Neutrophils and Circulating Inflammatory Biomarkers in Diabetes Mellitus and Heart Failure With Preserved Ejection Fraction

Abstract

Heart failure with preserved ejection fraction (HFpEF) is characterized by low-grade chronic inflammation, which could be exacerbated by type 2 diabetes mellitus (DM). We hypothesized that neutrophils in patients with DM and patients with HFpEF with/without DM contribute to low-grade inflammation through the release of pro-inflammatory cytokines. Venous blood was withdrawn from patients with DM (n = 22), HFpEF (n = 15), HFpEF with DM (n = 13), and healthy controls (CTL) (n = 21). Levels of circulating cytokines and in vitro cytokines released by isolated neutrophils were assessed by enzyme-linked immunosorbent assay. Compared with CTL, there was a significant decrease in circulating nitric oxide in patients with DM (p ≤0.001), HFpEF (p ≤0.05), and HFpEF with DM (p ≤0.001) up to 44%. Circulating soluble intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 levels increased (up to 2.5-fold and 1.9-fold, respectively; p ≤0.001) in patients with HFpEF and patients with HFpEF and DM, whereas soluble E-selectin only increased in patients with HFpEF and DM (1.4-fold, p ≤0.001). Circulating vascular endothelial growth factor levels were similar in CTL and patients with DM but were decreased in patients with HFpEF with/without DM (up to 94%; p ≤0.001). Circulating C-reactive protein, interleukin (IL)-8, IL-6, and IL-receptor antagonist increased in all patient groups with a maximum of 3.3-fold, 4.7-fold, 4.8-fold, and 1.6-fold, respectively, in patients with HFpEF and patients with DM. In vitro, lipopolysaccharide increased neutrophils IL-6 release from HFpEF with DM (3.7-fold; p ≤0.001), and IL-8 release from DM and HFpEF with DM versus CTL (2.8-fold and 10.1-fold, respectively; p ≤0.001). IL-1 receptor antagonist and vascular endothelial growth factor release from HFpEF neutrophils significantly decreased up to 87.0% and 92.2%, respectively, versus CTL. Neutrophils from patients with DM and HFpEF release more cytokines than CTL. This increase in pro-inflammatory status may explain the greater event rate in patients with HFpEF and DM.