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Arrhythmogenic right ventricular cardiomyopathy: Diagnostic evaluation and diagnosis
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Arrhythmogenic right ventricular cardiomyopathy: Diagnostic evaluation and diagnosis
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jul 2017. | This topic last updated: Nov 16, 2016.

INTRODUCTION — Arrhythmogenic right ventricular cardiomyopathy (ARVC), formerly called "arrhythmogenic right ventricular dysplasia" (ARVD), is an underrecognized clinical entity characterized by ventricular arrhythmias and a characteristic ventricular pathology [1-3]. Macroscopically, there is a scarred appearance with fibrous or fibro-fatty replacement of myocardium. Multiple reports have historically characterized these pathologic changes as the "triangle of dysplasia" involving the inflow tract, outflow tract, and/or apex of the RV. However, more recent data have noted involvement of the posterolateral left ventricle (LV) with sparing of the right ventricle (RV) apex early in the disease [4]. The RV myocardial scarring initially produces typical regional wall motion abnormalities but later may involve the free wall and become global, producing RV dilation. The tissue replacement can also involve areas of the LV with relative sparing of the septum [5].

Clinical perspectives of ARVC primarily arise from experience with patients who present with arrhythmias of RV origin and/or sudden death. Presentation is most common between the ages of 10 and 50 years, with a mean age at diagnosis of approximately 30 years [6-9]. The disease is virtually never diagnosed in infants or toddlers and uncommonly before the age of 10. The diagnosis of ARVC requires a high degree of clinical suspicion and frequently multiple diagnostic tests or procedures. Because many of the clinical findings and test results are neither highly sensitive nor specific for ARVC, diagnostic criteria have been published by professional societies in an effort to standardize the diagnostic.

The diagnostic evaluation of a patient with suspected ARVC, and the diagnosis/diagnostic criteria of ARVC, will be reviewed here. The pathogenesis, genetics, anatomy, histology, clinical manifestations, treatment, and prognosis of ARVC are discussed separately. (See "Arrhythmogenic right ventricular cardiomyopathy: Pathogenesis and genetics" and "Arrhythmogenic right ventricular cardiomyopathy: Anatomy, histology, and clinical manifestations" and "Arrhythmogenic right ventricular cardiomyopathy: Treatment and prognosis".)

DIAGNOSTIC EVALUATION

General approach — As an initial approach, we recommend a thorough family history as well as a 12-lead electrocardiogram (ECG), transthoracic echocardiography, ambulatory ECG monitoring, signal-averaged ECG, and cardiac magnetic resonance (CMR) imaging in all patients with a suspected diagnosis of ARVC. Some experts also perform exercise ECG testing in all patients with suspected ARVC, but this is not universally done. Most patients who present with arrhythmia and a suspected diagnosis of ARVC can be diagnosed using a combination of noninvasive electrocardiographic and imaging evaluations. (See "Arrhythmogenic right ventricular cardiomyopathy: Anatomy, histology, and clinical manifestations".)

Selected additional testing should be performed based on the clinical scenario or when the results of initial testing are non-diagnostic and may include one or more of the following:

Exercise ECG testing

Right ventriculography

Endomyocardial biopsy

Electrophysiologic testing

Genetic testing

Family history — Family history and, when feasible, clinical evaluation of relatives are important parts of the approach to diagnosing ARVC. The pre-test probability of an ARVC diagnosis will range from 1:2 to 1:2000-5000 and is important in interpreting symptoms or abnormal test results.

In an individual with unexplained arrhythmia features or electrocardiographic abnormalities, the family history focusing on unexplained premature deaths, arrhythmia symptoms, and conduction disease may identify familial disease, which facilitates diagnosis/clarification of abnormalities in the proband. In a patient who fulfills diagnostic criteria, clinical evaluation of at least first-degree relatives is strongly recommended, given the possible 50 percent probability of inheriting a disease-causing mutation. Otherwise unexplained abnormalities in the context of proven familial disease will have a high probability of reflecting disease expression, which may or may not be complete. (See 'Genetic testing' below.)

