Increased productivity of tumor necrosis factor-alpha in helper T cells in patients with systolic heart failure

Background and aims Whereas increased circulating proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), play an important role in heart failure, where and how TNF-α production is upregulated remains largely unknown. We studied the productivity of TNF-α in peripheral lymphocytes and underlying mechanisms in patients with heart failure. Methods Symptomatic NYHA II–IV patients with chronic heart failure with systolic dysfunction (n = 39, aged 74 ± 11, ejection fraction [EF] less-than over equal to 50%) were compared with asymptomatic NYHA I patients (n = 18, aged 72 ± 10, EF > 50%) and normal subjects (n = 15, aged 67 ± 11). Lymphocyte subsets (CD3, CD4, and CD8) and intracellular production of TNF-α in peripheral leukocytes were quantified by immunofluorescent flow cytometry, and relationships between these parameters and circulating proinflammatory cytokines were analyzed. Results Subpopulation of TNF-α-producing CD4 was larger in NYHA II–IV patients (23.7% [18.0–28.6]) than in normal subjects (17.1% [6.5–19.5], p < 0.05) and was correlated with plasma TNF-α levels (r = 0.26, p < 0.05), EF (r = − 0.26, p < 0.05), CD4/CD8 ratios (r = 0.42, p < 0.001), and subpopulation of TNF-α-producing monocytes (r = 0.47, p < 0.0001). Plasma levels of soluble CD14 and interleukin-12 (IL-12) were significantly higher in NYHA II–IV patients than in normal subjects (1971 ng/mL [1740–2375] vs. 1607 ng/mL [1530–1930], p < 0.01; and 121 pg/mL [62–230] vs. 62 pg/mL [54–99], p < 0.05, respectively), and plasma IL-12 levels were correlated with plasma TNF-α levels (r = 0.41, p < 0.001). Conclusions Increased productivity of TNF-α in helper T cells, associated with their dominance over cytotoxic T cells, may partially contribute to an increase in circulating TNF-α levels in heart failure.