ARVC: Arrhythmogenic Right Ventricular Cardiomyopathy

Desmosomes are the cell-cell adhesion junctions that hold cardiac myocytes together under mechanical stress. Every time the ventricle contracts, myocytes pull against each other. Desmosomes absorb this force and keep the tissue intact.

In ARVC, mutations in desmosomal genes weaken these junctions. Plakophilin-2 (PKP2) is the most commonly mutated gene, accounting for roughly 40% of genotype-positive cases. Other culprits include desmoglein-2 (DSG2), desmoplakin (DSP), desmocollin-2 (DSC2), and plakoglobin (JUP).

The consequence is straightforward. Under the repetitive mechanical stress of ventricular contraction, myocytes with weakened desmosomal connections detach from their neighbors and die. The body cannot regenerate cardiac muscle. It replaces the lost myocytes with fat and fibrous tissue.

This replacement is patchy. Some regions are completely replaced while adjacent areas retain normal myocardium. The boundary zones, where surviving muscle islands sit embedded within fibrofatty tissue, are where reentry circuits form.

The RV free wall is thin. It generates much lower pressures than the left ventricle, and it relies on a wall thickness of only 3-5 mm (compared to 10-15 mm for the LV). Despite the lower pressures, the thin wall experiences significant wall stress during each contraction.

When desmosomes are deficient, this thin wall is the most vulnerable to mechanical uncoupling. It is the weakest link. Myocyte loss begins here first, and it progresses most rapidly in regions of greatest wall stress: the subtricuspid area, the RV apex, and the infundibulum (the "triangle of dysplasia").

The disease does not always confine itself to the RV. Left-dominant forms exist, where the left ventricle is primarily involved (particularly with DSP mutations). Biventricular forms are common in advanced disease. The broader term arrhythmogenic cardiomyopathy (ACM) encompasses these variants.

Intense endurance exercise accelerates myocyte loss. Every training session increases the mechanical stress on already-weakened desmosomes. More stress means more cell detachment, more cell death, more fibrofatty replacement.

This is why ARVC disproportionately presents in athletes. It is also why exercise restriction is a cornerstone of management, even in genotype-positive patients who have not yet developed overt disease. Reducing mechanical load slows the rate of myocyte loss and substrate progression.

The disease is progressive regardless, but exercise dramatically accelerates the timeline. Early stages may show only subtle ECG changes with preserved RV function. Intermediate stages produce regional wall motion abnormalities and episodic VT. Advanced stages show extensive RV dilation, reduced systolic function, and recurrent sustained VT that may become refractory to therapy.

The ECG changes of ARVC reflect the progressive loss and delayed activation of RV myocardium. Three findings matter most:

T-wave inversions in V1-V3. These reflect repolarization abnormalities in the right ventricle. In an adult with a fully developed conduction system, T-wave inversions beyond V1 are abnormal. Extension to V3 or beyond carries higher diagnostic weight.

Epsilon waves. These are small positive deflections that appear just after the end of the QRS complex in leads V1-V2. They represent the delayed, fragmented activation of surviving myocyte islands embedded within fibrofatty scar. The impulse reaches these isolated pockets late because it must find tortuous paths through the scar tissue. Epsilon waves are specific but not sensitive; their absence does not rule out the disease.

Prolonged S-wave upstroke duration in V1-V3. When the terminal portion of the QRS takes longer than 55 ms to return to baseline in the right precordial leads, it suggests delayed RV activation. This is often the earliest and most sensitive ECG marker.

No single test diagnoses ARVC. The revised 2010 Task Force Criteria use a multi-domain scoring system that combines structural, histological, electrocardiographic, arrhythmic, and genetic findings. Each domain contributes major or minor criteria.

Structural criteria (echo or MRI): Regional RV akinesia, dyskinesia, or aneurysm, combined with either RV dilation or reduced RV ejection fraction. More severe abnormalities score as major criteria; milder versions as minor.

Tissue characterization: Histological evidence of fibrofatty replacement on endomyocardial biopsy (residual myocytes less than 60% by morphometry with fibrous replacement, with or without fatty replacement).

ECG criteria: T-wave inversions in V1-V3 (major), epsilon waves (major), prolonged terminal activation duration > 55 ms (minor), late potentials on signal-averaged ECG (minor).

Arrhythmic criteria: Sustained or non-sustained VT with LBBB morphology and superior axis (major) or inferior axis (minor). More than 500 PVCs per 24 hours (minor).

Family history/genetics: A pathogenic mutation in a desmosomal gene (major). First-degree relative with confirmed ARVC (major). Unexplained SCD before age 35 in a first-degree relative (minor).

Definite diagnosis requires 2 major, or 1 major plus 2 minor, or 4 minor criteria from different categories.

MRI is the single most informative imaging study. It provides tissue characterization that echocardiography cannot.

On T1-weighted sequences, fat appears bright. Fibrofatty infiltration of the RV free wall produces signal intensity that is clearly distinguishable from normal myocardium. Regional wall motion abnormalities (akinesia, dyskinesia, dyssynchronous contraction) are visible on cine imaging.

Late gadolinium enhancement (LGE) identifies fibrosis. In ARVC, LGE appears in the RV free wall and may extend into the interventricular septum or LV free wall in biventricular disease. The distribution of LGE correlates with the location of VT circuits on electroanatomic mapping.

RV dilation and systolic dysfunction are quantified precisely with volumetric analysis. These measurements feed directly into the Task Force Criteria.

Exercise restriction. No competitive sports. Limit endurance exercise intensity. This applies to confirmed patients and to genotype-positive family members, even without overt disease. The goal is to reduce the mechanical stress that drives disease progression.

Beta-blockers. First-line therapy for reducing catecholamine-driven arrhythmia triggers. They do not halt fibrofatty replacement, but they decrease the frequency of ventricular ectopy and may reduce VT episodes.

Antiarrhythmics. Sotalol (combined beta-blockade and class III action) or amiodarone for patients with recurrent VT despite beta-blockers. Neither is curative; both reduce VT burden.

ICD implantation. Indicated for patients at high risk of sudden death: prior cardiac arrest, sustained VT, severe RV dysfunction, or extensive disease with syncope. The ICD does not prevent VT. It terminates VT that would otherwise degenerate into VF.

Catheter ablation. For patients with recurrent VT despite antiarrhythmics. Because fibrofatty replacement often extends to the epicardium, an epicardial approach is frequently necessary. Recurrence rates are high (roughly 50% at 5 years) because the substrate is progressive. Each ablation procedure targets the current circuits, but new circuits form as disease advances.

Transplantation. Reserved for end-stage disease with refractory heart failure or incessant VT storms that cannot be managed with ablation and antiarrhythmics.