Electrocardiography

12-lead ECG — All patients in whom ARVC is being considered should have a resting 12-lead electrocardiogram (ECG) performed. The sensitivity of ECG alone for the presence of ARVC is suboptimal, with as many as 40 to 50 percent of patients having a normal ECG at presentation [7,10,11]. However, by six years of follow-up, virtually all patients with ARVC have one or more ECG findings during normal sinus rhythm [10]. ECG abnormalities observed in ARVC include the following, some of which are included in the 2010 revised Task Force Criteria (table 1) [12]:

Prolonged S wave upstroke (interval from the nadir of the S wave to the isoelectric baseline ≥55 msec) – This finding was identified in 91 to 95 percent of ARVC patients who did not have RBBB [6,13]. Terminal activation duration of QRS ≥55 msec 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 right bundle-branch block is a minor criterion in the 2010 revised Task Force Criteria [12].

Epsilon wave – Thirty percent of patients with ARVC have an epsilon wave (a reproducible distinct wave between the end of the QRS complex and the onset of the T wave) in the right precordial leads, particularly V1 (waveform 1). This finding represents low amplitude potentials caused by delayed activation of some portion of the RV. This abnormality is a major criterion in the 2010 revised Task Force Criteria; however, reproducibility in evaluation, even amongst experts, limits its diagnostic value [12,14].

Inversion of T waves in the right precordial leads (V1, V2, and V3) – T wave inversion occurs in one-half of cases presenting with ventricular tachycardia (VT) (figure 1). The extent of T-wave inversion has been correlated with the degree of RV enlargement as well as the risk for ventricular arrhythmias or sudden cardiac death [15,16]. Inverted T waves are included in the following 2010 revised Task Force Criteria [12]:

Inverted T waves in right precordial leads (V1, V2, V3) or beyond in individuals >14 years of age (in the absence of complete right bundle branch block with QRS ≥120 msec) is a major criterion.

Inverted T waves in leads V1 and V2 in individuals >14 years of age (in the absence of complete right bundle-branch block QRS ≥120 msec) or in V4, V5, or V6 is a minor criterion.

Inverted T waves in leads V1, V2, V3, and V4 in individuals >14 years of age in the presence of complete right bundle branch block is a minor criterion.

ECG evolution over several years — Although a significant fraction of patients with ARVC will not have identifiable ECG abnormalities on initial presentation, the majority of patients develop characteristic ECG abnormalities within six years of presentation. The evolution of the ECG over time has been evaluated in several cohorts of ARVC patients [17,18].

The pace and nature of ECG progression was evaluated in a series of 35 patients who met diagnostic criteria for ARVC; 25 had a documented history of ventricular arrhythmias [17]. At a mean follow-up of 59 months, 32 patients (89 percent) demonstrated one or more of the following features of ECG progression:

Prolongation of S-wave upstroke by ≥10 msec – 69 percent

QRS prolongation by ≥10 msec – 66 percent

New T-wave inversion in ≥1 precordial lead – 37 percent

New bundle branch block – 11 percent

These findings are consistent with the progressive nature of ARVC. The incidence of ECG evolution is probably in part due to the high-risk cohort, as evidenced by the high rate of ventricular arrhythmias and the fact that all patients met diagnostic criteria for ARVC at the time of the baseline ECG [17].

In a study of 68 patients, 16 (23 percent) showed dynamic T wave changes and/or Epsilon waves during three-year follow-up; these changes/evolution were associated with younger age and markers of early disease [18].

Ambulatory monitoring — All patients in whom ARVC is being considered should have ambulatory ECG monitoring for 24 to 48 hours. Ambulatory monitoring is part of the diagnostic work up to determine the presence of ventricular premature beats (VPBs), a minor diagnostic criterion from the 2010 revised Task Force criteria (table 1). In one study of 40 patients with confirmed ARVC by 2010 revised Task Force criteria who underwent continuous ambulatory ECG monitoring for an average of 159 hours, average VPB count per 24 hours was 1091 VPBs, although significant day-to-day variation in VPB burden was noted in more than three-quarters of the patients [19]. In spite of this day-to-day variation, however, when the results for each 24-hour period (n = 249 24-hour periods) were analyzed using the 2010 revised Task Force criterion of 500 VPBs in a 24-hour period, the 24-hour VPB burden was accurate 90 percent of the time (223 of 249 24-hour periods).

