Arrhythmogenic right ventricular cardiomyopathy: evaluation of the current diagnostic criteria and differential diagnosis

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease characterized by progressive fibrofatty replacement of the right ventricular (RV) myocardium which may act as a substrate for ventricular arrhythmias and sudden cardiac death (SCD).1 , 2 The classic form of ARVC is a genetically determined cardiomyopathy caused by heterozygous or compound mutations in genes encoding proteins of desmosomes, which are specialized intercellular structures providing mechanical attachment of myocytes.3 However, there are other genetic (non-desmosomal) and non-genetic causes of the disease. Biventricular and left-dominant disease variants have been identified and have led some to use the term ‘arrhythmogenic cardiomyopathy’ (ACM) to define the broader spectrum of the disease phenotypic expressions.2–8 However, to avoid confusion of readers, in the present International Expert Report, the original designation of ARVC was maintained because the document is a critical appraisal of the 2010 International Task Force (ITF) criteria that were specifically designed to diagnose the ‘classic’ ARVC phenotype. The current classification of ARVC includes the following clinical variants: (i) the classic ARVC phenotype, i.e. the originally reported and most common disease variant, characterized by isolated RV involvement (Figure 1); (ii) the ‘biventricular disease variants’, i.e. ‘balanced’, ‘dominant-right’ or ‘dominant-left’, characterized by the parallel, predominant RV, and predominant left ventricular (LV) involvement, respectively; and (iii) the LV phenotype characterized by isolated LV involvement (i.e. without clinically demonstrable RV involvement) (Figure 2).1–8 Electrocardiographic and cardiac magnetic resonance features of a representative case of right-dominant (classic) phenotypic variant of arrhythmogenic right ventricular cardiomyopathy. (A) Basal electrocardiographic showing T-wave inversion in right precordial leads (V1–V4). (B) End-diastolic frame of cine cardiac magnetic resonance sequence in long-axis four-chamber view showing a dilated right ventricle (end-diastolic volume, 127 mL/m2) with a severely reduced ejection fraction (25%). The post-contrast orthogonal images in long-axis (C) and short-axis (D) views show late gadolinium enhancement as mid-wall stria in the mid-septum (white arrow). In C, late gadolinium enhancement is also visible in the anterolateral, mid, and apical regions of the right ventricular wall, with segmental transmural involvement (white arrowheads) associated with regional dyskinesia (not shown). From De Lazzari et al. 54 Electrocardiographic and cardiac magnetic resonance findings of a representative case of left-dominant phenotypic variant of arrhythmogenic right ventricular cardiomyopathy in a patient with a DSP-gene mutation and a history of sustained ventricular tachycardia. (A) Basal electrocardiographic showing low QRS voltages (<0.5 mV) in limb leads. (B) End-diastolic frame of cine cardiac magnetic resonance sequence in long-axis four-chamber view showing normal cavity size and function of both ventricles. (C) Post-contrast image showing myocardial fibrosis in the form of stria of late gadolinium enhancement in the epicardium of the left ventricular lateral wall (arrowheads) and mid-mural layer of the interventricular septum (arrows). From De Lazzari et al. 54 In 1994, an ITF proposed criteria for diagnosis of ARVC, in the form of a qualitative scoring system which encompassed familial, electrocardiographic, arrhythmic, morpho-functional, and disease features.9 The ITF criteria were revised in 2010 by international consensus with the intention to improve diagnostic accuracy, by providing quantitative criteria for diagnosing structural and functional RV abnormalities, improvement of electrocardiographic criteria, and adding molecular genetic criteria (Supplementary material online, Table S1).10 Clinical experience with the 2010 ITF diagnostic score system has identified limitations on the use of the criteria, potentially resulting in disease misdiagnosis.11 , 12 The following problems in the use of current ITF criteria have been identified: (i) overdiagnosis due to the inclusion of molecular genetic findings in the diagnostic criteria, misinterpretation of electrocardiographic (ECG) and imaging findings, and misdiagnosis with other diseases mimicking the ARVC phenotype; (ii) underdiagnosis due to absence of cardiac magnetic resonance (CMR) tissue characterization findings. In recent years, there have been evolving indications for the clinical and imaging tests for reaching definitive diagnosis of ARVC.13–15 Due to technological advances and increased experience in the interpretation of structural, functional and tissue characterization by contrast-enhanced CMR this has become an important imaging technique for the diagnosis of ARVC.14 In the era of CMR, some diagnostic tests have been abandoned because of the non-specific and limited accuracy, while others have been reserved for selected cases because of the invasive nature and the risk of serious complications. Since both the 1994 and 2010 guidelines were developed to diagnose the original right-dominant disease phenotype they did not include specific criteria for diagnosing LV involvement and the more recently