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Opinion |
1
Department of Laboratory Medicine, Children’s Hospital,
2
Center for Cardiovascular Disease Prevention, The Leducq Center for Molecular and Genetic Epidemiology of Cardiovascular Disorders,
3
Divisions of Cardiovascular Disease and Preventive Medicine, Brigham and Women’s Hospital, and, Departments of
4
Pathology and
5
Medicine, Harvard Medical School, Boston, MA 02115
a Address correspondence to this author at: Children’s Hospital, Department of Laboratory Medicine, 300 Longwood Ave., Boston, MA 02115. Fax 617-713-4347;
rifai{at}tch.harvard.edu.
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Introduction |
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 Top Introduction References |
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, the relative risk associated with being in the top vs the
bottom quartile for hs-CRP in the WHS was substantially greater than
that associated with other "novel" risk factors such as
homocysteine and lipoprotein(a) [Lp(a)], and in fact was greater than
that associated with the usual lipid markers of risk. In almost all of
these prospective studies, risk estimates associated with hs-CRP were
independent of other recognized cardiovascular risk factors.
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Data from both the PHS and WHS demonstrate that the joint effects of hs-CRP and lipid screening are greater than the product of the individual effects of each risk factor considered alone (8)(9). Furthermore, when study participants were stratified according to the quintile of hs-CRP and the quintile of the ratio of total cholesterol to HDL-cholesterol (TC:HDL-C ratio), the relative risk of first coronary events in those in the highest quintiles of both hs-CRP and TC:HDL-C ratio was approximately eight- to ninefold higher than that of those in the lowest quintiles of these analytes. In all of these analyses, risk prediction models that incorporated TC:HDL-C ratio were significantly better (P <0.001) than those based on hs-CRP alone (8)(9).
For the purpose of assessing risk of first coronary events, hs-CRP concentration should be interpreted using cut points established by prospective clinical studies. As the distribution of hs-CRP concentrations is (rightward) skewed, each patient should be classified into a quintile (or quartile) based on the measured hs-CRP concentration. Therefore, the focus with hs-CRP reporting is what quintile a given individual is in rather than on his or her actual mass concentration. Furthermore, to provide the greatest clinical utility, hs-CRP results should be interpreted in combination with lipid values.
On the basis of these data, we present a proposed algorithm for
cardiovascular risk prediction using both hs-CRP and TC:HDL-C ratio
(Fig. 2
). In this algorithm, hs-CRP concentrations were derived from
ongoing population-based surveys using a latex-based immunoassay
approved by the Food and Drug Administration for cardiovascular risk
prediction (10). Lipid values for men and women as well as
RRs of future cardiovascular events were derived from overview analyses
using data from the PHS and WHS. Computed RRs in the proposed models
were derived from multiple logistic regression analyses in these two
large-scale prospective cohort studies of currently healthy men and
women in which the outcome variable is the future development of first
ever myocardial infarction and stroke. In these models, risk estimates
did not differ significantly between men and women; thus, a
single risk assessment algorithm is currently suggested for both
genders. It is important to note, however, that this is a rapidly
evolving area of research. Clinical cut points used in these algorithms
may require modification as more comprehensive data sets become
available.
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Although CRP is a classical acute phase reactant, hs-CRP
concentrations are biologically stable over long periods of time. For
example, in one study with 5 years of follow-up, the
log-normalized correlation of baseline hs-CRP concentrations vs
those at year 5 (r = 0.60) was greater than that
associated with TC (r = 0.37) or with LDL-cholesterol
(r = 0.32) (11). In clinical practice,
hs-CRP evaluation should be avoided if there has been recent infection
or trauma. A period of 2 weeks is adequate in most cases for hs-CRP
concentrations increased as a result of infection to return to basal
values. Values of hs-CRP >15 mg/L (
99th percentile) likely indicate
active inflammation or the presence of an alternative chronic
inflammatory condition. The predictive value of hs-CRP is greatly
improved if two measurements are made 1 month apart and the lowest
of these values is used to determine the appropriate quintile for
cardiovascular risk prediction. This approach may not always be
clinically feasible. At a minimum, it is therefore suggested that
hs-CRP values >5 mg/L be repeated to avoid misclassification because
of clinically silent infection.
