Arrhythmogenic Right Ventricular Cardiomyopathy

Diagnosis, Risk Stratification, and Treatment

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic heart disease with a prevalence of 1 : 2000 to 1 : 5000. It is characterized by the progressive replacement of heart muscle tissue by fatty and connective tissue. It is associated with a high risk of sudden cardiac death. This review presents the current state of knowledge regarding the diagnostic assessment, risk stratification, and treatment of ARVC.

Methods: This review is based on pertinent publications retrieved by a search in PubMed using the keywords “ARVC” and “arrhythmogenic right ventricular dysplasia”. Guidelines, clinical registry studies, meta-analyses, and randomized controlled trials were evaluated.

Results: The diagnosis is established with the aid of (long-term) ECG, echocardiography, magnetic resonance imaging, and genetic tests. The ARVC risk calculator is used to assess the risk of ventricular arrhythmia. Patients’ participation in sports is restricted. Beta-blockers are recommended for patients with extrasystoles or ventricular tachycardia (grade I recommendation). If beta-blockers alone have an insufficient effect, amiodarone, flecainide or sotalol can be added (grade IIa). For patients with recurrent ventricular tachyarrhythmia, catheter ablation is an option (grade IIa). While there is a clear recommendation (grade I) for defibrillator implantation for patients who have survived sudden cardiac death, the ARVC risk calculator should be used for decision-making in patients for whom primary prophylactic implantation is considered (recommendation grade IIa).

Conclusion: ARVC is associated with an increased risk of sudden cardiac death. Risk assessment remains challenging in the absence of randomized controlled trials, particularly with regard to the primary prophylactic implantation of a defibrillator.

Cite this as:

Kreimer F, Saguner AM, Akin I, Milting H, Eckardt L, El-Battrawy I: Arrhythmogenic right ventricular cardiomyopathy: Diagnosis, risk stratification, and treatment. Dtsch Arztebl Int 2025; 122: 229–34. DOI: 10.3238/arztebl.m2024.0264

Sudden deaths among young adults and in particular athletes are always horrifying events. Genetic disorders, such as ion channel disorders (long QT syndrom, for example) and cardiomyopathies (hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy [ARVC], for example), play a special role here. ARVC is a myocardial disease, a type of primary cardiomyopathy which primarily involves the right ventricle (RV), although there have been increasing reports in recent years of left-ventricular (LV) involvement to varying degrees (1). In ARVC, RV dilation and/or dysfunction develop secondary to progressive myocardial atrophy with simultaneous connective tissue remodeling.

The prevalence of ARVC during adulthood varies according to region and is estimated to be between 1 : 2000 and 1 : 5000. In most cases it develops during the second to fourth decade of life, with men being three times more commonly affected (2, 3). Very often, progressive myocardial remodeling results in the increased occurrence of ventricular arrhythmia which can present as palpitations and syncopes, even to the extent of sudden cardiac death (Box 1). A meta-analysis showed that the annual risk of ventricular arrhythmias in those affected varies between 3.7% and 10.6% (4). However, ARVC can also present as heart failure, resembling dilated cardiomyopathy (1). As with other cardiomyopathies, heart failure secondary to ARVC is treated in accordance with the European Guideline (1). ACE inhibitors, sacubitril/valsartan, beta-blockers, aldosterone antagonists, or SGLT2 inhibitors are recommended for an LV ejection fraction of 40% and less. Life expectancy is often close to normal if ARVC is diagnosed early and treated appropriately (1).

Box 1

Red flags – when ARVC should be considered

Diagnosis, risk stratification, and treatment of ARVC are outlined below.

We used PubMed to conduct a search of the literature for guidelines, clinical registry-based studies, meta-analyses, randomized controlled studies, and systematic review articles which were subsequently evaluated. The keywords used were “arrhythmogenic right ventricular cardiomyopathy” and “arrhythmogenic right ventricular dysplasia”.

Pathophysiology

Results on the pathophysiology of ARVC are presented in Box 2.

