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 SCD Sickle cell disease (SCD) is a group of genetic disorders in which an abnormal Hb molecule (HbS) transforms RBCs into sickle-shaped cells, resulting in chronic anemia, vasoocclusive episodes, pain, and organ damage. Sickle Cell Disease). 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 Syncope Syncope is a short-term loss of consciousness and loss of postural stability followed by spontaneous return of consciousness to the previous neurologic baseline without the need for resuscitation. The condition is caused by transient interruption of cerebral blood flow that may be benign or related to a underlying life-threatening condition. Syncope, dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, or chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. Chest Pain. Diagnosis is based on clinical, ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG), echocardiographic, and imaging findings. Management aims to prevent SCD SCD Sickle cell disease (SCD) is a group of genetic disorders in which an abnormal Hb molecule (HbS) transforms RBCs into sickle-shaped cells, resulting in chronic anemia, vasoocclusive episodes, pain, and organ damage. Sickle Cell Disease 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 SCD Sickle cell disease (SCD) is a group of genetic disorders in which an abnormal Hb molecule (HbS) transforms RBCs into sickle-shaped cells, resulting in chronic anemia, vasoocclusive episodes, pain, and organ damage. Sickle Cell Disease)
  • 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 Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance form = most common pattern of inheritance
    • Autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancedisease = associated with palmoplantar keratosis and woolly hair
  • Acquired disease can result from viral myocarditis Myocarditis Myocarditis is an inflammatory disease of the myocardium, which may occur alone or in association with a systemic process. There are numerous etiologies of myocarditis, but all lead to inflammation and myocyte injury, most often leading to signs and symptoms of heart failure. Myocarditis.
  • Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of 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 Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. 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 Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables 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 Ventricular tachycardia Ventricular tachycardia is any heart rhythm faster than 100 beats/min, with 3 or more irregular beats in a row, arising distal to the bundle of His. Ventricular tachycardia is the most common form of wide-complex tachycardia, and it is associated with a high mortality rate. Ventricular Tachycardia
      • The most common arrhythmia is ventricular tachycardia Ventricular tachycardia Ventricular tachycardia is any heart rhythm faster than 100 beats/min, with 3 or more irregular beats in a row, arising distal to the bundle of His. Ventricular tachycardia is the most common form of wide-complex tachycardia, and it is associated with a high mortality rate. Ventricular Tachycardia that originates in the right ventricle (RV) with a left bundle branch block (BBB L) pattern
    • Syncope
    • Atypical chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. 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 Aneurysm An aneurysm is a bulging, weakened area of a blood vessel that causes an abnormal widening of its diameter > 1.5 times the size of the native vessel. Aneurysms occur more often in arteries than in veins and are at risk of dissection and rupture, which can be life-threatening. Extremity and Visceral Aneurysms
    • 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 Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the patient
    • ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG)
      • 12-lead
      • Ambulatory ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG) monitoring
    • Echocardiogram
    • Cardiac MRI
  • Select patients:
    • Electrophysiology testing
    • Exercise ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (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 ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (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 ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (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 SCD Sickle cell disease (SCD) is a group of genetic disorders in which an abnormal Hb molecule (HbS) transforms RBCs into sickle-shaped cells, resulting in chronic anemia, vasoocclusive episodes, pain, and organ damage. Sickle Cell Disease in high-risk patients
      • Secondary prevention of SCD SCD Sickle cell disease (SCD) is a group of genetic disorders in which an abnormal Hb molecule (HbS) transforms RBCs into sickle-shaped cells, resulting in chronic anemia, vasoocclusive episodes, pain, and organ damage. Sickle Cell Disease in patients with previous episodes of ventricular arrhythmia