recognized left-sided phenotypic variants.7 , 8 Moreover, peculiarities of diagnosis in the paediatric population, which represents approximately one-sixth of the overall ARVC-population, were not addressed.16 The present international expert report is not intended to redesign the 2010 ITF diagnostic criteria, which in the general view of the authors are still valid and do not need substantial changes. However, the increasing risk of misdiagnosis resulting from the inappropriate use of the criteria has prompted this international expert document aimed to critically review the clinical performance and highlight the potential limitations of current criteria, to propose some solutions for a better clinical use and to identify potential areas of improvement, with particular reference to diagnosis of left-sided phenotypes and identification of early disease in the paediatric population. (See Supplementary material online, Text). The following sections of the document focus on the critical evaluation of each group of current diagnostic criteria and provide key suggestions for improving their use in the clinical practice. Mutations in the genes encoding desmosomal proteins play a key role in the pathogenesis of fibrofatty replacement of the myocardium and the development of the disease phenotype.2 , 3 Pooled data from major studies on molecular genetic screening for desmosomal gene mutations showed that the overall rate of successful genotyping in patients meeting the ITF diagnostic criteria is approximately 50%.17 , 18 The most common mutant gene is PKP2 (10–45%), followed by DSP (10–15%), DSG2 (7–10%), and DSC2 (2%).19–21 Screening for non-desmosomal genes marginally increases the rate of detection of gene mutations, even though some mutations in specific genes such as TMEM43 p.P358L22 and PLN p.R14del23 can be highly prevalent in certain populations because of a founder effect (Supplementary material online, Table S2). Compound/digenic heterozygosity has been identified in up to 25% of patients and has been reported to account for both phenotypic variability and more malignant life-time arrhythmic outcome (‘dose-effect’).24–26 Different from all other forms of cardiomyopathy, the ARVC diagnostic criteria include the presence of a pathogenic variant in ARVC related genes as a major criterion to establish the diagnosis.10 However, it has not been defined which mutations have sufficient evidence to be considered as disease-causing and conferring pathogenicity to a variant can be challenging. Moreover, a negative genetic test does not exclude the possibility that the phenotype is due to a mutation in an unknown gene or that the molecular genetic screening technique does not detect all disease-causing variants, including large deletions or duplications.27 An increasingly emerging problem with the use of the current ITF criteria is that the incorrect classification of a desmomosal-gene variant as ‘pathogenic’ (major criterion) or the identification of a pathogenic variant in a gene with insufficient evidence for disease causation may lead to a (mis)-diagnosis of ARVC in probands who otherwise may not fulfil the ITF criteria for a (definite) phenotypic diagnosis (see Supplementary material online, Text). The limitations of current understanding of the genetic basis of ARVC and the high genetic noise due to frequent disease-associated genetic variants both in the normal population and other cardiomyopathies are associated with the risk of misdiagnosis if molecular genetic results are integral part of the diagnostic scoring to the general for molecular genetic in inherited genotyping is to identify a pathogenic or pathogenic mutation in a who phenotypic diagnostic criteria for ARVC, and to genetic for detection of gene genetic is for following the identification of a pathogenic or pathogenic mutation in the with a clinical diagnosis of ARVC, in to identify genetically a to a diagnosis in a patient with phenotypic may be considered in selected cases that the results are by on the disease molecular because the high of variants of may the genotyping results more screening can be also for arrhythmic risk In heterozygosity of variants a more serious arrhythmic outcome because of a gene is important to the of genes including specific non-desmosomal if founder mutations in genes are present in specific such as TMEM43 in and PLN in the or a with specific tissue characterization by has been part of the diagnostic evaluation of ARVC technique the potential for an in tissue characterization with of the disease i.e. the of myocardium with fibrofatty that has been considered the for the clinical diagnosis of ARVC diagnostic of the RV myocardium is not specific for ARVC, reported in normal in the and In this the revised ITF criteria the that the presence of fibrosis is also and quantitative for evaluation of on the of and fibrosis on of The diagnosis of ARVC that is for the or also probands and The diagnostic tissue characterization can be by of cardiac for other or in or cardiac The evidence of fibrofatty replacement of the ventricular myocardium with a or with transmural involvement in the absence of the is a diagnostic criterion for An of for the diagnosis of ARVC has been developed with the of in the of desmosomal (see Supplementary material online, Text). ventricular is an imaging technique which may be of for the diagnosis of ARVC it