Abstract & Commentary
Synopsis: CRP values as a continuous variable have independent predictive value for subsequent coronary events in apparently healthy women.
Sources: Ridker PM, Cook N. Circulation. 2004;109: 1955-1959; Verma S, et al. Circulation. 2004;109:2058-2067; Verma S, et al. Circulation. 2004;109:1914-1917; Khreiss T, et al. Circulation. 2004;109:2016-2022.
In a new analysis by Ridker from the large Women’s Health Study, levels of C-reactive protein (CRP) at baseline were correlated with first cardiovascular events over a 9-year period. The particular focus of this report was very low and very high CRP levels, as well as looking at deciles of baseline CRP with and without adjustment for diabetes and Framingham Risk Score. In this study, 28,000 low-risk women were evaluated at entry, who were "similar to that of the general population in terms of . . . lipid levels . . . and metabolic syndrome." Framingham Risk Scores (FRS) were computed and analyses were carried out adjusted for both FRS and diabetes.
A graded relative risk was demonstrated for each of 10 CRP groups, all highly statistically significant. Thus, CRP has again been shown to have an independent predictive value on subsequent events in patients without clinical CAD. The analysis of very low (< 0.5 mg/L and very high (> 10 mg/L) levels correlate with both crude and FRS adjusted risk groups. Thus, unadjusted event rates were 6-fold higher in individuals with an initial CRP > 10 compared to an initial CRP < 0.5; adjusted rates in FRS and diabetes were 2-fold higher for CRP >10 mg/L. In fact, even between 0.5 and 1.0 mg/L there was a near doubling of adjusted risk. The authors conclude that "there is no evidence . . . of any threshold affect." They also point out that unusually low or unusually high values generally do not represent false negatives or positives. They believe that actual CRP levels provide considerable value over and above the recommended cut points of < 1, 1-3, and > 3 established by the recent CDC/AHA guidelines for use CRP. Although the highest CRP group (> 10 mg/L) represented only 5.5% of the total population, their risk was strikingly elevated. Those women with levels of > 20 at baseline (2.2% of the total population) were at an even greater risk. Fifteen percent of the population had an initial level of < 0.5 with an extremely low event rate. The authors conclude that CRP may play a direct role in atherothrombosis, given the precisely graded increases in risk across 9 cut points, and that at very high CRP levels, the increased CV risk is consistent with the hypothesis that CRP may have direct vascular effects. They furthermore suggest that the data supports the concept that chronic inflammatory states, such as arthritis, periodontal disease, etc, may be disposed to increased CV events, rather than high CRP being considered a false positive response. Furthermore, the authors emphasize that only a high sensitivity assay should be used for evaluation of CRP and two measurements are recommended for any level of > 10 mg/L.
Comment by Jonathan Abrams, MD
This report, and many others, link vascular events to gradations of CRP. CRP has been studied in many different populations and the data are consistent. The marked differential of risk between very low and very high CRP levels suggests a pathogenetic role for CRP itself. An in vitro basic science report from Canada suggests that CRP may have an adverse effect on endothelial progenitor cells (EPC) which are believed to be responsible for (favorable) neovascularization and angiogenesis. Investigators found that adding CRP to the experimental medium reduced EPC cell counts, inhibited the expression in specific endothelial cell markers, and increased endothelial cell apoptosis. Angiogenesis was impaired and endothelial nitric oxide synthase expression was diminished. Of great interest, the diabetes drug, rosiglitazone, attenuated these effects. These authors concluded that CRP (in this case, human recombinant CRP) has inhibitor effects on EPC differentiation, survival, and function, and thus may decrease the angiogenesis response to chronic ischemia. Verma et al conclude that CRP should now be seen as a "prominent partaker in endothelial dysfunction and atherosclerosis." Verma et al address conformational modification of CRP, such that differing subunits of CRP can have a greater or lesser pro-inflammatory phenotype, which may modulate subsequent cardiovascular risk. Furthermore, they emphasize a wide variety of cellular effects in multiple experiments which support a direct role of CRP in promoting endothelial dysfunction and a variety of pro-inflammatory and pro-atherosclerotic actions. Transgenic animals that can express human CRP have been developed; these mice are prothrombotic and atherogenic, and are associated with "adverse cardiovascular processes," including impaired NO production, and enhanced endothelin release. These authors suggested that in the future, strategies to decrease CRP and modify its structure may become available to modulate atherosclerotic plaque initiation, progression, and rupture.
Although considerable controversy remains regarding the putative role of CRP as a participant or a marker for adverse cardiovascular events, it appears that there is a great deal of evidence that C-reactive protein itself, particularly with certain structural conformational profiles, can become pro-inflammatory. Thus, the hypothesis shared by many but not all, strongly supports an active role of CRP in the early as well as late atherothrombotic process. It is well-known that LDL cholesterol lowering results in decreased CRP levels; other interventions that reduce CRP itself may result in decreased atherothrombosis ". . . and that a virtual absence of CRP may in fact be protective." CRP can be produced within vascular vessel muscle of diseased coronary arteries in addition to the liver. While many of these basic science reports have no direct effect on clinical practice as yet, it does appear that CRP status, either directly or as a surrogate for an inflammatory state, is a valid and important construct relating to both healthy as well as unhealthy arteries.
Dr. Abrams is Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque.