Impact of Genetic Variant Reassessment on the Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy Based on the 2010 Task Force Criteria.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy, which is associated with life-threatening ventricular arrhythmias. Approximately 60% of patients carry a putative disease-causing genetic variant, but interpretation of genetic test results can be challenging. The aims of this study were to systematically reclassify genetic variants in patients with ARVC and to assess the impact on ARVC diagnosis. METHODS: This study included patients from the Multicenter Zurich ARVC Registry who hosted a genetic variant deemed to be associated with the disease. Reclassification of pathogenicity was performed according to the modified 2015 American College of Medical Genetics criteria. ARVC diagnosis (categories: definite, borderline, possible) based on the 2010 Task Force Criteria was reclassified after genetic readjudication. RESULTS: In 79 patients bearing 80 unique genetic variants, n=47 (58.8%) genetic variants were reclassified, and reclassification was judged to be clinically relevant in n=33 (41.3%). Variants in plakophilin-2 (PKP2) were shown to reclassify less frequently as compared with other genes (PKP2, n=1, 8.3%; desmosomal non-PKP2, n=20, 66.7%; nondesmosomal, n=26, 68.4%; P=0.001for overall comparison; PKP2 versus desmosomal non-PKP2, P=0.001; PKP2 versus nondesmosomal, P<0.001). Genetic reclassification impacted ARVC diagnosis. Eight patients (10.1%) were downgraded from definite to borderline/possible disease at the time of initial genetic testing as well as last follow-up, respectively. Separate genetic reclassification in family members led to downgrading of n=5 (38.5%) variants. CONCLUSIONS: Given that approximately half of genetic variants were reclassified, with 10.1% of patients losing their definite disease status, accurate determination of variant pathogenicity is of utmost importance in the diagnosis of ARVC.

State of the Art Review on Genetics and Precision Medicine in Arrhythmogenic Cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiomyopathy characterised by ventricular arrhythmia and an increased risk of sudden cardiac death (SCD). Numerous genetic determinants and phenotypic manifestations have been discovered in ACM, posing a significant clinical challenge. Further to this, wider evaluation of family members has revealed incomplete penetrance and variable expressivity in ACM, suggesting a complex genotype-phenotype relationship. This review details the genetic basis of ACM with specific genotype-phenotype associations, providing the reader with a nuanced perspective of this condition; whilst also proposing a future roadmap to delivering precision medicine-based management in ACM.

A novel genotype-based clinicopathology classification of arrhythmogenic cardiomyopathy provides novel insights into disease progression.

AIMS: Arrhythmogenic cardiomyopathy (AC) shows large heterogeneity in its clinical, genetic, and pathological presentation. This study aims to provide a comprehensive atlas of end-stage AC and illustrate the relationships among clinical characteristics, genotype, and pathological profiles of patients with this disease. METHODS AND RESULTS: We collected 60 explanted AC hearts and performed standard pathology examinations. The clinical characteristics of patients, their genotype and cardiac magnetic resonance imaging findings were assessed along with pathological characteristics. Masson staining of six representative sections of each heart were performed. Digital pathology combined with image segmentation was developed to calculate distribution of myocardium, fibrosis, and adipose tissue. An unsupervised clustering based on fibrofatty distribution containing four subtypes was constructed. Patients in Cluster 1 mainly carried desmosomal mutations (except for desmoplakin) and were subjected to transplantation at early age; this group was consistent with classical 'desmosomal cardiomyopathy'. Cluster 2 mostly had non-desmosomal mutations and showed regional fibrofatty replacement in right ventricle. Patients in Cluster 3 showed parallel progression, and included patients with desmoplakin mutations. Cluster 4 is typical left-dominant AC, although the genetic background of these patients is not yet clear. Multivariate regression analysis revealed precordial QRS voltage as an independent indicator of the residual myocardium of right ventricle, which was validated in predicting death and transplant events in the validation cohort (n = 92). CONCLUSION: This study provides a novel classification of AC with distinct genetic backgrounds indicating different potential pathogenesis. Cluster 1 is distinct in genotype and clinicopathology and can be defined as 'desmosomal cardiomyopathy'. Precordial QRS amplitude is an independent indicator reflecting the right ventricular remodelling, which may be able to predict transplant/death events for AC patients.

