Right Ventricle Abnormality Clinical Trial
Official title:
The Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia From Real World Autoptic Data: Diagnosis in the Absence of Clinical Criteria
The arrhythmogenic right ventricular cardiomyopathy, also known as arrhythmogenic right ventricular dysplasia (ARVC/D) is a rare myocardial disease with a prevalence estimated to range from 1 case on 5000 persons in the general population. It have a dominant genetic transmission characterized by alterations of desmosomial proteins and predominantly affects the right ventricle. The morphological alteration of the myocardium characterized by fibro-fatty substitution predisposes to arrhythmic events that can be fatal and cause death especially in young people and athletes. International guidelines provide a classification that includes clinical and histological criteria for diagnosis based on fibrous tissue substitution, percentage and right ventricle localization. Indeed, it is mainly affected 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. Authors identified 10 cases of arrhythmogenic cardiomyopathy in forensic autopsy collocated in the 2003 to 2017, included 8 males and 2 females. Their age ranged from 16 to 45 years with an average age of 28.8±8.1 years. However, authors would like to demonstrate that with ARVC/D cannot be include only cases with increased fibrosis and exclusive localization to the right ventricle nor even cases with electrocardiographic alterations and other evident clinical criteria. Indeed, in the analyzed cases authors observed an amount of fibrosis often less than the percentage reported in the literature and an involvement not only of the right ventricle but also of the septum and associated sinister ventricular modifications. To this must be added that the cases of death did not have a sudden death of relatives in family history as described in guidelines and therefore this criterion is not reliable for the purpose of a classification.
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.
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