Version May 2024
INTRODUCTION — Arrhythmogenic cardiomyopathy (ACM) is defined by a clinical presentation with documented or symptomatic arrhythmia and myocardial structural abnormalities. Professional society guidelines on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy have been published [1]. Arrhythmogenic right ventricular cardiomyopathy (ARVC), formerly called "arrhythmogenic right ventricular dysplasia" (ARVD), is the best characterized of the ACMs in relation to diagnosis, treatment and outcomes. It is an underrecognized clinical entity characterized by ventricular arrhythmias of RV origin and a characteristic ventricular pathology [2-4]. 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 RV apex early in the disease [5]. Early reports highlighted the increase in RV myocardial fat; however, this is now recognized to be of very low diagnostic specificity, present in normal and difficult to differentiate from the aging process, particularly in an obese individual, and of low reproducibility when measured with cardiac magnetic resonance imaging [6]. 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 [7].
Clinical perspectives of ARVC primarily arise from experience with patients who present with arrhythmias of RV origin and/or sudden death. However, additional information has been learned regarding the clinical features and clinical course of subjects identified based on electrocardiographic (ECG) abnormalities and by cascade family screening [8]. Presentation is most common between the ages of 10 and 50 years, with a mean age at diagnosis of approximately 30 years [8-11]. 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 ECG, transthoracic echocardiography, ambulatory ECG monitoring, and cardiac magnetic resonance (CMR) imaging in all patients with a suspected diagnosis of ARVC [1,12,13]. Some experts also perform exercise ECG but some experts place little value in an exercise ECG. to detect arrhythmias in patients with suspected ARVC who have exertion-related symptoms. Electrophysiology testing can also be of value in select patients as it can help distinguish ARVC from idiopathic premature ventricular contractions (PVCs) and/or ventricular tachycardia. Most patients who present with arrhythmia and a suspected diagnosis of ARVC can be diagnosed using a combination of noninvasive ECG and imaging evaluations. If this initial noninvasive evaluation strongly points toward a diagnosis of ARVC, or if definite or borderline Task Force diagnostic criteria are met, genetic testing should also be performed. (See "Arrhythmogenic right ventricular cardiomyopathy: Anatomy, histology, and clinical manifestations".)
Whereas right ventriculography and endomyocardial biopsy were commonly performed when ARVC was first described in the early 1980s, these tests are very rarely employed today. This reflects the widespread availability of CMR, which is able to very accurately assess RV and LV volumes and function and also provide information regarding myocardial fibrosis.
Family history — Family history (preferably covering at least three generations) and, when feasible, clinical evaluation of relatives are important parts of the approach to diagnosing ARVC [1]. 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 ECG 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, genetic testing should be performed to guide therapy and also to allow cascade family screening to determine which first-degree family members are at risk of the disease. Regardless of the results of the genetic testing of the proband, all first-degree family members should be screened for ARVC, given the possible 50 percent probability of inheriting a disease-causing mutation. Abnormalities that are otherwise unexplained 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 ECG performed [1]. More than 85 percent of patients with ARVC demonstrate one or more characteristic ECG features of ARVC [14]. While a completely normal ECG makes the diagnosis of ARVC extremely unlikely, some studies have reported a normal ECG in patients who otherwise meet Task Force Criteria for ARVC [10,14,15]. 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 [10,14,15].
ECG abnormalities observed in ARVC include the following, some of which are included in the 2010 revised Task Force Criteria (table 1) [16]:
●Prolonged S wave upstroke (interval from the nadir of the S wave to the isoelectric baseline ≥55 milliseconds) – This finding was identified in 91 to 95 percent of ARVC patients who did not have RBBB (waveform 1) [9,17]. Terminal activation duration of QRS ≥55 milliseconds 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 [16].
●Epsilon wave – Between 5 and 30 percent of patients with ARVC have an epsilon wave (a reproducible distinct wave after the end of the QRS complex as defined by simultaneous measurements in leads V1 to V3 separated from the QRS complex by an isoelectric interval) (waveform 2 and waveform 3). 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, subsequent studies have made it clear that the presence of an epsilon wave should not be relied on for diagnosis of ARVC. This reflects the fact that those patients with true epsilon waves have severe disease and will meet the diagnostic criteria without inclusion of the epsilon wave. Furthermore, there is very poor inter- and intra-reader reproducibility in the interpretation of epsilon waves [16,18].
