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Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a frequently inherited cardiomyopathy characterized by ventricular arrhythmias and structural abnormalities of the right ventricle (1). The diagnosis of ARVC is established based on the criteria set by the Task Force of the Working Group of 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 1994 (2). ARVC is defined histologically by the presence of progressive replacement of right ventricular myocardium with adipose and fibrous tissue often confined to a ‘triangle of dysplasia’ comprising the right ventricular inflow- and outflow tract, and the apex (3). While these pathologic abnormalities can result in functional and morphological right ventricular abnormalities, they also occur in the left ventricle, producing a DCM phenotype, or can be present in the absence of clinically detectable structural changes in either ventricle.
Specific cardiac investigations recommended in all patients suspected of having ARVC include an ECG, a signal-averaged ECG, a Holter monitor and an echocardiogram. Analysis of right ventricular size and function can be also obtained by cardiac magnetic resonance and/or computed tomography. If the results of the noninvasive tests point toward a diagnosis of ARVD, invasive testing including right ventricular angiography, endomyocardial biopsy, and electrophysiology testing is recommended to establish the diagnosis.
Summary of the paper
Aim of the recently published paper by Basso et al. (4) was to provide a standardized endomyocardial biopsy protocol and diagnostic quantitative parameters for ARVC as the Task Force criteria for the in vivo diagnosis if ARVC include tissue characterization by EMB as a major criterion.
Investigated heart specimens were taken in vitro using a Cordis bioptome from three standardized sampling sites of the right ventricle involved in the pathological process of ARVC and in addition from the right side of the septum and the free left ventricular wall. Histomorphometric analysis was performed on the stained slides to calculate total surface area, myocardium, and fibrous and fatty tissues. The presence of apoptosis and/or inflammatory infiltrates associated with myocyte necrosis was evaluated independently by two observers as well as myocyte diameters and abnormalities. The 60 heart specimen were classified into six groups according to the autopsy diagnosis and/or the clinical data into 1) diffuse ARVC, 2) segmental ARVC, 3) DCM, 4) normal controls, 5) adipositas cordis from obese people and 6) heart from people >80 years to compare the means of the different groups for the parameters considered.
The authors point out that diagnostic cut-offs and sensitivity were determined by receiver operating characteristic curves by selecting a standard specificity of 95%, because candidates to endomyocardial biopsy (EMB) have been already screened by other tests and this investigation is a third-level invasive exam which is usually requested to confirm the diagnosis. A multivariable logistic regression analysis was performed to assess which histological variable is the most useful for ARVC diagnosis in RV cumulative EMB samples.
No useful diagnostic cut-off for fatty tissue was identified at the antero-apical and RVOT sites. By applying the calculated histomorphometric cut-offs, a diagnostic EMB in at least one RV sampling site was obtained in 18 ARVC/D hearts (90%), including all diffuse forms (100%) and eight segmental forms (80%). Diagnostic tissue parameters were found for all three RV sampling sites in nine (45%), for two RV sampling sites in seven (35%) and for one RV sampling site in two (10%). EMB was not diagnostic in two ARVC/D hearts (10%), both characterized by a segmental form affecting the distal RVOT. Diagnostic EMB samples were obtained from the antero-apical area in 19 (95%), from the inferior-subtricuspid area in 13 (65%), and from the RVOT in 12 (60%). The logistic regression analysis confirmed that the residual myocardium is the discriminating tissue parameter between ARVC/D and the other groups, though the presence of fibrosis seems to be important. In fact, 14 of 20 ARVC/D cases had more fibrous than fatty tissue, and even in those cases where fat was prevalent, fibrosis was always at least 20%. In three segmental ARVC/D forms, fatty tissue was poorly represented (4%), whereas fibrosis was greatly increased 16%).
No diagnostic cut-off for any tissue parameter (myocardium, fatty tissue, and fibrosis) was found for the septal or left ventricular sampling sites. Patchy, focal myocarditis was detected in 3 (15%) and apoptotic myocytes in 7 (35%) of 20 ARVC/D cases. Myocyte abnormalities, dysmetric and dysmorphic nuclei, and cytoplasm vacuolisation were a constant finding in both ARVC/D and DCM EMB, when compared with the other groups. Moreover, small empty cells with peripheral nucleus in keeping with early adipogenesis were observed only in ARVC/D.
By selecting a 95% specificity, the ARVC/D diagnostic cut-offs on cumulative RV EMB samples are myocardium ,59%, fibrosis .31% and fat .22% (80, 50, and 50% sensitivity, respectively). By excluding elderly and obese people groups a lower cut-off for fat was found (.9%). A high variability between different RV sampling sites was observed; the antero-apical was the most informative region although fat at this level is non-specific. No useful diagnostic cut-off for fatty tissue was identified at the antero-apical and RVOT area. No significant difference was found for any tissue parameter either in septal or in LV EMB. Increased RV myocyte diameters and cytological changes were detected in ARVC/D and DC.
In summary, the residual myocardium is the main diagnostic morphometric parameter in ARVC/D, whereas fat at the apex is nonspecific. Sensitivity and specificity vary according to the RV region. Target sampling of the triangle of dysplasia is required, although only a single region is often informative, emphasizing the usefulness of imaging-guided EMB. There is no diagnostic value of either septal or LV EMB. Cardiomyopathic changes of the myocytes also appear important for establishing a pathological diagnosis.
The authors conclude, that of course, they cannot recommend routine histomorphometric investigation of EMB. On the basis of their findings, in the setting of an RV EMB with replacement fibrosis+fatty tissue, their proposal is to consider an amount of residual myocytes ,60% by morphometric analysis a major diagnostic criterion; and of 60–75% a minor diagnostic criterion. However, since histomorphometric investigation of EMB cannot be routinely available, at least a visual estimation at a glance of the amount of tissue parameters on EMB should be provided, taking into account that tissue characterization is considered a diagnostic criterion for ARVC/D.
Thus, to make these data useful for the clinical pathologist in the real world, an amount of residual myocytes,50% by visual estimation could be regarded as a major criterion. Nevertheless, prospective validation of these quantitative criteria by serial assessment of EMBs performed in living patients with suspected ARVC/D is needed and ongoing international registries will be useful to this purpose.
The same group recently investigated whether 3-dimensional electroanatomical voltage mapping (EVM) may help in the differential diagnosis between idiopathic right ventricular outflow tract (RVOT) tachycardia and arrhythmogenic right ventricular cardiomyopathy/dysplasia (5).
They demonstrated that some patients with RVOT tachycardia in the absence of RV dilation/dysfunction show RVOT electroanatomical scars in association with histopathological features pathognomonic of ARVD/C (i.e., fibrofatty myocardial replacement) and have a malignant arrhythmic course. These findings are consistent with the current perspective on the ARVC/D natural history, with an early “concealed” phase characterized by subtle RV structural changes, which may be confined to one region of the so-called triangle of dysplasia, and, nevertheless, predispose to ventricular tachyarrhythmias or sudden death.
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