ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic myocardial disease characterized by the progressive replacement of myocardial tissue with fibro-fatty tissue, predisposing individuals to ventricular arrhythmias, heart failure, and sudden cardiac death.
The primary involvement affects the right ventricle, but in more advanced cases, it can extend to the left ventricle, leading to the so-called biventricular arrhythmogenic disease.

This condition is one of the leading causes of sudden cardiac death in young individuals and athletes, due to its predisposition to sustained ventricular tachycardia and ventricular fibrillation. Diagnosis is complex and based on clinical, instrumental, and genetic criteria, while therapy focuses on arrhythmia prevention and heart failure management.

Epidemiology

Arrhythmogenic right ventricular cardiomyopathy is a rare genetic disease, with an estimated prevalence of 1 case per 2,000-5,000 individuals, although it is more common in some populations (such as in Italy and the Netherlands).

ARVC is a genetically determined disease, inherited in an autosomal dominant manner with variable penetrance.

The most frequently involved mutations affect desmosomal genes, particularly:

• PKP2 (Plakophilin-2): the most common mutation, present in approximately 40-50% of cases.
• DSP (Desmoplakin): associated with more severe forms and early biventricular involvement.
• JUP (Junction Plakoglobin): involved in syndromic forms such as Naxos Syndrome.
• DSG2 (Desmoglein-2) and DSC2 (Desmocollin-2): less frequent, but associated with variable phenotypes.

The age of onset is highly variable, but symptoms and arrhythmias tend to appear between 10 and 50 years, with a peak incidence in young adults. The risk of sudden death is particularly high in young individuals and athletes, especially during intense physical exertion.

Pathophysiology

Arrhythmogenic right ventricular cardiomyopathy is characterized by the progressive degeneration of the myocardium with replacement of contractile tissue by fibrosis and adiposity.
This process leads to:

• Structural alterations of the right ventricle: progressive dilation, aneurysm formation, and systolic dysfunction.
• Electrical instability: predisposition to polymorphic ventricular tachycardias and ventricular fibrillation.
• Disruption of myocardial tissue: alterations in intercellular junctions due to mutations in desmosomal proteins.
• Biventricular involvement: in advanced stages, the process may extend to the left ventricle, leading to systolic dysfunction and clinical deterioration.

Intense physical activity accelerates myocardial damage, promoting disease progression and increasing the risk of fatal arrhythmic events. For this reason, in patients with ARVC, it is crucial to avoid intense physical exertion and monitor arrhythmic risk with Holter monitoring and provocative tests.

Clinical Presentation

The clinical presentation of ARVC varies significantly, from asymptomatic patients to those with malignant ventricular arrhythmias or advanced heart failure.

The disease progresses through three main phases:

• Subclinical phase: the patient is asymptomatic, but ECG abnormalities and changes on cardiac magnetic resonance imaging (MRI) may be present.
• Arrhythmic phase: the patient develops ventricular extrasystoles or ventricular tachycardia, often triggered by physical exertion.
• Heart failure phase: progression to ventricular dilation and involvement of the left ventricle, leading to a form of dilated cardiomyopathy.

Main Signs and Symptoms

• Palpitations: rapid ventricular arrhythmias, often with a left bundle branch block morphology.
• Syncope or presyncope: due to sustained ventricular tachycardia or ventricular fibrillation.
• Dyspnea and fatigue: in patients with advanced ventricular dysfunction.
• Atypical chest pain: often related to arrhythmic episodes.
• Sudden cardiac death: a possible initial manifestation, especially in young individuals and athletes.

Physical Examination

The physical examination is often normal in the early stages, but in advanced cases, the following findings may be observed:

• Jugular vein distension: in patients with advanced right ventricular dysfunction.
• Tricuspid regurgitation murmur: caused by right ventricular dilation.
• Irregular ventricular pulsations: indicative of frequent ventricular arrhythmias.

Diagnosis

The diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC) is based on clinical, electrocardiographic, imaging, and genetic criteria.

In patients with suspected ARVC, instrumental tests are essential to confirm the diagnosis and stratify arrhythmic risk. These include:

• ECG: evaluation of inverted T waves in V1-V3, right bundle branch block patterns, and late potentials (epsilon wave).
• Holter ECG: useful for detecting frequent ventricular extrasystoles (>500 in 24 hours) or ventricular tachycardia with a left bundle branch block morphology.
• Echocardiography: assessment of right ventricular kinetics, with detection of dyskinesia, ventricular aneurysms, or progressive dilation.
• Cardiac magnetic resonance (CMR): key examination to document fibro-fatty myocardial replacement, regional dysfunction, and right ventricular aneurysms.
• Genetic testing: recommended to identify mutations in desmosomal genes (e.g., PKP2, DSG2, DSP), useful for familial diagnosis and risk stratification.
• Endomyocardial biopsy: indicated in selected cases to confirm the presence of fibro-fatty replacement and structural myocardial alterations.

The diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC) is established using the 2010 Task Force criteria, updated in 2020.

The diagnosis can be classified as:

• Definite: presence of 2 major criteria or 1 major criterion + 2 minor criteria or 4 minor criteria.
• Probable: presence of 1 major criterion + 1 minor criterion or 3 minor criteria.
• Possible: presence of 1 major criterion or 2 minor criteria.

Diagnostic Criteria

The criteria for defining arrhythmogenic right ventricular cardiomyopathy (ARVC) are divided into five categories, each containing major and minor criteria.

1. Structural and Functional (Imaging)

• Major Criteria:
  • CMR or echocardiography showing right ventricular dilation and dysfunction, with an ejection fraction <40%.
  • Presence of right ventricular aneurysms.
• Minor Criteria:
  • CMR or echocardiography showing mild dilation or moderate dysfunction of the right ventricle (EF 40-45%).
  • Segmental wall motion abnormalities in the right ventricle.