Box 2

Pathophysiology of ARVC

Genetics and family screening

ARVC is commonly inherited by autosomal dominant transmission with varying penetrance, depending on age and sex. Regardless of genotype, male sex is a predictor for the risk of arrhythmia (5, 6). Ventricular arrhythmia occurs almost twice as often in male than in female patients (4).

The majority of ARVC-related genes code for proteins associated with desmosomes. Pathogenic variants, or those presumed to be pathogenic, associated with ARVC include the five desmosomal proteins plakophilin-2, desmocollin-2, desmoglein-2, desmoplakin, and plakoglobin, as well as other non-desmosomal proteins such as the transmembrane protein-43, phospholamban, desmin, cadherin 2, and filamin c (7, 8, 1).

Genetic testing should be offered to all patients with ARVC. In Germany, costs for the examination are covered by the statutory health insurance funds. A panel using next-generation sequencing is conducted as part of the genetic testing process. Apart from family and pregnancy counseling, genetic testing is also used for early detection screening and diagnosis of ARVC: Genetic testing can help detect the disorder at an early stage, especially in patients with no obvious symptoms in whom the clinical signs are not yet fully developed or in whom further diagnostic assessment has remained inconclusive. Furthermore, genetic testing can provide information about the severity of the disorder, given that certain genetic variants are associated with a poorer prognosis or a higher risk of severe arrhythmia or sudden cardiac death.

It is recommended to offer genetic testing based on the so-called cascade principle. This means that relatives at risk should receive counseling before and after the test if an individual in the family has a confirmed genetic diagnosis of ARVC. The test begins with first-degree relatives and can then be successively extended to other relatives if necessary (1).

Diagnosis

The Task Force Criteria, revised and published by Marcus et al. (7) in 2010, are considered standard for diagnosing ARVC (eTable). Recently, what are known as the Padua Criteria were introduced and include additional involvement of the left ventricle (2). The Task Force Criteria (7) are used to diagnose classic ARVC in which the right ventricle is primarily affected.

eTable

Revised Task Force and Padua Criteria

They combine various diagnostic parameters. Their interpretation should be made with caution, however, since their sensitivity (early detection of positive cases) and specificity (exclusion of other disorders) are limited, despite their wide application. The presence of several criteria is therefore essential for reaching a diagnosis.

Key elements for diagnostic assessment include electrocardiogram (ECG), 24-hour ECG, cardiac imaging studies such as echocardiography, magnetic resonance imaging (MRI), and RV angiography as well as genetic testing (Figure 1, eFigures 2–4) (1). An endomyocardial biopsy may be obtained if necessary to exclude myocarditis and sarcoidosis as possible differential diagnoses if the previous diagnostic workup has been inconclusive.

Figure 1

Echocardiography

eFigure 2

cardiac magnetic resonance imaging shows pronounced RV dilatation with wall motion abnormalities in the sub-tricuspid region as an important feature of arrhythmogenic right-ventricular cardiomyopathy

eFigure 3

Autopsy specimen demonstrating replacement of myocardial tissue in the free wall of the right ventricle with fibrofatty tissue

eFigure 4

This ECG example shows ventricular tachycardia emanating from the free wall of the right ventricle in a patient with ARVC

Additional diagnostic measures to be considered include stress tests and invasive electrophysiological examination with 3D mapping (eFigure 1) (1).

eFigure 1

three-dimensional electroanatomic mapping of the right ventricle

Electrocardiographic findings

Electrocardiographic changes are amongst the most important findings during diagnostic assessment, albeit with only low specificity and sensitivity (eTable) (1). Patients with ARVC commonly present depolarization and repolarization abnormalities. So-called epsilon waves in leads V1 to V3 may be evident in extreme cases (Figure 2) (1, 9). Patients with ARVC often demonstrate ventricular extrasystoles in their 24-hour ECG as well as non-sustained or sustained ventricular tachycardia (eFigure 4) (1, 10, 11). A typical feature are ventricular extrasystoles or ventricular tachycardias of left bundle branch block morphology. T-wave inversions in the right precordial leads V1 to V3 and beyond are also suspicious, as are low peripheral QRS voltage with biventricular involvement (1, 11) (Figure 2).

