Arrhythmogenic right ventricular cardiomyopathy, clinical manifestations, and diagnosis

Abstract

This review aims to give an update on the pathogenesis, clinical manifestations, and diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC). Arrhythmogenic right ventricular cardiomyopathy is mainly an autosomal dominant inherited disease linked to mutations in genes encoding desmosomes or desmosome-related proteins. Classic symptoms include palpitations, cardiac syncope, and aborted cardiac arrest due to ventricular arrhythmias. Heart failure may develop in later stages. Diagnosis is based on the presence of major and minor criteria from the Task Force Criteria revised in 2010 (TFC 2010), which includes evaluation of findings from six different diagnostic categories. Based on this, patients are classified as having possible, borderline, or definite ARVC. Imaging is important in ARVC diagnosis, including both echocardiography and cardiac magnetic resonance imaging for detecting structural and functional abnormalities, but importantly these findings may occur after electrical alterations and ventricular arrhythmias. Electrocardiograms (ECGs) and signal-averaged ECGs are analysed for depolarization and repolarization abnormalities, including T-wave inversions as the most common ECG alteration. Ventricular arrhythmias are common in ARVC and are considered a major diagnostic criterion if originating from the RV inferior wall or apex. Family history of ARVC and detection of an ARVC-related mutation are included in the TFC 2010 and emphasize the importance of family screening. Electrophysiological studies are not included in the diagnostic criteria, but may be important for differential diagnosis including RV outflow tract tachycardia. Further differential diagnoses include sarcoidosis, congenital abnormalities, myocarditis, pulmonary hypertension, dilated cardiomyopathy, and athletic cardiac adaptation, which may mimic ARVC.

Arrhythmogenic right ventricular cardiomyopathy, Desmosomal mutations, Signal-averaged ECG, Ventricular arrhythmias

Introduction

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a chronic, progressive, heritable cardiomyopathy and is one of the leading causes of sudden unexpected cardiac death in young, apparently healthy individuals.¹ Prevalence of ARVC is estimated to be 1:1000–1:5000^2,3 and sudden death may be the first symptom of disease. Previously, the condition was named arrhythmogenic right ventricular dysplasia, due to the belief that the condition was a developmental defect. However, myocardial alterations are rarely detected at birth and recent knowledge has classified the condition as a genetically determined progressive cardiomyopathy. Arrhythmogenic right ventricular cardiomyopathy most frequently affects the right ventricular (RV) myocardium, but involvement of the left ventricular (LV) myocardium is commonly recognized and also a left dominant type may occur.^4,5 Recent reports therefore suggest using the term arrhythmogenic cardiomyopathy. This paper will give an overview of the pathogenesis, clinical manifestations, and diagnosis in ARVC.

Pathogenesis and related genes

Molecular genetic reports have revealed ARVC to be mainly an autosomal dominant inherited disease. The genes associated with ARVC disease predominantly encode desmosomal proteins.⁶ Recently, more genes have been reported to be associated with ARVC, but the frequencies of gene variations in these genes are unknown^7–12 (Table 1). The desmosomes contribute to tissue strength and are numerous in tissues exposed to mechanical stress. Defect desmosomes result in progressive loss of cardiac myocytes, followed by fibro-fatty replacement.¹³ The components of the intercalated disk proteins, such as desmosomal proteins, Connexin43 (gap junctions), and Nav1.5 (sodium channels), work together as a protein-interacting network that regulates excitability, cell–cell adhesion, and intercellular coupling in the heart.⁹ Reduced cell–cell adhesion by desmosomal dysfunction has been discussed as a pathomechanism in ARVC and reduced junctional plakoglobin at the intercalated disks appears to be related with the ARVC phenotype.¹⁴ Defects in desmosomal or desmosome-related proteins also result in altered intercellular connections with effects on ion channel remodeling.^15,16 Dysregulated intracellular signaling has been suggested to promote inflammation and fibroadiposis in ARVC.¹⁷ Mechanical stress has been shown to exaggerate desmosomal dysfunction, which may be one explanation for the frequent finding of ARVC disease in athletes.^18,19 Experimental studies support that vigorous exercise accelerates right ventricular dysfunction in mice with ARVC-related mutations.^19,20 Several studies have shown that exercise is an important trigger for ventricular arrhythmias²¹ and may worsen prognosis in ARVC.^18,22,23

