Expression of FAS adjacent to fibrotic foci in the failing human heart is not associated with increased apoptosis

Fibrosis in the heart may result from loss of myocytes, which are replaced by collagens. Apoptosis is now known to contribute to myocyte loss in the f ailing human heart. The mechanisms underlying the induction of cardiomyocyt e apoptosis, and thus the expansion of fibrotic foci in the failing heart, are poorly understood. We hypothesized that viable heart cells adjacent to fibrotic foci might become "predisposed" to apoptosis by expression of the receptor FAS (APO1, CD95). We therefore studied the spatial relationship of FAS expression and fibrosis in patients with heart failure. Left ventricul ar biopsies were obtained from seven patients undergoing coronary artery by pass grafting. All patients had reduced ejection fraction but varied in New York Heart Association class score at the time of surgery. Heart cell apop tosis, fibrosis, and FAS expression were studied by propidium iodide and in situ end labeling (ISEL) of DNA, Picrosirius red staining, and immunohisto chemistry. All patient samples exhibited, albeit to varying degrees, apopto sis detected by ISEL, chromatin condensation, and nuclear fragmentation. In all samples, fibrosis (collagen) was evident both perivascular and in isol ated regions of scarring. Regardless of the extent of fibrosis or detectabl e apoptosis, FAS expression was observed in regions immediately adjacent to the fibrosis, but not in regions distal to fibrosis, nor in fibrotic areas devoid of nuclei. Expression of FAS was found adjacent to both perivascula r and diffuse fibrosis, and ISEL-positive nuclei were found within cells re acting positively with anti-FAS antibodies. However, ISEL-positive nuclei w ere no more abundant in FAS-positive regions (67.6 +/- 5.8% of total nuclei ) than in FAS-negative ar eas (69.5 +/- 9.8%). We conclude that expression of FAS occurs in remaining heart cells adjacent to fibrosis of either periv ascular or presumed reparative origin. Although this phenomenon could contr ibute to the expansion of fibrotic foci, FAS-induced apoptosis in the faili ng heart may not be more prevalent than apoptosis initiated by other signal ing mechanisms.