Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/ARVC) Workup

Updated: Dec 29, 2020
  • Author: Gyanendra K Sharma, MD, FACC, FASE; Chief Editor: Jose M Dizon, MD  more...
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Workup

Laboratory Studies

The diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/ARVC) poses a great challenge because of its variable presentation and requires greater attention in at-risk populations. In the past, the diagnosis was made based on postmortem findings or histological confirmation on endomyocardial biopsy. However, endomyocardial biopsy has limited sensitivity owing to patchy involvement of the RV. [32]

In 1994, an International task force first proposed the major and minor diagnostic criteria of ARVD based on family history, arrhythmias, ECG abnormalities, tissue characterization, and structural and functional RV abnormalities. [1] These criteria were highly specific but lacked sensitivity to detect early and familial disease.

In 2010, the task force criteria were revised to include quantitative criteria and abnormalities defined based on normal subject data. [33] The proposed terminology for the diagnosis of ARVD include major or minor criteria from 6 different categories.

The different categories include the following:

  • Global or regional dysfunction and structural alterations on echocardiography, CMRI, and/or RV angiography

  • Tissue characterization of wall as shown on endomyocardial biopsy

  • Repolarization abnormalities on ECG

  • Depolarization/conduction abnormalities on ECG and/or signal-averaged ECG (SAECG)

  • Arrhythmias on Holter monitoring

  • Family history (see below)

A definite diagnosis is defined as the presence of 2 major criteria, 1 major and 2 minor criteria, or 4 minor criteria.

A borderline diagnosis is defined as the presence of 1 major and 1 minor criteria or 3 minor criteria.

A possible diagnosis is defined as the presence of 1 major criterion or 2 minor criteria.

Major criteria include associated with family history include (1) confirmed diagnosis of ARVD based on task force criteria/autopsy or surgery in a first-degree relative (2) or identification of a pathogenic mutation categorized as associated or probably associated with ARVD/C. Minor criteria include (1) history of ARVD (not confirmed based on task force criteria) or premature sudden death (< 35 years) from suspected ARVD in a first-degree relative or (2) confirmed diagnosis of ARVD in a second-degree relative.

All other categories require diagnostic workup, as discussed below.

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Electrocardiography

Electrocardiography

Electrocardiographic (ECG) findings may be normal in the latent phase of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/ARVC), but abnormalities (depolarization/repolarization and/or conduction) are seen in most patients upon progression of the disease. [21, 34]  The images below represent ECG abnormalities in ARVD.

Arrhythmogenic Right Ventricular Dysplasia/Cardiom Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/ARVC). Intraventricular conduction abnormality
Arrhythmogenic Right Ventricular Dysplasia/Cardiom Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/ARVC). T-wave abnormalities in the presence of right bundle branch block.
Arrhythmogenic Right Ventricular Dysplasia/Cardiom Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/ARVC). Anteroseptal T-wave inversion.

According to the revised task force criteria, major ECG criteria include the following:

  • Inverted T waves in right precordial leads (V1 -V3) or beyond in individuals older than 14 years in the absence of complete right bundle branch block (RBBB); this feature is seen in 87% of patients with ARVD [35]

  • Epsilon waves (low-amplitude signals between end of QRS complex to the onset of T wave) in leads V1 -V3; these are seen in 33% of patients with ARVD

    Arrhythmogenic Right Ventricular Dysplasia/Cardiom Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/ARVC). Arrhythmogenic right ventricular dysplasia epsilon wave.

Minor ECG criteria include the following:

  • Inverted T waves in leads V1 and V2 in individuals older than 14 years in the absence of complete RBBB or in V4, V5, or V6

  • Terminal activation of QRS =55 ms measured from the nadir of the S wave to the end of the QRS, including R', in V1, V2, or V3, in the absence of complete RBBB

Ventricular ectopics, when present, have a LBBB configuration.

Signal-averaged electrocardiography

Abnormalities on signal-averaged electrocardiogram (SAECG) are common and have excellent sensitivity and specificity but do not reliably predict spontaneous or inducible ventricular tachycardia. [36, 37, 38]  SAECG abnormalities are included as minor criteria and should have at least 1 of 3 parameters in the absence of a QRS duration of 110 ms or more on standard ECG. These parameters include the following:

  • Filtered QRS duration =114 ms

  • Duration of terminal QRS < 40 µV (low-amplitude signal duration) =38 ms

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

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Twenty-Four–Hour Holter Monitoring

Twenty-four-hour Holter monitoring is helpful in detecting arrhythmias (eg, ventricular premature contractions, nonsustained or sustained ventricular tachycardia of left bundle branch block [LBBB] morphology).

