C-Reactive Protein Reassessed
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《新英格兰医药杂志》
In this issue of the Journal, Danesh and colleagues report that elevated levels of C-reactive protein (CRP) are associated with only a moderate increase in the risk of coronary heart disease (CHD).1 Although these findings are in line with those of other large studies, the independent relative risk associated with increased CRP levels is considerably less than in some earlier reports. Using a multivariate analysis, the authors found that the predictive value of CRP measurement adds relatively little to that provided by assessments of traditional risk factors. In contrast, a smaller study suggested that the CRP level could be more predictive than the level of low-density lipoprotein (LDL) cholesterol in the assessment of the risk of CHD.2 The new findings call into question the clinical value of measuring CRP as a predictor of the risk of CHD and indicate that further research is needed to clarify the place of this approach in clinical medicine. Recent recommendations that CRP measurements be offered as an optional adjunct to a global assessment of risk factors in persons whose calculated 10-year risk of CHD is 10 to 20 percent3 may have to be revisited.
The analysis of CRP and the risk of CHD in the Reykjavik prospective cohort study involved 2459 patients with CHD and 3969 selected controls.1 A single measurement of CRP in stored samples obtained at base line was studied in relation to the 20-year incidence of CHD. This is by far the largest number of cases that have been examined in such analyses. Other strengths of the study include the fact that it was conducted in an Icelandic population with high rates of participation and follow-up. The consistency in the relationship of traditional risk factors to CHD suggests that in terms of cardiovascular risk, this is a typical European population. Patients with a CRP value in the top third (cutoff value, 2.0 mg per liter) had an unadjusted relative risk of CHD of 1.92, as compared with patients whose values were in the bottom third. However, after adjustment for risk factors such as smoking status, blood pressure, body-mass index, and total cholesterol level, the relative risk was reduced to 1.45. Moreover, a meta-analysis of the four largest studies of CRP levels and the risk of CHD indicated a similar relative risk of about 1.49. In contrast, the independent relative risk for patients who had high cholesterol levels or who smoked was considerably higher.
Although these findings confirm pioneering work showing that the CRP level is an indicator of the risk of CHD,4,5 they call into question the magnitude of the effect. A comparison of the various studies reveals substantial heterogeneity in the results1 that is not easily explained by methodologic differences. There is some evidence that the relationship of CRP to the risk of CHD decreases over time, and a preliminary analysis suggested a stronger relationship between base-line CRP values and the risk of newly diagnosed CHD during the initial decade of follow-up than in subsequent periods. However, in the comparison of different studies, there was no evidence that the heterogeneity of results was related to the duration of follow-up, the study design, or the storage temperature of the samples.
There was evidence that the strength of the relationship of CRP levels to the risk of CHD may have been overestimated in earlier reports as compared with more recent and larger studies. This is typical of the publication bias inherent in the description of emerging risk factors. Further epidemiologic research may help to refine the risk-factor status of CRP. Pooling of data from individual subjects in different studies would allow more meaningful statistical adjustment for various risk factors. A further potentially powerful approach will be to study the effect of genetic variation on CRP levels in the prediction of the risk of CHD.
What do we know of the mechanisms underlying the link between CRP levels and the risk of CHD? CRP was initially described as an acute-phase reactant that binds pneumococcal capsular polysaccharide. CRP is a highly sensitive marker of inflammation and tissue damage, and levels can rise to more than 500 mg per liter in a variety of acute or chronic inflammatory conditions.6 In contrast, base-line CRP levels are roughly divided into population thirds of less than 1 mg per liter, 1 to 3 mg per liter, and more than 3 mg per liter. The introduction of high-sensitivity assays for CRP has permitted the routine measurement of base-line CRP, an option that was formerly available only in research laboratories.
CRP is principally produced in hepatocytes, and cytokines, especially interleukin-6, induce the expression and release of CRP.6 Cytokines made in adipose tissue may induce the production of CRP in the liver, leading to elevated plasma levels. In a striking parallel to atheroma formation, macrophages infiltrate adipose tissue in obese persons, contributing to the release of cytokines and insulin resistance.7 Thus, an appealing idea is that elevated plasma CRP levels are in part a marker of a low-grade inflammatory state, especially in visceral adipose tissue, and that CRP is an indicator of cardiovascular risk in part because of the relationship of adiposity to insulin resistance and dyslipidemia. In short, CRP may be a hallmark of the metabolic syndrome.
Similarly, CRP could also reflect a state of arterial inflammation. A new idea in cardiology is that patients with acute coronary syndromes may have underlying, diffuse atherothrombosis of the coronary arteries, precipitated by the infiltration of atheroma by macrophages, the secretion of proteases, and the erosion or rupture of plaque. This inflammatory reaction, initiated in response to the retention of atherogenic lipoproteins in the artery wall, could also lead to the release of cytokines and the production of CRP by hepatocytes. There may also be some local production of CRP by cells in the arterial wall, but this would be unlikely to make a major contribution to systemic levels.