ECG with isoproterenol infusion — Isoproterenol, a beta-agonist medication, may be helpful for the provocation of ventricular arrhythmias in patients suspected of having ARVC. In a study of 412 consecutive patients referred for evaluation of ventricular premature beats (VPBs) or suspected ARVC, patients were given a three-minute infusion of isoproterenol (45 mcg/minute) with continuous ECG monitoring during the infusion and for 10 minutes post-infusion; a positive test was defined as the development of polymorphic VPBs (three or more morphologies) or at least one ventricular couplet, or the development of ventricular tachycardia with left bundle branch block morphology [20]. Testing was positive in 32 of 35 patients previously diagnosed with ARVC (91.4 percent) and 42 of 377 patients (11.1 percent) without a known diagnosis of ARVC. The negative predictive value of isoproterenol testing exceeded 99 percent.

While these results are intriguing, whether isoproterenol testing is valuable above and beyond using the 2010 ARVC diagnostic criteria remains undetermined, and these data should be replicated in additional populations prior to recommending isoproterenol testing as part of the routine evaluation of patients with suspected ARVC.

Signal-averaged ECG — When feasible (ie, the technology is available to perform the test), we obtain a signal-averaged ECG (SAECG) in all patients in whom ARVC is being considered, as abnormalities in the SAECG are frequently detected in patients with ARVC and are a minor criterion for making the diagnosis. [21-26]. (See "Technical aspects of the signal-averaged electrocardiogram" and "Clinical applications of the signal-averaged electrocardiogram: Overview".)

A minor criterion in the 2010 revised Task Force guidelines is the presence of one or more of the following three SAECG abnormalities in the absence of a QRS duration ≥110 msec on the standard ECG [12] (table 1):

Filtered QRS duration ≥114 msec.

Duration of terminal QRS <40 microV (low amplitude signal duration) ≥38 msec

Root-mean-square voltage of terminal 40 msec ≤20 microV

This minor criterion has been found to have a sensitivity of 69 to 74 percent and specificity of 92 to 95 percent when applied to known ARVC probands [12,26].

The SAECG may contribute to the detection of ARVC in family members. Late potentials were found in 16 percent of 101 asymptomatic family members compared with 3 percent of control subjects. ECG abnormalities were found in 34 percent of the 101 family members, with the combination of late potentials and/or ECG abnormalities being present in 38 percent [27]. These findings suggest that there is a significant incidence of a familial form of the disease that may be undetected in many family members. (See 'Screening of family members' below and "Use of the signal-averaged electrocardiogram in arrhythmia evaluation and management".)

Cardiac imaging — The majority of patients who present with arrhythmia in whom ARVC is being considered can be diagnosed using the combination of noninvasive electrocardiographic and imaging evaluations [28]. Echocardiography and/or other noninvasive imaging modalities, most commonly cardiac magnetic resonance (CMR), are frequently performed to look for structural or functional abnormalities (particularly in the RV) in patients without known heart disease who present with VT of left bundle branch block (LBBB) morphology [29].

Echocardiography — All patients in whom the diagnosis of ARVC is being considered should have a transthoracic echocardiogram performed. Echocardiography is readily available and provides adequate visualization of the right ventricle in most patients. However, if echocardiographic imaging is deemed to be non-diagnostic, additional imaging with cardiovascular magnetic resonance should be performed.

The echocardiographic characteristics of ARVC have been reported in a number of cohorts [7,30]. In a report from the Multidisciplinary Study of Right Ventricular Dysplasia which compared 29 probands with newly diagnosed ARVC by the 1994 task force criteria and 29 carefully matched controls, the following echocardiographic findings were noted [30]:

Right ventricular dimensions were increased (image 1), particularly the right ventricular outflow tract (RVOT, 37.9 versus 26.2 mm in controls).

Right ventricular fractional area change, a marker of right ventricular systolic function, was reduced (27.2 versus 41.0 percent).

Right ventricular morphologic abnormalities were present in many probands but no controls (trabecular derangement in 54 percent, hyperreflective moderator band in 34 percent, and sacculations in 17 percent).