Ventricular tachycardia of LBBB morphology with superior axis is a major criterion, while ventricular tachycardia with inferior or indeterminate axis and/or more than 500 ventricular extra systoles per 24 hours are considered minor criteria per the revised task force.

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Echocardiography

Echocardiography serves as a screening tool to evaluate patients with suspected arrhythmogenic right ventricular cardiomyopathy (ARVC). [39, 40]

RV dilatation and wall motion abnormalities constitute diagnostic criteria for ARVC. The abnormalities of the RV posterior wall underneath the tricuspid valve are most common. RV outflow dilatation was seen with increasing frequency upon progression of disease severity. [41]  Left ventricular (LV) involvement was seen in 16% of cases in this series. The RV morphologic abnormalities include trabecular derangement (most common), hyperreflective moderator band, and sacculations seen in the probands, but not in controls. [42]

Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/ARVC). Apical four-chamber transthoracic echocardiogram (TTE) showing right ventricular dilatation and dysfunction.
Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/ARVC). Parasternal long-axis view with right ventricular outflow tract dilatation and dysfunction.

Revised task force criteria using two-dimensional echocardiography are discussed below.

Major criteria are defined as regional RV akinesia or dyskinesia or aneurysm and one of the following (end-diastole):

  • Parasternal long-axis view (PLAX) right ventricular outflow tract (RVOT) = 32 mm (= 19 mm/m2 body surface area [BSA] corrected)

  • Parasternal short-axis view (PSAX) RVOT >36 mm (= 21 mm/m2 BSA corrected)

  • Fractional area change = 33%

Minor criteria are defined as regional RV akinesia or dyskinesia and one of the following:

  • PLAX RVOT =29 to < 32 mm (= 16 to < 19 mm/m2 BSA corrected)

  • PSAX RVOT =32 to < 36 mm (= 18 to < 21 mm/m2 BSA corrected)

  • Fractional area change >33 to = 40%

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Cardiac Magnetic Resonance Imaging

The right ventricle (RV) is better visualized on cardiac magnetic resonance imaging (CMRI) than on echocardiography, making CMRI the modality of choice for evaluation. CMRI is used to evaluate RV size, function, wall motion abnormalities, intramyocardial fat (using fat suppression sequence), and late gadolinium enhancement to assess areas of fibrosis. [43] RV wall thickening or thinning and prominent trabeculations are also seen in arrhythmogenic right ventricular cardiomyopathy (ARVC). [44, 45, 46, 47, 48]

Arrhythmogenic Right Ventricular Dysplasia/Cardiom Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/ARVC). Axial black blood image of the right ventricle showing fatty infiltration in the free wall of the right ventricle.

Major limitations of CMRI include limited experience of readers due to low prevalence and significant interobserver variability, resulting in high false-positive rates. Fatty infiltration of the RV wall is no longer considered pathognomonic of ARVC, as it may be seen as a normal variant, especially in elderly persons. RV fat infiltration is less reproducible and lacks specificity compared with RV kinetic abnormalities. [49]  In a cohort of 70 patients, RV fatty infiltration was seen in 28.9% patients whereas LV late gadolinium enhancement was found in 35.5% patients. [50] These abnormalities were most often found in patients who met major task force criteria for ARVD/ARVC.  [50]

In a tagged MRI study, regional LV dysfunction was seen in 37.5% of segments in definite ARVD and 18.7% in probable ARVD based on task force criteria. [51]

Revised task force criteria for RV abnormalities are discussed below.

Major criteria are defined as regional RV akinesia or dyskinesia or dyschronous RV contraction and one of the following:

  • Ratio of RV end-diastolic volume to BSA in males = 110 mL/m2 or BSA = 100 mL/m2 in females

  • RV ejection fraction (RVEF) = 40%

Minor criteria are defined as regional RV akinesia or dyskinesia or dyschronous RV contraction and one of the following:

  • Ratio of RV end-diastolic volume to BSA = 100 to < 110 mL/m2 in males or BSA = 90 to < 100 mL/m2 in females

  • RVEF >40% to = 45%

Increased native T1 mapping in the LV has been reported in patients with ARVD; however, the RV could not be evaluated because of its thin walls.  [52]

 Lack of MRI abnormalities does not exclude ARVD, and the diagnosis should be based on task force criteria. 

