Special Feature
The Clinical Significance of C-Reactive Protein
By Leon Speroff, MD
I was motivated to review the role of c-reactive protein (CRP) in cardiovascular disease because CRP has been implicated as an etiologic factor in the HERS Study results, specifically for the increase in cardiac events recorded in the first year by the hormone users.1
The development of atherosclerotic plaques involves the immune system (monocytes, cytokines, and cell adhesion molecules).2 For this reason, studies indicate that CRP is a marker of cardiovascular risk in men and women.3-5 This risk is limited, however, to arterial disease; CRP levels are not linked to venous thrombosis or pulmonary embolus.3 CRP predicts an increased risk of cardiovascular events even in individuals who have normal lipid levels.5
CRP is a protein synthesized in the liver and was given its name because it reacts with the C-polysaccharide of Streptococcus pneumoniae. Thus, the circulating level of CRP increases in response to various inflammatory stimuli, but specifically bacterial infections and chronic inflammatory conditions such as systemic lupus erythematosus. New sensitive assays now detect small increases associated with low-grade inflammation in the vascular system.
Increased levels of CRP in patients with angina predict poor outcome, an increase in the relative risk of a coronary event. Prospective studies have documented an increased risk of cardiovascular events in patients without known cardiovascular disease who have high CRP levels, an association that is even greater in smokers.6 In general, women have higher CRP levels than men. Higher mean levels are found in both men and women who subsequently have myocardial infarctions. Stroke and peripheral vascular disease are also increased in men with higher CRP levels, but this has not been adequately assessed in women. In a meta-analysis of 14 prospective studies, individuals with CRP levels in the top third compared with individuals in the bottom third, had a relative risk of 1.9 (CI = 1.5-2.3) for coronary heart disease (CHD).7 Thus, CRP levels have predictive value in both healthy individuals and individuals with cardiac disease. In addition, statin treatment lowers CRP levels,8 and evidence indicates that statins and aspirin achieve greater benefits in individuals with high CRP levels.3, 9
Hormonal Effects
In general, studies have indicated that estrogen treatment (with or without progestin) increases CRP levels and raloxifene does not. In a double-blind, randomized trial, postmenopausal hormone therapy and raloxifene equally lowered homocysteine levels, but estrogen-progestin treatment increased CRP levels, whereas raloxifene had no effect.10 These results were duplicated in a Dutch randomized study.11 A cross-sectional study found higher levels of CRP in healthy postmenopausal women using hormone therapy.12 However, there are reports that indicate inconsistencies. In the PEPI randomized trial, hormone therapy increased CRP levels; however, the levels of E-selectin, another marker of inflammation, were reduced.13 Hormone therapy (in a randomized trial) improved (reduced) CRP levels in postmenopausal women with type-2 diabetes.14
Electron beam (ultrafast) computerized tomography (CT) is a sensitive technique to detect and quantify calcification in the coronary arteries, and it has been proposed that the calcium score by ultrafast CT is a marker of atherosclerosis in women.15 In a surprising finding, CRP levels did not correlate with calcium scores in 172 asymptomatic postmenopausal women at risk for cardiac disease.16 This suggests that CRP and calcium score measure different things, and either calcium score is a poor predictor of cardiac events or CRP levels are not as good as have been proposed. In the Pittsburgh Healthy Women Study, coronary calcium scores were strongly correlated with other risk factors for coronary disease (high LDL-cholesterol levels, low HDL-cholesterol levels, hypertension, higher triglyceride and glucose levels, and smoking), and postmenopausal hormone therapy was associated with less coronary calcium.17 This would suggest that CRP levels should correlate with the calcium score.
Important Clinical Questions
Are elevated CRP levels specific for cardiac outcomes, or is CRP a more general marker that is elevated in many conditions, even unrelated conditions? At least one study has found that elevated CRP levels were not specific for stroke or cardiovascular disease mortality.18 Is vascular inflammation a primary factor or a secondary response? Is CRP a marker for a specific pathophysiologic process, such as clotting and thrombosis? Is CRP an independent risk factor for CHD? The increased relative risks are in the range of 1.5 to 2.0, recognized as not a strong association and difficult to separate from confounding factors.
It doesn’t make sense to me that estrogen stimulates a vascular inflammatory response. It makes more sense that an increase in CRP levels is due to estrogen’s well-known effect to stimulate the hepatic synthesis of proteins. Most important, we don’t know if the decrease in CRP levels with statins and the increase with estrogen (if this is indeed the case) are instrumental in clinical outcomes or reflect other effects. Thus, raising or lowering CRP levels will not necessarily increase and decrease the risk of clinical disease.
Conclusion
The uncertainties and questions regarding the clinical meaning of CRP levels make it premature to conclude that changes in CRP levels with hormone therapy have a direct clinical consequence. How do you reconcile an estrogen-induced increase in CRP levels (and supposedly an increase in clinical cardiac risk) with the recent report from the American Cancer Study that found a 34% reduced risk of CHD mortality in estrogen users (except in markedly obese women)? In my view, at this point in time, the effect of various postmenopausal treatments on CRP levels should not be included in clinician and patient decision-making.
References
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19. Rodriguez C, et al. Am J Epidemiol 2001;153:145-152.
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