Novel Risk Factors for Predicting Systemic Atherosclerosis

Abstract & Commentary

Synopsis: The total cholesterol-HDL-cholesterol ratio and the C-reactive protein are strong predictors of peripheral vascular disease.

Source: Ridker PM, et al. JAMA. 2001;285:2481-2485.

Several novel risk factors have been proposed as potential criteria for improved detection of early atherosclerosis. Ridker and colleagues noted that there were no comparative data to guide the clinical use of these potential biomarkers.

The objective of this study was to compare the predictive value of 11 lipid and nonlipid biomarkers as risk factors for the development of symptomatic peripheral arterial disease (PAD).

This was a nested case-control study of 14,916 initially healthy male physicians aged 40-84 years, of whom 140 subsequently developed symptomatic PAD. One hundred forty age- and smoking-matched men who remained free of vascular disease during a 9-year follow-up period were randomly selected as controls.

The main outcome measure was incident PAD, as determined by baseline total cholesterol, high-density 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-1 and B-100.

In univariate analysis, plasma levels of total cholesterol, LDL-C, triglycerides, apo-B, total cholesterol-HDL-C (all with P < .001), fibrinogen (P < .02), and CRP (P < .006) were significantly higher at baseline among men who subsequently developed PAD while HDL-C and apo A-1 were significantly lower. The total cholesterol-HDL ratio was the strongest lipid predictor of risk (relative risk [RR], 3.9) for those in the highest quartile vs. the lowest quartile. The CRP was the strongest nonlipid predictor for the highest vs. the lowest quartile (RR, 2.8). In assessing joint effects, addition of CRP to standard lipid screening significantly improved risk prediction models based on lipid screening alone (P < .001).

Ridker et al concluded that of the 11 biomarkers assessed at baseline cholesterol HDL-C ratio and CRP were the strongest independent predictors of the development of PAD. CRP provided additive prognostic information over standard lipid measures.

Comment by Ralph R. Hall, MD, FACP

This study provides long awaited answers to our questions about which tests we should be ordering to assist us in estimating our patients’ risk for atherosclerosis.

How do we manage the patient with elevated CRP? Studies are now underway to evaluate the effects of statins on patients with elevated CRP.1 In a subgroup analysis of the Cholesterol and Recurrent Events trial (CARE trial), CRP levels decreased 20% in patients taking pravastatin and increased by 20% in the patients taking placebo over a 5-year period.2 In the Air Force/Texas Coronary Prevention Study, simvastatin, pravastatin, and atorvastatin in equipotent doses each reduced CRP levels after 6 weeks of treatment.3 The statins in general then appear to be somewhat effective in reducing CRP levels.

As Maseri has pointed out, "inflammation appears to be a cause and not just a consequence of acute coronary syndromes."4 We will have to wait for further trials to be completed to be certain that statins are the current best approach for managing patients with elevated CRP.


1. Azar RR, Waters DD. Am Heart J. 2001;141:881-883.

2. Ridker PM, et al. Circulation. 1999;100:230-235.

3. Jialal I, et al. Circulation. 2000;102(suppl 2):118-133.

4. Maseri A. N Engl J Med. 1997;336:1014-1016.