title: Alterations in immunocyte tumor necrosis factor receptor and apoptosis in patients with congestive heart failure.
abstract: OBJECTIVE
  To examine systemic immune cell proinflammatory receptor expression and apoptosis in patients with congestive heart failure (CHF).
  
  
  BACKGROUND
  Prior studies have demonstrated that CHF is associated with a chronic myocardial inflammatory state, including increased plasma proinflammatory cytokine and soluble receptor expression. By contrast, it has also been shown that tumor necrosis factor (TNF) receptor protein expression is decreased in the failing myocardium. However, no studies to date have examined systemic immune cell proinflammatory receptor expression or function as disease markers in patients with heart failure.
  
  
  METHODS
  Twenty-nine patients were studied prospectively over an 8-month period at a single institution. One group (n = 16) had a history of clinical symptoms of CHF and moderate to severe left ventricular dysfunction. The second group (n = 13) consisted of patients who had coronary artery disease without symptoms of CHF and documented preservation of left ventricular function. Blood samples were analyzed for polymorphonuclear cell (PMN) and monocyte TNF and CD95 membrane-associated receptor expression, spontaneous and CD95 (Fas)-mediated PMN apoptosis, and plasma cytokine and soluble TNF receptor levels. Isolated PMNs were incubated for 6 hours with or without CH 11, a CD95 agonist. Propidium iodide/RNAase staining and flow cytometry was used to assess apoptosis, defined as PMNs expressing hypodiploid DNA (<2 n DNA). Membrane-associated TNF receptor and CD95 were also measured by flow cytometry. Plasma levels of TNF, interleukin (IL)-6, IL-10, and soluble TNF receptors 1 and 2 were quantified using enzyme-linked immunosorbent assay.
  
  
  RESULTS
  Compared to patients without CHF, circulating PMN and monocyte TNF receptor levels were significantly decreased in patients with CHF. By contrast, PMN and monocyte CD95 expression was not significantly changed in patients with CHF versus those without CHF. Patients with CHF had a 60% decrease in spontaneous PMN apoptosis compared to patients without CHF, whereas no significant difference in CD95-mediated apoptosis was observed between the two groups. Pearson-product movement correlation of monocyte TNF receptor expression and spontaneous PMN apoptosis rates versus patients' ejection fraction was performed and was statistically significant. Plasma levels of soluble TNF receptor 2 (p75) were elevated in CHF patients versus patients without CHF, while there was no significant difference in soluble TNF receptor 1 (p55), TNF, IL-6, and IL-10 between the two groups.
  
  
  CONCLUSIONS
  These data demonstrate a systemic alteration in immune cell phenotype and apoptosis in patients with CHF. These findings provide support for the concept that inflammatory mediators either contribute to myocardial dysfunction or are elaborated systemically by left ventricular compromise. This present study suggests that immune cell TNF receptor expression and diminished PMN apoptosis may serve as biologic markers of myocardial failure.
authors.affiliation: Division of Surgical Sciences, Department of Surgery, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08903-0019, USA.
authors.forename: Vishnu K
authors.initials: VK
authors.lastname: Rumalla
authors.forename: Steve E
authors.initials: SE
authors.lastname: Calvano
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Spotnitz
authors.forename: Tyrone J
authors.initials: TJ
authors.lastname: Krause
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Hilkert
authors.forename: Edward
authors.initials: E
authors.lastname: Lin
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Lowry
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000276:immunology*; D015415:Biomarkers / Q000097:blood; D016207:Cytokines / Q000097:blood; D006333:Heart Failure / Q000276:immunology* / Q000503:physiopathology; D006801:Humans; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D011446:Prospective Studies; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology*; D019014:fas Receptor / Q000276:immunology
chemical_list: D015415:Biomarkers; D016207:Cytokines; D018124:Receptors, Tumor Necrosis Factor; D019014:fas Receptor