Rôle des biomarqueurs dérivés des neutrophiles dans la pathologie de l’insuffisance cardiaque

Heart failure (HF) is characterized by the inability of the heart to provide sufficient cardiac output when there is an increase in demand. This may result from a decrease in 1) contractile function, defined as heart failure with reduced ejection fraction (HF-REF) or 2) filling related to stiffness of the myocardium or pericardium, defined as HF with preserved EF (HF-PEF). Alterations in cardiac function contribute to neuro-hormonal activation and subclinical inflammation during the onset and progression of HF. HF is characterized by multiple abnormalities in the peripheral vascular and muscular system. Decreased peripheral perfusion can cause vascular and peripheral muscular disorders in HF-REF and HF-PEF. However, the cellular mechanisms involved in these observations remain unknown. Subclinical inflammation significantly contributes to the progression of HF. Since neutrophils are the first players for the inflammatory cytokines release, the main objective of this doctoral thesis is to characterize the pro and anti-inflammatory profile derived from neutrophils in patients suffering from HF-REF and HF-PEF, as well as the impact of diabetes (DM) on this profile. The plasma and neutrophil released biomarkers from the blood of 20 healthy control volunteers (CTL), 52 HF-REF and 25 HF-PEF and 22 DM were quantified. The major finding of our study is the significant reduction (>90%) of the circulating levels of vascular endothelial growth factor (VEGF) in HF-REF and HF-PEF patients with or without diabetes compared to CTL. In parallel, we observed a significant decrease of the VEGF secretion by the neutrophils from HF-REF and HF-PEF patients with a maximal reduction (92%) in HF-PEF+DM compared to CTL after pro-inflammatory agonists stimulation. The decrease of VEGF associated with an increased inflammation of the coronary microvascular endothelium leads to a deregulation of nitric oxide (NO) generation. A marked decrease in circulating NO levels was indeed observed in diabetic and HF patients compared to CTL. Circulating levels of IL-6 and IL-8 increased significantly in HF and DM patients, being maximal in HFPEF+DM. These data, when combined with a decrease in VEGF and NO, support a significant impairment of macrovascular and microvascular function in HF-PEF patients, which is increased by the presence of diabetes. The release of IL-8 and IL-6 from neutrophils was significantly increased in DM and HF-PEF+DM patients after treatment with lipopolysaccharide (LPS). We also observed an increase in circulating IL-1RA, an anti-inflammatory cytokine in all patients’ cohorts. However, IL-1RA secretion by the neutrophils was decreased in all cohorts compared to CTL, independently of the agonist used. These observations suggest that neutrophils are not the main cells that secrete IL-1RA, but rather monocytes, hepatocytes, epithelial cells and adipocytes.  The scientific data from these studies have allowed us to better characterize the role of neutrophils in HF and will validate the hypothesis that biomarkers derived from neutrophils play a significant role in the HF.

Keyphrases: inflammation, Heart failure, Heart failure with reduced ejection fraction, Heart failure with preserved ejection fraction, Biomarkers, Neutrophils, Diabetes