Table 1

Genes involved in ARVC and in ARVC-mimicking disease^7,8,10

Structure genes	Gene	Reported incidence7
Genes involved in ARVC
Desmosomal protein	Desmocollin 2	2–7%
	Desmoglein 2	5–10%
	Desmoplakin	2–12%
	Junctionplakoglobin	Unknown
	Plakophilin 2	25–40%
Genes involved in ARVC-mimicking diseases
Calcium/sodium handling	Ryanodine receptor 2	Unknown
	Phospholamban	Unknown
Nuclear envelope protein	Lamin A/C	Unknown
Cytoskeletal protein	Desmin	Unknown
	Titin	Unknown
Others	Alpha-T-catenin	Unknown
	Transforming growth factor β3	Unknown
	Transmembrane protein 43	Unknown

Clinical manifestations

Arrhythmogenic right ventricular cardiomyopathy presents with clinical manifestations typically in adolescence, but can also present later. Penetrance is age and gender dependent, and the clinical manifestations and progression of disease are highly variable.^11,12,24 Although inheritance is autosomal dominant and genders are genetically equally affected, clinical manifestations of ARVC are three times more frequent in males than females.²⁵

The clinician should consider ARVC in adolescents or young individuals with palpitations, premature ventricular contractions (PVCs), ventricular arrhythmias, suspected cardiac syncope, or aborted cardiac arrest. Ventricular tachycardia (VT) with left bundle branch block morphology and superior axis is the typical VT indicating ARVC; however, other morphologies do not exclude ARVC.

Three phases have been described in ARVC disease progression:⁵ Disease progression including life-threatening ventricular arrhythmias may present as periodic bursts and ‘hot phases’ rather than a continuous process. Environmental factors, such as exercise and inflammation, may facilitate disease progression.^2,18,22,27

1. In the early ‘concealed phase’, individuals are often asymptomatic, but are at risk of ventricular arrhythmias and sudden cardiac death.^12,26

2. In the overt ‘electrical phase’, individuals present with symptomatic arrhythmias, and RV morphological abnormalities may or may not be detectable by conventional imaging modalities.

3. Diffuse, progressive disease may result in right, left, or biventricular heart failure, often combined with ventricular arrhythmias.

Diagnosis

In 2010, the diagnostic criteria for ARVC were revised primarily by introducing precise quantitative aspects into the various criteria.²⁸ Current Task Force Criteria for ARVC diagnosis (2010 TFC) combine diagnostic criteria from six categories, including repolarization or depolarization abnormalities on electrocardiography (ECG), presence of ventricular arrhythmias, morphological, and functional changes, in addition to histopathology, family history, and genetic findings. Combinations of findings establish diagnostic grades of ‘definite’, ‘borderline’ or ‘possible’ ARVC. Criteria are classified as major and minor criteria for ARVC (Table 2).²⁸

• Definite ARVC diagnosis includes: two major criteria or one major and two minor criteria or four minor from different categories.

• Borderline ARVC diagnosis includes: one major and one minor criteria or three minor criteria from different categories.

• Possible ARVC diagnosis includes: one major or two minor criteria from different categories.