has the potential to identify and RV regions of with showing or ventricular is an and highly technique with a risk of interpretation of in areas of normal myocardium due to Moreover, a be also from the of RV, which a not for diagnostic is not as a diagnostic test for be reserved for selected patients such as probands with a form of ARVC and predominant LV involvement, in the diagnosis on of such as or other heart muscle In to of myocardial for evaluation of desmosomal the may provide diagnostic ventricular is not for diagnostic be reserved for selected ARVC patients cardiac for and in with a large experience in of the RV wall is not in the of and be proposed for structural and functional by imaging include ventricular reduced RV ejection regional wall abnormalities, and fibrofatty myocardial , 3 , , and CMR are the 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the and may not be large to a wall (Figure of criteria for characterization of myocardial fibrofatty replacement the potential (i) to the of the interpretation of RV wall has a high variability and by the myocardial (ii) to the for forms of ARVC which are more by with of the segmental in the LV wall which may be the imaging of left-dominant phenotypic variants of of high negative contrast-enhanced CMR has the potential to become the imaging test for evaluation of structural and functional ventricular of ARVC (see Supplementary material online, Text). the technological advances and improvement of interpretation of CMR tissue characterization and image evaluation of myocardial and contrast-enhanced CMR is for definitive diagnosis and better characterization of the disease phenotypic is as part of the evaluation of a patient with The of findings evaluation is important in view of the imaging evaluation be on the genetic and clinical avoid of structural and functional ventricular is to a diagnosis in a ventricular may be not in because clinical are more and may the disease due to the and and the phenotypic the large of and of the normal RV, the presence of both regional wall and be in orthogonal long-axis and short-axis magnetic resonance be in high with particular experience and in imaging and interpretation of ARVC CMR is and due to of data and with CMR studies is CMR be considered in patients with a diagnosis of ARVC who of clinical abnormalities, arrhythmic or findings. ventricular is not of diagnostic and be reserved to patients in is is is for diagnosis ARVC and heart diseases with a left to right The spectrum of ventricular arrhythmias in ARVC from isolated ventricular to sustained ventricular or ventricular to cardiac , , , 18 , The of the is patients and the of the , The of the of the arrhythmic QRS on may identification of the ventricular of and the of the to the 2010 ITF diagnostic criteria, the of has an on diagnosis.10 with a left right ventricular is considered a diagnostic criterion because of low which may lead to misdiagnosis of ARVC in patients with right ventricular However, with an and or RV wall is more specific for ARVC and this is as a diagnostic with a right may as a of or predominant LV with have that most ARVC patients have frequent isolated or with a ITF criteria the of without the of the represents a because ventricular from the RV wall have for ARVC the of ventricular or ventricular from the is to on 12 leads by or The has a limited role in the diagnosis of The test can provide the by ventricular of or more with may be in ARVC from which is a and arrhythmic characterized by a and by ventricular , of RV may be of diagnostic for diagnosis with that is to and or to avoid inappropriate misdiagnosis from with a large of view may also the presence of the use of a to is to the of ventricular which may the ventricular of with ventricular and RV are not as integral part of the diagnostic evaluation of patients with studies be limited to selected patients an invasive evaluation to from tachycardia. is a diagnostic test in ARVC and in up to of patients with in the right precordial leads are the most common (Figure QRS voltages (<0.5 mV) in the limb leads are in ARVC patients with of the LV as by CMR (Figure an of RV low QRS voltages LV involvement of the RV disease and of voltages of the LV wall and replacement by fibrofatty The resulting from RV include and QRS of right precordial QRS with a and The of the presence of as a diagnostic has been are related to and to large can also be in the form of late in the of the QRS by The use of technique for diagnosis of ARVC in probands and has been abandoned by most because of non-specific findings and limited diagnostic (see Supplementary material online, Text). The presence of be with in patients without other diagnostic QRS with in right precordial leads is a specific diagnostic if followed by negative QRS voltages (<0.5 mV) in the limb leads can be an of LV to and be considered as a normal variant in who do not other diagnostic features of LV involvement in ARVC include T-wave inversion in the leads and low QRS voltages (<0.5 mV) in limb which the of myocardium and voltages of the LV , is with a which form the , The LV imaging phenotype is characterized by a ventricular of LV and or LV in with a of LV the wall (Figure The of LV related to the of which in disease and LV wall In variants of ARVC, clinically demonstrable RV involvement is an important criterion for diagnosis with dilated