●Inversion of T waves in the right precordial leads (V1, V2, and V3) – T wave inversion (waveform 2) occurs in one-half of cases presenting with ventricular tachycardia (VT). 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 [19,20]. Inverted T waves are included in the following 2010 revised Task Force Criteria [16]:
•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 milliseconds) 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 milliseconds) 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 great majority of patients have some ECG abnormalities at the time of presentation. However, the evolution of the ECG over time has been evaluated in several cohorts of ARVC patients [21,22].
●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 [21]. 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 milliseconds – 69 percent
•QRS prolongation by ≥10 milliseconds – 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 [23]. 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 [21].
●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 [22].
Ambulatory monitoring — All patients in whom ARVC is being considered should have ambulatory ECG monitoring for 24 to 48 hours [1]. Ambulatory monitoring is part of the diagnostic work up to determine the presence of premature ventricular complex/contraction (PVC; also referred to a premature ventricular beats or premature ventricular depolarizations) and nonsustained VT, both of which are minor diagnostic criteria 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 PVC count per 24 hours was 1091 PVCs, although significant day-to-day variation in PVC burden was noted in more than three-quarters of the patients [24]. 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 PVCs in a 24-hour period, the 24-hour PVC burden was accurate 90 percent of the time (223 of 249 24-hour periods). The QRS interval of the PVC when prolonged may help distinguish PVCs related to ARVC from other causes, including right ventricular outflow tract (RVOT) VT [25].
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 PVCs 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 PVCs (three or more morphologies) or at least one ventricular couplet, or the development of VT with left bundle branch block morphology [26]. 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 — While the presence of positive SAECG is included as a minor diagnostic criterion in patients with ARVC, in many centers it is not routinely employed in the diagnostic evaluation of patients with suspected ARVC. This reflects the fact that it has low sensitivity and specificity for the diagnosis of ARVC. It is for this reason that few centers today continue to employ this diagnostic test. (See "Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications".)
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 milliseconds on the standard ECG [16] (table 1):
●Filtered QRS duration ≥114 milliseconds
●Duration of terminal QRS <40 microvolts (low amplitude signal duration) ≥38 milliseconds
●Root-mean-square voltage of terminal 40 milliseconds ≤20 microvolts
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 [16,27].
Cardiac imaging — The majority of patients who present with arrhythmia in whom ARVC is being considered can be diagnosed using the combination of noninvasive ECG and imaging evaluations [28]. Echocardiography and/or other noninvasive imaging modalities, most commonly 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 [1,29].
Echocardiography — All patients in whom the diagnosis of ARVC is being considered should have a transthoracic echocardiogram performed [1]. 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. Echocardiography is also a good option for serial follow-up of patients with ARVC who have an implantable cardioverter defibrillator (ICD) implanted and therefore cannot obtain serial MRIs [23].
The echocardiographic characteristics of ARVC have been reported in a number of cohorts [10,30]. 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 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 [16]. 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 CMR imaging (or rarely with 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 [1]. 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 (movie 1A-B), global and regional ventricular dysfunction, intramyocardial fat, late gadolinium enhancement (LGE) (image 2), and focal wall thinning (image 3) [32-37]. It is important to note that neither wall thinning nor intramyocardial fat is included in the diagnostic criteria for ARVC, and they should not be relied on for diagnosis. Abnormalities on CMR are rare in the absence of ECG, echocardiographic, and/or arrhythmic 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) [16].
●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 [22,39]. 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'.)
CMR may play a role in risk stratifying patients with ARVC. Among a cohort of 175 patients (52 definite, 50 borderline, and 73 possible ARVC by 2010 revised Task Force criteria) who underwent CMR and were followed for a median of 4.3 years, 35 patients experienced a hard cardiac event (sudden cardiac death [SCD], resuscitated cardiac arrest, or appropriate ICD shock) [40]. Of the 35 patients with an event, 34 had CMR abnormalities (defined as RV or LV wall motion abnormality, RV or LV dilation, RV or LV systolic dysfunction, fat infiltration, or LGE), suggesting that patients with a normal CMR are at low risk for cardiac arrhythmic events. Measurements of myocardial strain by CMR correlate well with scar (as detected by LGE or by electroanatomic mapping during invasive electrophysiology studies) and may be helpful in identifying patients at risk for VT with arrhythmogenic substrate for ablation [41].
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 [34,37,42]. 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 [43]. 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 VT, 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 [44].
●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 [45]. 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 rarely perform right ventriculography in patients suspected of having ARVC. This reflects the fact that CMR imaging provides extremely high-quality quantitative information concerning RV size and function. However, in centers where CMR is not available, or in patients in whom right ventricular EMB is planned, right ventriculography may be performed.
