At present, considerable importance is given to the finding of fatty infiltration of the myocardium, since cardiac magnetic resonance imaging has the ability to identify adipose tissue in vivo with consequent diagnostic and therapeutic implications. It is still a matter of debate whether fatty infiltration of the right ventricle per se should be considered a morphologic hallmark of ARVC/D . We must recognize that the original distinction in two histologic variants, i.e., fatty and fibro-fatty, has been a source of confusion, since it has not been sufficiently appreciated that even in the fatty variant a certain amount of replacement-type fibrosis and myocyte abnormalities should be found to label it as ARVC/D .
Several authors reported that fat is a normal finding in the heart in a large series of patients, particularly at older age, and since they were not convinced of the clinical or pathological significance of isolated fat infiltration, they concluded that this entity is different from ARVC/D [20-24]. In particular, Burke et al.  found that, in autopsy hearts of people dying suddenly with pure fatty infiltration, the right ventricular myocardium was of normal or increased thickness, the left ventricle was mostly normal and there was no inflammation or myocyte atrophy. Moreover, the authors pointed out that while up to 15% fatty replacement is distinctly abnormal in the right ventricular outflow tract or posterior wall, it is probably normal in the anterior wall near the apex. Tansey et al.  found that 85% of hearts from people who died of noncardiac causes contained at least some intramyocardial fatty tissue, in the absence of fibrosis or inflammation, with significantly more fat replacement noted in the right ventricle of older subjects and in females than in males.
Massive fatty infiltration of the right ventricle, without any evidence of fibrosis and myocyte degeneration, represents a questionable cause of sudden death and does not have a familial tendency  (Fig. 4.6). In this condition, the myocytes seem to be pushed apart rather than replaced and they appear structurally normal. In contrast to fatty infiltration of the right ventricle, both the so-called fatty and the fibro-fatty ARVC/D variants consistently show degenerative changes of the myocytes and nuclei, often resembling those observed in dilated cardiomyopathy .
Thus, in addition to fat, two additional histologic features are essential in order to provide an unequivocal diagnosis of ARVC/D: (a) replacement-type fibrosis; and/or (b) degenerative changes of the
In a patient with sudden death, where extensive right ventricular fatty infiltration is observed in the heart, it would be preferable to state this finding without implying a cause and effect relationship. In other words, this would not necessarily indicate that death was due to ARVC/D . If pathologists would ascribe sudden death as due to ARVC/D based on simple observation of adipose infiltration, there will be a huge increase in its frequency as a cause of sudden death which in most instances will be totally spurious, as forecast by Davies . Noteworthy, a recent forensic autopsy investigation reported an extreme ly high incidence (more than 10%) of ARVC/D in people aged 1-65 years who died suddenly in France: in the majority of cases there was not any evidence of fibrous tissue replacement .
Nowadays, disease-causing genes are potentially available for mutational analysis [28-33], even at postmortem or in family members of sudden death cases. In the reported genotyped ARVC/D forms, due to desmosomal protein encoding genes, in which the heart was available for morphological investigation, the specimens were characterized by biventricular involvement, typical fibro-fatty replacement, myocyte death and nuclear abnormali ties [34-36]. Noteworthy, if cardiac arrest occurs in the early phase of the disease, we have observed massive myocyte injury, with early fibrous tissue replacement and very few adipocytes  (Fig. 4.7). These data are consistent with those by Fletcher et al. , who found that the pathology of ARVC/D varies with age in both ventricles, fibrosis being the earliest hallmark of ARVC/D in younger patients, and fatty infiltration being more prominent in older patients. Similar findings were reported in an earlier histomorphometric EMB study from our group, demonstrating a higher amount of fat in older patients . Thus, the changing face of the disease
morphology, depending on its stage, should be taken into consideration, when evaluating a case of sudden death due to ARVC/D.
Recently, Garcia Gras et al. , reported their findings with heterozygous desmoplakin-deficient mice. They showed excess adipocytes and fibrosis in the myocardium, increased myocyte apoptosis, cardiac dysfunction, and ventricular arrhythmias, mimicking the phenotype of human fibro-fatty ARVC/D. The authors provided evidence that expression and nuclear localization of PPAR-y, a major regulator of adipogenesis, was restricted to fibrotic areas in desmoplakin-deficient mouse hearts, suggesting a possible origin of adipocytes from fibrocytes or pre-fibroblasts, which are considered adipocyte progenitor cells, rather than cardiac myoblasts or resident and circulating mesenchymal stem cells. This possibility is strengthened by the colocalization of adipocytes and fibrosis both in the hearts of desmo-plakin-deficient mice and in the myocardium of human patients affected by ARVC/D.
ARVD2  is an exception to the unifying hypothesis that desmosomal protein abnormalities cause ARVC/D. This is due to a defective ryanodine cardiac receptor 2 (RYR2) gene, which regulates the release of Ca++ from sarcoplasmic reticulum to cy-tosol for excitation-contraction coupling. This variant is clinically characterized by effort-induced polymorphic ventricular arrhythmias, whereas the resting 12 lead ECG is normal. In a minority of cases, there is mild right ventricular involvement. Pathologically, the heart is usually normal or shows segmental right ventricular fatty infiltration at the apex. Thus, the question is whether this disease is truly an ARVC/D variant [40,41]. In an index case with effort-induced polymorphic ventricular arrhythmias, d'Amati et al. , in addition to segmental fibro-fatty replacement, reported a specific morphological substrate consisting of calcium phosphate deposits within cardiac myocytes. Thus ARVD2 variant should be viewed as an ion channel disease, with some secondary myocyte injury related to the underlying molecular defect.
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