One limitation of these observations is that the patients met the 1994 Task Force Criteria (table 1), so applicability to patients with mild disease is uncertain [31].

In the 2010 revised Task Force Criteria, echocardiographic criteria include quantitative measures of RVOT enlargement and reduction in RV fractional area changed. Major echocardiographic criteria were selected to yield 95 percent specificity [12]. Minor echocardiographic criteria were selected to yield sensitivity equal to specificity (table 1 and table 2). (See 'Diagnostic criteria' below.)

Cardiovascular magnetic resonance — We proceed with cardiovascular magnetic resonance (CMR) imaging or right ventriculography in all patients with suspected ARVC, particularly in those patients whose other test results and clinical features have led to a definite diagnosis of ARVC based on the 2010 revised task force criteria. CMR, rather than right ventriculography, is the preferred imaging modality, and CMR should ideally be performed in a center with expertise in the evaluation of CMR for abnormalities suggestive of ARVC.

CMR imaging is an important investigation in the diagnostic assessment of ARVC. CMR examination enables identification of global and regional ventricular dilation, global and regional ventricular dysfunction, intramyocardial fat, late gadolinium enhancement (LGE), and focal wall thinning (image 2) [32-37]. Abnormalities on CMR are rare in the absence of ECG, echocardiographic, and/or arrhythmia manifestations of ARVC, though the possible role of late enhancement as an isolated, early marker of disease expression requires additional evaluation [38].

The 2010 revised Task Force Criteria include CMR parameters for regional RV dysfunction, RV volume, and RV global dysfunction (table 1 and table 2) [12].

The CMR major criterion requires regional RV wall motion abnormality (akinesis or dyskinesis or dyssynchronous RV contraction) and either increased RV end-diastolic volume (≥110 mL/m2 in men; ≥100 mL/m2 in women) or depressed RV ejection fraction (RVEF ≤40 percent). The sensitivity and specificity of this criterion were 76 and 90 percent in men and 68 percent and 98 percent in women.

The CMR minor criterion requires regional RV wall motion abnormality (as above) and milder degrees of RV end-diastolic volume dilation (≥100 mL/m2 in men; ≥90 mL/m2 in women) or RVEF ≤45 percent. The sensitivity and specificity of this criterion were 79 and 85 percent in men and 89 and 97 percent in women.

The diagnostic accuracy of CMR was assessed in a series of 232 patients undergoing evaluation for suspected ARVC using the 1994 Task Force Criteria [36]. In this series, 64 patients fulfilled 1994 Task Force Criteria for the diagnosis of ARVC, 63 fulfilled diagnostic criteria modified for familial ARVC, and another 7 were obligate gene carriers. The following findings were noted:

183 of the CMR studies were interpreted as diagnostic or strongly suspicious for ARVC.

All 134 patients who fulfilled 1994 Task Force Criteria modified for familial ARVC, or those who were obligate gene carriers had abnormal CMR results (diagnostic or strongly suspicious). Thus the sensitivity and specificity of CMR for clinical ARVC were 100 and 50 percent.

In general, data support the view that ECG abnormalities and arrhythmia are usually the earliest manifestations of ARVC [18,39]. The CMR results quoted above, however, suggest that CMR may also be sensitive in identifying early changes leading to the diagnosis of ARVC, although the number of gene positive-phenotype negative individuals was small. However, they also reveal a high rate of possible CMR false positive diagnoses of ARVC.

Although clinical studies and the Task force criteria have focused predominantly on RV abnormalities, LV involvement is more common than previously appreciated. CMR identification of LV abnormalities has provided evidence for the frequency and extent of LV disease. (See "Arrhythmogenic right ventricular cardiomyopathy: Anatomy, histology, and clinical manifestations", section on 'Left ventricular involvement'.)

Concerns with CMR — Although some CMR parameters were highly specific for gene-carrier status (eg, specificity of 100 percent for each of these three parameters: RV dilation and/or systolic impairment, RV late enhancement, and severe RV segmental dilation/regional wall motion abnormalities and/or aneurysms), others demonstrated low specificity (eg, specificity of 56 percent for abnormal trabeculations and 44 percent for mild RV localized dilation and/or regional wall motion abnormalities).

