Detectable interleukin-9 plasma levels are associated with impaired cardiopulmonary functional capacity and all-cause mortality in patients with chronic heart failure.

Inflammatory activation plays a pivotal role in chronic heart failure (CHF) through the increased expression of pro-inflammatory cytokines. Decreased plasma levels of Interleukin (IL-) 5, IL-7 and Interferon-γ (IFN-γ) and increased levels of IL-9 have been already described in CHF, and a negative correlation was also reported between IL-9 and left ventricular ejection fraction (LVEF). Yet, there are only limited data exploring the association between cytokines and functional capacity in CHF and their prognostic role; therefore, primary end-point of the current study was to evaluate all-cause mortality according to changes in cytokines plasma levels in CHF patients. For this purpose, 75 CHF patients (mean age ± standard deviation (SD) = 65.7 ± 9.5 yrs. 15 F/60 M), with reduced (< 35%) LVEF, (mean = 32.7 ± 4.3%), clinically stable for at least 6 months, were recruited in 3 outpatient CHF clinics (Naples, Salerno and San Daniele del Friuli) and followed up for 55 + 24 months (median 50 months). Exclusion criteria were significant comorbidities (active cancer, advanced liver cirrhosis, and end-stage renal failure, autoimmune disease, allergies). At baseline, plasma concentration of 27 cytokines and growth factors (interleukin IL-1b; IL-1 receptor a; IL-2; IL-4; IL-5; IL-6; IL-7; IL-8; IL-9; IL-10; IL-12 p70; IL-13; IL-15; IL-17; eotaxin; FGFb; G-CSF; GM–CSF; IFN-γ; IP-10; MCP-1; MIP-1a; MIP-1b; PDGF;TNF- α; VEGF and RANTES) were assayed using Bio-Plex protein array systems (Bio-Rad, Hercules, CA), based on xMAP technology (Luminex, Austin, TX) in the CHF patients and in 24 age- and sex-matched healthy controls. Cytokines and growth factors levels were measured by an experienced core lab (G.M. and S.M.) to minimize inter- and intra-assay variability. All patients underwent physical examination, Doppler-echocardiography and Cardiopulmonary Exercise Stress Testing (CPET) as described elsewhere. Optimal therapy was administered with 98% of patients taking ACE-I or ARB, 96% β-blockers, and 37% aldosterone receptor antagonists.