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Arrhythmogenic Right Ventricular Cardiomyopathy
Introduction
Arrhythmogenic right ventricular cardiomyopathy (ARVC), a condition also known as arrhythmogenic right ventricular dysplasia, is part of the arrhythmogenic cardiomyopathies—constituting a genetic disorder of the myocardium that undergoes progressive fibrofatty infiltration, causing arrhythmias. The right ventricle is usually involved, but the left can also be affected. A trend toward using the term "arrhythmogenic cardiomyopathy" takes into account that biventricular and left ventricular-predominant symptoms can also be present.[1]
ARVC is fundamentally a structural heart disease; therefore, criteria must be fulfilled showing functional abnormalities or evidence of fibrofatty myocardial replacement. Another common feature of this disease is ventricular tachycardia with a left bundle branch block pattern that commonly presents during exercise. The most feared complication is sudden cardiac death; therefore, risk stratification is important in this condition. Genetic testing is essential to identify at-risk individuals, as cardiac arrest can be the first presentation of ARVC.[1]
The revised 2020 criteria for diagnosing ARVC take into account the importance of biventricular and left-sided symptoms, which can have atypical presentations. They also recognize that cardiac magnetic resonance imaging (cardiovascular magnetic resonance) is the preferred test to help diagnose ARVC over endomyocardial biopsy because ARVC can have focal or patchy tissue involvement, increasing the risk of false negative biopsies. Cardiovascular magnetic resonance also gives a more holistic picture of the structural abnormalities.
Etiology
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Etiology
ARVC is caused by genetic disorders that affect the myocardium of 1 or both ventricles, which undergo progressive loss of ventricular myocardium, replaced by fibrofatty tissue. ARVC is typically inherited in an autosomal dominant pattern with variable penetrance and incomplete expression; therefore, phenotypic expression within a family is not always predictable. Familial disease constitutes a major diagnostic criterion.[2][3]
Literature states that around two-thirds of patients affected with ARVC have a positive genetic test. Currently, 8 known genes are responsible for most of the pathogenesis of ARVC. Out of these, 5 are desmosomal genes (PKP2, DSP, DSG2, DSC2, and JUP), and 3 are non-desmosomal genes (TMEM43, DES, and PLN). Study results demonstrated that 50% to 60% of patients with ARVC have gene mutations encoding for desmosomal proteins. PKP2 is the most frequently reported gene mutation, accounting for 20% to 46% of clinically manifest ARVC cases, followed by DSP and DSG2, each accounting for 10%.[4] Patients with left ventricular or biventricular disease are more likely to have non-desmosomal gene mutations.[3]
An autosomal recessive trait caused by JUP mutations causes Naxos disease (named after the Greek island where patients affected were first described). This mutation disrupts the plakoglobin protein, which is essential for cellular adhesion at the desmosomal level by forming mechanical connections between cardiomyocytes and desmin filaments. When these connections rupture, keratin cannot attach properly, leading to hyperplasia of the keratin layer. Clinical symptoms include palmoplantar keratosis and wooly hair. This condition has a penetrance of 90%.[3][5] Caravajal syndrome is an autosomal recessive cardiomyopathy, phenotypically similar to Naxos disease, but with earlier presentation during childhood.[6]
Epidemiology
The prevalence of ARVC in the general population is estimated to be between 1/5000 to 1/2000 in certain European countries such as Italy and Germany. There is a slightly higher prevalence in men than women where it is more severe, possibly due to hormonal factors affecting its expression or differences in exercise intensity.[7] Although not common, this condition represents a high percentage of sudden cardiac death in young people.[3]
Pathophysiology
The disease primarily affects the intercalated disk, which plays a critical role in cardiac function, providing cell-to-cell interaction between adjacent cardiomyocytes. The intercalated disk also connects to intracellular actin through the transmembrane glycoprotein N-cadherin. When the intercalated disk is damaged, a loss of structural integrity in the cardiomyocytes occurs, which worsens during mechanical stress. Other structural proteins like plakoglobin and desmoplakin connect the desmosome to the myocyte cytoskeleton, contributing to the desmosome's support during mechanical stress. The intercalated disk is also involved in intercellular electric coupling through the sodium and potassium ion channels. A sodium current deficit decreases the velocity of the action potential phase 0 upstroke.[8] This leads to a combination of progressive cardiomyopathy and ventricular arrhythmias.[4]
