Penetrance of mutations in plakophilin-2 among families with arrhythmogenic right ventricular dysplasia/cardiomyopathy.

OBJECTIVES: The purpose of our study was to characterize the penetrance of PKP2 mutations among family members of people with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) and to examine clinical features and predictors of disease among PKP2 mutation carriers. BACKGROUND: Arrhythmogenic right ventricular dysplasia/cardiomyopathy is an inherited cardiomyopathy characterized by fatty-fibrous myocardial replacement of the right ventricle, ventricular arrhythmias, and right ventricular dysfunction. Mutations in PKP2, the gene encoding plakophilin-2, are found in 11% to 43% of ARVD/C probands. METHODS: The study population was composed of 64 individuals in 9 families with an ARVD/C proband previously shown to carry a pathogenic PKP2 mutation. The diagnosis of ARVD/C was established based on task force criteria (TFC) set by the European Society of Cardiology. RESULTS: In addition to the probands, PKP2 mutations were present in 52% of relatives screened. Forty-nine percent of PKP2 mutation carriers met TFC. Among mutation carriers who did not meet full TFC, 50% met at least some TFC criteria besides family history. Pedigrees showed wide intra-familial variability, ranging from severe disease with early death to individuals who were completely asymptomatic late in life. Male PKP2 mutation carriers were more likely to have structural and conduction abnormalities as determined by imaging studies, signal-averaged electrocardiography, and 24-h ambulatory electrocardiography (p < 0.05). CONCLUSIONS: PKP2 mutations in a group of North American families with ARVD/C have both reduced penetrance and variable expressivity. Gender may have an influence on penetrance of PKP2 mutations, with male mutation carriers more likely to develop specific phenotypic manifestations of this disease.     

Review on the genetics of arrhythmogenic right ventricular dysplasia.

Arrhythmogenic right ventricular dysplasia (ARVD) is a clinical and pathologic entity whose diagnosis rests on electrocardiographic and angiographic criteria; pathologic findings, replacement of ventricular myocardium with fatty and fibrous elements, preferentially involve the right ventricular (RV) free wall. There is a familial occurrence in about 50% of cases, with autosomal dominant inheritance with variable penetrance and polymorphic phenotypic expression, and is one of the major genetic causes of juvenile sudden death. When the dysplasia is extensive, it may represent the extensive form of ARVCM (arrhythmogenic right ventricular cardiomyopathy). In this review, we focus on the some candidate genes mutations and information on some genotype-phenotype correlation in the ARVD. Our findings are in agreement with those of European Society of Cardiology who stated that: genetic analysis is usefull in families with RV cardiomyopathy because whenever a pathogenetic mutation is identified, it becomes possible to establish a presymptomatic diagnosis of the disease among family members and to provide them with genetic counseling to monitor the development of the disease and to assess the risk of transmitting the disease offspring. On the basis of current knowledge, genetic analysis does not contribute to risk stratification of arrhythmogenic RV cardiomyopathy.     

Arrhythmogenic Right Ventricular Cardiomyopathy With Recessive Inheritance Related to a New Homozygous Desmocollin-2 Mutation

Arrhythmogenic right ventricular cardiomyopathy/dysplasia is an inherited cardiomyopathy that is transmitted in autosomal dominant and autosomal recessive forms and involves mutations in desmosomal and extradesmosomal genes. We present a case of arrhythmogenic right ventricular cardiomyopathy that cosegregates in a Lebanese family with a previously unreported desmocollin-2 mutation (c.712_714delGAT). We believe this newly described genetic variant displays autosomal recessive inheritance without the cutaneous manifestations expected in recessive genotypes, and represents the latest addition to the compendium of desmosomal mutations with pathogenic potential.     

