Andrea Nava

Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria.

BACKGROUND In 1994, an International Task Force proposed criteria for the clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) that facilitated recognition and interpretation of the frequently nonspecific clinical features of ARVC/D. This enabled confirmatory clinical diagnosis in index cases through exclusion of phenocopies and provided a standard on which clinical research and genetic studies could be based. Structural, histological, electrocardiographic, arrhythmic, and familial features of the disease were incorporated into the criteria, subdivided into major and minor categories according to the specificity of their association with ARVC/D. At that time, clinical experience with ARVC/D was dominated by symptomatic index cases and sudden cardiac death victims-the overt or severe end of the disease spectrum. Consequently, the 1994 criteria were highly specific but lacked sensitivity for early and familial disease. METHODS AND RESULTS Revision of the diagnostic criteria provides guidance on the role of emerging diagnostic modalities and advances in the genetics of ARVC/D. The criteria have been modified to incorporate new knowledge and technology to improve diagnostic sensitivity, but with the important requisite of maintaining diagnostic specificity. The approach of classifying structural, histological, electrocardiographic, arrhythmic, and genetic features of the disease as major and minor criteria has been maintained. In this modification of the Task Force criteria, quantitative criteria are proposed and abnormalities are defined on the basis of comparison with normal subject data. CONCLUSIONS The present modifications of the Task Force Criteria represent a working framework to improve the diagnosis and management of this condition. Clinical Trial Registration clinicaltrials.gov Identifier: NCT00024505.

Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Task Force of the Working Group Myocardial and Pericardial Disease of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the International Society and Federation of Cardiology.

Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Task Force of the Working Group Myocardial and Pericardial Disease of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the International Society and Federation of Cardiology.

Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia Proposed Modification of the Task Force Criteria

Background— In 1994, an International Task Force proposed criteria for the clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) that facilitated recognition and interpretation of the frequently nonspecific clinical features of ARVC/D. This enabled confirmatory clinical diagnosis in index cases through exclusion of phenocopies and provided a standard on which clinical research and genetic studies could be based. Structural, histological, electrocardiographic, arrhythmic, and familial features of the disease were incorporated into the criteria, subdivided into major and minor categories according to the specificity of their association with ARVC/D. At that time, clinical experience with ARVC/D was dominated by symptomatic index cases and sudden cardiac death victims—the overt or severe end of the disease spectrum. Consequently, the 1994 criteria were highly specific but lacked sensitivity for early and familial disease. Methods and Results— Revision of the diagnostic criteria provides guidance on the role of emerging diagnostic modalities and advances in the genetics of ARVC/D. The criteria have been modified to incorporate new knowledge and technology to improve diagnostic sensitivity, but with the important requisite of maintaining diagnostic specificity. The approach of classifying structural, histological, electrocardiographic, arrhythmic, and genetic features of the disease as major and minor criteria has been maintained. In this modification of the Task Force criteria, quantitative criteria are proposed and abnormalities are defined on the basis of comparison with normal subject data. Conclusions— The present modifications of the Task Force Criteria represent a working framework to improve the diagnosis and management of this condition. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00024505.

Spectrum of Clinicopathologic Manifestations of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia: A Multicenter Study☆

OBJECTIVES The aim of the present investigation was to redefine the clinicopathologic profile of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC), with special reference to disease progression and left ventricular (LV) involvement. BACKGROUND Long-term follow-up data from clinical studies indicate that ARVC is a progressive heart muscle disease that with time may lead to more diffuse right ventricular (RV) involvement and LV abnormalities and culminate in heart failure. METHODS Forty-two patients (27 male, 15 female; 9 to 65 years old, mean [+/-SD] age 29.6 +/- 18) from six collaborative medical centers, with a pathologic diagnosis of ARVC at autopsy or heart transplantation, and with the whole heart available, were studied according to a specific clinicomorphologic protocol. RESULTS Thirty-four patients died suddenly (16 during effort); 4 underwent heart transplantation; 2 died as a result of advanced heart failure; and 2 died of other causes. Sudden death was the first sign of disease in 12 patients; the other 30 had palpitations, with syncope in 11, heart failure in 8 and stroke in 3. Twenty-seven patients experienced ventricular arrhythmias (ventricular tachycardia in 17), and 5 received a pacemaker. Ten patients had isolated RV involvement (group A); the remaining 32 (76%) also had fibrofatty LV involvement that was observed histologically only in 15 (group B) and histologically and macroscopically in 17 (group C). Patients in group C were significantly older than those in groups A and B (39 +/- 15 years vs. 20 +/- 8.8 and 25 +/- 9.7 years, respectively), had significantly longer clinical follow-up (9.3 +/- 7.3 years vs. 1.2 +/- 2.1 and 3.4 +/- 2.2 years, respectively) and developed heart failure significantly more often (47% vs. 0 and 0, respectively). Patients in groups B and C had warning symptoms (80% and 87%, respectively, vs. 30%) and clinical ventricular arrhythmias (73% and 82%, respectively, vs. 20%) significantly more often than patients in group A. Hearts from patients in group C weighed significantly more than those from patients in groups A and B (500 +/- 150 g vs. 328 +/- 40 and 380 +/- 95 g, respectively), whereas hearts from both group B and C patients had severe RV thinning (87% and 71%, respectively, vs. 20%) and inflammatory infiltrates (73% and 88%, respectively, vs. 30%) significantly more often than those from group A patients. CONCLUSIONS LV involvement was found in 76% of hearts with ARVC, was age dependent and was associated with clinical arrhythmic events, more severe cardiomegaly, inflammatory infiltrates and heart failure. ARVC can no longer be regarded as an isolated disease of the right ventricle.