Whether the slight chronic elevations in base-line CRP levels that are associated with an increased risk of CHD can cause atherothrombosis is unknown. There is evidence that CRP can cause tissue damage. The binding of CRP to its ligands can activate the complement system, leading to the deposition of C3 in tissues. In animal models of myocardial infarction, this can lead to an increased area of infarction.6 The deposition of C3 and the activation of complement in arteries could potentially promote atherogenesis. A variety of in vitro studies suggest the existence of additional mechanisms of atherogenesis. CRP binds phosphocholine moieties such as those presented by oxidized phospholipids in LDL, perhaps promoting the uptake of LDL and the formation of foam cells.8 CRP might promote endothelial activation and impair the production of nitric oxide. Although a plethora of in vitro studies have suggested that CRP has direct toxic effects on cells, concern has been expressed about the methods used in these studies.6 In apolipoprotein E–knockout mice, the overexpression of transgenic human CRP had little or no effect on the extent of atherosclerosis.9,10 However, mice make very little of their own CRP, and such studies may have limited relevance to humans. Overall, the evidence that CRP is directly responsible for atherothrombosis is relatively weak. Thus, the value of lowering CRP levels by means of a variety of drugs and exercise is of uncertain clinical significance.
Although the clinical relevance of CRP measurements in the prediction of the risk of CHD remains unproven, the epidemiologic research on CRP has sparked interest in the inflammatory underpinnings of atherothrombosis. Further elucidation of the inflammatory response may provide new insights into the mechanisms of insulin resistance, diabetes, and atherothrombosis. There is a pressing need for research that will lead to the development of better genetic, biochemical, or imaging indicators of risk and thus allow the earlier identification of patients who are at risk for CHD and stroke.
Source Information
From the Division of Molecular Medicine, Department of Medicine, Columbia University Medical Center, New York.
References
Danesh J, Wheeler JG, Hirschfield GM, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 2004;350:1387-1397.
Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002;347:1557-1565.
Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003;107:499-511.
Kuller LH, Tracy RP, Shaten J, Meilahn EN. Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Am J Epidemiol 1996;144:537-547.
Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973-979.
Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest 2003;111:1805-1812.
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003;112:1796-1808.
Chang MK, Binder CJ, Torzewski M, Witztum JL. C-reactive protein binds to both oxidized LDL and apoptotic cells through recognition of a common ligand: phosphorylcholine of oxidized phospholipids. Proc Natl Acad Sci U S A 2002;99:13043-13048.
Hirschfield GM, Gallimore R, Gilbertson JA, Benson M, Pepys MB. Systemic inflammation and atherogenesis in apoE knockout mice expressing transgenic human C-reactive protein. Circulation 2003;108:Suppl IV:IV-41. abstract.
Paul A, Ko KW, Li L, et al. C-reactive protein accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice. Circulation 2004;109:647-655.
Related Letters:
C-Reactive Protein and Coronary Heart Disease
Glynn R. J., Cook N. R., Libby P., Willerson J. T., Braunwald E., Foody J. M., Gotto A. M., Wenger N., Ridker P. M., Koenig W., Fuster V., Danesh J., Pepys M., Gudnason V.(Alan R. Tall, M.B., B.S.)
The analysis of CRP and the risk of CHD in the Reykjavik prospective cohort study involved 2459 patients with CHD and 3969 selected controls.1 A single measurement of CRP in stored samples obtained at base line was studied in relation to the 20-year incidence of CHD. This is by far the largest number of cases that have been examined in such analyses. Other strengths of the study include the fact that it was conducted in an Icelandic population with high rates of participation and follow-up. The consistency in the relationship of traditional risk factors to CHD suggests that in terms of cardiovascular risk, this is a typical European population. Patients with a CRP value in the top third (cutoff value, 2.0 mg per liter) had an unadjusted relative risk of CHD of 1.92, as compared with patients whose values were in the bottom third. However, after adjustment for risk factors such as smoking status, blood pressure, body-mass index, and total cholesterol level, the relative risk was reduced to 1.45. Moreover, a meta-analysis of the four largest studies of CRP levels and the risk of CHD indicated a similar relative risk of about 1.49. In contrast, the independent relative risk for patients who had high cholesterol levels or who smoked was considerably higher.
Although these findings confirm pioneering work showing that the CRP level is an indicator of the risk of CHD,4,5 they call into question the magnitude of the effect. A comparison of the various studies reveals substantial heterogeneity in the results1 that is not easily explained by methodologic differences. There is some evidence that the relationship of CRP to the risk of CHD decreases over time, and a preliminary analysis suggested a stronger relationship between base-line CRP values and the risk of newly diagnosed CHD during the initial decade of follow-up than in subsequent periods. However, in the comparison of different studies, there was no evidence that the heterogeneity of results was related to the duration of follow-up, the study design, or the storage temperature of the samples.
There was evidence that the strength of the relationship of CRP levels to the risk of CHD may have been overestimated in earlier reports as compared with more recent and larger studies. This is typical of the publication bias inherent in the description of emerging risk factors. Further epidemiologic research may help to refine the risk-factor status of CRP. Pooling of data from individual subjects in different studies would allow more meaningful statistical adjustment for various risk factors. A further potentially powerful approach will be to study the effect of genetic variation on CRP levels in the prediction of the risk of CHD.