Table 2

Modified task force criteria from 2010

Global or regional dysfunction and structural alterations
MAJOR
2D echo criteria
Regional RV akinesia, dyskinesia, or aneurysm and one of the following measured at end diastole
PLAX RVOT ≥32 mm (BSA corrected ≥ 19 mm/m2)
PSAX RVOT ≥36 mm (BSA corrected ≥ 21 mm/m2)
Fractional area change ≤33%
MRI criteria
Regional RV akinesia or dyskinesia or dyssynchronous RV contraction and one of the following
Ratio of RV end-diastolic volume to BSA ≥110 mL/m2 (male) or ≥100 mL/m2 (female)
RV ejection fraction ≤40%
RV angiography criteria
Regional RV akinesia, dyskinesia, or aneurysm
MINOR
2D echo criteria
Regional RV akinesia or dyskinesia and one of the following measured at end diastole
PLAX RVOT ≥29 to <32 mm (BSA corrected ≥ 16 to <19 mm/m2)
PSAX RVOT ≥32 to <36 (BSA corrected ≥ 18 to <21 mm/m2)
Fractional area change >33 to ≤40%
MRI criteria
Regional RV akinesia or dyskinesia or dyssynchronous RV contraction and one of the following
Ratio of RV end-diastolic volume to BSA ≥100 to <110 mL/m2 (male) or ≥90 to <100 mL/m2
RV ejection fraction >40 to ≤45%
Tissue characterization of wall
MAJOR
Residual myocytes <60% by morphometric analysis (or <50% if estimated) with fibrous replacement of the RV-free wall myocardium in ≥1 sample, with or without fatty replacement of tissue on endomyocardial biopsy
MINOR
Residual myocytes 60–75% by morphometric analysis (or 50–65% if estimated),with fibrous replacement of the RV-free wall myocardium in ≥1 sample, with or without fatty replacement of tissue on endomyocardial biopsy
Repolarization abnormalities
MAJOR
Inverted T waves in right precordial leads (V1, V2, and V3) or beyond in individuals >14 years of age (in the absence of complete RBBB QRS ≥ 120 ms)
MINOR
Inverted T waves in V1 and V2 in individuals >14 years of age (in the absence of complete RBBB) or in V4, V5, or V6
Inverted T waves in leads V1, V2, V3, and V4 in individuals >14 years of age in the presence of a complete RBBB
Depolarization/conduction abnormalities
MAJOR
Epsilon wave (reproducible low-amplitude signals between end of QRS complex to onset of T wave) in the right precordial leads (V1 to V3)
MINOR
Late potentials by SAECG in ≥1 of three parameters in the absence of a QRS duration of ≥110 ms on standard ECG
Filtered QRS ≥ 114 ms
Duration of terminal QRS < 40 μV ≥38 ms
Root-mean-square voltage of terminal 40 ms ≤20 μV
Terminal activation duration ≥55 ms measured from the nadir of the S wave to the last depolarization deflection29
Arrhythmias
MAJOR
Non-sustained or sustained VT of LBBB morphology with superior axis
MINOR
Non-sustained or sustained VT of RVOT configuration, LBBB morphology with inferior axis or of unknown axis
>500 PVCs per 24 h (Holter)
Family history
MAJOR
ARVC in first-degree relative who meets Task Force criteria
ARVC confirmed pathologically at autopsy or surgery in first-degree relative
Identification of pathogenic mutation categorized as associated or probably associated with ARVC in the patient under evaluation
MINOR
History of ARVC in first-degree relative in whom it is not possible to determine whether the family member meets Task Force criteria
Premature sudden death (<35 years of age) due to suspected ARVC in a first-degree relative
ARVC confirmed pathologically or by current Task Force criteria in second-degree relative

Diagnostic criteria in ARVC modified from Marcus et al.

ARVC, arrhythmogenic right ventricular cardiomyopathy; BSA, body surface area; LBBB, left bundle branch block; PLAX RVOT, parasternal long axis right ventricular outflow tract; PSAX RVOT, parasternal short-axis right ventricular outflow tract; PVC, premature ventricular contraction; RBBB, right bundle branch block; RV, right ventricle; SAECG, signal-averaged electrocardiography; VT, ventricular tachycardia.

Thus, several different diagnostic modalities must be combined to evaluate a patient for ARVC, including clinical examination and family history, ECG, signal-averaged ECG, Holter monitoring, imaging (echo and cardiac magnetic resonance (CMR) imaging), and genetic testing. If needed, further evaluation by exercise testing, myocardial biopsy, and supplementary diagnostic procedures such as invasive electrophysiological study with electro-anatomical mapping, and coronary angiography/coronary CT scanning may be performed.