Pathological specimens show a combined loss of myocytes in the right ventricle with fibrofatty replacement. The replacement often starts in the subepicardium to midmyocardium and then progresses to transmural fibrosis with advanced ARVC.[1] Study results indicate that endurance sports and frequent strenuous exercise promote the development and progression of ARVC by increasing the ventricular load and mechanical stress on the heart.[9] Presentation usually occurs in late adolescence or early adulthood; however, pediatric presentations are being detected more often, with the importance of family history being recognized. Although family history is a major criterion for diagnosis, variable penetrance and phenotypic expression make symptoms unpredictable.[3]
As noted above, the criteria for ARVC were updated in 2020 to recognize the importance of left-sided ventricular symptoms and that cardiac magnetic resonance imaging is the diagnostic test of choice. The criteria involve 6 different categories/groups:
I. Structural alterations/function
II. Tissue characterization
III. Repolarization abnormalities
IV. Depolarization/conduction abnormalities
V. Arrhythmias
VI. Family history
Each group can have major and minor criteria. Diagnosis is made by any of the following 3 criteria groupings:
- Two major criteria
- One major plus 2 minor
- Four minor criteria from different categories
However, as noted above, at least 1 criterion must be fulfilled from groups I or II, representing cardiac structural or tissue abnormalities.[1]
The 2020 International Criteria also include criteria for diagnosing the left ventricle phenotype (see Table 1. 2020 International Criteria for Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy). The criteria differ because left ventricular dysfunction is common in other pathologic cardiac diseases, such as ischemic or dilated cardiomyopathy. Also due to the focal nature of ARVC, left ventricle dysfunction is not sensitive, as well as not specific.[1]
Table 1. 2020 International Criteria for Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy
| Group |
Major and Minor Criteria |
| I. Global or regional dysfunction and structural alteration |
Major By 2D echocardiogram, CMR, or angiography:
plus 1 of the following:
or
Minor By 2-dimensional echocardiogram, CMR, or angiography:
|
| II. Tissue characterization |
Major By CE-CMR:
Major By EMB (limited indications):
|
| III. Repolarization abnormalities |
Major
Minor
|
| IV. Depolarization and conduction abnormalities |
Minor
|
| V. Arrhythmias |
Major
Minor
|
| VI. Family history/genetics |
Major
Minor
|
Histopathology
One of the major criteria for diagnosing ARVC is fibrofatty replacement of the myocardium, which primarily affects the subepicardial layer. The microscopic features of ARVC also include abnormalities and loss of desmosomes, as confirmed by ultrastructural studies of endomyocardial biopsy (EMB) samples. Additionally, intercalated disk remodeling has been observed in EMB samples obtained from patients with ARVC.[7]
Skin biopsy of patients with DSP variants can show irregular desmoplakin and plakoglobin in the basal epidermal layers instead of the usual membranous distribution.[10] Cardiac magnetic resonance imaging (CMR) is replacing the need for EMB. According to the 2020 International criteria, the presence of transmural late gadolinium enhancement or fibrosis by CMR, affecting at least 1 region of the right ventricle in 2 orthogonal views, with or without fatty tissue replacement, has been classified as a major structural myocardial criterion for ARVC diagnosis. The available data suggests that CMR tissue characterization is highly consistent with EMB in identifying myocardial fibrosis.[1]
History and Physical
ARVC is typically diagnosed between 20 and 40 years. The most common symptoms are palpitations or syncope during exercise. One study estimated the most common complaints as palpitations (30%-60%), lightheadedness (20%), and syncope (10%-30%). These symptoms are linked to ventricular arrhythmia; however, 60% of patients with cardiac arrest had no preceding symptoms. In addition, sudden cardiac death can be the first sign of ARVC, and up to 20% of patients diagnosed with ARVC first present with cardiac arrest.[11]
Three stages are suggested for ARVC:
1) Concealed stage
2) Clinically overt stage
3) Right, left, or biventricular failure (about half of patients progress to this)
Few cardiac structural abnormalities are apparent during the concealed stage, and patients are asymptomatic. However, as noted above, cardiac arrest can still present during this phase.
