a first episode of potentially life-threatening arrhythmia ranges widely, depending on age, sex, cardiac syncope within 6 months of diagnosis, non-sustained VT, ventricular premature beat frequency, the extent of T-wave inversion, right ventricular and left ventricular ejection fraction, VT inducibility during an electrophysiologic study, and the specific genetic abnormality (3, 4, 5). An online risk calculator for patients with ARVC is available (https://www.ARVCrisk.com).

Prevention of sudden death is by an ICD (see also table Indications for an ICD). The decision to place an ICD is shared between the patient and physician, with the following indications (2):

• Resuscitated cardiac arrest with VT or VF

• Prior sustained VT with hemodynamic instability

• Prior sustained VT without hemodynamic instability

• Syncope suspected to be due to ventricular arrhythmia

• Severe left ventricular systolic dysfunction

• Various combinations of major and minor risk factors for ventricular arrhythmia

Significant right or left ventricular dysfunction will require medical therapy for heart failure (2).

A beta-blocker should be used in most patients. In addition to heart failure indications, a beta-blocker can be used in patients without an ICD or in patients with an ICD and inappropriate discharges (2).

Antiarrhythmic therapy with flecainide or with a Antiarrhythmic therapy with flecainide or with aclass III medication, particularly sotalol or amiodarone, may reduce symptomatic ventricular tachyarrhythmias but is not a substitute for an ICD. These medications may benefit patients who have frequent, appropriate ICD discharges despite adequate beta-blocker therapy. Transcatheter ablation of the arrhythmogenic substrate may also be useful in such patients (, particularly sotalol or amiodarone, may reduce symptomatic ventricular tachyarrhythmias but is not a substitute for an ICD. These medications may benefit patients who have frequent, appropriate ICD discharges despite adequate beta-blocker therapy. Transcatheter ablation of the arrhythmogenic substrate may also be useful in such patients (6).

• Arrhythmogenic right ventricular cardiomyopathy and its variants are genetic disorders in which myocytes are replaced by fibrofatty tissue, leading to arrhythmias and later right and/or left ventricular failure.

• The disorder progresses quicker in patients who engage in frequent, high-intensity endurance exercise.

• Diagnosis is based on consensus criteria involving clinical and electrocardiographic factors, cardiac imaging, and genetic testing.

• First-degree relatives have a significant risk of disease and require initial screening (including genetic testing when the causative mutation is known) and regular testing.

• Treatment requires moderation of physical activity, beta-blockade, and often an ICD.