An additional concern with CMR is interobserver variability in identifying features of ARVC. Substantial interobserver variability has been identified between experts, although this variability appears to be at least partially related to lack of experience with CMR in the diagnosis of ARVC [34,37,40]. Because of this, CMR should ideally be performed in a center with expertise in the evaluation of CMR for abnormalities suggestive of ARVC.

CMR use in children — CMR is part of the diagnostic evaluation in children with suspected ARVC, particularly when there are ECG abnormalities or a high suspicion of ARVC because of arrhythmias or family background. While the technique of CMR generally results in high quality imaging, the sensitivity of CMR, however, will be low, as arrhythmic manifestations usually precede structural changes, though the exact sensitivity of CMR remains to be determined.

In a series of 81 children (average age 11 years) who were referred to a single center for CMR for the purpose of diagnosing ARVC, only one child fulfilled diagnostic criteria for ARVC, and only two additional patients had any findings consistent with ARVC [41]. Because the number of patients who actually had ARVC in this series was not reported, the diagnostic performance of CMR could not be quantified. However, among these 81 patients, 16 had a history of ventricular tachycardia, another 15 had a history of syncope or cardiac death, and 26 had a family history of ARVC. The very low incidence of CMR abnormalities in this at-risk cohort may reflect age-related penetrance and incomplete phenotypic expression in childhood [42].

In a subsequent multicenter cohort of 142 children (mean age 12 years) evaluated with CMR between 2005 and 2009, only 23 patients (16 percent) were diagnosed with definite ARVC, with another 32 patients (23 percent) with borderline ARVC based on the revised 2010 task force criteria [43]. Among those diagnosed with definite ARVC, however, CMR was critically important as 11 of the 23 patients (48 percent) would not have been categorized as having definite ARVC without the findings from CMR.

Right ventriculography — We do not routinely perform right ventriculography in all patients with suspected ARVC, particularly in those patients whose other test results and clinical features have led to a definite diagnosis of ARVC based on the 2010 revised task force criteria. However, in patients with suspected ARVC and non-diagnostic results of other imaging modalities (ie, echocardiography and CMR), in centers where CMR is not available, or in patients in whom right ventricular endomyocardial biopsy is planned, right ventriculography may be performed.

In expert hands, right ventriculography may provide an important contribution to the evaluation of the RV structure and function in patients suspected of having ARVC. Angiographic findings include transversely arranged hypertrophic trabeculae separated by deep fissures, and coarse trabeculae in the apical region distal to the moderator band. RV trabeculae may be considered hypertrophic when there is a thickness greater than or equal to 4 mm [44]. The RV volume is almost always increased, but it is often difficult to quantitatively assess RV enlargement because of the complex geometric shape of this chamber.

It is important to obtain the RV angiogram in at least two orthogonal views during sinus rhythm, and to avoid premature ventricular complexes. Biplane angiography should be performed in the 30º right anterior oblique and 60º left anterior oblique views in order to assess the typical areas of involvement, including the infundibulum, anterior RV free wall, apex, and the inferior wall, particularly in the subtricuspid area [45].

The 2010 revised Task Force Criteria (table 1) include as a major criterion the presence of regional RV akinesis, dyskinesis, or aneurysm by RV angiography [12].

Radionuclide ventriculography — Historically, radionuclide ventriculography has been used to detect global and/or regional RV dysfunction in ARVC (table 3) [46-48]. However, in current clinical practice, echocardiography and CMR provide better visualization and have replaced radionuclide ventriculography in the diagnosis of ARVC.

Multidetector computed tomography (MDCT) — MDCT can identify morphologic features of ARVC such as increases in RV chamber size and RV trabeculation, intramyocardial fat, and scalloping [49]. If further evidence of utility becomes available, MDCT may serve as an alternative to CMR for patients in whom CMR is contraindicated due to the presence of a pacemaker or implantable cardioverter-defibrillator. However, until such time, we do not recommend the routine use of MDCT in the evaluation of ARVC.