Imaging

Echocardiography

Echocardiography is the first line imaging modality in ARVC, and the most commonly used imaging tool for follow-up of ARVC patients. The typical morphological features in ARVC patients are RV dilatation and reduced regional or global RV function. The 2010 TFC²⁸ include echocardiographic evaluation of RV akinesia, dyskinesia, or aneurysms together with measurements of right ventricular outflow tract (RVOT) diameter and RV fractional area change (Table 2) (Figure 1). The RVOT diameter can be measured from parasternal long axis (Figure 1, right upper panel) or from parasternal short axis (Figure 1, left upper panel). When measured from parasternal short axis, the proximal diameter should be assessed. To diagnose ARVC by echocardiography is challenging and requires high expertise. The visualization of the right ventricle requires more views than usually included in a standardized echocardiographic study. Quantitative assessment of RV function is challenging due to complex anatomy and load dependency. RV function can be further assessed by strain echocardiography.³⁰ Both RV and LV function by strain echocardiography are reduced in ARVC,³¹ but strain echocardiography is not included in current 2010 TFC.

Figure 1

Echocardiographic measurements in a patient with ARVC. Upper left panel shows measurement of an increased RVOT diameter from parasternal short-axis view. The diameter should be assessed in the proximal position. The upper right panel shows RVOT diameter measurement form parasternal long axis. Lower panels show enlarged right ventricular volumes and decreased right ventricular fractional area change. ARVC, arrhythmogenic right ventricular cardiomyopathy; RV, right ventricle; RVFAC, right ventricular fractional area change; RVOT plax, right ventricular outflow tract parasternal long axis; RVOT sax, right ventricular outflow tract parasternal short axis.

Cardiac magnetic resonance imaging

Cardiac magnetic resonance imaging is the preferred imaging modality in ARVC, when available. Cardiac magnetic resonance can provide tissue characterization and identification of intra-myocardial fat and fibrosis in addition to assessment of biventricular structure and function^32,33 (Figure 2). Late gadolinium enhancement (LGE) is used to assess myocardial fibro-fatty infiltration, which may help to distinguish ARVC from other cardiomyopathies.³³ However, fibro-fatty replacement of the myocardium in ARVC typically occurs in the sub-epicardium and might be difficult to detect by LGE CMR. Furthermore, the risk to over-diagnose ARVC by CMR has been acknowledged. The major disadvantage of CMR is the limited availability and the requirement of high expertise during assessment and interpretation of data. Also, the complex RV anatomy is a clear limitation for all imaging modalities including CMR. The major and minor criteria for ARVC by CMR imaging are listed in Table 2.

Figure 2

Cardiac magnetic resonance imaging in a patient with ARVC. The figure shows enlarged right ventricular volume and decreased right ventricular ejection fraction by cardiac magnetic resonance. ARVC, arrhythmogenic right ventricular cardiomyopathy; RV, right ventricle; RVEF, right ventricular ejection fraction.

Tissue characterization

Myocardial biopsy can be performed in patients with unclear cardiomyopathies and in patients with VTs and structural changes not typical for ARVC.³⁴ The characteristic histopathology includes fibro-fatty replacement of cardiac myocytes² (Table 2). To fulfil 2010 TFC major criterion, tissue abnormalities should be quantified by morphometry, but many centers use visual estimation of pathology. Myocardial biopsy has low diagnostic sensitivity due to the patchy distribution of the disease. Biopsies are most often obtained only from the RV septum, while diseased tissue is most often located to the RV-free wall.^35,36 However, when targeting the thin dyskinetic areas of the RV-free wall, the risk of perforation and tamponade cannot be neglected.

Depolarization and repolarization abnormalities

Twelve-lead electrocardiography

Repolarization abnormalities are presented as T-wave inversion in right precordial leads progressively extending from V1 through V3, which represent a major criterion when present in individuals >age 14 in the absence of right bundle branch block (RBBB) (Figure 3).

Figure 3

Twelve-lead resting ECG from an ARVC patient. T-wave inversions are visible in most leads. Terminal activation duration is prolonged with 120 ms, and the terminal depolarizations may be interpreted as epsilon waves in leads V1 to V4.

