Arrhythmogenic Right Ventricular Cardiomyopathy

Clinical characteristics.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) – previously referred to as arrhythmogenic right ventricular dysplasia (ARVD) – is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle, and it may also involve the left ventricle. The presentation of disease is highly variable even within families, and some affected individuals may not meet established clinical criteria. The mean age at diagnosis is 31 years (±13; range: 4-64 years).

Diagnosis/testing.

The diagnosis of ARVC is made using a combination of noninvasive and invasive tests to evaluate cardiac structure and rhythm. The common genetic causes known to be associated with ARVC are: DSC2, DSG2, DSP, JUP, PKP2, and TMEM43. Less common genetic causes include CTNNA3, DES, LMNA, PLN, RYR2, TGFB3, and TTN. A subset of these 13 genes encode components of the desmosome.

Management.

Treatment of manifestations: Management is individualized and focused on prevention of syncope, cardiac arrest, and sudden death through use of antiarrhythmic medication and an implantable cardioverter-defibrillator. Heart transplantation is considered when ARVC has progressed to right or left ventricular heart failure, although severe diffuse biventricular involvement simulating dilated cardiomyopathy and requiring heart transplantation appears to be rare.

Agents/circumstances to avoid: Regular, vigorous athletic activity including competitive athletics should be discouraged because of the strain caused on the right heart and its promotion of ARVC and associated arrhythmias.

Evaluation of relatives at risk: Molecular genetic testing of at-risk relatives in families in which the pathogenic variant is known; those with the family-specific pathogenic variant warrant annual clinical screening of cardiac function and rhythm between ages ten and 50 years. If genetic testing has not been performed or did not identify a pathogenic variant in an affected family member, clinical screening for cardiac involvement is recommended for asymptomatic at-risk first-degree relatives every three to five years after age ten years.

Genetic counseling.

ARVC is typically inherited in an autosomal dominant manner. A proband with autosomal dominant ARVC may have the disorder as a result of a de novo pathogenic variant. The proportion of cases caused by a de novo variant is unknown. Each child of an individual with autosomal dominant ARVC has a 50% chance of inheriting the pathogenic variant. ARVC may also be inherited in a digenic manner (i.e., a single allele of two different genes has a pathogenic variant). Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant(s) have been identified in the family.

Suggestive Findings

Arrhythmogenic right ventricular cardiomyopathy (ARVC) should be suspected in individuals with any of the following findings:

• Syncope
• Palpitations
• Sudden cardiac death
• Abnormal ECG
• Abnormal right ventricle seen through cardiac imaging

Diagnostic criteria for ARVC, initially proposed by an international task force [McKenna et al 1994], were revised by Marcus et al [2010] (see full text) to incorporate new knowledge and technology to improve diagnostic sensitivity while maintaining diagnostic specificity. Individuals are classified as having a definite, borderline, or possible diagnosis of ARVC based on the number of major and/or minor diagnostic criteria present (see Establishing the Diagnosis).

Establishing the Diagnosis

The diagnosis of ARVC is established in a proband with the following findings from different categories (see Suggestive Findings):

• Two major criteria; OR

• One major AND two minor criteria; OR

• Four minor criteria

In the task force criteria, a heterozygous pathogenic variant in one of the genes listed in Table 1a or Table 1b detected by molecular genetic testing is considered a major criterion.

Molecular genetic testing approaches can include use of a multigene panel and more comprehensive genomic testing:

• A multigene panel that includes DSC2, DSG2, DSP, JUP, PKP2, and TMEM43 and other genes of interest (see Differential Diagnosis) is recommended as the primary test for the proband. Other genes to include on the panel are CTNNA3, DES, LMNA, PLN, RYR2, TGFB3, and TTN. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Alternatively, broader cardiomyopathy gene panels can be considered as first-line testing since there is phenotypic and genotypic overlap with dilated, hypertrophic, and left ventricular noncompaction cardiomyopathies. A broader cardiomyopathy panel can also be considered as an intermediate test prior to using comprehensive genomic testing. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Note: With the expansion of gene panel testing for ARVC, individuals with two pathogenic variants may be found (digenic/biallelic inheritance). The estimate of digenic/biallelic inheritance varies from 4% to 47% [Xu et al 2010, Bao et al 2013, Rigato et al 2013, Bhonsale et al 2015, Groeneweg et al 2015]. In most studies, digenic/biallelic carriers have a more severe arrhythmia phenotype. See Genotype/Phenotype Correlations.

Note:

(1) Molecular genetic testing should be considered in individuals who are suspected of having ARVC based on international task force criteria [Marcus et al 2010], but who do not meet criteria for a definite clinical diagnosis*. For some of these individuals, identification of a pathogenic variant in one of the ARVC-related genes fulfills the remaining criteria (see Suggestive Findings).