Figure 2

ECG example of a patient diagnosed with ARVC

Diagnostic imaging

Comprehensive diagnostic imaging of the heart is recommended for all patients with ARVC: echocardiography, cardiac MRI, and electroanatomic voltage mapping. This will allow recognition of structural and functional changes (1). Key features include wall motion abnormalities, such as RV dyskinesia, RV dilatation, and RV dysfunction. Cardiac MRI is the preferred imaging modality, with its higher sensitivity than echocardiography (eTable, Figure 1, eFigure 2) and ability to demonstrate fibrosis using contrast enhancement, so-called late gadolinium enhancement (12).

Initially, an echocardiographic assessment should be obtained for every patient with suspected ARVC—for example, in the presence of frequent ventricular extrasystoles, ventricular tachycardia, or positive family history. In recent years cardiac MRI has become increasingly important for diagnosing ARVC, so nowadays a cardiac MRI scan is also recommended for all patients with suspected ARVC. An electrophysiological examination, including voltage mapping, is optional, on the other hand, and is obtained primarily for catheter ablation of recurrent ventricular tachycardia.

Recommendations for sports activities

Early detection of ARVC allows prompt treatment and lifestyle adjustments, which can ultimately slow down disease progression (13, 14, 15). Patients with ARVC are recommended to avoid intensive and competitive sports which can increase the risk of ventricular arrhythmia and sudden cardiac death by fivefold (1, 16, 17). Studies have shown that intensive training increases the risk of arrhythmia and disease progression in individuals with ARVC (18, 19, 20, 21). Patients with desmosomal variants are particularly affected (1, 22, 23).

Low-intensity activities, such as light jogging, hiking, or yoga are probably safe for people with ARVC but should be discussed individually with a cardiologist or in the context of prospective studies (18).

Pharmacologic therapy

Beta-blockers, amiodarone, sotalol, and flecainide should be considered for pharmacologic therapy of ARVC (1). Recently, in a retrospective registry-based study, the benefit of antiarrhythmic medications—beta-blockers, sotalol, amiodarone—was compared in 123 patients with ARVC for a median follow-up of 132 months (24). A propensity score analysis showed that none of the antiarrhythmic drugs was associated with a lower risk of recurrent ventricular arrhythmia. However, if beta-blockers were given at more than 50% of the target dose, this was associated with a significant risk reduction in comparison with patients who did not take beta-blockers (hazard ratio [HR] 0.10; 95% confidence interval [0.02; 0.46], p = 0.004) (24). So, beta-blockers are therefore also the first choice for pharmacological management and the only group of medication which is unequivocally indicated according to the current guidelines (1). It is important that they are dosed as high as possible (25). If beta-blocker treatment alone is not sufficient for reducing ventricular extrasystoles and tachycardia, then amiodarone or flecainide may be supplemented (26, 27). Flecainide appears to be of particular advantage in patients with a plakophilin-2 variant. Given that ARVC predominantly affects young people, flecainide is also a good alternative to amiodarone which has a number of adverse drug reactions. A retrospective study on safety and efficacy of flecainide was recently conducted in 100 patients with ARVC who were treated with flecainide and beta-blockers between 1999 and 2017. The study did not include a control group. During the course of treatment, flecainide was discontinued in only ten percent of the patients. The use of flecainide was associated with a significant reduction in ventricular extrasystoles on the 24-hour ECG (27).

Risk stratification

Today, risk stratification for individuals with ARVC is increasingly being conducted using the published ARVC risk calculator (www.arvcrisk.com) (Box 3). The c-statistic of this predictive model is 0.77 [0.73; 0.81] (28).