Ventricular depolarization abnormalities in ARVC are related to progressive conduction delay in the right ventricle and are confined to the right precordial leads. Conduction delay is most commonly manifested in prolongation of so-called terminal activation duration (TAD) of QRS complex exceeding a cut off value of 55 ms in leads V1 to V3.²⁹ Terminal activation duration is measured from the nadir of the S wave to the last depolarization deflection.²⁹ In severe ARVC disease, low-amplitude signals defined as epsilon waves may appear in V1 to V3 and are a major criterion in the 2010 TFC. These are defined as separated from the end of the QRS complex.³⁷ The end of the QRS complex is however not always clear. Measurement of TAD avoids this dilemma by including the last depolarization deflection in the definition, thus including epsilon waves if present²⁹ (Figure 3).

Signal-averaged electrocardiography

Signal-averaged electrocardiography (SAECG) averages multiple QRS recordings (typically 250 consecutive QRS complexes), to filter out random noise and display late potentials if present.³⁷ Late potentials are thought to represent electrical depolarization abnormalities and are defined as minor criteria in 2010 TFC. The following values are considered abnormal: If ≥1 of these parameters is abnormal, a minor depolarization criterion in the 2010 TFC is fulfilled.

• Filtered QRS duration ≥114 ms

• Duration of terminal QRS < 40 μV: ≥ 38 ms

• Root-mean-square voltage of terminal 40 ms: ≤20 μV

Abnormal SAECG is not specific for ARVC but is also seen in other conditions with abnormal myocardial tissue including scarring in ischaemic heart disease and myocarditis.

Ventricular arrhythmias

Ventricular arrhythmias in ARVC include ventricular premature complexes, non-sustained VT, sustained VT, and ventricular fibrillation leading to cardiac arrest. In later phases of the disease, ventricular arrhythmias originate from re-entry circuits due to lengthened conduction pathways, and slow conduction and load mismatch at pivotal points in vital myocardial bundles embedded in fibrotic tissue. Other mechanisms of arrhythmias may be increased automaticity during adrenergic stimulation such as exercise. Dispersion in action potential duration between abnormal epicardial and intramural myocardium and intact subendocardium may result in polymorphic VT. Ventricular arrhythmias are considered a major criterion if they originate from the RV inferior wall or apical sites with typical VT of left bundle branch block morphology and superior axis. Sustained or non-sustained VTs with other or unknown axis are considered minor criteria. Ventricular fibrillation seems to be rare in older patients with a long-lasting ARVC, who more often have scar-related, haemodynamically stable VT.¹²

Holter monitoring

Holter monitoring is used for diagnosing ARVC, but is even more important in follow-up of ARVC subjects. A frequency of >500 PVCs/24 h is considered a minor 2010 TFC diagnostic criterion. The 2010 TFC do not stipulate any requirement for the QRS configuration of ventricular premature complexes, as the number of leads commonly used for Holter monitoring is limited and may not allow morphology diagnostics.

Electrophysiological investigations

An electrophysiological study is not included in the standard diagnostic work up of ARVC patients. The predictive value of inducibility of VT for the occurrence of VT during follow-up has been debated.^38,39 Electrophysiological studies can be indicated in ARVC patients with recurrent monomorphic VT for evaluation of VT ablation or as part of the differential diagnostic work up in patients presenting with wide QRS tachycardia with left bundle branch morphology. In selected patients, electro-anatomical mapping can be used to demonstrate areas of diseased myocardium and help in the differential diagnosis against outflow tract tachycardia.^40,41

Family history and genetic findings

The importance of genetic testing in the diagnosis of ARVC is increasing. Identification of a pathogenic or likely pathogenic ARVC-associated mutation in patients with suspected ARVC is considered a major diagnostic criterion.²⁸ Currently, mutations in ∼12 different genes are known to be disease causing.⁴² A pathogenic or likely pathogenic mutation is only found in 40–60% of ARVC probands, and in another 16% the analysis yields variants of uncertain significance.⁷ Often the judgment of the potential pathogenicity of a variant is challenging ^8,12,43 and the signal-to-noise ratio for ARVC appears to be as low as 4:1, i.e. markedly lower than for other inherited arrhythmic syndromes.^43,44 Improved technology and major progress in next-generation sequencing has revolutionized the approach to genetic testing. A large database of mutations in ARVC has become publicly available (www.arvcdatabase.info), which may be of help when interpreting genetic findings in ARVC. Genetic variants initially believed to be pathogenic have in larger exome studies shown genotypic prevalence up to a thousand times higher than expected from the phenotype prevalence in the general population,⁸ and may be only modest disease-modifiers or even non-pathogenic.⁷