*Borderline diagnosis of ARVC:

• One major AND one minor criterion; OR
• Three minor criteria from different categories

*Possible diagnosis of ARVC:

• One major criterion; OR
• Two minor criteria from different categories

(2) The overall yield of genetic testing for all available genes in probands who meet the revised task force criteria [Marcus et al 2010] approximates 50% [Quarta et al 2011]. Thus, if molecular genetic testing does not identify a pathogenic variant in an individual who meets diagnostic criteria, the clinical diagnosis of ARVC is unchanged.

Beyond the Diagnostic Criteria: Additional Information

Note: The phenotype of ARVC is widely variable and some affected individuals may not meet the specific criteria [McKenna et al 1994, Marcus et al 2010]; however, such individuals may still be at risk for cardiovascular events including arrhythmias and, therefore, warrant continuing care by a cardiologist.

Additional considerations regarding the noninvasive and invasive tests of cardiac structure and rhythm are outlined here (pdf).

Clinical Description

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a myocardial disorder affecting the right ventricle and in some cases also the left ventricle. ARVC is progressive and characterized by fibrofatty replacement of the myocardium, predisposing to ventricular tachycardia and sudden death in young individuals [Marcus et al 1982, Thiene et al 1988, Corrado et al 1998, Fontaine et al 1998]. The disease often affects the right ventricular apex, the base of the right ventricle, and the right ventricle outflow tract. The arrhythmias in ARVC most frequently arise from the right ventricle and have left bundle branch block morphology.

Pathology in ARVC may also extend to involve the left ventricle [Horimoto et al 2000, Hamid et al 2002]. Cardiac MRI studies have identified regional left ventricular dysfunction in individuals with ARVC [Sen-Chowdhry et al 2006, Jain et al 2010]. Delayed enhancement may also be seen in the left ventricle [Marra et al 2012].

Presentation. The most common presenting symptoms are heart palpitations, syncope, and death. As expected, probands / index cases have a more severe presentation. See Penetrance.

Age at diagnosis and survival. ARVC typically presents in adults, although it may be seen in children during the second decade. Two long-term studies following individuals with ARVC suggest that survival is greater than 72% after six years of follow up. In ARVC overall, cardiac mortality and need for transplant are less than 5% [Bhonsale et al 2015, Groeneweg et al 2015].

Gender differences. Males are more likely to present as probands with ARVC, although females constituted nearly half of a large cohort (45%) [Bhonsale et al 2015]. In a multivariate analysis of indviduals with genetically confirmed ARVC, male sex was more likely to associate with arrhythmia events [Protonotarios et al 2016].

Progression. The four described stages of ARVC [Dalal et al 2006]:

1.

Concealed phase (no clinical manifestations of ARVC, but potential risk of sudden cardiac death)

2.

An overt electrical disorder (characterized by symptomatic arrhythmias)

3.

Right ventricular failure

4.

A biventricular pump failure (resembling dilated cardiomyopathy) [Dalal et al 2006]

Left ventricle involvement can occur at any of the above stages [Sen-Chowdhry et al 2007].

Symptomatic arrhythmia. Symptomatic arrhythmias include palpitations, syncope, and presyncope attributable to ventricular ectopy or sustained or nonsustained ventricular tachycardia.

Arrhythmia and sudden death. The principal characteristic of arrhythmogenic cardiomyopathies is the tendency for ventricular arrhythmia and sudden death in the absence of overt ventricular dysfunction. The increased risk for sudden death in ARVC is thought to relate to sudden ventricular arrhythmias.

Studies that have investigated the propensity to arrhythmia in ARVC include the following:

• Bhonsale et al [2015] evaluated 541 individuals (220 probands and 321 family members); 53% were asymptomatic at the time of first evaluation. Twenty-five percent presented with sustained ventricular tachycardia; this included 54% of probands versus 4% of family members. The median age range at symptom onset was 30 years (range 10-84 years). Of the overall cohort, 30% had spontaneous sustained VT over the follow up of six years.
• Rigato et al [2013] examined a cohort of 113 individuals of whom 84% had a single desmosomal gene variant and 16% had compound heterozygous or digenic inheritance. Over an observation period that averaged 39 years, 16% had major arrhythmic events. Specific risk factors for having events were male sex and having multiple genetic variants.
• Groeneweg et al [2015] reviewed the outcomes in a cohort of 439 individuals who met task force criteria and 562 family members. Over a median follow-up interval of seven years, 72% of living probands experienced sustained ventricular arrhythmias. Of family members of probands who carried pathogenic variants, 11% experienced ventricular arrhythmias over the follow-up interval.
• Protonotarios et al [2016] followed 105 individuals with desmosomal gene variants finding that males were more likely to have an arrhythmic event than females. Furthermore, 41% experienced a primary arrhythmic event by age 29 (range 21-46 years). Of note, definitive diagnosis by task force criteria in the presence of a desmosomal variant showed a 57% positive and 100% negative predictive value for the occurrence of an arrhythmic event.

