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Cytokine signatures in atherosclerotic claudicants
Ralph G DePalma1, Virginia W Hayes, H Treat Cafferata
1Veterans Affairs Central Office, 20420, Washington, DC 20040, USA. Ralph.DePalma@med.va.gov
Insights
Phlebotomy reduced elevated inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), in patients with peripheral vascular disease (PVD). This suggests iron reduction may impact atherosclerosis by modulating inflammation.
Area of Science:
- Cardiovascular Science
- Immunology
- Hematology
Background:
- Iron accumulation and inflammation are implicated in the progression of atherosclerosis.
- Peripheral vascular disease (PVD) patients exhibit distinct inflammatory profiles.
- The role of serum ferritin in modulating atherosclerotic inflammation requires further investigation.
Purpose of the Study:
- To identify a specific cytokine signature in patients with atherosclerotic claudication.
- To evaluate the impact of reducing serum ferritin levels through phlebotomy on this cytokine signature.
- To test the hypothesis that ferritin reduction can ameliorate atherosclerosis.
Main Methods:
- Ninety-one PVD patients were enrolled in the VA Cooperative Iron and Atherosclerosis Study (FeAST).
- Cytokine levels (TNF-alpha, IL-2, IL-6, IL-10) and inflammatory markers (CRP, fibrinogen) were quantified.
- Patients were randomized to phlebotomy or a control group, with analyses conducted at 6 and 12 months.
Main Results:
- PVD patients showed higher levels of TNF-alpha, IL-6, and CRP, and lower IL-10 compared to healthy controls.
- Phlebotomy significantly reduced serum ferritin levels at 6 months.
- Elevated TNF-alpha and IL-6 levels were reduced in patients undergoing phlebotomy.
Conclusions:
- A distinct inflammatory cytokine signature characterizes atherosclerosis.
- Phlebotomy-induced reduction in serum ferritin effectively lowered key pro-inflammatory cytokines (TNF-alpha, IL-6).
- These findings support the iron-inflammatory hypothesis in atherosclerosis and warrant further clinical outcome studies.
Background:
Iron accumulation and inflammation may affect atherosclerosis. This study intended to define a cytokine signature in atherosclerotic claudicants and to determine whether reduction in serum ferritin by phlebotomy influenced this pattern.
Methods:
Ninety-one subjects with peripheral vascular disease (PVD; mean age, 67 years) were recruited from the VA Cooperative Iron and Atherosclerosis Study (FeAST) testing the hypothesis that ferritin reduction to 25 ng/ml may ameliorate atherosclerosis. Cytokines TNF-a, IL-2, IL-6, and IL-10 were analyzed by enzyme amplified sensitivity assay (EASIA). Fasting iron and cholesterol panels, complete blood count, C-reactive protein (CRP), uric acid, fibrinogen, glucose, and hemoglobin A1c levels were also quantified. Values were compared with "healthy" controls (n = 21; mean age, 56 years). After randomization of PVD to phlebotomy (intervention group [IG], n = 44) or control (nonintervention group [NG], n = 47), analyses were compared at 6 and 12 months using t test, Wilcoxon rank sum test, chi-square, and robust MM regression.
Findings:
Age, glucose, and hemoglobin A1c were higher in PVD compared with healthy controls (P < 0.01), whereas serum iron (P < 0.01) and percentage of transferrin saturation (P < 0.05) were lower. Tumor necrosis factor-alpha (TNF-alpha; P < 0.05), IL-6 (P < 0.01), and CRP (P < 0.05) levels were higher in the PVD group, whereas IL-10 was lower (P < 0.01). At 6 months post phlebotomy, ferritin levels were reduced (P < 0.01), although ferritin levels were reduced less in smokers. IL-6 and fibrinogen, CRP and ferritin levels correlated positively. At 6 and 12 months, subjects with TNF-alpha (n= 15) and IL-6 (n = 10) levels in the upper 25th percentile were reduced by phlebotomy.
Interpretation:
An inflammatory cytokine signature exists in atherosclerosis. Elevated levels of TNF-alpha and IL-6, reportedly associated with recurrent and future myocardial infarction, were reduced by phlebotomy. The utility of the iron/inflammatory hypotheses will ultimately relate to clinical outcomes obtained prospectively by the FeAST trial.