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 [16].
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 — Multidetector computed tomography (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 [1]. However, until such time, we do not recommend the routine use of MDCT in the evaluation of ARVC.
Electrophysiologic testing and electroanatomic mapping — While not a part of the 2010 Diagnostic Criteria for ARVC, EP testing can be of value in select patients in differentiating idiopathic PVCs or idiopathic VT from ARVC. EP testing may also be of value for risk stratification, though the data from different expert centers are conflicting [50]. EP testing combined with VT ablation may also be of value for treatment of patients with ARVC who have refractory symptomatic PVCs and/or recurrent episodes of sustained VT [1]. (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 catheter 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 fractionated 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.
EP testing, with or without electroanatomic voltage mapping, is of diagnostic value in patients in whom idiopathic VT or PVCs are being considered in the differential diagnosis. EP testing in patients with idiopathic VT/PVCs typically reveals one PVC/VT morphology with EP induction features suggestive of an autonomic/triggered mechanism. Radiofrequency catheter ablation is curative in patients with idiopathic VT/PVCs. By contrast, patients with ARVC often have multiple morphologies of PVCs/inducible VT. Electroanatomic voltage mapping may have diagnostic value, but the results need to be interpreted with caution, as low-voltage signals can be the result of poor contact and therefore have limited diagnostic specificity. By contrast, the presence of low-voltage electrograms that demonstrate marked fractionation are more compatible with a diagnosis of ARVC. The sensitivity and specificity of fractionated electrograms are also somewhat limited as ARVC typically starts in the epicardium.
Patients with ARVC may also have a completely normal endocardial voltage map and yet have evidence of significant disease with epicardial mapping. High-dose isoproterenol infusion during EP testing is another diagnostic option [54]. Patients with suspected ARVC are administered an infusion of isoproterenol for several minutes. Patients with ARVC have been reported to demonstrate nonsustained or sustained multimorphic VT. EMB has an extremely low diagnostic yield and is rarely if ever employed in the diagnosis of ARVC today. Perhaps the one situation where it may be of value is when cardiac sarcoidosis is suspected and there is no other tissue to biopsy to establish a diagnosis.
Genetic testing — We recommend genetic testing in all patients with ARVC (per Task Force criteria) and suggest it in patients with suspected ARVC who have evidence of ARVC on noninvasive evaluation (at least two minor criteria or one major criterion) [1]. Our approach to genetic testing is as follows [55,56]:
●We recommend comprehensive (DSC2, DSG2, DSP, JUP, PKP2, and TMEM43) genetic testing of an index patient who has satisfied the Task Force criteria for definite or borderline 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 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 [16]. A probable-disease causing desmosomal mutation can be identified in more than 50 percent of ARVC probands in most series from referral centers [55]. 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 [8]. The genetics and pathogenesis of ARVC are discussed in detail separately. (See "Arrhythmogenic right ventricular cardiomyopathy: Pathogenesis and genetics".)
Endomyocardial biopsy — While EMB remains one of the Task Force diagnostic criteria for ARVC, it is rarely performed in the modern diagnosis of ARVC as 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 histologic diagnosis, including a novel immunohistochemical approach to diagnosis, have been proposed, the clinical utility of this approach is currently limited [57]. The histopathologic detection of fibrous or fibro-fatty tissue in the myocardium is not specific to ARVC [58]. A major cause of limited sensitivity of biopsy is sampling error [59,60]. 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 [59]. Since tissue changes in ARVC are often patchy, imaging or electroanatomic voltage mapping guidance has been suggested to improve the diagnostic yield of biopsy [61].
The 2010 revised Task Force Criteria (table 1) include the following criteria for EMB samples [16]:
●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 [39,62-64].
General considerations and recommendations for EMB are discussed separately. (See "Endomyocardial biopsy".)
Serum antibody testing — Among patients with a clinical diagnosis of ARVC who undergo genetic testing, desmosomal gene mutations are sometimes identified; when identified, this allows for cascade genetic testing of family members. Anti-desmosomal antibodies have been identified in desmosomal skin diseases, leading to the hypothesis that they may also be present among patients with ARVC. In a multicenter study involving patients from Canada and Switzerland, testing for antibodies to three desmosomal proteins (desmoglein-2, desmocollin-2, and N-cadherin) was performed in a cohort of 45 patients with ARVC (37 "definite" and 8 "borderline" by 2010 Task Force criteria) and 32 controls without ARVC [65]. Anti-desmoglein-2 antibodies were present in 44 of 45 patients with ARVC (all 37 "definite" and seven of eight "borderline") and absent in 31 of 32 control patients. While this may prove to be a tool for diagnosing ARVC, these data need to be confirmed in additional populations of patients with ARVC, especially in patients with cardiac sarcoidosis in which similar antibodies may be present [56].