Clinical classification of rare cardiac arrhythmogenic and conduction disorders, and rare arrhythmias.

INTRODUCTION Rare cardiovascular diseases and disorders (RCDDs) constitute an important clinical problem, and their proper classification is crucial for expanding knowledge in the field of RCDDs. OBJECTIVES The aim of this paper is to provide an updated classification of rare arrhythmogenic and conduction disorders, and rare arrhythmias (RACDRAs). METHODS We performed a search for RACDRAs using the Orphanet inventory of rare diseases, which includes diseases with a prevalence of no more than 5 per 10 000 in the general population. We supplemented this with a search of PubMed and Scopus databases according to a wider definition proposed by the European Parliament and the Council of the European Union. RESULTS RACDRAs are categorized into 2 groups, primary electrical disorders of the heart and arrhythmias in specific clinical settings. The first group is further divided into subgroups of major clinical presentation: disorders predisposing to supraventricular tachyarrhythmias, ventricular tachyarrhythmias, bradyarrhythmias, and others. The second group includes iatrogenic arrhythmias or heart rhythm disturbances related to medical treatment, arrhythmias associated with metabolic disorders, and others. We provide a classification of RACDRAs and supplement them with respective RCDDs codes. CONCLUSION The clinical classification of RACDRAs may form a basis to facilitate research and progress in clinical practice, both in diagnostic and therapeutic approaches.

Right Ventricular Imaging and Computer Simulation for Electromechanical Substrate Characterization in Arrhythmogenic Right Ventricular Cardiomyopathy.

BACKGROUND: Previous studies suggested that electrical abnormalities precede overt structural disease in arrhythmogenic right ventricular cardiomyopathy (ARVC). Abnormal RV deformation has been reported in early ARVC without structural abnormalities. The pathophysiological mechanisms underlying these abnormalities remain unknown. OBJECTIVES: The authors used imaging and computer simulation to differentiate electrical from mechanical tissue substrates among ARVC clinical stages. METHODS: ARVC desmosomal mutation carriers (n = 84) were evaluated by electrocardiography (ECG), Holter monitoring, late-enhancement cardiac magnetic resonance imaging, and echocardiographic RV deformation imaging. Subjects were categorized based on the presence of 2010 International Task Force criteria: 1) subclinical stage (n = 21); 2) electrical stage (n = 15); and 3) structural stage (n = 48). Late enhancement was not present in any subclinical or electrical stage subjects. RESULTS: Three distinctive characteristic RV longitudinal deformation patterns were identified: type I: normal deformation (n = 12); type II: delayed onset of shortening, reduced systolic peak strain, and mild post-systolic shortening (n = 35); and type III: systolic stretching with large post-systolic shortening (n = 37). A majority (69%) of structural staged mutation carriers were type III, whereas a large proportion of both electrical and subclinical stage subjects (67% and 48%, respectively) were type II. Computer simulations demonstrated that the type II pattern can be explained by a combination of reduced contractility and mildly increased passive myocardial stiffness. This evolved into type III by aggravating both mechanical substrates. Electrical activation delay alone explained none of the patterns. CONCLUSIONS: Different ARVC stages were characterized by distinct RV deformation patterns, all of which could be reproduced by simulating different degrees of mechanical substrates. Subclinical and electrical staged ARVC subjects already showed signs of local mechanical abnormalities. Our novel approach could lead to earlier disease detection and, thereby, influence current definitions of electrical and subclinical ARVC stages.