Cardiomyopathy. The cohort of individuals with ARVC followed by Bhonsale et al [2015] had an overall incidence of left ventricular dysfunction of 14% over the follow-up interval, with 5% experiencing heart failure.

Genotype-Phenotype Correlations

Few genotype-phenotype correlations have emerged correlating specific ARVC genotypes to clinical outcomes. One observation is that DSP variants are more likely to be associated with left ventricular dysfunction [López-Ayala et al 2014, Bhonsale et al 2015]. A second observation is that having more than one variant increases propensity to arrhythmias and progression to cardiomyopathy [Bao et al 2013, Rigato et al 2013, Bhonsale et al 2015, Groeneweg et al 2015]. It has also been suggested that PKP2 pathogenic variants are more likely to be associated with ventricular tachycardia [Bao et al 2013].

Penetrance

Probands are more likely to have ventricular arrhythmias than their family members [Groeneweg et al 2015]. Of family members with a pathogenic variant, 324 of 385 were asymptomatic, and of these 324 asymptomatic subjects, 221 (68%) did not meet task force criteria. Therefore, penetrance for ventricular arrhythmias appears to be relatively low in this disorder.

Nomenclature

Arrhythmogenic right ventricular cardiomyopathy (ARVC) has had numerous names, including Uhl anomaly and right ventricular dysplasia. Until 1996, ARVC was called arrhythmogenic right ventricular dysplasia (ARVD) [Richardson et al 1996]. Currently the term "ARVC" is favored.

Prevalence

The prevalence of ARVC is estimated at 1:1,000 to 1:1,250 in the general population [Peters 2006].

The prevalence of ARVC is greater in certain regions; in Italy and Greece (Island of Naxos), it can be as high as 0.4%-0.8% [Thiene & Basso 2001].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC), the following evaluations are recommended if not performed at the time of diagnosis:

• ECG
• Echocardiogram and/or MRI, depending on the expertise of the imaging center
• Noninvasive monitoring. Cardiac rhythm can be monitored noninvasively through Holter or event monitoring, and this is an effective means of detecting ventricular ectopy including nonsustained ventricular tachycardia. Implantable loop recorders can also be used in individuals with ARVC for whom arrhythmia risks are not clear. Signal-averaged ECGs may also be useful [Philips & Cheng 2016].
• Electrophysiology study to assess the risk for ventricular arrhythmias and the appropriateness of device insertion (e.g., an implantable cardioverter defibrillator). A cardiac catheter ablation of tissue causing abnormal rhythms can be performed during the electrophysiology study; however, ablation may not be effective long-term in individuals with ARVC because of the multiple sites of primary ventricular tachycardias.

Treatment of Manifestations

Affected individuals should be monitored by a cardiologist who is knowledgeable about ARVC. Management of individuals with ARVC is complicated by its variable course and the limited specificity of clinical findings to predict arrhythmia risk. Management should be individualized and based on the specific results of detailed clinical and genetic investigation.

• Management is focused on prevention of syncope, cardiac arrest, and sudden death (see Prevention of Primary Manifestations).
• Beta blockers are considered first line therapy. Although their efficacy has not been shown in a randomized, prospective clinical trial, beta blockers are recommended [Yancy et al 2013, Corrado et al 2015].
• Amiodarone may also be effective [Corrado et al 2015].
• The mainstay of arrhythmia prevention relies on device insertion and management. Risk-benefit analysis for device insertion and management should be balanced against clinical risk stratification for arrhythmias.

Education regarding sudden death risk to affected adults and parents of affected children is an important aspect of management.

Physical exercise ‒ specifically regular, intense exercise ‒ is thought to promote ARVC and its associated arrhythmias. Therefore, those with fully diagnosed ARVC are usually recommended to reduce or eliminate prolonged exercise and participation in competitive sports [James et al 2013]. Supporting this idea that intense exercise hastens the onset of ARVC, Ruwald et al [2015] reported that a history of participation in competitive sports was associated with an earlier age of onset. These findings support the notion that intense exercise can induce ARVC even in the absence of an identifiable genetic predisposition.

Heart transplantation is considered when ARVC has progressed to right or left ventricular heart failure. Severe diffuse biventricular involvement simulating dilated cardiomyopathy and requiring heart transplantation appears to be rare.

