Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease.
BACKGROUND
Several novel risk factors for atherosclerosis have recently been proposed, but few comparative data exist to guide clinical use of these emerging biomarkers.


OBJECTIVE
To compare the predictive value of 11 lipid and nonlipid biomarkers as risk factors for development of symptomatic peripheral arterial disease (PAD).


METHODS
Nested case-control study using plasma samples collected at baseline from a prospective cohort of 14 916 initially healthy US male physicians aged 40 to 84 years, of whom 140 subsequently developed symptomatic PAD (cases); 140 age- and smoking status-matched men who remained free of vascular disease during an average 9-year follow-up period were randomly selected as controls.


METHODS
Incident PAD, as determined by baseline total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol-HDL-C ratio, triglycerides, homocysteine, C-reactive protein (CRP), lipoprotein(a), fibrinogen, and apolipoproteins (apo) A-I and B-100.


RESULTS
In univariate analyses, plasma levels of total cholesterol (P<.001), LDL-C (P =.001), triglycerides (P =.001), apo B-100 (P =.001), fibrinogen (P =.02), CRP (P =.006), and the total cholesterol-HDL-C ratio (P<.001) were all significantly higher at baseline among men who subsequently developed PAD compared with those who did not, while levels of HDL-C (P =.009) and apo A-I (P =.05) were lower. Nonsignificant baseline elevations of lipoprotein(a) (P =.40) and homocysteine (P =.90) were observed. In multivariable analyses, the total cholesterol-HDL-C ratio was the strongest lipid predictor of risk (relative risk [RR] for those in the highest vs lowest quartile, 3.9; 95% confidence interval [CI], 1.7-8.6), while CRP was the strongest nonlipid predictor (RR for the highest vs lowest quartile, 2.8; 95% CI, 1.3-5.9). In assessing joint effects, addition of CRP to standard lipid screening significantly improved risk prediction models based on lipid screening alone (P<.001).


CONCLUSIONS
Of 11 atherothrombotic biomarkers assessed at baseline, the total cholesterol-HDL-C ratio and CRP were the strongest independent predictors of development of peripheral arterial disease. C-reactive protein provided additive prognostic information over standard lipid measures.
Ridker
P M
PM
Brigham and Women's Hospital, 900 Commonwealth Ave E, Boston, MA 02215, USA. pridker@partners.org
Stampfer
M J
MJ
Rifai
N
N
D000328:Adult; D000368:Aged; D001053:Apolipoproteins / Q000097:blood; D001161:Arteriosclerosis / Q000097:blood* / Q000453:epidemiology*; D015415:Biomarkers / Q000097:blood*; D002097:C-Reactive Protein / Q000378:metabolism; D016022:Case-Control Studies; D002784:Cholesterol / Q000097:blood; D005340:Fibrinogen / Q000378:metabolism; D006710:Homocysteine / Q000097:blood; D006801:Humans; D016013:Likelihood Functions; D017270:Lipoprotein(a) / Q000097:blood; D008297:Male; D008875:Middle Aged; D016491:Peripheral Vascular Diseases / Q000097:blood* / Q000453:epidemiology*; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012044:Regression Analysis; D012307:Risk Factors; D018709:Statistics, Nonparametric
D001053:Apolipoproteins; D015415:Biomarkers; D017270:Lipoprotein(a); D006710:Homocysteine; D005340:Fibrinogen; D002097:C-Reactive Protein; D002784:Cholesterol