Effect of the 2010 task force criteria on reclassification of cardiovascular magnetic resonance criteria for arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: We sought to evaluate the effect of application of the revised 2010 Task Force Criteria (TFC) on the prevalence of major and minor Cardiovascular Magnetic Resonance (CMR) criteria for Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) versus application of the original 1994 TFC. We also assessed the utility of MRI to identify alternative diagnoses for patients referred for ARVC evaluation. METHODS: 968 consecutive patients referred to our institution for CMR with clinical suspicion of ARVC from 1995 to 2010, were evaluated for the presence of major and minor CMR criteria per the 1994 and 2010 ARVC TFC. CMR criteria included right ventricle (RV) dilatation, reduced RV ejection fraction, RV aneurysm, or regional RV wall motion abnormalities. When quantitative measures of RV size and function were not available, and in whom abnormal size or function was reported, a repeat quantitative analysis by 2 qualified CMR physicians in consensus. RESULTS: Of 968 patients, 220 (22.7%) fulfilled either a major or a minor 1994 TFC, and 25 (2.6%) fulfilled any of the 2010 TFC criterion. Among patients meeting any 1994 criteria, only 25 (11.4%) met at least one 2010 criterion. All patients who fulfilled a 2010 criteria also satisfied at least one 1994 criterion. Per the 2010 TFC, 21 (2.2%) patients met major criteria and 4 (0.4%) patients fulfilled at least one minor criterion. Eight patients meeting 1994 minor criteria were reclassified as satisfying 2010 major criteria, while 4 patients fulfilling 1994 major criteria were reclassified to only minor or no criteria under the 2010 TFC.Eighty-nine (9.2%) patients had alternative cardiac diagnoses, including 43 (4.4%) with clinically significant potential ARVC mimics. These included cardiac sarcoidosis, RV volume overload conditions, and other cardiomyopathies. CONCLUSIONS: Application of the 2010 TFC resulted in reduction of total patients meeting any diagnostic CMR criteria for ARVC from 22.7% to 2.6% versus the 1994 TFC. CMR identified alternative cardiac diagnoses in 9.2% of patients, and 4.4% of the diagnoses were potential mimics of ARVC.

Impact of new task force criteria in the diagnosis of arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy that can lead to sudden cardiac death. The diagnostic criterion has recently been revised and through the use of cardiac magnetic resonance (CMR) imaging this study aimed to assess the clinical impact of comparing the original 1994 task force (TF) criterion to the revised 2010 criterion. METHODS: We evaluated 173 consecutive CMR scans of patients referred with clinical suspicion of ARVC between 2008 and 2011. We then compared the prevalence of major and minor CMR criteria by applying the two criteria. RESULTS: Using the 1994 TF criterion, 13 (7.5%) patients had definite, 11 (6.4%) had borderline, and 39 (22.5%) had possible ARVC. Using the 2010 TF criterion, 10 (5.8%) patients had definite, 1 had borderline, and 7 had (0.04%) possible ARVC. With the 1994 criterion, 81 patients satisfied CMR criterion, of which 36 (44%) had major and 45 (56%) had minor criteria. Upon reclassification with the revised criterion, 61 of the 81 patients were not assigned any criteria, even though many patients had significant risk factors. The negative predictive values (NPV) for both CMR criteria were 100% but the positive predictive values (PPV) for combined CMR major or minor criteria improved from 23% to 55%. CONCLUSIONS: Revision of the criterion has enhanced the diagnostic capabilities of CMR but has resulted in a large cohort of patients not classified. In these patients, there is presently no official consensus on imaging or clinical strategy for surveillance of the evolution of pathology over time.

Sudden death with circumferential subepicardial fibrofatty replacement: left-sided arrhythmogenic ventricular cardiomyopathy.

We report 5 cases of sudden cardiac death, with similar cardiac findings. All 5 cases had circumferential left ventricular subepicardial fibrofatty replacement of the myocardium, similar to the histologic features of arrhythmogenic right ventricular cardiomyopathy (ARVC). In these cases, the findings were predominantly in the left ventricle with minimal or no involvement of the right ventricle. Four of the 5 cases had siblings with either sudden death or cardiac symptoms. This report highlights 5 cases of sudden death in the young with histologic findings similar to ARVC, with predominant left ventricular involvement and questions whether the cases represent a larger spectrum of the cardiomyopathy known as ARVC, which perhaps should be more correctly termed as "arrhythmogenic cardiomyopathy" or represent a separate, potentially inheritable cardiomyopathic entity. We report these cases to familiarize forensic pathologists with this uncommon and potentially inheritable condition.

