Background/Purpose: Patients with gout have an increased cardiovascular morbidity and mortality, not fully explained by traditional cardiovascular risk factors. Xanthine oxidase-induced oxidative stress, increased lipid oxidization and chronic low-grade inflammation have been suggested as important contributors. Neutrophils, through formation of neutrophil extracellular traps (NETs), partake in pro-thrombotic and atherogenic processes contributing to cardiovascular disease. However, the role of NETs in cardiovascular disease in human gout is not known.

Our objective is to investigate the association between neutrophil activation and cardiovascular risk in gout patients. We hypothesize that neutrophil activation mediates inflammation, as well as activation of and damage to endothelial cells, thus partaking in atherosclerosis development.

Methods: Plasma samples from 75 gout patients participating in the ‘Reade gout cohort Amsterdam’ were analyzed. Patient data was collected on disease activity, demographics, comorbidities, medication and cardiovascular risk assessments. Measurements included anthropometry, vital parameters (RR, HF) and lab variables. Levels of NETs, and NET-derived markers (cell-free DNA and peroxidase activity) were analyzed using an MPO-DNA ELISA, and fluorimetry. Levels of calprotectin were analyzed by ELISA. Markers of NETosis were related to traditional cardiovascular risk factors and 10 year risk of cardiovascular mortality (SCORE EU).

Results: No associations were found between markers of cell death (cfDNA and NETs) and cardiovascular risk. However, markers of neutrophil activation, including peroxidase activity correlated with BMI (r=0.31, p=0.008), waist-hip ratio (r=0.52, p< 0.001), cholesterol ratio (r=0.51, p< 0.001), and triglycerides (r=0.42, p< 0.001). These associations were even stronger in patients with chronic, polyarticular gout. Peroxidase activity was strongly associated with the 10 year risk of cardiovascular comorbidity (r=0.47, p< 0.001, Figure 1A). Calprotectin levels were elevated in gout patients with hypertension (p=0.005) and diabetes (p=0.02), with calprotectin levels associating with diabetes independently of BMI (OR=6.2, p=0.04). Finally, we constructed a neutrophil risk score ranging from 0-2 based on positivity for peroxidase and/or calprotectin to identify patients with a ‘neutrophil activation signature’. The neutrophil risk score strongly associated with CVD risk (Figure 1B). Patients with neutrophil activation signature (risk score 1-2) had markedly elevated cardiovascular risk score (p=0.001), with 67.7% of the patients having high cardiovascular risk, versus 32.3% of the patients without a neutrophil activation signature (OR=2.9, p=0.03).

Conclusion: We have demonstrated that neutrophil activation markers are associated with a 10-year risk of cardiovascular comorbidity in gout patients. These results highlight an important, an unappreciated, role of neutrophils in development of fatal comorbidities in gout. Further studies are warranted to determine the prognostic value of a neutrophil activation signature in development of cardiovascular disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-neutrophil-signature-is-strongly-associated-with-cardiovascular-risk-in-gout/