During the clinically overt stage, morphologic abnormalities are detectable in the ventricles, and ventricular arrhythmias are present. Arrhythmias include premature ventricular complexes, non-sustained or sustained ventricular tachycardia, and ventricular fibrillation. Atrial arrhythmias, such as atrial fibrillation, are also more common in patients with ARVC. Up to 60% of patients may present with hemodynamically stable ventricular tachycardia as the initial presentation.[11]
Some patients will progress to right, left, or biventricular failure. One estimate is that about half of patients diagnosed with ARVC will have at least 1 symptom of heart failure, most commonly exertional dyspnea. Heart failure is the most common indication for heart transplant related to ARVC and is highly associated with sudden cardiac death.[12]
Another possible presentation is chest pain accompanied by elevated cardiac enzymes (but no evidence of coronary artery disease). This presentation, similar to myocarditis, is common in certain genetic variants and especially in children with ARVC. Pediatric myocarditis, especially concerning family history, should prompt testing for ARVC.[3]
As noted above, patients with Naxos disease (JUP mutation) demonstrate wooly hair and, less commonly, alopecia. Alopecia is also common in patients with DSP variants.[3][10] Patients with desmoplakin mutations can also demonstrate wooly hair and keratotic skin lesions. Other cutaneous manifestations are eczema, fragile skin, perioral or sacral ulcers, and pemphigus-like vesicular lesions. Dental abnormalities and nail dystrophy are also reported. Cases of neonatal lethal epidermolysis have been reported in patients homozygous for JUP and DSP mutations.[3][10]
Evaluation
Laboratory, radiographic, and other required tests to evaluate this disease:
Electrocardiogram: The electrocardiogram is rarely normal in ARVC. A common abnormality is a T-wave inversion in the right precordial leads (V1 through V4).[13] Inverted T-waves extending to V5 and V6 suggest left-sided involvement. About 15% of patients will show incomplete right bundle-branch block.
Ventricular tachycardia with a left bundle-branch block pattern can quickly become ventricular fibrillation. These arrhythmias are often triggered or worsened by adrenergic stimulation (such as during exercise). Ventricular ectopy of left bundle branch block morphology with the QRS axis -90 to +100 degrees can originate from the right ventricle apex, right ventricle inflow tract, or right ventricle outflow tract.[11][14][15]
The epsilon wave is found in 50% of ARVC cases and was downgraded to minor criteria after 2020. These are due to post-excitation electrical impulses of small amplitude, and they tend to occur at the end of QRS complexes and during the beginning of ST segment; they result from delayed right ventricular activation.[16]
Holter monitoring: Long-term monitoring (24 hours or longer) is often conducted to establish the presence of arrhythmia, especially in symptomatic patients; this often reveals intermittent ventricular arrhythmias.[17]
Echocardiography: Echocardiography may reveal an enlarged, hypokinetic, or thin right ventricle free wall. Changes like systolic akinesia, dyskinesia, or diastolic bulging in certain areas may also be present. The left ventricle and septum can also be affected. Patients with long-standing disease may develop end-stage right ventricular or biventricular pump failure.[7] Wall motion abnormalities should be confirmed in two orthogonal planes. The echocardiogram should be repeated every 1 to 3 years, depending on the clinical picture.[18]
Cardiac magnetic resonance: CMR is an excellent tool for visualizing the right ventricle. CMR may reveal a transmural diffuse brightness on T1 if fatty infiltration is present; it can also image right ventricle volume, systolic function, and regional wall motion abnormalities. In patients with CMR is contraindicated, a computed tomography scan can be used for many of the same measurements but with less resolution.[17][19]
Electrophysiologic studies: These studies are rarely indicated. They can be performed to differentiate ARVC from ventricular tachycardia associated with idiopathic right ventricular outflow tract tachycardia—a usually benign, non-inherited condition characterized by a non-inducible arrhythmia.[18]
Endomyocardial biopsy: A transvenous biopsy of the right ventricle can be highly specific for ARVC but can have a high false-negative rate as it requires obtaining a diseased portion of the endocardium. This biopsy is not required if the criteria for ARVC are fulfilled otherwise.