An updated review on the clinicopathologic aspects of arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC) is a disease that affects young adults and perhaps is the most common cause of sudden death in this age group. Many of these cases are faced by forensic pathologists, without a prior history, and unless suspected by the pathologist at the time of autopsy, the diagnosis is likely to be missed. Since some of these cases are hereditary, consequences of missing the diagnosis have a medicolegal implication that extends to involve other family members of the deceased. ARVC raises many controversial issues with regard to its existence, defining and diagnostic criteria, pathologic spectrum of changes, and pathogenesis. We reviewed the recent literature and included our experience to dictate a novel approach to the inherent problems faced by pathologists. In this review, we identified the most characteristic and distinct histopathologic features that are diagnostic or highly suggestive of ARVC, even in the absence of clinical history. We also highlighted the new insights on the disease pathogenesis. Hence, this review provides a better understanding of the disease and sheds light on many controversial issues regarding ARVC.

Tratamiento de pacientes con extrasístoles ventriculares / Treatment of ventricular patients with extrasystoles

Las contracciones ventriculares prematuras son frecuentemente identificadas en la práctica clínica, generalmente son asintomáticas y los pacientes asisten a consulta por otra causa; se encuentran incidentalmete al realizar el examen físico. En la mayoría de veces no con llevan ningún significado clínico y los pacientes nunca presentan síntomas, pero en algunos, sobre todo en aquellos con enfermedad cardiaca de base, estas pueden llegar a ser sintomáticas o ser el desencadenante de una arritmia que ponga en peligro la vida del paciente. Además, se debe tener en consideración el número de extrasístoles ventriculares que ocurren en un minuto, ya que a mayor número (mayor de 7), es mayor el riesgo de desarrollar una arritmia que puede comprometer la vida del paciente. Pueden ser identificadas al realizar un electrocardiograma de 12 derivaciones y en los pacientes que existe la sospecha y no se identifican en este, se puede realizar un Holter de 24 - 48 horas en donde se detectan en un 40 – 75. Debido a la frecuencia con que los pacientes presentan este tipo de alteraciones, que en su mayoría son benignas, es importante que los médicos en atención primaria sean capaces de reconocerlas y en los casos pertinentes referirlos para recibir el tratamiento adecuado, sobre todo en los pacientes con enfermedad cardiaca de base...

Tratamiento de pacientes con extrasístoles ventriculares / Treatment of ventricular patients with extrasístoles

Las contracciones ventriculares prematuras son frecuentemente identificadas en la práctica clínica, generalmente son asintomáticas y los pacientes asisten a consulta por otra causa; se encuentran incidentalmete al realizar el examen físico. En la mayoría de veces no con llevan ningún significado clínico y los pacientes nunca presentan síntomas, pero en algunos, sobre todo en aquellos con enfermedad cardiaca de base, estas pueden llegar a ser sintomáticas o ser el desencadenante de una arritmia que ponga en peligro la vida del paciente. Además, se debe tener en consideración el número de extrasístoles ventriculares que ocurren en un minuto, ya que a mayor número (mayor de 7), es mayor el riesgo de desarrollar una arritmia que puede comprometer la vida del paciente. Pueden ser identificadas al realizar un electrocardiograma de 12 derivaciones y en los pacientes que existe la sospecha y no se identifican en este, se puede realizar un Holter de 24 - 48 horas en donde se detectan en un 40 – 75%. Debido a la frecuencia con que los pacientes presentan este tipo de alteraciones, que en su mayoría son benignas, es importante que los médicos en atención primaria sean capaces de reconocerlas y en los casos pertinentes referirlos para recibir el tratamiento adecuado, sobre todo en los pacientes con enfermedad cardiaca de base...(AU)

Twenty years of progress and beckoning frontiers in cardiovascular pathology: cardiomyopathies.

