Arrhythmogenic Cardiomyopathy (ARVC)

About this condition

Arrhythmogenic Cardiomyopathy (ARVC)

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by progressive fibrofatty replacement of myocardium, predominantly affecting the right ventricle, which predisposes to ventricular arrhythmias, heart failure, and sudden cardiac death — particularly during exercise. Prevalence is estimated at 1 in 1,000 to 1 in 5,000. ARVC is a leading cause of sudden cardiac death in young athletes and accounts for up to 20% of sudden death cases in those under 35 years old. Inheritance is autosomal dominant with incomplete penetrance and variable expressivity. Approximately half of ARVC cases are familial; the other half result from de novo variants. Left-dominant and biventricular variants of ARVC are now recognized, expanding the original right-ventricular-dominant phenotype.

Three desmosomal genes account for the majority of ARVC cases. PKP2 (plakophilin-2) is the most frequently mutated gene, found in 20–46% of ARVC cases and predominantly associated with classic right-dominant disease. DSP (desmoplakin) and DSG2 (desmoglein-2) each account for approximately 10% of cases and are more frequently associated with biventricular or left-dominant phenotypes with higher heart failure risk. These proteins form the cardiac desmosome, the mechanical junction that couples cardiomyocytes. Pathogenic variants weaken cell-cell adhesion, particularly under mechanical stress (exercise), triggering cardiomyocyte detachment and replacement by fibrofatty scar tissue.

Identifying an ARVC mutation has major implications for patient management and family screening. Affected individuals are advised to restrict strenuous exercise, which is a potent trigger for arrhythmias. Medical therapy with beta-blockers and antiarrhythmic drugs (sotalol, amiodarone) is initiated. Implantable cardioverter-defibrillators (ICDs) are recommended for patients with recurrent arrhythmias or family history of sudden death. Genetic testing enables cascade screening of relatives — identifying asymptomatic mutation carriers who may have no cardiac symptoms yet but who benefit from surveillance and activity restriction. Gene-specific risk stratification is now recognized: PKP2 variants generally have better prognosis than DSP or DSG2 variants.

PKP2, DSP, and DSG2 variants differ in their phenotypic expression — PKP2 typically right-dominant, DSP and DSG2 more often biventricular or left-dominant with higher heart failure risk.

Gene locus: PKP2 (12p11.21), DSG2 (18q12.1), DSP (6p24.3)

Standard ARVC panels test 5–8 desmosomal genes but find mutations in only 40–60% of clinically diagnosed patients.

The mutation may be in a region standard panels miss

Standard ARVC panels typically test 5–8 desmosomal genes plus select non-desmosomal genes. However, a pathogenic variant is identified in only 40–60% of patients meeting clinical diagnostic criteria for ARVC. The remaining cases may involve non-desmosomal genes, digenic or oligogenic inheritance, deep intronic variants affecting splicing, or complex structural variants not detected by standard sequencing. PKP2 is particularly challenging — missense variants are common but difficult to interpret due to high background variation. VUS rates are high in desmosomal genes. Whole genome sequencing captures the full sequence including non-coding regions and enables detection of structural variants.

A finding enables activity restriction and preventive ICD placement

When a pathogenic desmosomal mutation is confirmed, it triggers cascade testing of first-degree relatives — identifying asymptomatic mutation carriers who may have no ECG abnormalities yet. Management becomes gene-informed: PKP2 carriers typically have better long-term prognosis and may tolerate some athletic activity; DSP and DSG2 carriers warrant more stringent activity restriction and lower threshold for ICD implantation. Medical therapy with beta-blockers and antiarrhythmics is initiated. For high-risk carriers with prior arrhythmias or family history of sudden death, ICD placement is a life-saving intervention. Early identification of at-risk relatives through cascade genetic testing enables preventive strategies before the first arrhythmia occurs.

Heart palpitations during exercise. A family member with an unexplained cardiac event. The connection between the two could be a single gene — and knowing changes everything.