Cytokine signatures in atherosclerotic claudicants.
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.


RESULTS
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.


CONCLUSIONS
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.
DePalma
Ralph G
RG
Veterans Affairs Central Office, 20420, Washington, DC 20040, USA. Ralph.DePalma@med.va.gov
Hayes
Virginia W
VW
Cafferata
H Treat
HT
Mohammadpour
Hamid A
HA
Chow
Bruce K
BK
Zacharski
Leo R
LR
Hall
Mark R
MR
D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D001161:Arteriosclerosis / Q000097:blood* / Q000628:therapy; D001786:Blood Glucose / Q000032:analysis; D002097:C-Reactive Protein / Q000032:analysis; D002784:Cholesterol / Q000097:blood; D016207:Cytokines / Q000097:blood*; D005293:Ferritins / Q000097:blood; D005340:Fibrinogen / Q000032:analysis; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D016753:Interleukin-10 / Q000097:blood; D007376:Interleukin-2 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D007501:Iron / Q000097:blood; D008875:Middle Aged; D016491:Peripheral Vascular Diseases / Q000097:blood*; D018962:Phlebotomy; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D001786:Blood Glucose; D002097:C-Reactive Protein; D002784:Cholesterol; D016207:Cytokines; D005293:Ferritins; D005340:Fibrinogen; D006442:Glycated Hemoglobin; D016753:Interleukin-10; D007376:Interleukin-2; D015850:Interleukin-6; D007501:Iron; D014409:Tumor Necrosis Factor-alpha