Comprehensive or targeted ARVC genetic testing can be useful (class IIa) for patients with 2010 TFC ARVC diagnosis. The lack of an identifiable mutation does not exclude the diagnosis. Genetic testing may be considered (class IIb) in possible ARVC, but is not recommended (class III) for individuals with only a single minor criterion according to 2010 TFC. First-degree relatives of a mutation-positive ARVC proband have 50% risk of carrying the disease causing mutation with incomplete penetrance and mutation-specific testing is recommended (class I) in these family members.⁷ Mutation-positive family members require diagnostic work up and monitoring tailored to age (ref submitted recommendations paper).

Compound heterozygosity or digenic heterozygosity is found in a moderate number of ARVC patients.⁶ Some reports have shown signs of more severe disease in these individuals.^6,12

Autosomal recessive inherited forms of ARVC are rare and have been described in Naxos disease.⁴⁵ Naxos disease included the extra cardiac features of woolly hair and palmoplantar dermatokeratosis in addition to the typical and severe ARVC cardiac disease.

The genuine form of ARVC is characterized by diseases caused by desmosomal mutations. Arrhythmogenic right ventricular cardiomyopathy mimicking phenotypes may be caused by mutations in e.g. the titin, desmin, and lamin genes. Titin mutations have been reported also in hypertrophic and dilated cardiomyopathy. Plakophilin 2 mutations have been described in patients with Brugada syndrome.⁹ Also, the Ryanodin receptor 2 gene has been considered an ARVC-related gene, although recent studies have shown a stronger association with catecholaminergic polymorphic VT.²⁸

Other tests important for clinical decision-making and follow-up of arrhythmogenic right ventricular cardiomyopathy patients

Exercise test

Most ARVC patients are young, previously healthy individuals, often engaged in athletic activity. The role of exercise testing in the diagnosis and management of ARVC is not well established in the literature. In a recent study, exercise testing exposed latent ARVC typical ECG abnormalities in a significant number of ARVC subjects.⁴⁶ Furthermore, arrhythmogenicity during high dose isoproterenol was highly sensitive for the diagnosis of early ARVC.⁴⁷ The clinical significance of these observations remains to be determined.

Other diagnostic modalities like coronary angiography, coronary CT, RV angiography, and electrophysiological studies are performed on an individual basis.

Differential diagnoses

In a patient presenting with palpitations due to PVC and/or VT, one challenging differential diagnosis is the more benign idiopathic RVOT ventricular tachycardia (RVOT-VT). In contrast, ARVC patients have a more severe prognosis and are treated differently; hence, a correct diagnosis is important. Furthermore, one might be more reluctant to ablate foci of PVC in ARVC, due to the recurrent and progressive character of the disease.

In patients presenting with structural abnormalities and dilated RV, differential diagnoses include congenital heart disease such as the very rare Uhl's disease which in contrast to ARVC is a developmental defect. Pulmonary hypertension, atrial and ventricular septal defects with left-to-right shunt, right ventricular myocardial infarction, dilated cardiomyopathy and myocarditis are other possible differential diagnoses including a dilated RV. Furthermore, sarcoidosis is a well-known phenocopy of ARVC and may share potential mechanistic links.⁴⁸ Sarcoidosis may present with inverted T waves in ECG leads V1 to V3, VT, frequent ventricular premature contractions and various morphologic RV abnormalities.⁴⁹ The use of novel CMR sequences as well as endomyocardial biopsy may help a correct diagnosis. Finally, physiological changes due to athletic activities can mimic ARVC and there is an obscure grey zone of physiological vs. pathological changes in high-level activity athletes.⁵⁰

Funding

This work was supported by the Norwegian Research Council, the South-Eastern Norway Regional Health Authority, and the Norwegian Health Association.

Conflict of interest: none declared.