Electrophysiologic testing and electroanatomic mapping — Electrophysiological (EP) testing in ARVC may be considered but is rarely necessary as part of diagnostic evaluation and is of limited prognostic value [50]. In patients with refractory ventricular arrhythmias, however, EP testing may be of value in enabling ablation treatment and in differentiating RV outflow tract tachycardia from ARVC. (See "Arrhythmogenic right ventricular cardiomyopathy: Anatomy, histology, and clinical manifestations", section on 'Differential diagnosis for ARVC' and "Arrhythmogenic right ventricular cardiomyopathy: Treatment and prognosis", section on 'Radiofrequency ablation'.)

Electroanatomic mapping, which uses low-intensity magnetic field energy to determine the location of sensor-tipped catheter electrodes in the ventricles, has been applied for mapping of arrhythmias. Low voltage local RV electrograms indicate the presence of abnormal right ventricular substrate in ARVC, and preliminary mapping and biopsy correlation studies suggest that the presence, location, and extent of affected regions can be identified [51]. The presence of low-voltage areas identified during EP testing correlate with risk of future ventricular arrhythmias [52]. (See "Overview of catheter ablation of cardiac arrhythmias", section on 'Electroanatomical mapping'.)

The diagnostic accuracy of right ventricular endocardial electroanatomic mapping and contrast enhanced CMR were compared in a single center study of 23 consecutive patients who met the 2010 diagnostic criteria for ARVC [53]. Electroanatomic mapping identified a total of 45 scars in 21 of 23 patients, compared with a total of 23 scars in 9 of 23 patients identified by delayed enhancement CMR (DE-CMR), suggesting that electroanatomic mapping is more sensitive for the detection of RV scarring. However, 9 of the 12 patients with RV scars detected by mapping but not seen with DE-CMR were found to have abnormal late enhancement involving the left ventricle, highlighting the additional diagnostic power of DE-CMR for the detection of non-RV involvement in ARVC.

Genetic testing — We recommend genetic testing in all patients with ARVC (per task force criteria) but not in all patients with suspected ARVC who have not satisfied the task force criteria for definite ARVC. Our approach to genetic testing is as follows [54]:

We recommend comprehensive (DSC2, DSG2, DSP, JUP, PKP2, and TMEM43) genetic testing of an index patient who has satisfied the task force criteria for ARVC. Comprehensive testing (for all known ARVC mutations) is appropriate for probands, and such testing should take place prior to genetic screening of family members, as this will allow more targeted genetic screening in first-degree relatives.

We suggest comprehensive genetic testing for patients with possible ARVC (one major or two minor criteria) according to the 2010 task force criteria.

We do not recommend genetic testing for patients with only a single minor criterion according to the 2010 task force criteria.

We recommend mutation-specific genetic testing for family members and appropriate relatives following the identification of the ARVC-causative mutation in an index case.

The 2010 revised Task Force criteria (table 1) include as a major criterion the identification of a pathogenic mutation categorized as associated or probably associated with ARVC in the patient under evaluation [12]. A probable-disease causing desmosomal mutation can be identified in more than 50 percent of ARVC probands in most series from referral centers [54]. In a cohort of 1001 patients (439 index patients, 562 family members) who fulfilled the 2010 criteria for ARVC, 63 percent of index patients and 73 percent of family members had an identified probable disease-causing mutation [9]. The genetics and pathogenesis of ARVC are discussed in detail separately. (See "Arrhythmogenic right ventricular cardiomyopathy: Pathogenesis and genetics".)

Endomyocardial biopsy — While endomyocardial biopsy (EMB) remains one of the Task Force diagnostic criteria for ARVC, it is invasive and lacks sensitivity and specificity. We do not recommend EMB in the initial diagnostic evaluation for ARVC. While novel histologic criteria for histological diagnosis, including a novel immunohistochemical approach to diagnosis, have been proposed, the clinical utility of this approach is currently limited [55]. The histopathologic detection of fibrous or fibro-fatty tissue in the myocardium is not specific to ARVC [56]. A major cause of limited sensitivity of biopsy is sampling error [57,58]. Because of concerns that RV free wall biopsy may increase the risk of myocardial perforation, the RV side of the interventricular septum is the usual site of EMB. However, septal biopsy is generally not helpful in patients with ARVC as the septum is the myocardial segment which is usually thickest and least affected in ARVC [57]. Since tissue changes in ARVC are often patchy, imaging or electroanatomic voltage mapping guidance has been suggested to improve the diagnostic yield of biopsy [59].

