Boston, MA - A modestly sized case-control study has offered further evidence that elevated levels of C-reactive protein (CRP) point to increased cardiovascular risk independently of standard CHD risk factors, including diabetes and hypertension.[1] The prognostic power of CRP was especially pronounced in men, according to a report in the December 16, 2004 New England Journal of Medicine. The analysis also found little independent predictive value to measurements of several other inflammatory markers, including interleukin-6.

"Although the ratio of total to HDL cholesterol was more strongly associated with the risk of coronary heart disease than were the levels of inflammatory markers, the level of C-reactive protein was still a significant contributor to the prediction of coronary heart disease," write Jennifer K Pai (Harvard School of Public Health, Boston, MA) and colleagues. Their study was supported by grants from the National Institutes of Health and Merck Research Laboratories.

Our study suggests that measuring CRP may identify subjects at risk for coronary heart disease after accounting for traditional risk factors.

The analysis encompassed 239 women participating in the Nurses' Health Study and 265 men enrolled in the Health Professionals Follow-up Study who had blood drawn at baseline when CHD-free and who subsequently experienced a nonfatal MI or fatal CHD event. A control population of 469 women and 529 men matched for age, smoking status, and date of blood sampling was randomly selected from among the studies' patients who were CHD-free at the time CHD developed in the other patients.

The group found a significant and independent 68% increase in the relative risk of a nonfatal MI or fatal CHD event associated with CRP levels >3.0 mg/L in the pooled population of men and women.

"Our study suggests that measuring CRP may identify subjects at risk for coronary heart disease after accounting for traditional risk factors," Pai told heartwire. As an addition to the ongoing debate in the literature on CRP's value in assessing CHD risk, Pai said, this analysis strengthens the case for pursuing further investigation of the inflammatory marker as a screening tool.

It's not even a doubling of risk.

Dr Peter WF Wilson (Medical University of South Carolina, Charleston), who is not connected with the study, agrees that it supports such a case for CRP but said it also shows CRP to have only a "modest" independent effect on risk compared with other risk factors that would be identified in a standard clinic visit, such as smoking, hypertension, and diabetes status. "It's not even a doubling of risk," he noted.

Pai observed that the extra independent risk discrimination provided by CRP, "used in conjunction with what physicians already ask, identifies patients that might ordinarily be missed," such as those who don't display the other risk factors.

When CHD risks were separated by "recently proposed" ranges for low, medium, and high CRP readings, medium and high levels among men and women combined pointed to significantly increased risk relative to low levels. But breaking the data out by sex suggested that men accounted for much of the effect.

"It would appear from our study that the effect is stronger in men and less so among women," Pai said, although "there's a suggestion of a trend" in the women-only analysis.

Among women, increasing concentrations of all measured inflammatory markers—soluble tumor-necrosis factor types 1 and 2, interleukin-6, and CRP—were associated with rising CHD risk after controlling for the case-matching criteria. But as the analysis was controlled for more risk factors, the weaker the associations became. None remained significant among women after controlling for all other factors in the analysis, including diabetes and hypertension.

Men followed a parallel pattern for all inflammatory markers except CRP, which remained significantly predictive with increasing concentrations, ultimately showing a relative risk of 2.55 (p=0.02) at the highest measured levels after adjustment for all risk factors.

For context, Pai and colleagues compared CRP's risk-assessment power with that of a more traditional risk factor. The CHD risk for the highest total cholesterol (TC)/HDL-C ratio quintile, relative to the lowest, was higher at 4.33 in women (p<0.001) and 3.29 (p<0.001) in men after controlling for the same set of confounders.