Arrhythmogenic Right Ventricular Cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy is an inherited disorder of the heart muscle that affects the right ventricle (RV); it can cause rhythm disturbances and sudden cardiac death (SCD). The disorder results from mutations in the genes that encode desmosomal proteins involved in cell-to-cell adhesion. Symptomatic patients develop palpitations, arrhythmias leading to syncope, dyspnea, or chest pain. Diagnosis is based on clinical, ECG, echocardiographic, and imaging findings. Management aims to prevent SCD and symptom-causing arrhythmias. Treatment includes implantable cardioverter-defibrillator (ICD) placement, radiofrequency ablation to correct arrhythmias, and antiarrhythmic medications if possible. Prevention of disease progression with lifestyle changes is important, and cardiac transplantation may be necessary after 15 years.

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Overview

Definition

Arrhythmogenic right ventricular cardiomyopathy is a genetic disease of the heart muscle characterized by the fibrofatty replacement of the right ventricular myocardium.

Epidemiology

  • The prevalence is 1:2000 to 1:5000.
  • In 11% of cases: sudden cardiac death (SCD)
  • Mean age at presentation is 30 years.
  • Men-to-women predominance is almost 3:1.
  • Presentation is most common between ages 10 and 50.
  • 35% of patients with arrhythmogenic right ventricular cardiomyopathy have a family history, although it may not be known at the time of presentation.

Etiology

  • Most cases of arrhythmogenic right ventricular cardiomyopathy are inherited:
    • Autosomal dominant form = most common pattern of inheritance
    • Autosomal recessive disease = associated with palmoplantar keratosis and woolly hair
  • Acquired disease can result from viral myocarditis.
  • Genetics: mutations in the genes encoding desmosomal proteins
    • Plakoglobin
    • Desmoplakin
    • Plakophilin-2
    • Desmoglein-2
    • Desmocollin-2

Pathophysiology

  • Abnormal desmosomes cause the disruption of the intercellular junctions → myocyte detachment → apoptosis
  • Strenuous exercise can precipitate myocyte detachment and death.
  • Myocardial injury → inflammation → fibrofatty replacement of the damaged myocardium → development of the ventricular arrhythmias

Clinical Presentation and Diagnosis

The clinical presentation of arrhythmogenic right ventricular cardiomyopathy is variable and may remain silent for decades, making it difficult to recognize.

Clinical presentation

  • Up to 40% of patients are asymptomatic.
  • Symptomatic patients present with:
    • Palpitations
      • Most common symptom
      • Usually due to frequent ventricular premature beats 
    • Arrhythmias 
      • Ventricular arrhythmias range from premature ventricular contractions to sustained ventricular tachycardia
      • The most common arrhythmia is ventricular tachycardia that originates in the right ventricle (RV) with a left bundle branch block (BBB L) pattern
    • Syncope
    • Atypical chest pain
    • Dyspnea 
    • RV heart failure in 6%
    • Sudden cardiac death: can be the 1st clinical manifestation
    • Lower extremity swelling
    • Left ventricular involvement: can lead to biventricular heart failure
    • Palmoplantar keratosis
    • Woolly hair

Diagnosis

The details of the 2017 Report of the American College of Cardiology/American Heart Association Task Force and the Heart Rhythm Society (ACC/AHA/HRS) are beyond the scope here. The report defines global or regional dysfunction and structural alterations with detailed echocardiographic measurements of the RV outflow tract.

  • The task force defines major and minor criteria for the “definitive diagnosis” of arrhythmogenic right ventricular cardiomyopathy.
    • Criteria such as regional RV akinesia, dyskinesia, or aneurysm
    • Criteria for arrhythmia:
      • Ventricular tachycardia of RV outflow configuration and BBB L morphology
      • > 500 ventricular extrasystoles per 24 hours
    • Also “borderline” and “possible” diagnosis of arrhythmogenic right ventricular cardiomyopathy
  • All patients with suspected arrhythmogenic right ventricular cardiomyopathy:  
    • Family history
      • 1st- or 2nd-degree relatives with arrhythmogenic right ventricular cardiomyopathy
      • Confirmed genetic mutation in the patient
    • ECG
      • 12-lead
      • Ambulatory ECG monitoring
    • Echocardiogram
    • Cardiac MRI
  • Select patients:
    • Electrophysiology testing
    • Exercise ECG
    • Genetic testing if definite or borderline ACC/AHA/ task force diagnostic criteria are met
12-lead ECG Arrhythmogenic right ventricular cardiomyopathy (ARVC)

Left: 12-lead ECG shows (a) inverted T waves in V1–V4 and (b) ventricular ectopic beats.
Right: cross-section of the heart with the right ventricular dilatation, anterior and posterior aneurysms

Image: “12 lead ECG of 17 year old asymptomatic male athlete who died suddenly during a soccer game” by Thiene G et al. License: CC BY 2.0

Management

The main goal in the management of arrhythmogenic right ventricular cardiomyopathy is to prevent life-threatening arrhythmias. Slowing the progression of the disease is also a priority.