The 2010 revised Task Force Criteria (table 1) include the following criteria for EMB samples [12]:

Residual myocytes <60 percent by morphometric analysis (or <50 percent if estimated), with fibrous replacement of the RV free wall myocardium in ≥1 sample, with or without fatty replacement of tissue on EMB.

Residual myocytes 60 to 75 percent by morphometric analysis (or 50 to 65 percent if estimated), with fibrous replacement of the RV free wall myocardium in ≥1 sample, with or without fatty replacement of tissue on EMB.

The observation in ARVC patients with desmosomal mutations of altered plakoglobin and connexin43 signal on immunohistochemical analysis at the intercalated disk provides a marker of disease expression, which has been useful in studies of pathogenesis and disease expression, but which has not been proven to be of clinical diagnostic utility [39,60-62].

General considerations and recommendations for EMB are discussed separately. (See "Endomyocardial biopsy".)

DIAGNOSIS — The diagnosis of ARVC is most commonly made in patients with suspicious clinical manifestations (eg, palpitations, ventricular tachyarrhythmias, etc) using information obtained from surface electrocardiogram (ECG) and cardiac imaging (typically echocardiography with or without CMR). The diagnosis of ARVC can be challenging, requiring a high degree of clinical suspicion and frequently multiple diagnostic tests or procedures to arrive at the correct diagnosis. Because many of the clinical findings and test results have reduced sensitivity and/or specificity for ARVC, diagnostic criteria have been published by professional societies in an effort to standardize the process of arriving at the correct diagnosis [12,46]. The gold standard for diagnosis of ARVC remains endomyocardial biopsy, but even this has a relatively low sensitivity for making the diagnosis.

The diagnosis of ARVC should be considered in a variety of clinical situations:

Patients who present with symptomatic or asymptomatic ventricular tachycardia (VT) of left bundle branch block (LBBB) configuration in the absence of apparent heart disease

Patients with multiple QRS morphologies when VT is induced during electrophysiology testing

Survivors of SCD, particularly SCD occurring during exercise [63]

Diagnostic criteria — The 2010 revised Task Force Criteria were selected based on analysis of receiver operator curves generated from data from 108 probands with newly diagnosed ARVC and data from normal subjects [12]. Both the original and revised criteria are divided into minor and major criteria and are classified into six categories (table 1):

Global and/or regional dysfunction and structural alterations

Tissue characterization of wall

Repolarization abnormalities on the ECG

Depolarization/conduction abnormalities on the ECG

Arrhythmias

Family history

Definite diagnosis of ARVC using the 2010 revised Task Force criteria requires the presence of:

Two major criteria OR

One major and two minor criteria OR

Four minor criteria from different categories

Borderline diagnosis of ARVC using the 2010 revised Task Force criteria requires the presence of:

One major and one minor criteria OR

Three minor criteria from different categories

Possible diagnosis of ARVC using the 2010 revised Task Force criteria requires the presence of:

One major criteria OR

Two minor criteria from different categories

The 2010 revised criteria (table 1 and table 2) included quantitative measures for improved diagnostic sensitivity with preserved specificity compared with the 1994 Task Force Criteria, which were based upon clinical experience with severe disease so they are highly specific but lack sensitivity for early and familial disease [46,64,65]. The improved sensitivity and preserved or improved specificity have been demonstrated in cohort studies [66,67]. As an example, in a cohort of 103 known carriers of a desmosome mutation and 102 mutation-negative relatives, abnormalities in ECG, SAECG, ambulatory ECG, and echocardiography with met 2010 criteria led to an additional 16 carriers being diagnosed with ARVC, increasing the sensitivity from 57 to 71 percent, with improved specificity from 92 to 99 percent [66].

SCREENING OF FAMILY MEMBERS — Screening of first-degree relatives with a history, physical examination, ECG, and echocardiogram is reasonable with selective use of cardiac magnetic resonance imaging (CMR) if there are any equivocal changes. Screening every five years for individuals younger than age 21 years is reasonable.

