Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically determined cardiomyopathy caused by mutations in genes encoding desmosomal proteins — the intercellular junctions responsible for mechanical coupling between cardiomyocytes. The five major desmosomal genes implicated are plakophilin-2 (PKP2), desmoglein-2 (DSG2), desmocollin-2 (DSC2), desmoplakin (DSP), and plakoglobin (JUP). PKP2 mutations are the most common, accounting for 25–40% of genotype-positive cases. Inheritance is typically autosomal dominant with variable penetrance and expressivity.

The hallmark pathological feature is progressive fibrofatty replacement of the right ventricular myocardium. This process preferentially involves the so-called triangle of dysplasia — three anatomic regions of the RV that are most vulnerable: the RV outflow tract (RVOT), the RV apex, and the subtricuspid region (RV inflow). These areas of fibrofatty infiltration serve as the substrate for reentrant ventricular arrhythmias by creating zones of slow conduction, conduction block, and abnormal automaticity.

ARVC follows a characteristic natural history through progressive clinical phases:

• Concealed phase: subtle structural changes present but clinically silent; patients may be at risk for sudden cardiac death as the first manifestation, particularly during vigorous exercise
• Overt arrhythmic phase: symptomatic ventricular arrhythmias (PVCs, sustained or non-sustained VT) with ECG and imaging abnormalities; RV function may be preserved or mildly reduced
• Structural RV failure: progressive RV dilation and dysfunction with right-sided heart failure
• Biventricular failure: end-stage disease with LV involvement mimicking dilated cardiomyopathy; may require transplantation

The mechanistic link between desmosomal dysfunction and fibrofatty replacement involves disruption of Wnt/beta-catenin signaling. Loss of desmosomal integrity leads to nuclear translocation of plakoglobin, which suppresses Wnt signaling and promotes adipogenesis and fibrogenesis in cardiac progenitor cells. This molecular pathway explains why the disease is progressive and why mechanical stress (exercise) accelerates the phenotype — weakened cell-cell junctions are more vulnerable to hemodynamic load.

The 12-lead ECG is a critical screening and diagnostic tool in ARVC. Abnormalities reflect the underlying RV myocardial disease — delayed and fragmented activation through fibrofatty scar. ECG changes may precede structural abnormalities detectable on imaging and are incorporated into the 2010 Task Force diagnostic criteria.

Depolarization Abnormalities

Epsilon waves are small-amplitude deflections occurring at the end of the QRS complex in leads V1–V3, representing delayed activation of isolated myocardial islands within fibrofatty scar. They are pathognomonic for ARVC but have low sensitivity (approximately 15–35%), as they require extensive disease to be visible on the surface ECG. High-gain ECG and signal-averaged ECG improve detection. A terminal activation delay (TAD) >55 ms — measured from the nadir of the S wave to the end of QRS in V1–V3 — is a more sensitive marker of RV conduction delay. Similarly, a prolonged S-wave upstroke duration >55 ms in V1–V3 reflects delayed RV activation and is included as a minor criterion.

Repolarization Abnormalities

T-wave inversion in the right precordial leads is one of the most sensitive ECG findings. In adults (age >14 years), T-wave inversion in V1–V3 in the absence of complete RBBB is a major criterion. T-wave inversion extending beyond V3 (to V4–V6) suggests more extensive disease or left ventricular involvement. Isolated T-wave inversion in V1–V2 is a minor criterion.

Arrhythmia Morphology

VT in ARVC characteristically has LBBB morphology because it originates from the RV. The axis helps localize the origin: superior axis suggests RVOT origin, inferior axis suggests subtricuspid or RV inflow origin, and left axis deviation may indicate RV apical origin. QRS fragmentation — the presence of multiple small deflections within the QRS complex — is an additional marker of myocardial scar and may be present even in sinus rhythm.

Electrophysiology study and electroanatomic mapping provide critical information for arrhythmic risk assessment, VT characterization, and ablation planning in ARVC. The EP study reveals the extent and distribution of myocardial scar that is often underestimated by conventional imaging.

Programmed Ventricular Stimulation

VT inducibility with programmed ventricular stimulation is common in ARVC patients, particularly those with prior sustained VT or aborted SCD. Up to 70–80% of patients with clinical VT have inducible sustained monomorphic VT. Multiple VT morphologies are frequently induced — reflecting the diffuse, patchy nature of the scar substrate with multiple potential reentrant circuits. Induction of VF or polymorphic VT is less specific and may occur even in the concealed phase.

Activation and Entrainment Mapping

During sustained VT, activation mapping can identify the reentrant circuit, including the critical isthmus within the scar. However, multiple VT morphologies and hemodynamic instability often limit the utility of activation mapping. Entrainment mapping can confirm circuit participation but carries the risk of VT acceleration or degeneration to VF. For these reasons, substrate-based ablation guided by electroanatomic voltage mapping is the preferred approach in most ARVC patients.

High-density mapping with multi-electrode catheters (e.g., PentaRay, Orion basket) has improved the resolution of scar characterization, enabling identification of surviving myocardial channels within scar that serve as VT isthmuses. These channels are key ablation targets and correlate with areas of fractionated electrograms and late potentials.

Catheter ablation plays an important adjunctive role in ARVC management, primarily for reducing VT burden and ICD therapies. However, it is critical to understand that ARVC is a progressive disease — ablation cannot cure the underlying cardiomyopathy, and new arrhythmogenic substrate will develop over time.

Endocardial vs Epicardial Approach

A fundamental principle of ARVC ablation is that the epicardial substrate often exceeds the endocardial substrate. Fibrofatty replacement in ARVC characteristically begins in the epicardial and mid-myocardial layers and progresses inward toward the endocardium. As a result, endocardial-only ablation misses a significant portion of the arrhythmogenic substrate and is associated with higher VT recurrence rates.

Substrate-Based Ablation Targets

Given the difficulty of mapping multiple VTs in hemodynamically unstable patients, substrate-based ablation is the standard strategy in ARVC. Key targets include:

• Fractionated electrograms: multicomponent, low-amplitude signals within the scar border zone indicating slow, heterogeneous conduction
• Local abnormal ventricular activities (LAVA): sharp, high-frequency potentials distinct from the far-field ventricular electrogram, occurring during or after the QRS complex; these represent surviving myocardial bundles within fibrotic tissue
• Late potentials: electrograms extending beyond the QRS duration, indicating delayed activation of isolated myocardial fibers
• Scar border zone: the transition zone between normal voltage (>1.5 mV) and dense scar (<0.5 mV) where reentrant circuits are most likely to anchor
• Pace-mapping: sites where pacing reproduces the clinical VT morphology (≥11/12 lead match) identify the exit site of the VT circuit

Cornerstone Therapies Beyond Ablation

ICD implantation remains the cornerstone of sudden death prevention in ARVC. Class I indications include prior sustained VT, aborted SCD, and severe RV or biventricular dysfunction. ICD programming should include long detection intervals and high rate cutoffs to minimize inappropriate therapies, as these patients are often young and active.

Exercise restriction is a critical and often underemphasized intervention. Competitive and endurance exercise should be avoided in all ARVC patients and genotype-positive family members, regardless of phenotype severity. Moderate recreational exercise may be acceptable but remains an area of active investigation. Antiarrhythmic drugs — particularly sotalol and amiodarone — are used as adjuncts to reduce VT burden and ICD shocks, especially when ablation is not feasible or has failed.