  • Lifestyle modifications:
    • Restriction from competitive sports
    • Can participate in low-intensity recreational activities:
      • Yoga
      • Golf
      • Walking
    • Recommendations also apply to family members with a negative phenotype.
  • Prevention of arrhythmias:
    • Implantable cardioverter-defibrillator (ICD) indications:
      • Primary prevention of SCD in high-risk patients
      • Secondary prevention of SCD in patients with previous episodes of ventricular arrhythmia
      • High-risk patients that require an ICD: unexplained syncope, male sex, ventricular tachycardia during electrophysiologic study testing, severe RV dilation, involvement of the left ventricle, prior cardiac arrest, or onset of disease before age 5
      • May need adjunctive medication therapy in patients with symptomatic arrhythmias 
    • Medications for management of arrhythmias:
      • Beta-blockers should be initiated in all patients.
      • Sotalol = the most effective medication in ventricular tachycardia
      • Amiodarone alone or in combination with beta-blockers
      • Not as effective as an ICD
      • Also used in patients who are not candidates for an ICD
    • Ablation 
      • Radiofrequency ablation (RFA) is not considered to be the primary step in management.
      • Indicated in patients with an ICD and persistent episodes of ventricular tachycardia or those who are not candidates for an ICD
      • Combined medication therapy may be needed in hemodynamically stable patients without an ICD.
  • Prevention of disease progression: 
    • Limiting activity is essential.
    • Medical therapy for heart failure:
      • ACE inhibitors
      • Mineralocorticoid receptor antagonist (e.g., spironolactone)
      • Diuretics
    • Cardiac transplantation for patients with:
      • Duration of AVRC longer than 15 years
      • Heart failure despite optimal medical therapy
      • Progressive ventricular arrhythmias 
  • Anticoagulation therapy in patients with:
    • Intracavitary thrombus
    • Atrial flutter
    • Atrial fibrillation
    • History of thromboembolic disease
  • Prognosis: Left ventricular involvement carries a worse prognosis.

Differential Diagnosis

  • Brugada syndrome: a rare inherited cardiac arrhythmia characterized by ST-segment elevation in the right precordial leads and right bundle branch block (BBB R). Patients can be asymptomatic or present with palpitations, dizziness, and syncope. A 12-lead ECG is required for the diagnosis. Management includes insertion of an ICD.
  • Idiopathic right ventricular tachycardia: an arrhythmia arising from the right ventricular outflow tract in the absence of the underlying structural heart disease. Patients have normal ECG findings (not found in patients with arrhythmogenic right ventricular cardiomyopathy after about 6 years) and are diagnosed on electrophysiologic studies. Idiopathic right ventricular tachycardia has a better prognosis than arrhythmogenic right ventricular cardiomyopathy and can be treated with ablation.
  • Myocarditis or cardiac sarcoidosis: inflammatory conditions of the myocardium. Myocarditis can be viral and present with fever, chest pain, dyspnea, fatigue, and myalgia. Cardiac sarcoidosis presents with palpitations, dyspnea, fatigue, and possibly syncope. A distinguishing feature of these inflammatory conditions is the presence of conduction disease, which is not often seen with arrhythmogenic right ventricular cardiomyopathy. Diagnosis relies on clinical findings, laboratory evaluation, and cardiac imaging. Management is mainly supportive but includes treatment of the underlying cause.
  • Uhl anomaly: differs from arrhythmogenic right ventricular cardiomyopathy in that there is no familial component, and it usually presents in childhood with heart failure. Clinically, Uhl anomaly produces a dilated cardiomyopathy due to the pathophysiology of a “paper-thin” RV wall with areas of partial or complete absence of myocardial tissue. Uhl anomaly is diagnosed on echocardiogram or MRI, and there are few treatment options available except palliative care or heart transplant.

References

  1. Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/ARVC). Medscape. Retrieved on June 10, 2021, from https://emedicine.medscape.com/article/163856-overview#a3
  2. Elias Neto, J, et al. (2019). Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D)–What we have learned after 40 years of the diagnosis of this clinical entity. Arquivos Brasileiros de Cardiologia, 112(1), 91–103. https://pubmed.ncbi.nlm.nih.gov/30673021/
  3. McKenna, WJ. (2020).  Arrhythmogenic right ventricular cardiomyopathy: Anatomy, histology, and clinical manifestations. UpToDate. Retrieved June 29, 2021, from https://www.uptodate.com/contents/arrhythmogenic-right-ventricular-cardiomyopathy-anatomy-histology-and-clinical-manifestations
  4. McKenna, WJ. (2019). Arrhythmogenic right ventricular cardiomyopathy: Treatment and prognosis. UpToDate. Retrieved June 29, 2021, from https://www.uptodate.com/contents/arrhythmogenic-right-ventricular-cardiomyopathy-treatment-and-prognosis
  5. McKenna, WJ. (2019) Arrhythmogenic right ventricular cardiomyopathy: Diagnostic evaluation and diagnosis. UpToDate. Retrieved June 29, 2021, from https://www.uptodate.com/contents/arrhythmogenic-right-ventricular-cardiomyopathy-diagnostic-evaluation-and-diagnosis

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