Is Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) a hereditary condition and how is it managed?

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is Hereditary

ARVC is inherited as an autosomal dominant genetic trait in most cases, caused by mutations in genes encoding desmosomal proteins including plakoglobin, desmoplakin, plakophilin-2, desmoglein-2, and desmocollin-2. 1

Genetic Basis and Inheritance Pattern

• ARVC is a desmosomal cardiomyopathy with approximately 60% of index patients having identifiable pathogenic mutations in genes encoding cardiac desmosome proteins 2
• The disease demonstrates autosomal dominant inheritance with incomplete penetrance, meaning not all mutation carriers will develop clinical disease 1
• Rare recessive forms exist (Carvajal syndrome and Naxos disease) that are associated with palmar and plantar hyperkeratosis 1
• The disease is familial in at least 30% of cases, though this likely underestimates true heritability given incomplete penetrance 1
• A minority of cases result from mutations in non-desmosomal genes 1

Clinical Characteristics and Natural History

• ARVC is a progressive heart muscle disorder characterized by replacement of cardiomyocytes with adipose and fibrous tissue, primarily affecting the right ventricle but with left ventricular involvement in >50% of patients 1, 3
• Clinical manifestations typically develop between the second and fourth decades of life, presenting with palpitations, syncope, ventricular tachycardia, and sudden cardiac death 1
• The estimated prevalence is 1 in 1,000 to 1 in 5,000 in the general population 1
• ARVC is an important cause of sudden cardiac death in athletes and young adults, accounting for approximately 25% of deaths in the pre-coronary artery disease age group (<35 years) 1

Diagnosis and Family Screening

Genetic counseling and testing are recommended for diagnosis and gene-specific targeted family screening in all clinically diagnosed or suspected ARVC cases 4, 3

• First-degree relatives require clinical screening including 12-lead ECG, 48-hour Holter monitoring, echocardiography, and cardiac MRI when the proband has an identified pathogenic mutation 4, 3
• The 2010 Task Force Criteria combine histological, genetic, electrocardiographic, imaging parameters, arrhythmias, and family history to classify patients into definite, borderline, and possible diagnostic categories 1, 3
• Cardiac MRI is essential for establishing diagnosis and risk stratification, providing superior assessment of right ventricular size, function, regional wall motion abnormalities, and detection of fibrofatty replacement 4

Management Approach

Exercise Restriction (Critical for All Patients)

Avoidance of competitive sports is mandatory in all patients with ARVC (definite, borderline, or possible diagnosis), with possible exception only for low-intensity class 1A sports 1

• This is a Class I recommendation from the European Society of Cardiology despite being based on observational data 1, 3
• Exercise increases penetrance and arrhythmic risk in mutation carriers, and frequent endurance exercise increases risk for ventricular tachycardia/ventricular fibrillation and heart failure 1
• High-intensity and endurance exercise widely increases disease expression and progression 5

Medical Therapy

Beta-blockers are recommended as first-line therapy for all ARVC patients with ventricular arrhythmias 4, 3

• Beta-blockers can be useful even in patients with clinical evidence of ARVC but without documented ventricular arrhythmias 4
• Amiodarone was superior to beta-blockers and sotalol in preventing ventricular arrhythmias in observational studies 1, 3
• Amiodarone or sotalol can be effective when ICD implantation is not feasible 1, 4

ICD Therapy for Sudden Cardiac Death Prevention

ICD implantation is recommended (Class I indication) for patients with ANY of the following high-risk markers AND meaningful survival >1 year expected: 1, 4

• Resuscitated sudden cardiac arrest
• Documented sustained ventricular tachycardia or ventricular fibrillation
• Significant ventricular dysfunction with RVEF or LVEF ≤35%

ICD can be useful (Class IIa indication) for: 1, 4, 3

• Syncope presumed due to ventricular arrhythmia when VT or VF has not been excluded
• Extensive disease including left ventricular involvement
• One or more affected family members with sudden cardiac death
• Unexplained syncope in the context of clinical ARVC

Prophylactic ICD placement solely to permit sports participation is NOT recommended due to device-related complications 1

Catheter Ablation

Catheter ablation is recommended for recurrent symptomatic sustained VT despite optimal medical therapy, primarily to reduce arrhythmia frequency and prevent ICD shocks 4, 3

• Combined endocardial/epicardial approach can be beneficial when beta-blockers are ineffective or not tolerated 4, 3
• Ablation serves as adjunctive therapy but does not eliminate need for ICD in high-risk patients 1

Risk Stratification Parameters

The most important risk factors for sudden cardiac death or appropriate ICD discharge include: 6, 7

• Prior cardiac arrest or sustained ventricular tachycardia (highest risk)
• Syncope (particularly unexplained or during exertion)
• Extensive structural disease with RV dilation and LV involvement
• Significant ventricular dysfunction (RVEF or LVEF ≤35%)
• Frequent premature ventricular contractions or nonsustained VT
• Male sex
• Younger age at diagnosis
• Proband status (index case in family)
• Multiple mutations or TMEM43 mutation
• Extensive T-wave inversion (V1-V3 and beyond)
• Epsilon waves on ECG 8

Electrophysiological study may be considered for risk stratification in asymptomatic patients with clinical evidence of ARVC, though its role remains poorly defined 1, 4

Prognosis and Monitoring

• Annual mortality rates from meta-analysis show 0.9% for cardiac mortality, 0.8% for non-cardiac mortality, and 0.9% for heart transplantation 1
• ARVC is a progressive disease requiring periodic reassessment with repeat imaging to follow disease progression and reassess risk 4
• Disease progression may result in right or biventricular heart failure requiring transplantation 1, 3