Mutation in Human Desmoplakin Domain Binding to Plakoglobin Causes a Dominant Form of Arrhythmogenic Right Ventricular Cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVD/C) is a genetically heterogeneous disease characterized by progressive degeneration of the right ventricular myocardium and increased risk of sudden death. Here, we report on a genome scan in one Italian family in which the disease appeared unlinked to any of the six different ARVD loci reported so far; we identify a mutation (S299R) in exon 7 of desmoplakin (DSP), which modifies a putative phosphorylation site in the N-terminal domain binding plakoglobin. It is interesting that a nonsense DSP mutation was reported elsewhere in the literature, inherited as a recessive trait and causing a biventricular dilative cardiomyopathy associated with palmoplantar keratoderma and woolly hairs. Therefore, different DSP mutations might produce different clinical phenotypes, with different modes of inheritance.

Arrhythmogenic Right Ventricular Cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy is a rare inherited heart-muscle disease that is a cause of sudden death in young people and athletes. Causative mutations in genes encoding desmosomal proteins have been identified and the disease is nowadays regarded as a genetically determined myocardial dystrophy. The left ventricle is so frequently involved as to support the adoption of the broad term arrhythmogenic cardiomyopathy. Clinical diagnosis can be achieved by demonstrating function and structure changes of the right ventricle, electrocardiogram depolarisation and repolarisation abnormalities, ventricular arrhythmias, and fibrofatty replacement through endomyocardial biopsy. Although specific, the standardised diagnostic criteria lack sensitivity for early disease and their primary application remains in establishing the diagnosis in probands. However, the main clinical targets are early detection of concealed forms and risk stratification for preventive strategies, which include physical exercise restriction, antiarrhythmic drugs, and implantable cardioverter-defibrillator therapy. Cascade genetic screening of family members of gene-positive probands allows the identification of asymptomatic carriers who would require lifelong follow-up due to the age-related penetrance.

Mutations in Desmoglein-2 Gene Are Associated With Arrhythmogenic Right Ventricular Cardiomyopathy

Background— Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by progressive myocardial atrophy with fibrofatty replacement. The recent identification of causative mutations in plakoglobin, desmoplakin (DSP), and plakophilin-2 (PKP2) genes led to the hypothesis that ARVC is due to desmosomal defects. Therefore, desmoglein-2 (DSG2), the only desmoglein isoform expressed in cardiac myocytes, was screened in subjects with ARVC. Methods and Results— In a series of 80 unrelated ARVC probands, 26 carried a mutation in DSP (16%), PKP2 (14%), and transforming growth factor-&bgr;3 (2.5%) genes; the remaining 54 were screened for DSG2 mutations by denaturing high-performance liquid chromatography and direct sequencing. Nine heterozygous DSG2 mutations (5 missense, 2 insertion-deletions, 1 nonsense, and 1 splice site mutation) were detected in 8 probands (10%). All probands fulfilled task force criteria for ARVC. An endomyocardial biopsy was obtained in 5, showing extensive loss of myocytes with fibrofatty tissue replacement. In 3 patients, electron microscopy investigation was performed, showing intercalated disc paleness, decreased desmosome number, and intercellular gap widening. Conclusions— This is the first investigation demonstrating DSG2 gene mutations in a significant number of ARVC-unrelated probands. Cardiac phenotype is characterized clinically by typical ARVC features with frequent left ventricular involvement and morphologically by fibrofatty myocardial replacement and desmosomal remodeling. The presence of mutations in desmosomal encoding genes in 40% of cases confirms that many forms of ARVC are due to alterations in the desmosome complex.