Arrhythmogenic right ventricular cardiomyopathy: clinical presentation, diagnosis, and management

Arrhythmogenic right ventricular cardiomyopathy, also known as right ventricular dysplasia, is a genetically determined heart muscle disease associated with arrhythmia, heart failure, and sudden death. Autosomal dominant inheritance is typical. The identification of causative mutations in cell adhesion proteins has shed new light on its pathogenesis. Fibrofatty replacement of the myocardium, the hallmark pathologic feature, may be a response to injury caused by myocyte detachment. Sudden death is often the first manifestation in probands, emphasizing the importance of evaluating asymptomatic relatives for the disease. Standardized guidelines facilitate the clinical diagnosis of right ventricular dysplasia. However, familial studies have highlighted the need to broaden the diagnostic criteria, which are highly specific but lack sensitivity for early disease. Modifications have been proposed for the diagnosis of right ventricular dysplasia in relatives. Early right ventricular dysplasia is characterized by a "concealed phase" in which electrocardiographic and imaging abnormalities are often absent, but patients may nonetheless be at risk for arrhythmic events. Detection at this stage remains a clinical challenge, underscoring the potential value of mutation analysis in identifying affected persons. Serial evaluation of patients with suspected right ventricular dysplasia is recommended as clinical features may develop during the follow-up period. The onset of symptoms such as palpitation or syncope may herald an active phase of a previously quiescent disease, during which patients are at increased risk for sudden death. Greater awareness of right ventricular dysplasia among physicians and judicious use of implantable cardioverter-defibrillators may help to prevent unnecessary deaths.     

Arrhythmogenic right ventricular dysplasia/cardiomyopathy. A review and update

The arrhythmogenic right ventricular dysplasia/cardiomyopathy is an important cause of sudden arrhythmic death, often exertional, in young individuals and athletes. Although the aetiology remains partially unknown, genetic abnormalities have been demonstrated. Reported prevalence is 1 in 5000 individuals but it is considered there are many non-diagnosed cases.

The characteristic pathologic finding is the progressive fibro-fatty replacement of the right ventricular myocardium. The clinical manifestations vary from asymptomatic patients with an episode of sudden cardiac death as first symptom to chronically symptomatic patients with recurrent palpitations and/or right or biventricular failure.

Approximately a third of the patients show the characteristic Epsilon wave in the 12-lead ECG which is a useful screening test. Signal-averaged ECG frequently demonstrates late potentials. The two-dimensional echocardiography, magnetic resonance imaging, computerized tomography and right ventricular cineangiography show morphologic abnormalities in the right ventricle.

Therapy is directed to prevent and/or treat malignant ventricular tachyarrhythmias with medications, implantable cardioverter defibrillator and radiofrequency ablation in selected cases.     

Genetic screening of cardiomyopathies

Cardiomyopathies comprise a heterogeneous group of primary heart muscle disorders with a strong genetic component. Nearly all cases of hypertrophic cardiomyopathy and at least 20-30% of cases with dilated cardiomyopathy are due to autosomal dominant mutations. The extent of genetic factors for arrhythmogenic right ventricular and restrictive cardiomyopathy is less clear. Recent studies have demonstrated that genetic causes of all cardiomyopathies are highly heterogeneous with more than 25 disease gene loci. Although the ability to diagnose cardiomyopathies at the molecular level has advanced, our understanding of disease pathways and the knowledge of individual diseases causing mutations has had little impact on the clinical management of patients. Once current technical limitations for large-scale mutation analysis are overcome, broad genotype/phenotype correlation studies may answer important clinical issues such as the precise relation between distinct mutations and the risk of sudden death, course of the disease and treatment of patients.     

Right ventricular dysplasia]

Arrhythmogenic right ventricular dysplasia is responsible for ventricular tachycardia affecting an apparently healthy heart. It can sometimes lead to sudden death, which may be the presenting symptomatology of the disease. It results from fibro-adipose infiltration of the free wall of the right ventricle, and sometimes of the septum, possibly secondary to myocarditis. The prognosis depends upon the quality of the left ventricle. If it is healthy, the only risk is that of arrhythmia. Treatment using anti-arrhythmic drugs is most often effective and, with proper management, the prognosis is good and the risk of sudden death eliminated. If the left ventricle is abnormal, there is the risk that dysplasia associated with arrhythmia will progress to right then congestive cardiac failure in the context of a dilated idiopathic cardiomyopathy with ventricular tachycardias originating on the right side. Arrhythmogenic right ventricular dysplasia is a notable cause of sudden death in athletes. Routine screening of such individuals is justified, as is that of those with high risk occupations (locomotive and vehicle drivers, etc.).     