Cardiac catheterization: Rarely is cardiac catheterization performed; this is primarily done when looking for a left-to-right shunt when differentiating ARVC from congenital heart disease. This procedure is sometimes done in preparation for an EMB.[18]
Treatment / Management
The goal of ARVC management is to minimize the risk of sudden cardiac death, slow the progression of the disease, and enhance the quality of life by reducing the burden of arrhythmia and symptoms of heart failure. The management of ARVC involves a range of approaches, such as clinical management, pharmacological treatment, catheter ablation, implantation of a cardiac defibrillator, and, if required, cardiac transplant.
1. Clinical management primarily involves restricting physical activity, as exercise can trigger arrhythmias and accelerate disease progression.[20] This measure aims to reduce the risk of sudden death and heart failure. The recommendation is that individuals (including those who are genotypically positive but phenotypically negative) limit their exercise to less than 650 MET hours per year. This corresponds to about 30 minutes of brisk walking per day. This restriction helps delay the manifestation of the disease's symptoms in phenotype-negative individuals.[4]
2. Pharmacological treatment for ARVC involves suppressing arrhythmia, preventing thrombus formation, and managing heart failure.
- Beta-blockers, especially long-acting and cardioselective like metoprolol, are recommended for all clinically affected ARVC patients to prevent arrhythmias and reduce the stress on the RV wall.
- Sotalol, a non-selective beta-blocker with class III antiarrhythmic properties, is the most effective antiarrhythmic agent in ARVC.[21]
- Amiodarone (class III antiarrhythmic) or adjunctive therapy with flecainide (class Ic antiarrhythmic) may be considered for patients with persistent ventricular arrhythmias despite the use of sotalol. Flecainide is usually avoided when the left ventricular ejection fraction is reduced (<40%).
- Standard pharmacological therapy, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and diuretics, can be used for patients with right or left heart failure.
- Anticoagulants should be reserved for patients with atrial fibrillation or thromboembolic complications.[7]
3. Radiofrequency catheter ablation is a treatment option for patients who suffer from refractory or incessant ventricular tachycardia.[22] This procedure is recommended for patients who have recurrent episodes of ventricular tachycardia or those who experience recurrent implantable cardioverter-defibrillator (ICD) discharges despite proper antiarrhythmic therapy. If the endocardial approach fails to control the ventricular arrhythmias, a combined endo/epicardial approach should be used. However, it is important to note that the recurrence rate of ventricular tachycardia after the procedure has been reported to be as high as 50% to 75% over 3 years due to disease progression.[23](B2)
4. The ICD is the most effective treatment for preventing sudden cardiac death.[24] Single-chambered ICDs are preferred over dual-chambered, and anti-tachycardia pacing should also be programmed.[11] ICDs are recommended for patients with ARVC in the following cases:
- History of cardiac arrest secondary to ventricular tachycardia or ventricular fibrillation
- Symptomatic ventricular tachycardia that cannot be controlled with antiarrhythmic medications
- Inducibility of ventricular tachycardia during an electrophysiology study
- Severe involvement of the right or left ventricle with dysfunction and poor tolerance to ventricular tachycardia
- Episodes of non-sustained ventricular tachycardia and syncope that are suspected to be of arrhythmic origin
- Sudden cardiac death of a first-degree relative
The survival benefit of an ICD is estimated at 26% but is associated with complications like lead infections.[11] Therefore, healthy gene carriers or asymptomatic patients without risk factors do not require an ICD as prophylaxis.[23]
5. Cardiac transplantation is reserved for those who have uncontrolled arrhythmias or who are unable to manage ventricular failure with pharmacologic therapy.[9] Post-transplant, the 5- and 10-year survival rates are 81% and 77%, respectively, similar to patients without ARVC and better than those transplanted for ischemic cardiomyopathy.[11](B3)
Differential Diagnosis
AVC is rare and must be differentiated from other pathological conditions with similar presentations.[11][25] Three more difficult conditions to differentiate from ARVC are right ventricular outflow tract tachycardia, Brugada syndrome, and cardiac sarcoidosis.