What do we know of the mechanisms underlying the link between CRP levels and the risk of CHD? CRP was initially described as an acute-phase reactant that binds pneumococcal capsular polysaccharide. CRP is a highly sensitive marker of inflammation and tissue damage, and levels can rise to more than 500 mg per liter in a variety of acute or chronic inflammatory conditions.6 In contrast, base-line CRP levels are roughly divided into population thirds of less than 1 mg per liter, 1 to 3 mg per liter, and more than 3 mg per liter. The introduction of high-sensitivity assays for CRP has permitted the routine measurement of base-line CRP, an option that was formerly available only in research laboratories.
CRP is principally produced in hepatocytes, and cytokines, especially interleukin-6, induce the expression and release of CRP.6 Cytokines made in adipose tissue may induce the production of CRP in the liver, leading to elevated plasma levels. In a striking parallel to atheroma formation, macrophages infiltrate adipose tissue in obese persons, contributing to the release of cytokines and insulin resistance.7 Thus, an appealing idea is that elevated plasma CRP levels are in part a marker of a low-grade inflammatory state, especially in visceral adipose tissue, and that CRP is an indicator of cardiovascular risk in part because of the relationship of adiposity to insulin resistance and dyslipidemia. In short, CRP may be a hallmark of the metabolic syndrome.
Similarly, CRP could also reflect a state of arterial inflammation. A new idea in cardiology is that patients with acute coronary syndromes may have underlying, diffuse atherothrombosis of the coronary arteries, precipitated by the infiltration of atheroma by macrophages, the secretion of proteases, and the erosion or rupture of plaque. This inflammatory reaction, initiated in response to the retention of atherogenic lipoproteins in the artery wall, could also lead to the release of cytokines and the production of CRP by hepatocytes. There may also be some local production of CRP by cells in the arterial wall, but this would be unlikely to make a major contribution to systemic levels.
Whether the slight chronic elevations in base-line CRP levels that are associated with an increased risk of CHD can cause atherothrombosis is unknown. There is evidence that CRP can cause tissue damage. The binding of CRP to its ligands can activate the complement system, leading to the deposition of C3 in tissues. In animal models of myocardial infarction, this can lead to an increased area of infarction.6 The deposition of C3 and the activation of complement in arteries could potentially promote atherogenesis. A variety of in vitro studies suggest the existence of additional mechanisms of atherogenesis. CRP binds phosphocholine moieties such as those presented by oxidized phospholipids in LDL, perhaps promoting the uptake of LDL and the formation of foam cells.8 CRP might promote endothelial activation and impair the production of nitric oxide. Although a plethora of in vitro studies have suggested that CRP has direct toxic effects on cells, concern has been expressed about the methods used in these studies.6 In apolipoprotein E–knockout mice, the overexpression of transgenic human CRP had little or no effect on the extent of atherosclerosis.9,10 However, mice make very little of their own CRP, and such studies may have limited relevance to humans. Overall, the evidence that CRP is directly responsible for atherothrombosis is relatively weak. Thus, the value of lowering CRP levels by means of a variety of drugs and exercise is of uncertain clinical significance.
Although the clinical relevance of CRP measurements in the prediction of the risk of CHD remains unproven, the epidemiologic research on CRP has sparked interest in the inflammatory underpinnings of atherothrombosis. Further elucidation of the inflammatory response may provide new insights into the mechanisms of insulin resistance, diabetes, and atherothrombosis. There is a pressing need for research that will lead to the development of better genetic, biochemical, or imaging indicators of risk and thus allow the earlier identification of patients who are at risk for CHD and stroke.
Source Information
From the Division of Molecular Medicine, Department of Medicine, Columbia University Medical Center, New York.
References
Danesh J, Wheeler JG, Hirschfield GM, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 2004;350:1387-1397.
Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002;347:1557-1565.
Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003;107:499-511.
Kuller LH, Tracy RP, Shaten J, Meilahn EN. Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Am J Epidemiol 1996;144:537-547.
Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973-979.
Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest 2003;111:1805-1812.
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003;112:1796-1808.
Chang MK, Binder CJ, Torzewski M, Witztum JL. C-reactive protein binds to both oxidized LDL and apoptotic cells through recognition of a common ligand: phosphorylcholine of oxidized phospholipids. Proc Natl Acad Sci U S A 2002;99:13043-13048.
Hirschfield GM, Gallimore R, Gilbertson JA, Benson M, Pepys MB. Systemic inflammation and atherogenesis in apoE knockout mice expressing transgenic human C-reactive protein. Circulation 2003;108:Suppl IV:IV-41. abstract.
Paul A, Ko KW, Li L, et al. C-reactive protein accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice. Circulation 2004;109:647-655.
Related Letters:
C-Reactive Protein and Coronary Heart Disease
Glynn R. J., Cook N. R., Libby P., Willerson J. T., Braunwald E., Foody J. M., Gotto A. M., Wenger N., Ridker P. M., Koenig W., Fuster V., Danesh J., Pepys M., Gudnason V.(Alan R. Tall, M.B., B.S.)