Prevention of Primary Manifestations

Prospective randomized trials have not been conducted in ARVC for the prevention of arrhythmias. Management relies on personalized recommendations based on clinical assessment.

Implantable cardioverter-defibrillators (ICDs). Observational studies support that ICD placement is effective in reducing the risk for sudden cardiac death in ARVC. ICD placement should be considered in anyone with a clinical diagnosis of ARVC. Corrado et al [2010] reported results of ICD implantation in 106 individuals with ARVC who met task force criteria. Device placement was based on the presence of arrhythmia risk factor defined as syncope, family history of sudden death, nonsustained ventricular tachycardia, and whether ventricular tachycardia or fibrillation was inducible in an electrophysiology done at the time of device implant. Over the follow-up interval of 58 months, 24% of subjects had an appropriate ICD discharge. Syncope was found to predict appropriate ICD discharge. The advisability of placing an ICD for primary prevention remains a question of debate [Zorzi et al 2016].

The ACC/AHA (American College of Cardiology / American Heart Association) and European Society of Cardiology (ESC) guidelines, which are based on experience and previously published reports, recommend as a Class I indication (i.e., procedure/treatment should be performed) ICD implantation for prevention of sudden cardiac death in individuals with documented sustained ventricular tachycardia or ventricular fibrillation who have a reasonable expectation of survival with good functional status for more than one year. Class II indications (i.e., it is reasonable to perform procedure/treatment) for ICD implantation include extensive disease (e.g., left ventricular involvement), family members with sudden death, or undiagnosed syncope when ventricular fibrillation or ventricular tachycardia cannot be excluded as the cause of syncope while the individual was on optimal medical therapy [Tracy et al 2013, Priori et al 2015].

Surveillance

Screening for degree of cardiac involvement in persons diagnosed with ARVC is essential to ascertain severity and disease progression over time. Screening recommendations:

• ECG, annually or more frequently depending on symptoms
• Echocardiogram, annually or more frequently depending on symptoms
• Holter monitoring, event monitoring, implantable loop recorder
• Exercise stress testing
• Cardiac MRI, with frequency depending on symptoms and findings

Agents/Circumstances to Avoid

Individuals with ARVC are discouraged from participating in vigorous athletic activity, including competitive athletics, because of the strain caused on the right heart [Corrado et al 2015].

Evaluation of Relatives at Risk

It is appropriate to offer molecular genetic testing to relatives at risk for ARVC (even those age <18 years) if the pathogenic variant(s) have been identified in an affected family member so that morbidity and mortality can be reduced by early diagnosis and treatment. Predictive testing should be offered in the context of formal genetic counseling.

Note: The initial molecular testing in the proband should encompass ARVC-related genes as a gene panel because of the high rate of digenic heterozygosity (a heterozygous pathogenic variant in two different genes) and to increase the yield of genetic testing [Barahona-Dussault et al 2010, Bauce et al 2010, Christensen et al 2010, Xu et al 2010, Nakajima et al 2012]. Once one (or more) family-specific variant(s) have been identified, targeted variant testing is performed in relatives.

Guidelines exist for screening for cardiac involvement in asymptomatic first-degree relatives at risk for ARVC [Hershberger et al 2009, Charron et al 2010]:

• If the family-specific pathogenic variant has been identified in the asymptomatic at-risk relative, screening for cardiac involvement is recommended yearly between ages ten and 50 years.
• If genetic testing has not been performed or did not identify a pathogenic variant in an affected family member, screening for cardiac involvement is recommended for asymptomatic at-risk first-degree relatives every three to five years after age ten years.

Screening for cardiac involvement comprises the following [Hershberger et al 2009, Charron et al 2010]:

• Medical history with attention to heart failure symptoms, arrhythmia, presyncope, and syncope
• ECG, with consideration of signal-averaged electrocardiogram
• Echocardiogram
• Holter monitoring
• Cardiac MRI

At-risk first-degree relatives with any abnormal clinical screening tests for cardiac involvement should be considered for repeat clinical screening in one year [Hershberger et al 2009].

Children younger than age ten are not usually screened, as ARVC features are not usually seen in children before this age. See Hamilton & Fidler [2009] for a review of screening for ARVC in the young. A recent MRI study of ARVC in the young suggested that MRI increases sensitivity but that it was still unusual, even with this more sensitive modality, to see ARVC in children before age ten years [Etoom et al 2015].

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Case reports describe successful outcomes in women with ARVC who are pregnant and give birth [Agir et al 2014, Cozzolino et al 2014]. Specific guidelines for managing ARVC in pregnancy have not been developed, but affected individuals need to be monitored by a multidisciplinary team.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.