Right ventricular outflow tract tachycardia often presents similarly to ARVC. Difficulty in differentiation is further compounded because the right ventricular outflow tract, RVOT, is often a site for arrhythmia origin in ARVC. Differences are that RVOT-VT (ventricular tachycardia) is not inherited, is not associated with a genetic mutation, and presents with monomorphic, non-sustained VT. The VT of ARVC is often polymorphic. In addition, RVOT-VT is not usually associated with precordial lead T-wave inversions. Imaging is crucial, as RVOT-VT will not show fibrofatty infiltration of the myocardium as ARVC does.
Brugada syndrome, like ARVC, is inherited and is associated with the SCN5A gene. An electrocardiogram, ECG, will show right precordial ST elevations in addition to T-wave inversions, and the ECG patterns may change (dynamic ECG). In contrast, the ECG with ARVC does not change in short periods. Cardiac imaging will show no significant structural abnormalities with Brugada syndrome. In addition, Brugada syndrome is more common in Southeast Asia, while ARVC is more common in European countries such as Greece and Italy.[26]
Cardiac sarcoidosis can sometimes be confused with ARVC on imaging. Certain factors favor the diagnosis of sarcoidosis, including the following: mediastinal lymphadenopathy, older age at presentation, a non-familial pattern of disease, signs of delayed gadolinium enhancement of the ventricular septum on CMR, intense positron emission tomography fludeoxyglucose uptake in the myocardium, and first degree or higher degrees of atrioventricular block. However, in some cases, endomyocardial biopsy may be necessary to confirm the diagnosis.[11]
Several congenital heart diseases, such as Ebstein anomaly, left-to-right shunt, and Uhl anomaly, may mimic the symptoms of ARVC. Cardiac imaging can often differentiate these conditions.
Left-sided dominant ARVC has many similarities in imaging with dilated cardiomyopathy, muscular dystrophies, myocarditis, cardiac sarcoidosis, congenital ventricular aneurysms, and Chagas heart disease. One key difference is the fibrofatty infiltration abnormalities in ARVC usually start with a subepicardial distribution and progress to transmural involvement over time.
Prognosis
The mortality rate for patients with ARVC can range from 0.08% to 3.6% per year, but it is less than 1% for those who receive treatment. The outcome for those with ARVC is largely determined by the severity of their arrhythmias and the extent of their ventricular dysfunction. Notably, a prior episode of syncope resulting from sustained ventricular tachycardia or cardiac arrest stemming from ventricular fibrillation is the most significant factor in predicting the recurrence of life-threatening arrhythmias. Other risk factors for arrhythmic events include having sustained or nonsustained ventricular tachycardia and depressed cardiac function.[27]
Major risk factors for sudden cardiac death or life-threatening arrhythmia include the following:
- Prior history of cardiac arrest related to ventricular arrhythmia
- A history of unexplained syncope
- Non-sustained ventricular tachycardia during an exercise stress test or on ambulatory monitoring (prognostic value of ventricular tachycardia or fibrillation induced by programmed stimulation during an electrophysiologic study is unclear)
- Severe systolic dysfunction of the right, left, or both ventricles [7][11]
Minor risk factors include more than 1000 premature ventricular contractions per day, T-wave inversion of more than 3 electrocardiogram leads, known genetic abnormalities, younger age at presentation, and male sex.[11]
Complications
Complications can occur from failure to treat ARVC, from diagnosing the disease, and from its treatment. Untreated individuals with ARVC may experience complications due to the progression of the disease, including ventricular tachycardia, ventricular fibrillation, heart failure, and sudden death. Heart failure can also cause thromboembolism, general organ failure, and death.[28] Thromboembolic complications can arise from intracardiac thrombus formation due to ventricular dysfunction.[9]
Differentiating between genotypes can help determine the risk of complications, allowing patients to be informed of the most probable outcomes. For instance, individuals with the PKP2 variant typically experience significant right ventricular involvement, while those with the DSG2 variant are likely to develop heart failure-related complications, leading to an increased risk of need for cardiac transplantation.[4]