Arrhythmogenic right ventricular cardiomyopathy/dysplasia: An update

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a genetic cardiomyopathy characterized by ventricular arrhythmias and structural abnormalities of the right ventricle (RV). The diagnosis is based on the International Task Force criteria. Cardiologists may not be aware of these diagnostic criteria for ARVC/D and may place too much importance on the results of MRI imaging of the right ventricle. Patients with ARVC/D usually have an abnormal 12-lead electrocardiogram, abnormal echocardiogram, and ventricular arrhythmias with a left bundle branch block morphology. If noninvasive testing suggests ARVC/D, invasive testing with an RV angiogram, RV biopsy, and electrophysiologic study is recommended. Once a diagnosis of ARVC/D is established, the main treatment decision involves whether to implant an implantable cardioverter-defibrillator. We also recommend treatment with β blockers. Patients with ARVC/D are encouraged to avoid competitive athletics. Recent advances in the understanding of the genetic basis of ARVC/D have revealed that ARVC/D is a disease of desmosomal dysfunction.     

Arrhythmogenic right ventricular dysplasia/cardiomyopathy: Screening, diagnosis, and treatment

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a heart muscle disorder characterized pathologically by fatty or fibrofatty replacement and electrical instability of the right ventricular myocardium. Clinical manifestations include structural and functional malformations (fatty infiltration, dilatation, aneurysms) of the right ventricle, ECG abnormalities, and presentation with ventricular tachycardias with left bundle branch block pattern or sudden death. The disease often is familial with an autosomal inheritance. The typical hallmarks of ARVD/C are distributed in the so-called "triangle of dysplasia." The functional and morphologic characteristics are relevant to clinical imaging approaches such as contrast angiography, echocardiography, radionuclide angiography, ultrafast computed tomography, and cardiovascular magnetic resonance imaging. Evident forms of the disease are straightforward to diagnose based on a series of diagnostic criteria proposed by the International Task Force for Cardiomyopathy. However, the diagnosis of early and mild forms of the disease often is difficult. Treatment is directed toward preventing life-threatening ventricular arrhythmias in which radiofrequency ablation and implantable defibrillators play an increasing role. Despite new diagnostic and therapeutic approaches in ARVD/C, uncertainties about the etiology of the disease, the genetic basis, the appropriate diagnosis and therapy, and the clinical course of patients with ARVD/C have resulted in several registries to increase our knowledge of this intriguing disease.     

Right ventricular dysplasia: a clinical and pathological study of two families with left ventricular involvement.

BACKGROUND--Right ventricular dysplasia is a heart muscle disease of unknown cause that is often familial and is anatomically characterised by adipose or fibroadipose infiltration of the right ventricular myocardium. It is generally regarded as a selective disorder of the right ventricle. AIM--To investigate the prevalence and characteristics of left ventricular involvement in two families in which at least one member had right ventricular dysplasia confirmed at necropsy. METHODS AND RESULTS--Eight patients were found to be affected by right ventricular dysplasia. In three of them this was confirmed at necropsy. Echocardiography or angiography or both showed left ventricular involvement in seven. This ranged from localised wall motion abnormalities to moderate or severe left ventricular dysfunction. The disease was progressive in four cases. At necropsy the left ventricular myocardium showed predominant fibrosis and degenerative changes of the myocardial cells. There were areas of myocardial thinning with fatty infiltration at the apex in two patients. CONCLUSIONS--Familial right ventricular dysplasia can be a progressive disorder that affects the left ventricle. Advanced disease may be clinically confused with dilated cardiomyopathy.     

Angiographic findings in arrhythmogenic dysplasia of the right ventricle

Arrhythmogenic right ventricular dysplasia is characterized by fibrous and adipose replacement of the right ventricular myocardium and recurrent ventricular arrhythmias of left bundle branch block morphologic pattern. Sometimes the diagnosis is difficult because not all the clinical and instrumental findings are present and the separation between arrhythmogenic right ventricular dysplasia and other right ventricular cardiopathies is uncertain. In such cases the angiographic appearance of the right ventricle has been considered the "gold standard". To assess the diagnostic value of right ventricular morphology in identifying arrhythmogenic right ventricular dysplasia, we compared the angiographic findings of 8 patients with arrhythmogenic right ventricular dysplasia, 10 with biventricular dilated cardiomyopathy and 10 with Ebstein's anomaly. The following aspects were considered: deep fissuring of the anterior or inferior wall, outflow tract enlargement, contrast persistence in the right ventricle during the levophase, regional wall motion abnormalities including aneurysmal formations and tricuspid regurgitation. Aneurysmal formations of the right ventricle were found only in arrhythmogenic right ventricular dysplasia whereas the other angiographic findings were common to all the above mentioned diseases. Right ventricular angiography is an important adjunct to the clinical and instrumental diagnosis of arrhythmogenic right ventricular dysplasia, but most of its angiographic features are common to other diseases which cause right ventricular dilatation.     

