Arrhythmogenic right ventricular cardiomyopathy/dysplasia

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a heart muscle disease clinically characterized by life-threatening ventricular arrhythmias. Its prevalence has been estimated to vary from 1:2,500 to 1:5,000. ARVC/D is a major cause of sudden death in the young and athletes. The pathology consists of a genetically determined dystrophy of the right ventricular myocardium with fibro-fatty replacement to such an extent that it leads to right ventricular aneurysms. The clinical picture may include: a subclinical phase without symptoms and with ventricular fibrillation being the first presentation; an electrical disorder with palpitations and syncope, due to tachyarrhythmias of right ventricular origin; right ventricular or biventricular pump failure, so severe as to require transplantation. The causative genes encode proteins of mechanical cell junctions (plakoglobin, plakophilin, desmoglein, desmocollin, desmoplakin) and account for intercalated disk remodeling. Familiar occurrence with an autosomal dominant pattern of inheritance and variable penetrance has been proven. Recessive variants associated with palmoplantar keratoderma and woolly hair have been also reported. Clinical diagnosis may be achieved by demonstrating functional and structural alterations of the right ventricle, depolarization and repolarization abnormalities, arrhythmias with the left bundle branch block morphology and fibro-fatty replacement through endomyocardial biopsy. Two dimensional echo, angiography and magnetic resonance are the imaging tools for visualizing structural-functional abnormalities. Electroanatomic mapping is able to detect areas of low voltage corresponding to myocardial atrophy with fibro-fatty replacement. The main differential diagnoses are idiopathic right ventricular outflow tract tachycardia, myocarditis, dialted cardiomyopathy and sarcoidosis. Only palliative therapy is available and consists of antiarrhythmic drugs, catheter ablation and implantable cardioverter defibrillator. Young age, family history of juvenile sudden death, QRS dispersion ≥ 40 ms, T-wave inversion, left ventricular involvement, ventricular tachycardia, syncope and previous cardiac arrest are the major risk factors for adverse prognosis. Preparticipation screening for sport eligibility has been proven to be effective in detecting asymptomatic patients and sport disqualification has been life-saving, substantially declining sudden death in young athletes

Diagnosis of arrhythmogenic cardiomyopathy: The Padua criteria.

The original designation of "Arrhythmogenic right ventricular (dysplasia/) cardiomyopathy"(ARVC) was used by the scientists who first discovered the disease, in the pre-genetic and pre-cardiac magnetic resonance era, to describe a new heart muscle disease predominantly affecting the right ventricle, whose cardinal clinical manifestation was the occurrence of malignant ventricular arrhythmias. Subsequently, autopsy investigations, genotype-phenotype correlations studies and the increasing use of contrast-enhancement cardiac magnetic resonance showed that the fibro-fatty replacement of the myocardium represents the distinctive phenotypic feature of the disease that affects the myocardium of both ventricles, with left ventricular involvement which may parallel or exceed the severity of right ventricular involvement. This has led to the new designation of "Arrhythmogenic Cardiomyopathy" (ACM), that represents the evolution of the original term of ARVC. The present International Expert Consensus document proposes an upgrade of the criteria for diagnosis of the entire spectrum of the phenotypic variants of ACM. The proposed "Padua criteria" derive from the diagnostic approach to ACM, which has been developed over 30 years by the multidisciplinary team of basic researchers and clinical cardiologists of the Medical School of the University of Padua. The Padua criteria are a working framework to improve the diagnosis of ACM by introducing new diagnostic criteria regarding tissue characterization findings by contrast-enhanced cardiac magnetic resonance, depolarization/repolarization ECG abnormalities and ventricular arrhythmia features for diagnosis of the left ventricular phenotype. The proposed diagnostic criteria need to be further validated by future clinical studies in large cohorts of patients

Variations in 123I-metaiodobenzylguanidine (MIBG) late heart mediastinal ratios in chronic heart failure: a need for standardisation and validation

BACKGROUND: There is lack of validation and standardisation of acquisition parameters for myocardial (123)I-metaiodobenzylguanidine (MIBG). This lack of standardisation hampers large scale implementation of (123)I-MIBG parameters in the evaluation of patients with chronic heart failure (CHF). METHODS: In a retrospective multi-centre study (123)I-MIBG planar scintigrams obtained on 290 CHF patients (82% male; 58% dilated cardiomyopathy; New York Heart Association [NYHA classification] > I) were reanalysed to determine the late heart-to-mediastinum ratio (H/M). RESULTS: There was a large variation in acquisition parameters. Multivariate forward stepwise regression showed that a significant proportion (31%, p < 0.001) of the variation in late H/M could be explained by a model containing patient-related variables and acquisition parameters. Left ventricular ejection fraction (p < 0.001), type of collimation (p < 0.001), acquisition duration (p = 0.001), NYHA class (p = 0.028) and age (p = 0.034) were independent predictors of late H/M. CONCLUSIONS: Acquisitions parameters are independent contributors to the variation of semi-quantitative measurements of cardiac (123)I-MIBG uptake. Improved standardisation of cardiac (123)I-MIBG imaging parameters would contribute to increased clinical applicability for this procedur

PET imaging of the autonomic myocardial function: methods and interpretation.