2. Histological

• Major Criterion: Endomyocardial biopsy showing fibro-fatty myocardial replacement.

3. Electrocardiographic

• Major Criteria:
  • Presence of an epsilon wave in right precordial leads (V1-V3).
  • Prolonged QRS duration ≥110 ms in V1-V3.
• Minor Criteria:
  • Inverted T waves in V1-V3 in patients older than 14 years, in the absence of right bundle branch block.

4. Arrhythmic

• Major Criteria:
  • Sustained ventricular tachycardia with a left bundle branch block morphology.
  • Nonsustained ventricular tachycardia with a left bundle branch block morphology and frequency >500 bpm in 24 hours.
• Minor Criteria:
  • Nonsustained ventricular tachycardia with a left bundle branch block morphology and frequency <500 bpm in 24 hours.
  • Ventricular extrasystoles >500/24h on Holter ECG.

5. Genetic and Familial

• Major Criterion: Presence of mutations in desmosomal genes (e.g., PKP2, DSG2, DSP).
• Minor Criterion: Positive family history of ARVC or sudden cardiac death under 35 years of age.

Early identification of ARVC is crucial to prevent life-threatening ventricular arrhythmias and sudden cardiac death.
Patients with borderline diagnostic criteria should be monitored over time with serial examinations to assess disease progression and the need for an implantable cardioverter-defibrillator (ICD) in high-risk individuals.

Treatment

The treatment of arrhythmogenic right ventricular cardiomyopathy (ARVC) aims to control ventricular arrhythmias, prevent sudden cardiac death, and manage ventricular dysfunction.
The therapeutic strategy depends on the severity of the disease and the patient's arrhythmic risk.

Pharmacological therapy is indicated for the prevention of ventricular arrhythmias and symptom control.
The main drugs used include:

• Beta-blockers (bisoprolol, metoprolol, carvedilol): reduce sympathetic activity and the risk of ventricular arrhythmias.
• Amiodarone or sotalol: indicated for patients with sustained ventricular tachycardia not controlled by beta-blockers.
• ACE inhibitors and aldosterone antagonists: used in patients with ventricular dysfunction to improve cardiac function.
• Anticoagulants: recommended for patients with atrial fibrillation or severe right ventricular dysfunction to prevent thromboembolic events.

For patients at high risk of sudden cardiac death, an implantable cardioverter-defibrillator (ICD) is indicated.
Main indications include:

• History of resuscitated cardiac arrest or sustained ventricular tachycardia.
• Syncope of cardiac origin in patients with evidence of ARVC.
• Severely reduced ventricular function (EF < 35%).
• High arrhythmic burden documented on Holter or stress testing.

Radiofrequency ablation can be an option for patients with recurrent ventricular tachycardias refractory to pharmacological therapy. However, the progressive remodeling of the right ventricle may make the success of ablation temporary, with a high risk of recurrence.

One of the most critical aspects of ARVC management is the absolute prohibition of competitive sports or intense physical exercise, even in asymptomatic patients. Physical activity can accelerate the fibro-fatty remodeling of the right ventricle and increase the risk of fatal ventricular arrhythmias.

In patients with advanced biventricular dysfunction and heart failure refractory to medical and interventional therapies, heart transplantation is the only definitive therapeutic option.

Prognosis

The prognosis of ARVC is highly variable and depends on the degree of ventricular involvement, disease progression, and arrhythmic risk.
Patients with mild, well-controlled forms may have a good quality of life, whereas those with biventricular involvement and refractory ventricular tachycardias have a high risk of adverse events.

Negative Prognostic Factors

• History of sudden cardiac arrest or sustained ventricular tachycardia.
• Early biventricular involvement (left ventricular dysfunction).
• Right ventricular ejection fraction <40%.
• Presence of multiple right ventricular aneurysms.
• Family history of sudden cardiac death.

Regular clinical monitoring and arrhythmic risk stratification are essential to optimize management and improve long-term prognosis.

Complications

The complications of ARVC primarily arise from disease progression and myocardial electrical instability. The main ones include:

Sudden Cardiac Death

Sudden cardiac death is the most feared complication of ARVC, particularly in young individuals and athletes. It is caused by sustained ventricular tachycardia or untreated ventricular fibrillation. The implantable cardioverter-defibrillator (ICD) is the primary preventive tool.

Ventricular Tachycardia and Ventricular Fibrillation

Ventricular arrhythmias are the hallmark of ARVC. In many patients, these arrhythmias may become refractory to pharmacological therapy, necessitating catheter ablation or ICD implantation.

Heart Failure

As the disease progresses, right ventricular dysfunction leads to heart failure with signs of systemic congestion (dependent edema, hepatomegaly, ascites). In more advanced cases, left ventricular involvement can lead to global heart failure.

Thromboembolic Events

In patients with severe ventricular dysfunction or atrial fibrillation, the risk of pulmonary thromboembolism or ischemic stroke increases. In such cases, anticoagulant therapy is indicated.

Ventricular Aneurysms

The formation of aneurysms in the right ventricle is a typical feature of advanced ARVC. These aneurysms can serve as foci for ventricular arrhythmias or, in rare cases, rupture with fatal consequences.

Conclusions

Arrhythmogenic right ventricular cardiomyopathy is a severe genetic disease with a high risk of sudden cardiac death. Early recognition of the disease, identification of high-risk patients, and ICD implantation in selected individuals are fundamental strategies to improve prognosis and prevent fatal events.

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