The first widely recognized clinical description of ARVC was reported in 1982,19
but it was not until the late 1980’s that pathological features of the disease were systematically assessed.20
In an autopsy study of sudden deaths from the Veneto region of Italy, Thiene and colleagues described two distinct patterns – a predominantly fatty (lipomatous) pattern characterized by infiltration of muscle by mature adipocytes only, and a fibrofatty (fibrolipomatous) pattern characterized by both fat and fibrous tissue. Both patterns extended from the epicardium to the endocardium and spared the trabecular myocardium.20
The fatty variant typically involved the RV anterolateral and infundibular regions, whereas the posteroinferior wall, the septum and the LV appeared normal. In the fibrofatty variant, the RV free wall appeared thinner and focally translucent, with saccular aneurysms of the apex, the infundibulum and the posteroinferior wall (the so-called triangle of dysplasia).20
In a subsequent study, the same group described pathological changes in 18 hearts showing the fibrofatty pattern. The RV was affected in all cases, whereas fibrofatty tissue accumulation in the LV was observed in 14 and septal involvement was seen in 6.21
Histologically, affected areas showed myocyte degeneration associated with extensive accumulation of fat and fibrous tissue. A majority of cases exhibited inflammatory cell infiltrates associated with focal myocyte necrosis.21
This was one of the first descriptions of LV involvement in “classical” ARVC, a pattern that has since become widely recognized. Although these authors reported septal involvement in roughly a third of the specimens, they did not provide details about the amount and specific location of fibrofatty tissue accumulation in the interventricular septum.21
In general, however, the septum tends to be the least frequently affected area in ARVC.
Since the original description of these two pathological variants, it has been recognized that individuals with purely fatty infiltration of the RV are older, tend not to have a family history of sudden death and do not appear to be at increased risk of sudden death during sleep or nonstrenuous activity.22
Fat is normally present on the epicardial surface of the RV and typically surrounds intramural coronary vessels.22
Small foci of intramyocardial fat also occur within the RV in healthy individuals and may be increased in association with chronic alcohol abuse or inherited myopathies.23
Intramyocardial fat has been observed in 85% of individuals who died of noncardiac causes, with greater amounts in older subjects and women.24
The lateral RV wall is most commonly affected, followed by the anterior wall, with the least amount of fat present posteriorly.24
Taken together, these observations suggest that infiltration of the myocardium by adipose tissue without demonstrable myocyte degeneration and fibrosis does not fall within the pathological spectrum of arrhythmogenic cardiomyopathy.24
For this reason, fibrofatty replacement, but not pure fatty infiltration, of the myocardium on EMB was considered to be a major diagnostic criterion in the original ARVC Task Force recommendations.5
However, this was included as a purely qualitative determination without an attempt to link diagnostic predictive power to the extent of this pathological change in a conventional septal biopsy.
Recently, Basso et al. analyzed “simulated biopsies” obtained using a clinical bioptome in explanted hearts from patients with ARVC, dilated cardiomyopathy and pure fatty infiltration of the RV to establish quantitative morphometric criteria for the diagnosis of ARVC.25
They sampled each heart in various locations and measured the amount of total biopsy section area occupied by fat, fibrosis, and “residual myocardium”. The most reliable indicator of ARVC was the amount of residual myocardium in biopsies that also contained a combination of fat and fibrous tissue. A diagnostic specific of 95% and sensitivity of 80% was achieved in biopsies containing <59% residual myocardium, with the remaining area occupied by a variable mixture of fat and fibrous tissue. However, the diagnostic yield varied considerably in biopsies obtained from different sites and the interventricular septum was among the least informative areas. The presence of fat without fibrosis was not considered of diagnostic value in ARVC.25
These observations, which have been incorporated in the updated Task Force Criteria,6
underscore the importance of sampling location as a factor in the diagnostic yield of EMB in ARVC. It should also be stressed that this morphometric study was limited to analysis of ARVC hearts in which diffuse or segmental pathological changes were well developed. These quantitative criteria would not be expected to be fulfilled in patients with early ARVC including those exhibiting frequent arrhythmias.