Complications can arise from the treatment as well. The estimated complications of having an intracardiac defibrillator include a 3.7% to 3.9% annual rate of inappropriate shocks and a 4.2% to 4.4% annual rate of infection or lead malfunction.[4][11] Furthermore, antiarrhythmic medications such as flecainide, sotalol, and amiodarone can cause long QT prolongation, while anticoagulation can cause minor or major bleeding.[7]
Complications may occur during diagnostic procedures. Endomyocardial biopsy, EMB, is an invasive test that can lead to complications such as cardiac perforation or damage to a valve or chordal apparatus. Therefore, the 2020 International Criteria recommends using EMB only in specific cases, such as individuals who lack a family history of the disease and have negative genotyping. In such cases, EMB is necessary to confirm the diagnosis of ARVC or arrhythmogenic cardiomyopathy (ACM) by demonstrating the presence of replacement fibrosis along with or without fatty replacement. EMB also helps to rule out diseases that mimic ARVC or ACM, such as cardiac sarcoidosis.[1]
Deterrence and Patient Education
Clinicians should accurately identify patients suspected of having ARVC due to the potential risk of sudden cardiac death (SCD). Identifying patients who are at increased risk of SCD or sustained ventricular tachycardia is the main goal of risk stratification. Age, sex, electrophysiological features, and cardiac imaging investigations are all factors that are considered. Patients who are asymptomatic with a definitive ARVC diagnosis should be exercise-restricted and re-evaluated every 1 to 2 years. Patients should be educated about their risks and prognosis and actively participate in their care through shared decision-making. Family members should be appropriately screened for ARVC. Patient education regarding therapeutic options is critical given the risk of SCD, along with the risks of antiarrhythmics and ICDs, such as inappropriate shocks.[4][7][9][11]
Pearls and Other Issues
Other pertinent information concerning ARVC includes:
- A late presentation, such as after the fifth decade of life, does not imply a benign course.[11]
- Pregnancy is generally well-tolerated in patients with ARVC. However, about 13% of patients may develop ventricular arrhythmias, which can require treatment such as cardioversion, antiarrhythmic medications like sotalol, or implantation of an ICD. High-risk pregnancies involving major structural abnormalities in the right ventricle can lead to heart failure. It is important to note that pregnancy does not appear to increase the risk of arrhythmias or heart failure, nor does it seem to accelerate the progression of the disease.[29]
Enhancing Healthcare Team Outcomes
Providing patient-centered care for individuals with ARVC requires a collaborative effort among healthcare professionals, including physicians, nurses, pharmacists, radiology, and ECG technicians. First and foremost, healthcare providers must possess the necessary clinical skills and expertise when diagnosing, evaluating, and treating this condition—including proficiency in interpreting ECG and cardiac magnetic resonance findings, recognizing potential complications, and understanding the nuances of differentiating ARVC from other cardiac diseases with similar presentations. The interprofessional team may consist of primary care providers, emergency room providers, radiologists, clinical cardiologists, electrophysiologists, geneticists, and genetic counselors. Moreover, a strategic approach involving evidence-based guidelines and individualized care plans tailored to each patient's unique circumstances is vital.
Ethical considerations come into play when determining treatment options and respecting patient autonomy in decision-making; this is especially important as pacemakers and ICDs can be associated with complications such as infection and inadvertent shocks. Patients may have different risk tolerance levels, and all options should be thoroughly discussed. Screening family members and frequent follow-ups are also important. Effective interprofessional communication fosters a collaborative environment where information is shared, questions are encouraged, and concerns are addressed promptly.
Lastly, care coordination is pivotal in ensuring seamless and efficient patient care. Physicians, advanced practitioners, nurses, pharmacists, and other healthcare professionals must work together to streamline the patient's journey, from diagnosis through treatment and follow-up. This coordination minimizes errors, reduces delays, and enhances patient safety, ultimately leading to improved outcomes and patient-centered care that prioritizes the well-being and satisfaction of those affected by ARVC.
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