Arrhythmogenic right ventricular dysplasia

*Adipose substitution of ventricular myocardium is characteristic of arrhythmogenic right ventricular cardiomyopathy, but is also found in other heart conditions. It is thought to be a consequence of myocyte loss due to myocarditis or other noxious stimuli. We describe a unique case of cardiomyopathy with a morphologic pattern suggestive of transdifferentiation from myocytes to mature adipocytes. Gross, histologic, and ultrastructural examination were performed on the heart of a female transplant patient with a clinical diagnosis of familial dilated cardiomyopathy. Gross examination showed fibroadipose substitution of the left ventricle and adipose replacement of the right. Histology, immunohistochemistry, and ultrastructure were highly suggestive of transdifferentiation from cardiac muscle to adipose tissue. Myocyte transdifferentiation could represent an alternative pathogenetic pathway to the myocyte-loss and adipose-replacement mechanism in arrhythmogenic right ventricular cardiomyopathy, or it could be the basis of a new type of familial cardiomyopathy.

(Arch Pathol Lab Med. 2000;124:287-290)

Fatty infiltration of ventricular myocardium is the prominent pathologic feature of so--called arrhythmogenic right ventricular cardiomyopathy (ARVC), a familial condition linked to chromosomes 1, 2, and 141-3 that is characterized by specific arrhythmias. Ventricular fatty infiltration may also be caused by other conditions, however, such as Chagas disease4 and myocarditis, possibly on a genetic basis.' Despite the original observation in the right ventricle, ARVC is often found in the left ventricle, too, where it usually displays a fibrofatty pattern.6.7 The most obvious and acknowledged pathogenetic hypothesis is that adipose replacement follows myocyte loss due to noxious stimuli," either on a genetic or an acquired basis.9,11,

We recently observed the unique case of a patient with a family history of dilated cardiomyopathy who showed fibroadipose substitution of the left ventricular myocardium and a fatty infiltration of the right ventricle, with a morphologic pattern suggestive of a progressive transdifferentiation from myocytes to adipocytes. This pattern could represent an alternative pathogenetic pathway to the myocyte-loss and adipose-replacement mechanism.

REPORT OF A CASE

A 40-year-old woman with a clinical diagnosis of dilated cardiomyopathy (left ventricular end-diastolic diameter, 57 mm; ejection fraction, 22%) with atrioventricular block and episodes of asystole underwent heart transplantation. The patients family history revealed dilated cardiomyopathy in her brother and in 2 nephews. Pretransplant laboratory tests showed high blood levels of triglycerides (450 mg/dL).

The patient is alive and well 27 months after cardiac transplant. However, she has persistently high levels of triglycerides, despite therapy, and she has been showing a significant degree of adipose replacement of the right ventricular myocardium on endomyocardial biopsies performed to monitor rejection.

PATHOLOGIC FINDINGS

On gross examination, the transplanted heart weighed 320 g, and the cardiac apex was rounded due to left ventricular enlargement (Figure 1). The coronary arteries were unremarkable. On cut surface, the left ventricular free wall was thinned (4 mm) and displayed extensive fibroadipose substitution. The right ventricle was mildly dilated, with a wall thickness of 3 mm. It showed diffuse adipose replacement, which was transmural at the infundibulum. The ventricular septum and the atrioventricular and semilunar valves were unremarkable.

Histologic examination confirmed the adipose replacement of the right ventricular wall, except for the trabecular myocardium, which showed interstitial fibrosis. The left ventricle showed histologic features of myocardial fibroadipose substitution. We found no evidence of myocarditis. The ventricular septum was unremarkable. According to these findings, the pathologic diagnosis was ARVC with biventricular involvement and pump failure. Interestingly, in both ventricles myocytes adjacent to the adipose tissue showed multiple sarcoplasmic vacuoles. These were mostly subsarcolemmal, replaced the myofibril component and, in several myocytes, obscured the nucleus (Figure 2). Myocytes showing such changes were often indistinguishable from preadipocytes. Accordingly, immunohistochemistry was performed using antibodies to the intermediate filaments desmin (Figure 3) and vimentin (Sigma-Aldrich, Milan, Italy; 1:100 dilution). The latter is normally present in adipocytes, but is not expressed in adult cardiomyocytes.11 Noticeably, a few myocytes with cytoplasmic vacuoles were positive for both desmin and vimentin (Figure 4, A and B).

Ultrastructural examination showed the lipidic nature of the sarcoplasmic vacuoles. The lipid droplets lacked a membrane; they were variable in size and were often surrounded by mitochondria (Figure 5). The myofibril component of myocytes appeared unremarkable.

COMMENT

After differentiation, functional cells usually maintain their specificities, although in some pathologic conditions, such as regeneration and carcinogenesis, a shift from one cell type to another can be observed. This phenomenon has been defined as transdifferentiation. 12.11

We describe a familial cardiomyopathy with histologic, immunohistochemical, and ultrastructural features suggestive of transdifferentiation from cardiac muscle into adipose tissue. At the border between the myocardium and the front of adipocytes, cardiomyocytes showed what seemed to be a progressive replacement of myofibrils by fat droplets. Immunohistochemistry revealed vacuolated cells positive for both desmin, which marks muscle tissue, and vimentin. Vimentin is normally expressed by adipocytes, but is absent in adult cardiomyocytes. These cells could be interpreted as transitional elements between myocardial and fat tissue. Ultrastructural examination confirmed the presence of lipid droplets within myocytes. At variance with previous reports, 14,15 these droplets were not surrounded by membrane, thus ruling out the hypothesis of pseudoinclusions due to adjacent adipocytes compressing the myocyte cytoplasmic membrane. Presence of fat droplets within myocytes is not unusual in dilated and ischemic cardiomyopathy; however, this presence is never so massive as to suggest a transdifferentiation from myocytes to adipocytes, as in the case we describe.

Striated muscle and adipose tissue often have a reciprocal relationship in vivo. For example, in Duchenne muscular dystrophy, muscle atrophy is accompanied by progressive adipose replacement16; moreover, cultured myoblasts can be induced to transdifferentiate into mature adipocytes by forced expression of 2 adipogenic transcription factors, PPAR-gamma and C/EBPalpha.17 A spliced variant of the former, PPARgammal, is expressed at low levels by normal adult cardiomyocytes.18

In conclusion, our observations lead to the following hypotheses, which are not mutually exclusive: (1) myocellular transdifferentiation can be an alternative mechanism to fatty replacement of lost myocytes in the pathogenesis of ARVC, and (2) due to the lack of the typical arrhythmic pattern of ARVC,19 the condition we describe could be a new entity in the setting of familial cardiomyopathy characterized by adipose change of ventricular myocardium.

We thank Mariarosaria Tramontano and Daniela Ferraro for their excellent technical assistance.

References

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Accepted for publication April 8, 1999.

From the Cattedra di Anatomia Patologica Card iovasco [are, Dipartimento di Medicina Sperimentale e Patologia, Policlinico Umberto 1, Roma, Italy.

Reprints: Pietro Gallo, MID, Cattedra di Anatomia Patologica Cardiovascolare, Dipartimento di Medicina Sperimentale e Patologia, Policlinico Umberto 1, V.le Regina Elena 324, 00161 Roma, Italy.

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