cardiomyopathy In the absence of clinically RV involvement, of a pathogenic mutation of such as and PLN may the diagnosis of ARVC (see Supplementary material online, Text). for diagnosis of left-sided ARVC phenotypes (i) such as low QRS voltages in limb leads and in the (ii) ventricular arrhythmias with a right and (iii) structural and functional imaging features with a and Clinical of some of or structural RV involvement be considered as an important criterion for diagnosis of or left-dominant In patients with clinical findings of left-sided ARVC and clinically RV involvement, genetic for the presence of pathogenic mutations in such as the DSP can the diagnosis (Supplementary material online, Table S2). Arrhythmogenic RV cardiomyopathy is a genetically determined heart muscle disease characterized by a which most clinically the and of Clinical of the disease are up to of patients are , Arrhythmogenic RV cardiomyopathy is a progressive heart muscle disease with and structural phenotypic is that of structural ventricular can be and by patients more present with sustained paediatric patients are more to experience or sudden cardiac , , cardiac death may be the clinical of the as it was reported by a in the of of in and were caused by The diagnosis of ARVC is in of in development as as in disease and the use of the current criteria for diagnosis of ARVC in this clinical be to this patient population due to the of some in paediatric patients and the low of disease in In and can be while is more 3 and cardiac CMR 8 in (see Supplementary material online, Text). 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outcome right ventricular arrhythmogenic right ventricular ventricular left ventricular RV, right right ventricular T-wave ventricular ventricular tachycardia. arrhythmogenic right ventricular cardiomyopathy left left right RV, right right ventricular T-wave ventricular ventricular tachycardia. of structural may clinical features of right-dominant ARVC including heart and heart (Figure 3 and Table (see Supplementary material online, Text). magnetic resonance features of heart diseases mimicking right-dominant (classic) phenotypic variant of arrhythmogenic right ventricular cardiomyopathy. and frame of cine cardiac magnetic resonance sequence in long-axis four-chamber view showing right ventricular cine view showing the of the right in the (white and frame of cine cardiac magnetic resonance sequence in short-axis view showing a right ventricular due to a large ventricular frame of cine cardiac magnetic resonance sequence in four-chamber view showing a apical of the of the (white and of 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interventricular septum and lateral left ventricular wall (white the of late gadolinium enhancement the and left ventricular regions and the areas of on to cardiomyopathy left-dominant arrhythmogenic right ventricular cardiomyopathy left left ventricular ventricular right RV, right right ventricular T-wave ventricular ventricular tachycardia. In of ARVC is a genetic disease caused by a mutation of desmosomal of patients may have non-desmosomal phenotype to ARVC may also in other genetic or , 3 a of patients have non-genetic diseases with a phenotype ARVC and characterized by the to ventricular arrhythmias which the of ventricular related to the large of myocardial fibrosis which is an arrhythmogenic risk with current of other cardiomyopathies such as and dilated cardiomyopathy and in with the Expert on arrhythmogenic it is to propose a disease classification which the large of ‘arrhythmogenic a spectrum of of the RV, the LV or genetic or common is the ventricular myocardial and the ventricular arrhythmias (Figure with the phenotype are associated with a risk of because myocardial fibrosis as a substrate of malignant ventricular in patients by genetic or the of an for be considered in the presence of large arrhythmogenic ventricular even if the ventricular function is not severely classification of arrhythmogenic The most common of arrhythmogenic cardiomyopathy is a genetic of desmosomal there are other genetic and non-genetic causes (see the for more use of the current ITF diagnostic criteria and of the scoring system for diagnosis of ARVC (i) the of current understanding of the genetic of the disease that the risk of misdiagnosis if molecular genetic test is an integral part of the diagnostic scoring (ii) the advances of and improvement of interpretation of tissue characterization images by CMR which has become the imaging technique for characterization of the disease phenotype; (iii) the spectrum of the ARVC phenotype which includes left-dominant disease variants and specific diagnostic criteria from clinical and the peculiarities of clinical features and diagnostic tests of ARVC in the paediatric population which represents a of patients due to the increasing clinical and genetic screening of The focus on better understanding of the genetic improvement of clinical and imaging characterization of the phenotype, with particular reference to left-sided variants and of diagnostic The clinical of the proposed classification of arrhythmogenic cardiomyopathy to be by of is to the of recently and who a role in the development of the International Task Force criteria for diagnosis of arrhythmogenic right ventricular cardiomyopathy. 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