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 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 [12,13,16,46].
The diagnosis of ARVC should be considered in a variety of clinical situations:
●Patients with exercise-related sustained palpitation and/or syncope
●Symptomatic or asymptomatic patients (>14 years) with unexplained right precordial ECG abnormalities, particularly T wave inversion V1-V3
●Symptomatic or asymptomatic patients with unexplained frequent ventricular premature beats (>500 beats in 24 hours)
●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 EP testing
●Survivors of SCD, particularly SCD occurring during exercise [66]
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 [16]. 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 [46,67,68]. The improved sensitivity and preserved or improved specificity have been demonstrated in cohort studies [69,70]. 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 [69].
SCREENING OF FAMILY MEMBERS — We recommend screening of all first-degree relatives of the ARVC proband, beginning around age 10 years or at the onset of puberty [1]. Approximately one-third of first-degree relatives of a proband diagnosed with ARVC will develop manifest ARVC. Siblings have a higher risk of development of ARVC as compared with parents or offspring [71]. Screening is divided into clinical evaluation and genetic testing:
●Clinical evaluation — Screening with a history, physical examination, ECG, ambulatory ECG monitoring, and echocardiogram is reasonable with selective use of cardiac magnetic resonance (CMR) imaging based on the experience of a particular center with CMR imaging for diagnosis of ARVC. First-degree relatives are to be screened every two to three years depending on their age and activity levels. For first-degree relatives who are endurance or competitive athletes, annual screening should be considered while the individual is participating in athletics at this level. The precise intervals for clinical evaluation will depend on the logistics and perceived risk for family members. Lifelong vigilance of mutation carriers is warranted, as ARVC may initially manifest in the later decades, though precise intervals and extent of evaluations will need to be individualized.
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 during nearly seven years of follow-up [71]. In one study, 30 percent of relatives experienced disease progression during four-year follow-up, and the disease manifestations were electrical rather than structural [72]. These data support initial clinical evaluation of relatives with ECG and echocardiography, and ongoing serial evaluation, focusing on electrical manifestations of disease detected on 12-lead, ambulatory, and exercise ECG [72,73].
More sensitive measures of myocardial dysfunction may be of value. When performed as part of a screening echocardiogram on first-degree relatives of probands, abnormal deformation imaging of the RV (performed using speckle tracking in the apical four-chamber view), has been associated with a 10-fold greater likelihood of disease progression over a follow-up of 3.7 years, even with an otherwise normal echocardiographic appearance of the RV [74].
●Genetic testing — Genetic testing should also be recommended for patients diagnosed with ARVC as well as those in whom the diagnosis is suspected. (See 'Genetic testing' above.)
If a pathogenic mutation is found in the proband, downstream genetic testing for the identified pathogenic mutation is advised as part of the screening process for all first-degree relatives. If a family member is shown not to carry the pathogenic mutation further screening of that family member's offspring is not recommended.
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" and "Society guideline links: Cardiomyopathy".)
SUMMARY AND RECOMMENDATIONS
●All patients in whom arrhythmogenic right ventricular cardiomyopathy (ARVC) is being considered should have a resting 12-lead electrocardiogram (ECG) performed. (See '12-lead ECG' above.)
●All patients in whom the diagnosis of ARVC is being considered should have a transthoracic echocardiogram or cardiac magnetic resonance (CMR) imaging 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 CMR imaging 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 (image 3). 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.)
●Electrophysiologic (EP) testing in ARVC is not part of the 2010 Diagnostic Criteria but may be of value in selected cases to help differentiate ARVC from idiopathic PVCs/VT. EP testing may also be of value for risk stratification to help determine if ICD implantation should be advised. (See 'Electrophysiologic testing and electroanatomic mapping' above.)
●We recommend genetic testing in all patients with definite ARVC (per Task Force criteria) (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 over 10 years of age with a history, physical examination, ECG, and echocardiogram and/or CMR is recommended every two to five years depending on their exercise levels and whether they are a sibling, parent, or child. (See 'Screening of family members' above.)
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