Research Center, Montreal Heart Institute, Montreal, Quebec, Canada; Department of Medicine, Université de Montréal, Montreal, Quebec, Canada.
Research Center, Montreal Heart Institute, Montreal, Quebec, Canada; Department of Pharmacology and Physiology, Université de Montréal, Montreal, Quebec, Canada.
Am J Cardiol. 2022 Sep 1;178:80-88. doi: 10.1016/j.amjcard.2022.05.026. Epub 2022 Jul 8.
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 Venous blood was withdrawn from patients with DM (n = 22), HFpEF (n = 15), HFpEF with DM (n = 13), and healthy controls (CTL) (n = 21).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.
射血分数保留的心力衰竭（HFpEF）的特征是低度慢性炎症，这种炎症可能会因 2 型糖尿病（DM）而加重。我们假设，DM 患者和 HFpEF 伴/不伴 DM 患者的中性粒细胞通过释放促炎细胞因子导致低度炎症。从 DM 患者（n=22）、HFpEF 患者（n=15）、HFpEF 伴 DM 患者（n=13）和健康对照组（CTL）（n=21）中抽取静脉血。通过酶联免疫吸附试验评估循环细胞因子和分离的中性粒细胞释放的体外细胞因子水平。与 CTL 相比，DM 患者（p≤0.001）、HFpEF 患者（p≤0.05）和 HFpEF 伴 DM 患者（p≤0.001）的循环一氧化氮水平显著降低，达 44%。HFpEF 患者和 HFpEF 伴 DM 患者的循环可溶性细胞间黏附分子-1 和血管细胞黏附分子-1 水平升高（分别升高 2.5 倍和 1.9 倍；p≤0.001），而可溶性 E-选择素仅在 HFpEF 伴 DM 患者中升高（1.4 倍，p≤0.001）。CTL 和 DM 患者的循环血管内皮生长因子水平相似，但 HFpEF 伴/不伴 DM 患者的水平降低（达 94%；p≤0.001）。所有患者组的循环 C 反应蛋白、白细胞介素（IL）-8、IL-6 和 IL 受体拮抗剂均升高，HFpEF 伴 DM 患者升高最大，达 3.3 倍、4.7 倍、4.8 倍和 1.6 倍，DM 患者和 HFpEF 伴 DM 患者分别升高 3.3 倍、4.7 倍、4.8 倍和 1.6 倍。体外，脂多糖增加了 HFpEF 伴 DM 患者中性粒细胞的 IL-6 释放（3.7 倍；p≤0.001）和 DM 患者及 HFpEF 伴 DM 患者的 IL-8 释放（2.8 倍和 10.1 倍；p≤0.001）。HFpEF 中性粒细胞的 IL-1 受体拮抗剂和血管内皮生长因子释放分别下降高达 87.0%和 92.2%，与 CTL 相比。DM 患者和 HFpEF 患者的中性粒细胞释放更多的细胞因子。这种促炎状态的增加可能解释了 HFpEF 伴 DM 患者更高的事件发生率。
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