Associations Between Macrophage Colony-Stimulating Factor and Monocyte Chemotactic Protein 1 in Plasma and First-Time Coronary Events: A Nested Case-Control Study

Abstract

Background: Myeloid cells play a central role in atherosclerosis. We investigated the associations between the plasma levels of growth factors and chemokines that regulate myeloid cell homeostasis and function and the risk of first-time acute coronary events in middle-aged persons.

Methods and results: We measured baseline plasma levels of macrophage colony-stimulating factor; monocyte chemotactic protein 1; C-C motif chemokine ligands 3, 4, and 20; C-X-C motif chemokine ligands 1, 6, and 16; and C-X3-C motif chemokine ligand 1 in 292 participants who had a coronary event during follow-up and 366 controls matched for age, sex, and time of inclusion who remained event free. Study participants were recruited from the Malmö Diet and Cancer Study population cohort and had no previous history of coronary artery disease. We found a strong independent negative association between macrophage colony-stimulating factor and incident coronary events in a forward stepwise Cox proportional hazards model including all biomarkers alongside the classic Framingham risk factors (age, sex, smoking, total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure), diabetes mellitus, and medication. Conversely, monocyte chemotactic protein 1 had the strongest independent positive association with the outcome. The addition of macrophage colony-stimulating factor and monocyte chemotactic protein 1 significantly improved the predictive ability of a model including traditional risk factors alone (C statistic 0.81 [95% CI 0.78-0.84] versus 0.67 [95% CI 0.63-0.71]; net reclassification index 0.52 [0.42-0.62]; P<0.001). The combined model led to a 54% net downclassification of participants who did not have a coronary event during follow-up and was particularly effective in the intermediate-risk group.

Conclusions: High levels of macrophage colony-stimulating factor and low levels of monocyte chemotactic protein 1 in plasma characterize middle-aged persons at low risk to develop clinically manifested coronary artery disease.

Keywords: coronary artery disease; inflammation; innate immunity; leukocytes; macrophage colony‐stimulating factor; monocyte chemotactic protein 1.

Figure 1

Study design. Diagram outlining how the matched sample of the case–control cohort was obtained. *Revascularization indicates coronary artery bypass grafting or percutaneous coronary intervention. CVD indicates cardiovascular disease; HDL, high‐density lipoprotein; MDC, Malmö Diet and Cancer Study; MI, myocardial infarction.

Figure 2

Partial correlation network of the relationships among clinical variables, myeloid biomarkers, and incident first‐time coronary events in the study group. Positive partial correlations are depicted in black, and negative partial correlations are shown in gray. Line thickness is proportional to the strength of the correlation. Only partial Pearson correlations with Bonferroni‐adjusted P values <0.05 are shown, with the partial correlation coefficients reported in boxes on the lines indicating correlations. Positive correlations for categorical variables indicate higher numbers of cases, patients with diabetes mellitus, current smokers, and women. BMI indicates body mass index; BP, blood pressure; CCL, C‐C motif chemokine ligand; CRP, C‐reactive protein; CXCL, C‐X‐C motif chemokine ligand; CX3CL1, C‐X3‐C motif chemokine ligand 1; DBP, diastolic blood pressure; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HDL, high‐density lipoprotein; MCP‐1, monocyte chemotactic protein 1; M‐CSF, macrophage colony‐stimulating factor; SBP, systolic blood pressure; TC, total cholesterol; TG, triglycerides; WBC, white blood cells.

Figure 3

Kaplan–Meier curves illustrating coronary event‐free survival of participants with high or low plasma levels of MCP‐1 and M‐CSF. Thin lines indicate low MCP‐1 levels (below median), and thick lines indicate high MCP‐1, whereas gray lines indicate low M‐CSF and black lines indicate high M‐CSF. The x‐axis was curtailed when <10% of participants remained in follow‐up. MCP‐1 indicates monocyte chemotactic protein 1; M‐CSF indicates macrophage colony‐stimulating factor.

Figure 4

Receiver operating characteristic curves of binary logistic regression models for acute coronary event risk discrimination. The broken line represents the model including traditional risk factors (age, sex, total cholesterol, high‐density lipoprotein, systolic blood pressure, smoking, diabetes mellitus) as well as blood pressure–lowering medication and lipid‐lowering medication. The continuous line represents the model with traditional risk factors, medication, MCP‐1, and M‐CSF. MCP‐1 indicates monocyte chemotactic protein 1; M‐CSF indicates macrophage colony‐stimulating factor.