Box 3

ARVC Risk Calculator

Recently, an analysis of programmed ventricular stimulation was also conducted in 288 patients with ARVC and no history of sustained ventricular tachycardias at diagnosis (29). Programmed ventricular stimulation is a diagnostic tool in which the heart in stimulated by electrical impulses during electrophysiologic examination to trigger ventricular tachycardia or ventricular fibrillation. The risk of ventricular tachyarrhythmia was assessed by using both the ARVC risk calculator and programmed ventricular stimulation over a period of five years. Eighty-three of 137 patients with inducible ventricular tachycardia (60.6%) and 37 of 151 patients with non-inducible ventricular tachycardia (24.5%) experienced sustained ventricular tachyarrhythmia during the median follow-up of 5.3 years. Inducibility of ventricular tachycardia during programmed stimulation was an independent predictor of ventricular arrhythmia (HR 2.52) and improved predictive accuracy (c-statistic 0.75 versus 0.72). Sensitivity was 76%, with 68% specificity. In patients with an ARVC risk calculator-predicted risk of ventricular tachycardia to be less than 25% within five years, the positive programmed ventricular stimulation even had a negative predictive value of 92.6%. Ventricular pacing at the time of diagnosis therefore appears to improve risk prediction for ventricular tachycardia in patients with ARVC, especially in those at low to moderate risk (29). Nonetheless, the low values for specificity, sensitivity, and c-statistic show that a precise estimation of the individual risk is difficult to make and should be discussed openly with the patient when it comes to deciding whether or not to implant a primary prophylactic defibrillator. An frank discussion is particularly important for patients at moderate risk. Those who have a high need for safety may be more inclined to implantation, while someone who is concerned about possible complications may be more skeptical about primary prophylactic implantation.

Catheter ablation

Catheter ablation is employed in the treatment of ARVC to prevent recurrent ventricular tachycardia. The fibro-fatty tissue acting as a substrate to aggravate ventricular tachycardia is selectively cauterized using heat (radiofrequency ablation). This method is used especially in those individuals with recurrent ventricular tachycardia that cannot be controlled with medication or in cases under particular stress from ICD shocks (known as electrical storm) to improve quality of life.

A meta-analysis recently compared the efficacy of the combined endocardial-epicardial method with the endocardial method alone to reduce the risk of ventricular tachycardia recurrence in patients with structural heart disease (30). The meta-analysis included 11 studies with a total of 977 patients, of which 434 had ARVC. Endocardial ablation was performed in 300 patients with ARVC and a combined endocardial-epicardial ablation in 134. The endocardial-epicardial approach had a significantly lower risk of recurrence (HR 0.54, p <0.001), although prospective randomized data are not available here either.

Catheter ablation may also be considered for slower monomorphic ventricular tachycardia as an alternative to treatment with an implantable cardioverter-defibrillator (ICD). A recent multicenter study examined the role of radiofrequency ablation in 65 patients with ARVC and hemodynamically well tolerated ventricular tachycardia (31). The patients had no ICD and preserved left-ventricular function. After a median follow-up of 52 months, there were no deaths or cardiac arrests. Ventricular tachycardia recurred in 19 patients (29%) patients. The authors concluded that radiofrequency ablation may represent an alternative to ICD in selected ARVC patients since hemodynamically well-tolerated ventricular tachycardia without a back-up did not result in fatal ICD arrhythmic events after radiofrequency ablation, although ventricular tachycardia recurrences did occur in some patients (31).

If ablation does appear to represent a reasonable option, despite the low level of evidence, it should be performed in a center with experience in epicardial ablation. Although endocardial, and often also epicardial, ablation does reduce the arrhythmia burden in the majority of cases, the probability of recurrence is nevertheless not low, even in specialized centers (1, 32, 33).