Cardiac positron emission tomography (PET) is mainly applied in myocardial perfusion and viability detection. Noninvasive imaging of myocardial innervation using PET is a valuable additional methodology in cardiac imaging. Novel methods and different PET ligands have been developed to measure presynaptic and postsynaptic function of the cardiac neuronal system. Obtained PET data can be analysed quantitatively or interpreted qualitatively. Thus far, PET is not a widely used clinical application in autonomic heart imaging; however, due to its technical advantages, the excellent properties of the imaging agents, and the availability of tools for quantification, it deserves a better position in the clinic. From a historical point of view, the focus of PET software packages for image analysis was mainly oncology and neurology driven. Actually, commercially available software for cardiac PET image analysis is still only available for the quantification of myocardial blood flow. Thus far, no commercial software package is available for the interpretation and quantification of PET innervation scans. However, image data quantification and analysis of kinetic data can be performed using adjusted generic tools. This paper gives an overview of different neuronal PET ligands, interpretation and quantification of acquired PET data

Biventricular myocardial strain analysis in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) using cardiovascular magnetic resonance feature tracking

BACKGROUND: Fibrofatty degeneration of myocardium in ARVC is associated with wall motion abnormalities. The aim of this study was to examine whether Cardiovascular Magnetic Resonance (CMR) based strain analysis using feature tracking (FT) can serve as a quantifiable measure to confirm global and regional ventricular dysfunction in ARVC patients and support the early detection of ARVC. METHODS: We enrolled 20 patients with ARVC, 30 with borderline ARVC and 22 subjects with a positive family history but no clinical signs of a manifest ARVC. 10 healthy volunteers (HV) served as controls. 15 ARVC patients received genotyping for Plakophilin-2 mutation (PKP-2), of which 7 were found to be positive. Cine MR datasets of all subjects were assessed for myocardial strain using FT (TomTec Diogenes Software). Global strain and strain rate in radial, circumferential and longitudinal mode were assessed for the right and left ventricle. In addition strain analysis at a segmental level was performed for the right ventricular free wall. RESULTS: RV global longitudinal strain rates in ARVC (−0.68 ± 0.36 sec(−1)) and borderline ARVC (−0.85 ± 0.36 sec(−1)) were significantly reduced in comparison with HV (−1.38 ± 0.52 sec(−1), p ≤ 0.05). Furthermore, in ARVC patients RV global circumferential strain and strain rates at the basal level were significantly reduced compared with HV (strain: −5.1 ± 2.7 vs. -9.2 ± 3.6%; strain rate: −0.31 ± 0.13 sec(−1) vs. -0.61 ± 0.21 sec(−1)). Even for patients with ARVC or borderline ARVC and normal RV ejection fraction (n=30) global longitudinal strain rate proved to be significantly reduced compared with HV (−0.9 ± 0.3 vs. -1.4 ± 0.5 sec(−1); p < 0.005). In ARVC patients with PKP-2 mutation there was a clear trend towards a more pronounced impairment in RV global longitudinal strain rate. On ROC analysis RV global longitudinal strain rate and circumferential strain rate at the basal level proved to be the best discriminators between ARVC patients and HV (AUC: 0.9 and 0.92, respectively). CONCLUSION: CMR based strain analysis using FT is an objective and useful measure for quantification of wall motion abnormalities in ARVC. It allows differentiation between manifest or borderline ARVC and HV, even if ejection fraction is still normal

Mutations with pathogenic potential in proteins located in or at the composite junctions of the intercalated disk connecting mammalian cardiomyocytes: a reference thesaurus for arrhythmogenic cardiomyopathies and for Naxos and Carvajal diseases

In the past decade, an avalanche of findings and reports has correlated arrhythmogenic ventricular cardiomyopathies (ARVC) and Naxos and Carvajal diseases with certain mutations in protein constituents of the special junctions connecting the polar regions (intercalated disks) of mature mammalian cardiomyocytes. These molecules, apparently together with some specific cytoskeletal proteins, are components of (or interact with) composite junctions. Composite junctions contain the amalgamated fusion products of the molecules that, in other cell types and tissues, occur in distinct separate junctions, i.e. desmosomes and adherens junctions. As the pertinent literature is still in an expanding phase and is obviously becoming important for various groups of researchers in basic cell and molecular biology, developmental biology, histology, physiology, cardiology, pathology and genetics, the relevant references so far recognized have been collected and are presented here in the following order: desmocollin-2 (Dsc2, DSC2), desmoglein-2 (Dsg2, DSG2), desmoplakin (DP, DSP), plakoglobin (PG, JUP), plakophilin-2 (Pkp2, PKP2) and some non-desmosomal proteins such as transmembrane protein 43 (TMEM43), ryanodine receptor 2 (RYR2), desmin, lamins A and C, striatin, titin and transforming growth factor-β3 (TGFβ3), followed by a collection of animal models and of reviews, commentaries, collections and comparative studies