DILATED CARDIOMYOPATHY - A CHRONIC MYOCARDITIS - IMMUNOHISTOLOGICAL CHARACTERIZATION OF LYMPHOCYTIC INFILTRATES

Experimental and clinical data suggest a relationship between myocarditis and dilated cardiomyopathy. One postulated pathomechanism is a viral infection triggering a host response with autoimmune features directed against the heart, resulting in an initial myocarditis which is followed by a dilated cardiomyopathy. Until now, the importance of an undetected myocarditis as an etiological factor in the pathogenesis of idiopathic cardiomyopathy is unknown. This investigation was undertaken to determine the frequency of lymphocytic infiltrations in endomyocardial biopsies of patients with dilated cardiomyopathy by immunohistological methods and to analyze T lymphocytic subsets and other immunological features in order to search for possible relationships between immunohistological-documented myocarditis and dilated cardiomyopathy. In our study, 48 of 130 biopsies (37%) from patients with clinically proven dilated cardiomyopathy contained lymphocytic infiltrates when stained by the immunoperoxidase method with lymphocyte surface markers (Table 1). 23% (n = 30) of these biopsies contained more than 2.0 (range: 2.0 to 13.8) T lymphocytes per high power light microscopy field (x 400), in 14% (n = 18) 1.5 to 2.0 cells/HPH were seen (Table 2). 82 biopsies (63%) with less than 0.8 cells/HPF were regarded as negative (dilated cardiomyopathy). By histological analysis, only seven cases (5%) were classified as borderline myocarditis by conventional histological evaluation according to the Dallas classification. In the other patients, our results were consistent with the clinical diagnosis of dilated cardiomyopathy (Table 1), 71% of biopsies with lymphocytic infiltrates contained activated T cells when analysed with activation markers in serial sections (Table 2). Activated macrophages were seen in 52% of biopsies with T cell infiltrations, but only in 31% of tissues containing normal numbers of lymphocytes (Table 2). In biopsy specimens with lymphocytic infiltrates HLA-class I and II antigen expression was increased. An enhanced HLA-DR antigen staining was seen in 80% on interstitial cells and vascular endothelium while HLA class I was found at an increased level in 67% (Table 3). In negative biopsies, an enhanced class I staining was seen in only 14%, class II in 30%. Because of the specific identification of lymphocytes by immunocytochemical methods, lymphocytic infiltrates are easily detected, even if the infiltrate is sparse or focal (Figure 1). The considerable interobserver variability in the quantitation of lymphocyte counts, which is a main problem in hematoxylin and eosin stained sections is neglectable when lymphocyte quantitation is performed by immunoperoxidase staining. Thus, our data indicate that in about 37% of patients with clinical suspected idiopathic cardiomyopathy an ongoing or reactivated myocarditic process is involved. A high percentage of CD3-positive biopsies shows an increased expression of human histocompatibility antigens on interstitial cells and the vascular endothelium (Figure 3). This indicates a generalized autoimmunologic process affecting the entire myocardium, regardless whether the lymphocytic infiltrate is diffuse or focal. By this, the new immunohistochemical approach helps to gain new insights into pathogenesis and pathophysiology of dilated cardiomyopathy. The additional evaluation of activated cells and enhanced HLA-antigen expression offers the possibility to find immunological criteria in addition to the demonstration of lymphocytic infiltration, which allows a more accurate diagnosis of myocarditis. Furthermore, these data should be useful to decide whether a patient might benefit from immunosuppressive therapy.