Plasma fas ligand, an inducer of apoptosis, and plasma soluble Fas, an inhibitor of apoptosis, in patients with chronic congestive heart failure

Objectives, This study sought to examine plasma levels of soluble Fas/APO-1 receptor (sFas), an inhibitor of apoptosis, and soluble Fas ligand (sFas-L), an inducer of apoptosis, and their relation to each other and to other clinical variables, such as New York Heart Association functional class, tumor necrosis factor (TNF) and interleukin-6 (IL-6) in congestive heart failure (CHF), Background It has been recently reported that apoptotic Cell death occurs in myocytes of dogs with CHF, Hypoxia is frequently seen in advanced CHF and can stimulate Fas/APO-1 receptors (Fas) to induce apoptosis in cultured myocytes. Fas and Fas ligand (Fas-L) are cell-surface proteins and representative apoptosis-signaling molecules, Fas on the cell membrane induces apoptosis when it binds Fas-L or sFas-L. However, plasma sFas, a molecule lacking the transmembrane domain of Fas, blocks apoptosis by inhibiting binding between Fas and Fas-L or sFas-L on the cell membrane, At present, it is unknown whether plasma sFas-L and plasma sFas increase in the presence of cardiac disease. Methods. The study included 70 patients (mean [+/-SEM] age 65 +/- 2 years, range 21 to 93) with chronic CHF (coronary artery disease in 28, dilated cardiomyopathy in 27, valvular heart disease in 15) and 62 age- and gender matched normal control subjects, Plasma levels of sFas, sFas L, TNF-alpha and IL-6 were measured by enzyme-linked immunosorbent assays using monoclonal anti-human antibodies, Results. There was no significant difference in sFas L levels between normal subjects and patients in functional classes I to IV; however, sFas increased with severity of functional classification, independent of the underlying disease, sFas levels were significantly higher even in patients in functional class II than in normal subjects and those in functional class I, and were highest in patients in functional class IV (normal subjects: 2.2 +/- 0.1 ng/ml; functional class I: 2.2 +/- 0.2 ng/ml; functional class II: 3.1 +/- 0.2 ng/ml; functional class III: 3.9 +/- 0.3 ng/ml; functional class IV: 5.1 +/- 0.6 ng/ml), Plasma sFas levels were significantly higher in patients with elevated pulmonary artery wedge pressure and a decreased cardiac index than in those with values in the normal range, In patients in functional class IV, there was no significant difference in plasma sFas levels between the survivors and nonsurvivors during 6-month follow-up, However, plasma levels of sFas tended to decrease in nine patients with clinical improve ment (baseline sFas: 5.2 +/- 0.8 ng/ml; 6-month sFas: 4.3 +/- 0.5 ng/ml, p = 0.07) but were similar in patients with no change In functional class, TNF-alpha and IL-6 were increased significantly only in patients in functional class IV, as previously reported, but were not related to sFas, Conclusions. We found elevated levels of plasma sFas and no increase in plasma sFas-L in human CHF, The increase in sFas may play an important role in the pathophysiologic mechanisms of CHF. (C) 1997 by the American College of Cardiology.