Arrhythmogenic Right Ventricular

Introduction

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), also referred to as Arrhythmogenic Cardiomyopathy (ACM), is a rare but clinically significant inherited cardiac disorder characterized by the gradual replacement of right ventricular myocardium with fibrous and fatty tissue. This structural remodeling predisposes individuals to life-threatening ventricular arrhythmias, heart failure, and sudden cardiac death (SCD), particularly in young athletes.

The prevalence of ARVC is estimated at 1 in 2,000 to 1 in 5,000 individuals worldwide, though underdiagnosis remains common due to its variable expression and incomplete penetrance. Unlike other cardiomyopathies, ARVC is notable for its strong genetic basis, often following an autosomal dominant inheritance pattern with variable penetrance. Advances in molecular genetics over the past three decades have revealed that ARVC is primarily a desmosomal disease, with mutations in genes encoding cell-cell adhesion proteins being the most common culprits.

In this article, we will explore the molecular basis of ARVC, its inheritance patterns, pathophysiology, clinical manifestations, diagnostic criteria, and therapeutic strategies, while emphasizing the role of genetic counseling and family screening.

Historical Background

The first detailed descriptions of ARVC appeared in the late 1970s and early 1980s, when pathologists and cardiologists in Italy recognized a unique pattern of right ventricular arrhythmias associated with fibrofatty myocardial replacement. By the 1990s, it was established as a distinct clinical entity separate from dilated or hypertrophic cardiomyopathies.

Advances in genetic research, particularly the mapping of mutations in desmosomal genes (e.g., plakophilin-2, desmoglein-2), transformed understanding of ARVC into a molecular cardiomyopathy, enabling targeted diagnosis and familial screening. Today, ARVC represents one of the best-studied models of genetically mediated sudden cardiac death in young adults.

Pathophysiology and Molecular Basis

1. The Central Role of Desmosomes

The hallmark of ARVC lies in defects in desmosomes, specialized intercellular junctions critical for mechanical stability of cardiomyocytes. Desmosomes anchor intermediate filaments across cells, ensuring tissue integrity during repetitive contraction-relaxation cycles.

Mutations impairing desmosomal proteins weaken adhesion, making cardiomyocytes susceptible to mechanical stress. This leads to cell detachment, apoptosis, and fibrofatty replacement, primarily in the right ventricle (RV), where wall stress is greatest.

Key desmosomal proteins include:

Plakophilin-2 (PKP2)
Desmoplakin (DSP)
Desmoglein-2 (DSG2)
Desmocollin-2 (DSC2)
Junctional plakoglobin (JUP)

2. Molecular Mechanisms of ARVC

a) Cell-Cell Adhesion Defects

Mutations disrupt desmosomal binding and compromise cardiac tissue integrity.

b) Wnt/β-catenin Signaling Dysregulation

Desmosomal disruption displaces plakoglobin to the nucleus, inhibiting Wnt/β-catenin signaling.
This promotes adipogenesis and fibrogenesis, explaining the fibrofatty replacement hallmark.

c) Inflammation and Immune Activation

Myocyte death activates inflammatory cascades, further contributing to structural remodeling.

d) Calcium Handling Abnormalities

Secondary effects include impaired calcium signaling, predisposing to arrhythmias.

3. Non-Desmosomal Genes

Although desmosomal mutations account for ~50–60% of cases, non-desmosomal mutations are also implicated:

TMEM43 (transmembrane protein 43) – associated with aggressive ARVC phenotype.
DES (desmin) – cytoskeletal protein linking desmosomes to intermediate filaments.
LMNA (lamin A/C) – nuclear envelope protein, overlaps with dilated cardiomyopathy.
RYR2 (ryanodine receptor 2) – linked to calcium dysregulation and arrhythmic susceptibility.

4. Genotype-Phenotype Correlations

PKP2 mutations: Most common, typically cause classical RV-predominant ARVC.
DSP and DSG2 mutations: Often lead to biventricular or left-dominant involvement.
TMEM43 p.S358L mutation: Particularly aggressive, associated with high SCD risk in Newfoundland population.

Inheritance Patterns

ARVC demonstrates significant genetic heterogeneity and variable inheritance patterns, which influences both diagnosis and counseling.