In the last 20 years, with the advent of cardiac transplantation and the availability of molecular biology techniques, major advancements were achieved in the understanding of cardiomyopathies. Novel cardiomyopathies have been discovered (arrhythmogenic right ventricular, primary restrictive, and noncompacted myocardium) and added in the update of WHO classification. Myocarditis was also included with the name "inflammatory cardiomyopathy." Adenoviruses and parvoviruses were found to be frequent cardiotropic viruses in addition to enteroviruses. The extraordinary progress accomplished in molecular genetics of inherited cardiomyopathies allowed to establish hypertrophic and restrictive cardiomyopathies as sarcomeric ("force generation") diseases, dilated cardiomyopathies as cytoskeleton ("force transmission") disease, and arrhythmogenic right ventricular cardiomyopathy (ARVC) as cell junction disease. If we consider also cardiomyopathy as ion channel disease (long and short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia), because they are diseases of the myocardium associated with electrical dysfunction, then a genomic/postgenomic classification of inherited cardiomyopathies may be put forward: cytoskeletal cardiomyopathy, sarcomeric cardiomyopathy, cell junction cardiomyopathy and ion channel cardiomyopathy.

Genetics of arrhythmogenic right ventricular cardiomyopathy--status quo and future perspectives.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary myocardial disorder of unknown origin. In recent years, the disease has been recognized as a major cause of ventricular tachyarrhythmias and sudden cardiac death in young patients with apparently normal hearts. Although characteristic structural, imaging and electrocardiographic features are included in a proposed catalogue of diagnostic criteria, the correct diagnosis of ARVC often remains difficult. Much effort has been undertaken to enlarge the knowledge on pathophysiological mechanisms of the disease. The role of molecular genetics for the pathogenesis of ARVC is discussed in the following review. On the basis of linkage analyses in large families affected by ARVC, there is growing evidence for genetic alterations in ARVC, which, in the majority of chromosomal loci (seven) reported so far, follow a Mendelian autosomal-dominant pattern of inheritance with variable penetrance and polymorphic phenotype. Besides this, two autosomal-recessive forms of ARVC are known. These can be differentiated from the autosomal-dominant forms not only in terms of the mode of inheritance but also as to their specific phenotype: patients with Naxos disease exhibit characteristic hair and skin abnormalities and experience a more severe course of disease. Patients with another autosomal-recessive form display the typical but milder signs of ARVC together with opacifications of the crystalline lens. So far, two mutations in cardiac genes responsible for the development of ARVC have been reported. A homozygous two base pair deletion in the gene encoding for the cytoskeletal protein plakoglobin seems to account for the evolution of Naxos disease. The second mutation affecting the cardiac ryanodine receptor gene was found in patients with ARVC-2. Routine genetic testing of patients or relatives with a suspected diagnosis of ARVC is not available at present but may become the future gold standard with potential implications for a better understanding of the pathogenesis and management of the disease.

[Arrhythmogenic right ventricular dysplasia and cardiomyopathy. Clinical and anatomic-pathologic aspects, nosologic approach]. / Dysplasie et cardiomyopathie ventriculaire droite arythmogènes. Aspects cliniques et anatomo-pathologiques, abord nosologique.

Arrhythmogenic right ventricular dysplasia is a polymorphous clinical entity. Its diagnosis is difficult in incomplete forms or at the onset of the disease. The diagnosis is based on the association of clinical, electrocardiographic and electrophysiologic signs which are the result of a specific pathological structure, consisting of fibromuscular bundles isolated from each other by fatty tissue resulting from apoptosis and/or the basic dysplastic phenomenon. These fibers are oriented in a parallel direction and connected at their extremities with normal myocardium. These fibromyocyte bundles seem to constitute a tissue with preferential conduction, which could explain reentry phenomena, and therefore the basis for the pathogenesis of ventricular arrhythmias. The various clinical aspects of ARVD have similar morphological patterns, but a completely different prognosis and outcome.