The arrhythmogenic right ventricle. Dysplasia versus cardiomyopathy

Summary Twenty-four patients presenting with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ventricular tachycardia of right ventricular origin associated with structural abnormalities of the right ventricle) were divided into two groups with left ventricular ejection fraction (LVEF) above or below 45%. The distribution of LVEF in the group with LVEF below 45% was comparable with the distribution in 6 patients with idiopathic dilated cardiomyopathy who had ventricular tachycardia originating in the left ventricle (P = 0.2). They also had the same unfavorable long-term prognosis. Therefore, it is suggested that the term, arrhythmogenic right ventricular cardiomyopathy (ARVC), be restricted to patients with a LVEF below 45%. Histological data obtained in the ARVC group showed signs of acute or chronic myocarditis (in the right and left ventricles). It can be hypothesized that patients with arrhythmogenic right ventricular dysplasia (ARVD) may be prone to develop infectious myocarditis. In patients in whom an abnormal host immune response had been seen, progressive deterioration of right and left ventricular function could be observed. This pattern may be superimposed on the genetically determined background of ARVD. This could explain the wide spectrum of clinical presentation observed in patients with tachycardia originating in an abnormal right ventricle.Presented at the ISFC International Symposium on Cardiomyopathies, Warsaw (Poland) October 1993     

Arrhythmogenic right ventricular dysplasia

Congestive cardiac failure could be as important as cardiac arrhythmias in the natural history of arrhythmogenic right ventricular dysplasia. This can be related to the progressive replacement of myocardium by fat and fibrosis of the right ventricle. The left ventricle may also be involved by the same disease process. Moreover, inflammation can be superimposed on ARVD, resulting in a wide spectrum of clinical presentation which can mimick idiopathic dilated cardiomyopathy. Right ventricular cardiac failure has been controlled by anterior dynamic cardiomyoplasty.     

Epsilon‐Like Electrocardiographic Pattern in a Patient with Brugada Syndrome

Both Brugada syndrome (BrS) and arrhythmogenic right ventricle dysplasia/cardiomyopathy (ARVD/C) can cause repolarization abnormalities in right precordial leads and predispose to sudden cardiac death (SCD) due to ventricular arrhythmias. Although there is controversy over whether BrS is distinct from ARVD/C, it is believed that both are different clinical entities with respect to both the clinical presentation and the genetic predisposition. The coexistence of these two relatively rare clinical entities is also reported, but, some hypothesized that it is more possible that disease of the right ventricular muscle might accentuate the Brugada electrocardiographic pattern. In clinic practice, there may be cases where the dividing line is not so clear. We report a 33‐year‐old male presenting with recurrent syncope, who has a peculiar pattern of coved‐type ST‐segment elevation (ST‐SE) with epsilon‐like wave in right precordial leads.     

致心律失常性右室心肌病诊断进展

摘要：致心律失常性右室心肌病,又称致心律失常性右室发育不良,是一种遗传性心肌病,其特征为右心室心肌进行性被纤维脂肪组织所替代,临床常表现为右心室扩大、心律失常和猝死。致心律失常性右室心肌病的具体发病机制不十分明确,在此病的临床诊断方面仍值得进一步探讨。     

Arrhythmogenic right ventricular cardiomyopathy: a 'final common pathway' that defines clinical phenotype.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)is a primary heart muscle disease with distinct characteristics.ARVD/C predominantly affects the right ventricle (RV), withRV dilation and thinning due to fibrofatty infiltration of theventricular myocardium, and ultimately depressed systolic functionleading to right heart failure or biventricular failure.¹ Earlyin its clinical course, ARVD/C typically presents with ventriculararrhythmias (usually with a left bundle branch pattern), syncope,or sudden cardiac death.² Tragically, this clinical scenariocommonly occurs in young, healthy, athletic individuals. A setof clinical criteria, known as the ‘Task Force Criteria’,first described by McKenna et al.³ in 1994 and later modifiedfor inclusion of family members,⁴ utilizes     

