Increased NETosis in Patients With Heart Failure Is Associated With Macrophage Activation Towards a Proinflammatory...

In this study, we tested the hypothesis that there is an interaction between neutrophils (N) undergoing NETosis and the activation of macrophages (Mf) in the myocardium of patients with heart failure (HF). Ventricular biopsies were examined from patients with HF due to dilated (DCM, n = 7), ischemic (ICM, n = 7), or inflammatory (InfCM, n = 7) cardiomyopathy, as well as from 5 control patients. Quantification of CD66b⁺/citrullinated histone 3⁺/myeloperoxidase⁺ neutrophils (N) revealed that 49.4% [IQR, 45-52] of N developed NETosis in InfCM, 45.3% [39-46] in ICM, 41.5% [37-45] in DCM, and 4% [3.8-4.2] in the control group. Quantification of the proportion of CD66b⁺/TNF-α⁺ Mf1 in infCM yielded a value of 78.5% [70-85], which differed significantly (p < 0.05) from that in DCM (53.1% [48.4-54.4]) or ICM (54.5% [51-60]). The proportion of Mf1 in the control group was 3% [1.6-5.5] and differed significantly (p < 0.01) from all HF groups. The proportion of CD66b⁺/CD206⁺ Mf2 was 20.9% [17.9-27.7] in DCM, 21.1% [17.8-22.8] in ICM, and 23.2% [21.2-25.1] in infCM. The proportion of Mf2 in the control group was 6.5% [4.8-7.6] and differed significantly (p < 0.01) from all HF groups. Correlation analysis revealed a statistically significant positive correlation (r = +0.79, p < 0.01) between Mf1 and the proportion of NETosis. In contrast, there was no significant correlation between Mf2 and the proportion of NETosis (r = -0.12, p = 0.28). It is concluded that the accumulation of N and Mf cells is a typical feature of chronic myocardial inflammation in HF, regardless of its aetiology. An increased number of N cells undergoing NETosis HF is associated with the activation of myocardial Mf cells and causes these cells to adopt a proinflammatory, Mf1-like phenotype.