      • High-risk patients that require an ICD: unexplained syncope Syncope Syncope is a short-term loss of consciousness and loss of postural stability followed by spontaneous return of consciousness to the previous neurologic baseline without the need for resuscitation. The condition is caused by transient interruption of cerebral blood flow that may be benign or related to a underlying life-threatening condition. Syncope, male sex, ventricular tachycardia Ventricular tachycardia Ventricular tachycardia is any heart rhythm faster than 100 beats/min, with 3 or more irregular beats in a row, arising distal to the bundle of His. Ventricular tachycardia is the most common form of wide-complex tachycardia, and it is associated with a high mortality rate. Ventricular Tachycardia during electrophysiologic study testing, severe RV dilation, involvement of the left ventricle, prior cardiac arrest Cardiac arrest Cardiac arrest is the sudden, complete cessation of cardiac output with hemodynamic collapse. Patients present as pulseless, unresponsive, and apneic. Rhythms associated with cardiac arrest are ventricular fibrillation/tachycardia, asystole, or pulseless electrical activity. 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 Ventricular tachycardia Ventricular tachycardia is any heart rhythm faster than 100 beats/min, with 3 or more irregular beats in a row, arising distal to the bundle of His. Ventricular tachycardia is the most common form of wide-complex tachycardia, and it is associated with a high mortality rate. 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 Ventricular tachycardia Ventricular tachycardia is any heart rhythm faster than 100 beats/min, with 3 or more irregular beats in a row, arising distal to the bundle of His. Ventricular tachycardia is the most common form of wide-complex tachycardia, and it is associated with a high mortality rate. 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 flutter Atrial flutter is a regular supraventricular tachycardia characterized by an atrial heart rate between 240/min and 340/min (typically 300/min), atrioventricular (AV) node conduction block, and a "sawtooth" pattern on an electrocardiogram (ECG). Atrial Flutter
    • Atrial fibrillation Atrial fibrillation Atrial fibrillation (AF or Afib) is a supraventricular tachyarrhythmia and the most common kind of arrhythmia. It is caused by rapid, uncontrolled atrial contractions and uncoordinated ventricular responses. 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 Syncope Syncope is a short-term loss of consciousness and loss of postural stability followed by spontaneous return of consciousness to the previous neurologic baseline without the need for resuscitation. The condition is caused by transient interruption of cerebral blood flow that may be benign or related to a underlying life-threatening condition. Syncope. A 12-lead ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG) is required for the diagnosis. Management includes insertion of an ICD.
  • Idiopathic right ventricular tachycardia Ventricular tachycardia Ventricular tachycardia is any heart rhythm faster than 100 beats/min, with 3 or more irregular beats in a row, arising distal to the bundle of His. Ventricular tachycardia is the most common form of wide-complex tachycardia, and it is associated with a high mortality rate. Ventricular Tachycardia: an arrhythmia arising from the right ventricular outflow tract in the absence of the underlying structural heart disease. Patients have normal ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (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 Ventricular tachycardia Ventricular tachycardia is any heart rhythm faster than 100 beats/min, with 3 or more irregular beats in a row, arising distal to the bundle of His. Ventricular tachycardia is the most common form of wide-complex tachycardia, and it is associated with a high mortality rate. Ventricular Tachycardia has a better prognosis than arrhythmogenic right ventricular cardiomyopathy and can be treated with ablation.
  • Myocarditis or cardiac sarcoidosis Sarcoidosis Sarcoidosis is a multisystem inflammatory disease that causes noncaseating granulomas. The exact etiology is unknown. Sarcoidosis usually affects the lungs and thoracic lymph nodes, but it can also affect almost every system in the body, including the skin, heart, and eyes, most commonly. Sarcoidosis: inflammatory conditions of the myocardium. Myocarditis can be viral and present with fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. Chest Pain, dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, fatigue, and myalgia. Cardiac sarcoidosis Sarcoidosis Sarcoidosis is a multisystem inflammatory disease that causes noncaseating granulomas. The exact etiology is unknown. Sarcoidosis usually affects the lungs and thoracic lymph nodes, but it can also affect almost every system in the body, including the skin, heart, and eyes, most commonly. Sarcoidosis presents with palpitations, dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, fatigue, and possibly syncope Syncope Syncope is a short-term loss of consciousness and loss of postural stability followed by spontaneous return of consciousness to the previous neurologic baseline without the need for resuscitation. The condition is caused by transient interruption of cerebral blood flow that may be benign or related to a underlying life-threatening condition. 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 Dilated Cardiomyopathy Dilated cardiomyopathy (DCM) is the most common type of non-ischemic cardiomyopathy and a common cause of heart failure (HF). The cause may be idiopathic, familial, or secondary to a variety of underlying conditions. The disease is characterized by the enlargement of 1 or both ventricles and reduced systolic function. 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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