Miocardiopatia arritmogénica do ventrículo direito. Contribuição de diferentes técnicas de eletrocardiografia

Arrhythmogenic right ventricular cardiomyopathy, also known as arrhythmogenic right ventricular dysplasia, is a condition in which myocardium is replaced by fibrous or fibrofatty tissue, predominantly in the right ventricle. It is clinically characterized by potentially lethal ventricular arrhythmias, and is a leading cause of sudden cardiac death. Its prevalence is not known exactly but is estimated at approximately 1:5000 in the adult population. Diagnosis can be on the basis of structural and functional alterations of the right ventricle, electrocardiographic abnormalities (including depolarization and repolarization alterations and ventricular arrhythmias) and family history. Diagnostic criteria facilitate the recognition and interpretation of non‐specific clinical features of this disease.The authors present a case in which the diagnosis of arrhythmogenic right ventricular cardiomyopathy was prompted by the suspicion of right ventricular disease on transthoracic echocardiography. This was confirmed by detection of epsilon waves on analysis of the ECG, which generally go unnoticed but in this case were the key to the diagnosis. Their presence was also shown by non‐conventional ECG techniques such as modified Fontaine ECG.The course of the disease culminated in the occurrence of ventricular tachycardia, which prompted placement of an implantable cardioverter‐defibrillator.     

Molecular biology and clinical management of arrhythmogenic right ventricular cardiomyopathy/dysplasia

In the last two decades the extraordinary advances in molecular biology of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) have provided significant insights into our understanding of the disease aetiology by showing that it is a genetic disorder of the cardiac desmosomes and that interactions between mechanical disruption of cell-cell adhesion and defects of desmosomal-mediated intracellular signalling are likely to be involved in the pathogenesis of the ARVC/D phenotype. The discovery of the causative genes for ARVC/D offers the possibility of identifying genetically-affected individuals before potentially malignant clinical phenotype occurs. Moreover, the evaluation of abnormal localisation of desmosomal proteins by immunohistochemical analysis on endomyocardial biopsy samples represents a promising test for ARVC/D diagnosis. Early detection of ARVC/D and preventive therapy of young individuals at highest risk of experiencing sudden cardiac death may be improved by molecular genetic screening within affected families and may alter the clinical management of patients. At present, however, the clinical use of genotyping is limited by the incomplete knowledge of causative mutations and the complex genetic background of the disease, which accounts for the incomplete penetrance and the marked variability of the phenotype expression. This review addresses the advances in the molecular biology of ARVC/D, with particular reference to the genetic basis of the disease, and how these advances have impacted on understanding the disease pathogenesis, on diagnosis and in establishing management strategies.     

Desmoglein-2 mutations in arrhythmogenic right ventricular cardiomyopathy: a genotype-phenotype characterization of familial disease.

AIMS: Mutations in the desmoglein-2 (DSG2) gene have been reported in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) but clinical information regarding the associated phenotype is at present limited. In this study, we aimed to clinically characterize probands and family members carrying a DSG2 mutation. METHODS AND RESULTS: We investigated 86 Caucasian ARVC patients for mutations in DSG2 by direct sequencing and detected eight novel mutations in nine probands. Clinical evaluation of family members with DSG2 mutations demonstrated penetrance of 58% using Task Force criteria, or 75% using proposed modified criteria. Morphological abnormalities of the right ventricle were evident in 66% of gene carriers, left ventricular (LV) involvement in 25%, and classical right precordial T-wave inversion only in 26%. Sustained ventricular arrhythmia was present in 8% and a family history of sudden death/aborted sudden death in 66%. CONCLUSION: Mutations in DSG2 display a high degree of penetrance. Disease expression was of variable severity with LV involvement a prominent feature. The low prevalence of classical ECG changes highlights the need to expand current diagnostic criteria to take account of LV disease, childhood disease expression, and incomplete penetrance.