Comparison of QT dispersion in hypertrophic cardiomyopathy between patients with and without ventricular arrhythmias and sudden death

Recent studies have suggested that interlead QT variability on the surface electrocardiogram, defined as QT dispersion, may reflect regional variations in myocardial recovery of excitability.1-4 The finding of a decreased QT dispersion in patients with different heart diseases treated with class III agents, sotalo13 and amiodarone,5T6 further supports this theory. A significant QT dispersion was found both in patients with congenital and acquired long QT interva12,5,7%s and in patients with myocardial infarction. 2,3,g~10 In hypertrophic cardiomyopathy (HC), the presence of electrical instability is a potentially important determinant of sudden death.“-l3 The pathologic substrate of the disease may create the conditions for QT interval prolongation and nonhomogeneous recovery of excitability.14 Dritsas et all5 recently showed a prolonged corrected QT interval (QTc) and increased QTc dispersion in 24 patients with HC compared with normal subjects, but a comparison between patients with and without ventricular arrhythmias was not done. This study assesses QT dispersion in HC patients with and without documented serious ventricular arrhythmias and sudden death. Twenty-six patients with NC (19 males and 7 females, mean age 37 t- 13 years, range 8 to 57) attending our institution for outpatient follow-up evaluation, or referred for risk stratification

Clinical profile and long-term follow-up of 37 families with Arrhythmogenic right ventricular cardiomyopathy

OBJECTIVES We sought to define the clinical picture and natural history of familial arrhythmogenic right ventricular cardiomyopathy (ARVC). BACKGROUND Arrhythmogenic right ventricular cardiomyopathy is a myocardial disease, often familial, clinically characterized by the impending risk of ventricular arrhythmias and sudden death. METHODS Thirty-seven ARVC families of northeast Italy were studied. Probands had a histologic diagnosis of ARVC, either at autopsy (19 families) or endomyocardial biopsy (18 families). Protocol of the investigation included basal electrocardiogram (ECG), 24-hour ECG, signal-averaged ECG, stress test and two-dimensional Doppler echocardiography. Invasive evaluation was performed when deemed necessary. RESULTS Of the 365 subjects, 151 (41%) were affected, 157 (43%) were unaffected, 17 (5%) were healthy carriers, and 40 (11%) were uncertain. Mean age at diagnosis was 31+/-13 years. By echocardiography, 64% had mild, 30% had moderate, and 6% had severe form. Forty percent had ventricular arrhythmias, 49 were treated with antiarrhythmic drugs, and two were treated with implantable cardioverter defibrillators. Sport activity was restricted in all. Of the 28 families who underwent linkage analysis, 6 mapped to chromosome 14q23-q24, 4 to 1q42-q43, and 4 to 2q32.1-q32.3. No linkage with known loci was found in four families and 10 had uninformative results. During a follow-up of 8.5+/-4.6 years, one patient died (0.08 patient/year mortality), and 15 developed an overt form of ARVC. CONCLUSIONS Arrhythmogenic right ventricular cardiomyopathy is a progressive disease appearing during adolescence and early adulthood. Systematic evaluation of family members leads to early identification of ARVC, characterized by a broad clinical spectrum with a favorable outcome. In the setting of positive family history, even minor ECG and echocardiographic abnormalities are diagnostic.

Familial occurrence of right ventricular dysplasia: A study involving nine families

Right ventricular pathologic involvement, with autopsy evidence of fibrous and fatty infiltration of the right ventricle, was investigated in members of families in which cases of juvenile sudden death had occurred. Seventy-two subjects from nine families were studied. Sixteen died at a young age and 56 are living. Postmortem investigation in 11 cases (mean age at death 24 years) revealed massive replacement of the right ventricular free wall by fat or fibrous tissue. In the 56 living patients clinical examination included an electrocardiogram (ECG) at rest, ambulatory ECG recording, posteroanterior and lateral chest roentgenograms, M-mode and two-dimensional echocardiograms and exercise stress tests. In 14 patients, hemodynamic, angiographic and electrophysiologic studies were also carried out; right ventricular endomyocardial biopsy was performed in four. Structural and dynamic right ventricular impairment was detected in 30 living patients (mean age 25 years), and concomitant mild left ventricular abnormalities were present in 4. In eight of the nine families studied at least two members were affected. Ventricular arrhythmias (Lown grade greater than or equal to 4a) were recorded in more than half of the cases. The data reveal that right ventricular dysplasia shows a familial clustering and causes electrical instability that may place affected subjects at risk of sudden death. The mean age of these subjects suggests that the disease is manifested at a young age with a polymorphic clinical and arrhythmic profile. Finally, because this disease is a primary disorder of the ventricular myocardium, it should be included among the cardiomyopathies.