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Conditions

Arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy is a genetically determined heart muscle condition characterised by fibrofatty replacement of the right ventricular myocardium. 

Clinical features

  • Arrhythmogenic right ventricular cardiomyopathy (ARVC), also referred to as arrhythmogenic right ventricular dysplasia, is a form of arrhythmogenic cardiomyopathy (ACM) and is the best characterised subtype in relation to diagnosis, management and outcomes.
  • Clinical manifestations of ARVC usually present in early adulthood, although the age range can be broad.
  • Prevalence of ARVC is estimated to be between 1 in 2,000 and 1 in 5,000, and a pathogenic or likely pathogenic variant is found in about half of cases.
  • ARVC can be difficult to diagnose, particularly in the early stages of disease and/or when no family history is present. Identification of a pathogenic variant alone does not establish the presence of ARVC, but can be a major criterion towards diagnosis when used alongside other clinical features. Diagnostic and predictive genomic testing play an important role in ARVC management.
  • A significant proportion of ARVC patients will remain asymptomatic throughout their lives. For those who do experience them, symptoms are caused mainly by ventricular arrhythmias and/or heart failure.
  • The most prevalent symptom of ARVC is palpitations, which are usually the result of ventricular ectopy or runs of non-sustained or sustained ventricular tachycardia. These can cause pre-syncope or syncope, or may result in cardiac arrest. Heart failure symptoms usually arise at an advanced disease stage.
  • Patients with ARVC may experience ‘hot phases’ of the disease. These acute myocarditis-type episodes often include cardiac chest pain, dynamic electrocardiogram (ECG) changes and elevations in serum troponin. Hot-phase episodes may be the first manifestation of the disease. Notably, as many as 3% of individuals with acutely presenting myocarditis are thought to have a genetically caused ACM.
  • ARVC is an important cause of sudden cardiac death, particularly in athletes. Strenuous exercise has been observed to hasten disease progression (myocardial injury as well as arrhythmia risk), meaning that avoidance of competitive and endurance sports is considered to be an important intervention.
  • Symptomatic ventricular arrhythmias, including sudden cardiac death, can be the first manifestation of ARVC. As asymptomatic individuals can be at risk of sudden cardiac death, early detection is a key prevention strategy, for which genomic testing plays an important part.

Arrhythmogenic left ventricular cardiomyopathy

The pathological changes associated with ARVC typically predominate in the right ventricle, although extension to biventricular involvement can occur. Increasingly, forms of arrhythmogenic ventricular cardiomyopathy that predominantly affect the left ventricle are being recognised. These are sometimes referred to as arrhythmogenic left ventricular cardiomyopathy, but may also be recognised as arrhythmic forms of dilated cardiomyopathy.

Genetics

  • ARVC is described as a disease of the desmosome because there is a high prevalence of deleterious variants in genes coding for desmosomal proteins in affected individuals.
  • ARVC is most commonly inherited in an autosomal dominant pattern, although autosomal recessive inheritance is also well described. In autosomal recessive forms of ARCV, the condition forms part of a cardiocutaneous syndrome that also includes palmar hyperkeratosis and wool-like hair.

Inheritance and genomic counselling

Autosomal dominant inheritance

  • Variants in DSP, PKP2, DSG2, DSC2 and JUP (which code for the desmosomal proteins desmoplakin, plakophilin-2, desmoglein-2, desmocollin-2 and plakoglobin respectively) have all been demonstrated as causal in ARVC.
  • DSP variants have been associated with predominantly, or even exclusively, left-sided ventricular involvement. Those with PKP2-driven disease generally present at an earlier stage compared to those with disease caused by other variants. Pathogenic variants in non-desmosomal genes (such as TMEM43 and PLN) also account for some cases.

Autosomal recessive inheritance

  • Autosomal recessive ARVC is associated with cutaneous signs as well as the cardiomyopathic process. Individuals who are homozygous for a JUP variant develop Naxos syndrome, which causes palmoplantar keratosis, woolly hair and ARVC. Carvajal disease has a similar phenotype and mode of inheritance, and is a result of a desmoplakin-coding gene variant.

Genomic counselling

  • Genomic testing should be offered and undertaken in specialist centres, in which patients can be adequately informed of the implications of testing outcomes and, where there is sufficient clinical expertise, results can be interpreted appropriately.
  • Diagnostic genomic testing should be offered to most probands with suspected or confirmed ARVC. If a genomic diagnosis is made, their relatives should be offered predictive genomic testing as part of a coordinated cascade approach to family screening.

Management

  • Clinical management of individuals diagnosed with ARVC often requires a multidisciplinary approach, and should be performed in conjunction with a specialist inherited cardiac conditions service.  A comprehensive approach to ARVC management will address the following.
    • Confirmation of the diagnosis of familial ARVC, including evaluation for alternative causes. A detailed personal and family history are key components of the assessment. Following this, family screening and genomic testing are central to confirming a diagnosis of familial ARVC.
    • Assessment of symptom status, including the identification of the pathophysiological mechanisms most likely responsible for symptoms, and indications for symptomatic therapies. Symptomatic management most often addresses ventricular arrhythmias and right ventricular systolic impairment; however, symptoms may also be the result of left ventricular involvement, valvular disease, atrial arrhythmias, conduction disease and other mechanisms.
    • Assessment of prognostic risks, including from sudden arrhythmic death, thrombo-embolic disease and progressive heart failure. Implantable defibrillators, anticoagulation and heart failure therapies (device, pharmacological and transplant) may be indicated to mitigate risks.
    • An individualised evaluation that considers the implications of ARVC and its treatment for the individual’s lifestyle (for example, competitive and/or endurance sports and recreational drug taking), life events (such as pregnancy, anaesthesia and comorbidities) and livelihood (for example, professional athletes and licensing regulations in public transportation).
    • Addressing implications of a genetic condition for family members. A genomic diagnosis greatly facilitates the accuracy, efficiency and cost-effectiveness of cascade family screening (such as predictive testing).

Resources

For clinicians

References:

For patients

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  • Last reviewed: 15/08/2023
  • Next review due: 15/08/2025
  • Authors: Dr Mihir Sanghvi
  • Reviewers: Dr Catherine Mercer, Professor Saidi Mohiddin