Cardioverter-defibrillator implantation

A meta-analysis showed that the average risk of ventricular arrhythmia ranged between 3.7% and 10.6% per year (4). ICD implantation is recommended as secondary prophylaxis if sustained ventricular tachycardia occurs or after surviving cardiac arrest (34, 35). However, available data is less clear with respect to the indication of primary prophylactic ICD in patients with ARVC, given that large, randomized trials are lacking. The ARVC risk calculator has established itself internationally as the gold standard for risk stratification in primary prevention ARVC patients.

The current guidelines of the European Society of Cardiology (ESC) recommend the following approach when evaluating the indication for ICD:

• ICD implantation is indicated for an ARVC patient following cardiac arrest or after suffering sustained ventricular tachycardia associated with syncope.
• ICD implantation should also be considered for a patient with sustained ventricular tachycardia without syncope. This also applies to patients with high-risk features such as rhythmogenic syncopes, non-sustained ventricular tachycardia, an RV ejection fraction of less than 40%, an LV ejection fraction of less than 45%, and sustained monomorphic ventricular tachycardia induced by programmed ventricular stimulation (1, 28).

Subcutaneous ICDs are an alternative to transvenous systems in patients with ARVC. The main disadvantage of a subcutaneous ICD lies in the fact that the system does not provide antitachycardia pacing (ATP) which can allow for effective and painless treatment of ventricular tachycardia (36, 37). Modern studies have, however, shown that subcutaneous ICDs are an effective alternative and can effectively treat ventricular tachyarrhythmia without shock delivery (36, 38, 39).

In the “International Subcutaneous Implantable Cardioverter Defibrillator Registry”(i-SUSI registry), a total of 75 patients with ARVC who received a subcutaneous ICD were analyzed in addition to other subgroups. Patients with ARVC demonstrated both the highest rate of appropriate shocks (9% per year; HR 2.492; p = 0.001) and of inappropriate shock deliveries (9.9% per year, HR 2.243) (38). Honarbakhsh et al. identified RV function as a significant predictor for the need of ATP (40). The implantation of a subcutaneous ICD should therefore potentially be considered in particular for patients without severe RV dysfunction as confirmed by echocardiography or MRI (40). Extravascular ICDs, with the shock electrode inserted behind the sternum, have been implanted in Germany for about a year. Additional ATP can also be delivered since they are located close to the heart. There has been no study to date which has examined the use of extravascular ICDs in patients with ARVC.

Future prospects

Causal gene therapy is already being tested in clinical studies in the USA and Europa (e1, e2). Since ARVC is a rather rare disorder, membership in a self-help group, such as the ARVC Patient Association in Germany (www.arvc-selbsthilfe.org), and participation in study registers are recommended. There are no large prospective, randomized controlled trials to date on medications, sports recommendations, catheter ablation, or direct comparisons of transvenous versus subcutaneous and extravascular ICDs.

Funding

The Zurich ARVC Program is supported by the Georg and Bertha Schwyzer-Winiker Foundation, the Baugarten Foundation, the USZ Foundation (Dr. Wild Grant), the Swiss Heart Foundation, and the Swiss National Science Foundation. Apart from the work submitted, the research was also funded by the German Research Foundation (DFG) and the German Heart Foundation.

Conflict of interest statement

AMS received speaker/advisory board/consultancy fees from Bayer Healthcare, Biotronik, Medtronic, Novartis, Pfizer, Stride Bio Inc., and Zoll.

LE received consultancy fees, lecture fees, and travel expenses from Abbott, Bayer Healthcare, Biosense Webster, Biotronik, Boehringer, Boston Scientific, Bristol-Myers Squibb, Daiichi Sankyo, Medtronic, Pfizer, and Sanofi Aventis. He is management board member of the German Cardiac Society (DGK) and chairman of the Clinical Commission of the DGK.

FK and the other authors declare that there are no conflicts of interest.

Manuscript received on 9 August 2024, revised version accepted on 22 December 2024.

Translated from the original German by Dr. Grahame Larkin.

Corresponding author:
Dr. med. Fabienne Kreimer

• Video 1 (mp4)
• Video 2 (mp4)

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