The Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia

The arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), have a prevalence estimated that range from 1 case on 5000 subjects in the general population to 1 in 2000 in some European countries such as Italy and Germany. It is a rare myocardial disease, with a dominant genetic transmission characterized by alterations of desmosomial proteins including desmoplakin (DSP), plakophilin 2 (PKP2), desmoglein 2 (DSG2), and desmocollin 2 (DSC2). ARVC/D mainly affects the right ventricle but in some cases also the left ventricle result involved and the fatty tissue or fibro-fatty tissue with particular arrangement may affect the full-thickness wall are pathognomonic. Progressive loss of right ventricular myocardium and its replacement by fibro-fatty tissue is the pathological hallmark of the disease and predisposes to the early onset of arrhythmias and sudden death especially in young people and athletes. The diagnosis is difficult and based on clinical major/minor criteria, including histological aspects based on fibrous tissue substitution (in percentage) and right ventricle localization. The introduction of the new term "borderline" ARVC allows to inform those individuals with undefined diseases for minor abnormalities that are at risk and require regular follow-up.

The histological criteria consist on microscopic observation of seven fields in five areas of the myocardium at a high magnification (40x) with the support of histochemical stains for the fibrous connective tissue and for the adipose tissue. Several studies have attempted to quantify the presence of adipose and fibrous tissue in the myocardial wall, and the value for histological diagnosis of ARVC provides a minimum 3% of adipose tissue and more than 40% of fibrous tissue. Conversely, other authors have suggested that a percentage of adipose tissue ranging from 5 to 20% is suspicious. This approach had limitations due to the lack of sensitivity of many of the criteria. Particularly, in ARVC families disease-causing mutation carriers often have very insidious results that do not usually lead to a diagnosis of ARVC in clinical practice. However, in te present research authors would demonstrated that with ARVC/D cannot be included only cases with increased fibrosis and exclusive localization to the right ventricle nor even cases with electrocardiographic alterations and other evident clinical criteria. The primary study goal of reviewing the guidelines will be reducing the dependence on subjective criteria to evaluate ventricular structure and function and to incorporating cardiac magnetic resonance and genetic analysis data. In the new system, patients should be diagnosed with "defined" ARVC if they have two major criteria, 1 major and 2 minor criteria, or 4 minor criteria of different categories and "borderline" ARVC with 1 major and 1 minor criteria, or 3 minors of different categories.

Materials and methods Patients and samples Authors will assay heart sections from 10 fatal cases of death, with an average age of 28.8±8.1 years (age ranged from 16 to 45 years), defined according to commonly accepted criteria and collected from January 2003 to December 2017 at the University of Naples Federico II. All the autopsies will be performed according to the Guidelines for autopsy investigation developed by the Association for European Cardiovascular Pathology, and in all cases they will be completely examined by macroscopic autopsy.

Histological evaluation In all cases, the sampling of ventricles, atria and septum including conduction system for the heart will be performed. The original tissues samples will be fixed in 10% neutral buffered formalin and embedded in paraffin blocks. Sections (4μm thick) will be stained with hematoxylin and eosin stain (H\&E) for diagnosis. After diagnosis, sections of the representative heart tissue will be stained with a PicroSirius Red/Fast Green for fibrosis evaluation. All stained samples will be examined under digital and light microscope. Beside the location of adipose/fibrous tissue in the right or left ventricles and in the septum, seven high magnification fields (40x) will be evaluated in five regions of the myocardium.