Once a diagnosis is confirmed in the proband, serial clinical evaluation of first-degree relatives is warranted, as one study of a cohort from two arrhythmia referral centers identified ARVC in 35 percent of first-degree relatives [68]. Genetic testing should also be recommended for patients diagnosed with ARVC as well as those in whom the diagnosis is suspected. If a pathogenic mutation is found in the proband, downstream genetic testing for the identified pathogenic mutation is advised for all first-degree relatives. The precise intervals for clinical evaluation will depend on the logistics and perceived risk for family members. In one study, 30 percent of relatives experienced disease progression during four-year follow-up, and the disease manifestations were electrical rather than structural [69]. These data support initial clinical evaluation of relatives with ECG and echocardiography, and serial evaluation annually, focusing on electrical manifestations of disease detected on 12 lead, ambulatory, and exercise electrocardiography [69,70]. (See 'Genetic testing' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults".)

SUMMARY AND RECOMMENDATIONS

All patients in whom Arrhythmogenic right ventricular cardiomyopathy (ARVC) is being considered should have a resting 12-lead electrocardiogram (ECG) performed. As many as 40 to 50 percent of patients with ARVC have a normal ECG at presentation. However, by six years, virtually all patients with ARVC have one or more of the following ECG findings during normal sinus rhythm: prolongation of S-wave upstroke by ≥10 msec, QRS prolongation by ≥10 msec, new T-wave inversion in ≥1 precordial lead, or new bundle branch block. (See '12-lead ECG' above.)

When feasible (ie, the technology is available to perform the test), we suggest performing a signal-averaged ECG as abnormalities in the signal-averaged electrocardiogram are frequently detected in patients with ARVC and are a minor criterion on the 2010 task force criteria. (See 'Signal-averaged ECG' above.)

All patients in whom the diagnosis of ARVC is being considered should have a transthoracic echocardiogram performed. Echocardiographic findings suggestive of ARVC include enlargement of the right ventricular outflow tract with reduced RV function and areas of akinesis, dyskinesis, or aneurysm. (See 'Echocardiography' above.)

We recommend cardiovascular magnetic resonance (CMR) imaging or right ventriculography in all patients with suspected ARVC, particularly in those patients whose other test results and clinical features have led to a definite diagnosis of ARVC based on the 2010 revised task force criteria. CMR should ideally be performed in a center with expertise in the evaluation of CMR for abnormalities suggestive of ARVC. CMR should be performed prior to implantable cardioverter defibrillator (ICD) implantation, as imaging of the right ventricle is suboptimal with an ICD lead in patients with magnetic resonance imaging (MRI) approved or compatible ICDs. (See 'Cardiovascular magnetic resonance' above and 'Right ventriculography' above.)

Electrophysiological (EP) testing in ARVC is rarely indicated as part of diagnostic or prognostic evaluation. In patients with refractory ventricular arrhythmias and in those with possible right ventricular outflow tract (RVOT) tachycardia, however, EP testing along with ablation of the arrhythmia may be performed. (See 'Electrophysiologic testing and electroanatomic mapping' above.)

We recommend genetic testing in all patients with definite ARVC (per task force criteria) but not in all patients with suspected ARVC who have not satisfied the task force criteria for definite ARVC. (See 'Genetic testing' above.)

The diagnosis of ARVC is most commonly made in patients with suspicious clinical manifestations (eg, palpitations, ventricular tachyarrhythmias, etc) using information obtained from surface ECG and cardiac imaging (typically echocardiography with or without CMR). The diagnosis of ARVC can be challenging, requiring a high degree of clinical suspicion and frequently multiple diagnostic tests or procedures to arrive at the correct diagnosis. Because many of the clinical findings and test results have reduced sensitivity and/or specificity for ARVC, diagnostic criteria have been published by professional societies in an effort to standardize the process of arriving at the correct diagnosis. (See 'Diagnosis' above.)

Screening of first-degree relatives with a history, physical examination, ECG, and echocardiogram is reasonable with selective use of CMR if there are any equivocal changes. (See 'Screening of family members' above.)

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REFERENCES

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