1. Autosomal Dominant Inheritance

Most common form.
Variable penetrance: Not all carriers develop disease.
Variable expressivity: Clinical severity differs even within families.

2. Autosomal Recessive Inheritance

Rare; exemplified by Naxos disease (mutation in JUP) and Carvajal syndrome (DSP mutation).
Associated with cutaneous features such as palmoplantar keratoderma and woolly hair.

3. Digenic and Polygenic Inheritance

Some cases result from multiple mutations across different genes, leading to more severe phenotypes.

4. De Novo Mutations

Sporadic cases without family history occur due to novel mutations.

5. Penetrance and Age Dependency

Disease typically manifests in adolescence or young adulthood (teens to 40s).
Children may carry mutations but remain asymptomatic until later, complicating early diagnosis.

Clinical Manifestations

ARVC is a progressive disease often described in four stages:

Concealed Phase

Asymptomatic carriers.
Risk of sudden cardiac death may still be present.

Overt Electrical Phase

Symptomatic arrhythmias (palpitations, syncope).
Electrocardiographic abnormalities become evident.

Right Ventricular Dysfunction

Structural abnormalities detectable on imaging.
Progressive RV dilation, aneurysms.

Biventricular/End-Stage Heart Failure

Involvement of left ventricle (LV).
Clinical overlap with dilated cardiomyopathy.

Symptoms include:

Palpitations and syncope (arrhythmia-related).
Ventricular tachycardia (VT), often with left bundle branch block morphology.
Sudden cardiac arrest, especially during exercise.
Progressive right heart failure in later stages.

Diagnostic Criteria

The diagnosis of ARVC remains challenging due to its heterogeneity.

1. Task Force Criteria (2010 Revised)

Diagnosis is based on major and minor criteria across six categories:

Global/regional RV dysfunction and structural abnormalities.
Tissue characterization (fibrofatty replacement).
Repolarization abnormalities (ECG T-wave inversions in V1–V3).
Depolarization abnormalities (epsilon waves, late potentials).
Arrhythmias (VT, frequent PVCs).
Family history/genetics (pathogenic mutation or SCD in relatives).

2. Genetic Testing

Identifies mutations in ~60% of probands.
Critical for cascade family screening.

3. Imaging

Cardiac MRI: Gold standard for visualizing RV fibrofatty infiltration.
Echocardiography: Useful but less sensitive.
Electrophysiological studies: Risk stratification.

Risk of Sudden Cardiac Death

One of the most feared complications of ARVC is sudden cardiac death in young individuals, especially athletes. Exercise increases wall stress and accelerates disease progression, explaining the strong association between sports participation and adverse outcomes.

Key predictors of SCD in ARVC:

History of sustained VT or cardiac arrest.
Extensive RV or biventricular involvement.
Multiple mutations (compound heterozygosity).
Male sex and endurance sports participation.

Management Strategies

Management focuses on arrhythmia prevention, heart failure treatment, and family screening.

1. Lifestyle Modification

Exercise restriction: Avoid competitive and endurance sports.
Mild recreational activity may be permissible under guidance.

2. Pharmacological Therapy

Antiarrhythmics: Beta-blockers (first-line), sotalol, amiodarone.
Heart failure therapy: Standard regimens (ACE inhibitors, ARBs, beta-blockers, diuretics).

3. Implantable Cardioverter Defibrillators (ICDs)

Mainstay for preventing SCD.
Indicated in patients with sustained VT, aborted cardiac arrest, or high-risk profiles.

4. Catheter Ablation

Used for recurrent VT refractory to medications.
High recurrence rates due to progressive nature of ARVC.

5. Heart Transplantation

Option for end-stage biventricular failure.

Genetic Counseling and Family Screening

Given the strong genetic basis of ARVC:

Cascade screening of first-degree relatives is essential.
Genetic counseling informs families about inheritance risks and lifestyle modifications.
Early identification of at-risk relatives allows proactive monitoring and intervention.

Future Directions

Gene-Specific Therapies
- RNA-based or CRISPR-Cas9 gene editing for desmosomal mutations.
Biomarkers
- Circulating desmosomal fragments, microRNAs, and inflammatory markers may improve early diagnosis.
Precision Medicine
- Tailoring treatment based on genotype-phenotype correlations.
Improved Risk Stratification
- Integration of genetics, imaging, and machine learning models for SCD prediction.