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Right Ventriculography

Right ventricular (RV) angiography may show RV enlargement, hypertrophic trabeculae, and wall motion abnormalities. However, since this method is invasive, it is rarely used.

RV regional akinesia, dyskinesia, or aneurysm on angiography is a major diagnostic criterion. The transversally arranged hypertrophic trabeculae, separated by deep fissures, were associated with the highest probability of arrhythmogenic RV cardiomyopathy (ARVC). [53]

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Other Tests

Exercise stress testing

Exercise-induced ventricular tachycardia of left bundle branch block (LBBB) morphology may be detected with this method.

Electrophysiology studies

Electrophysiology testing can be of value in reproducing ventricular tachycardia. The dysfunctional areas of the right ventricle (RV), as shown on magnetic resonance imaging (MRI) or echocardiography, are characterized by discrete areas of abnormally low-amplitude electrograms. [54]  Abnormal RV electrocardiograms correlate better with endomyocardial biopsy and improve its diagnostic yield. [55]

Genetic tests

ARVC is a genetic disorder, and gene mutation of desmosomes is seen in 40%-50% cases. Clinical application of genetic testing is limited owing to multiple types of gene mutations and variable penetrance and timing of disease expression, requiring long-term follow-up. [56, 57, 58]

Genetic testing is indicated for symptomatic patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/ARVC) and family members of a patient with a positive mutation.

Relatives with more than one genetic variant are at increased risk of developing clinical disease, potentially an important determinant of the phenotypic heterogeneity seen within families with ARVC. [59]  At present, genetic testing is available for seven types of abnormalities (DSC2, DSG2, DSP, JUP, PKP2, RYR2, TMEM43). [60]

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Endomyocardial Biopsy

Endomyocardial biopsy is not routinely performed owing to patchy distribution of the abnormalities, resulting in a poor diagnostic yield. Changes are typically seen in the right ventricular (RV) free wall, and the septum is rarely involved. RV free wall biopsy carries a small risk of perforation.

Histological demonstration of fibrofatty infiltration is not pathognomonic of arrhythmogenic RV cardiomyopathy (ARVC), as fatty infiltration may be a normal finding in elderly persons. [49] In a recent study, reduction of plakoglobin signal via immunohistochemical analysis of endomyocardial biopsy sample was found to be highly sensitive and specific for ARVC. [61]

Criteria used for tissue characterization (fibrofatty replacement of the myocardium) of the RV wall are discussed below.

Major criteria include residual myocytes < 60% by morphometric analysis (or < 50% by estimation), with fibrous replacement of the RV free wall myocardium in =1 sample, with or without fatty replacement of tissue.

Minor criteria include residual myocytes 60%-75% by morphometric analysis (or 50%-65% by estimation), with fibrous replacement of the RV free wall myocardium in =1 sample, with or without fatty replacement of tissue.

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Anatomy and Histology

The most classic feature of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/ARVC) is fatty infiltration of the RV free wall. This results in variable areas of fibrosis and scarring, causing aneurysm formation or generalized dilatation and loss of function. The RV wall may be thickened or thinned out.

The typical sites of involvement include the RV apex, inflow, and outflow, but the subendocardial layer is not involved. The epicardial and mediomural layers have a variable degree of fibrosis with interspersed strands of cardiomyocytes. In about two thirds of all cases, features of myocarditis are seen. Fatty infiltration of the RV apex and infundibulum is not uncommon and may represent the normal aging process. However, there is no fibrosis, and the risk of sudden death is minimal.

There is variable involvement of the LV, and trabeculae carneae of the apex and septum are hypertrophied.

In a small series of 21 patients diagnosed based on task force criteria, electron microscopy showed various abnormalities in the desmosomes (D) in 75% of patients and positive screening of D protein encoding genes in half of probands. [62] Desmosomes are responsible for cell-to-cell binding and function of the gap junction.

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