From a clinical perspective, the role of hs-CRP in predicting vascular risk is rapidly evolving. Current data suggest that the addition of hs-CRP to standard lipid screening can improve our ability to detect absolute coronary risk, a critical issue because one-half of all myocardial infarctions and strokes occur among individuals without overt hyperlipidemia (12). Indeed, several studies have demonstrated that increased hs-CRP concentrations are predictive of vascular events even among those without hyperlipidemia (3)(5)(8). Thus, accurate knowledge of risk can be expected to improve compliance with physician recommendations concerning diet, exercise, and smoking cessation, particularly among those with "normal" lipid concentrations.
In addition, screening for hs-CRP may have pharmacologic implications for patient treatment. At this time, evidence has been presented that suggests that both aspirin (3) and statin (11)(13) therapies modulate the inflammatory response. Thus, it has been hypothesized that hs-CRP screening may provide a method to better target these interventions. With particular regard to statin therapy, several large-scale epidemiologic evaluations are now underway specifically designed to determine whether the cost-to-benefit ratio for statin use in primary prevention can be dramatically reduced by hs-CRP screening. In addition, basic laboratory evidence suggests that angiotensin-converting enzyme inhibitors, a class of drugs now established as having potential antiatherogenic effects (14), may also function, in part, through anti-inflammatory pathways.
Finally, these data have implications for screening with regard to
other novel markers of coronary and cerebral risk. As shown in
Fig. 1
, risk estimates associated with hs-CRP either alone or in
combination with lipid screening appear to be substantially greater in
magnitude than that associated with either Lp(a) or homocysteine
evaluation. These data are thus consistent with the fundamental role
inflammation plays in atherothrombosis (15). Indeed, within
the cardiology community, acute coronary intervention studies as well
as postinfarction trials are now being designed with specific screening
for hs-CRP on an a priori basis.
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References |
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TopIntroductionReferences |
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The following articles in journals at HighWire Press have cited this article:
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  R. Kones The Jupiter study, CRP screening, and aggressive statin therapy-implications for the primary prevention of cardiovascular disease Therapeutic Advances in Cardiovascular Disease, August 1, 2009; 3(4): 309 - 315. [Abstract] [PDF]
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 M. Guardiola, R. Ferre, J. Salazar, C. Alonso-Villaverde, B. Coll, S. Parra, L. Masana, and J. Ribalta Protease Inhibitor-Associated Dyslipidemia in HIV-Infected Patients Is Strongly Influenced by the APOA5-1131T->C Gene Variation Clin. Chem., October 1, 2006; 52(10): 1914 - 1919. [Abstract] [Full Text] [PDF]
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 A. S. Jaffe, L. Babuin, and F. S. Apple Biomarkers in Acute Cardiac Disease: The Present and the Future J. Am. Coll. Cardiol., July 4, 2006; 48(1): 1 - 11. [Abstract] [Full Text] [PDF]
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A. Stefanska, G. Sypniewskay, and L. Senterkiewicz Inflammatory Markers and Cardiovascular Risk in Healthy Polish Women across the Menopausal Transition Clin. Chem., October 1, 2005; 51(10): 1893 - 1895. [Full Text] [PDF]
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 G. L. Myers, N. Rifai, R. P. Tracy, W. L. Roberts, R. W. Alexander, L. M. Biasucci, J. D. Catravas, T. G. Cole, G. R. Cooper, B. V. Khan, et al. CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: Report From the Laboratory Science Discussion Group Circulation, December 21, 2004; 110(25): e545 - e549. [Full Text] [PDF]
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R. Rej Clinical Chemistry through Clinical Chemistry: A Journal Timeline Clin. Chem., December 1, 2004; 50(12): 2415 - 2458. [Abstract] [Full Text] [PDF]
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S. S. Levinson, J. J. Miller, and R. J. Elin Poor Predictive Value of High-Sensitivity C-Reactive Protein Indicates Need for Reassessment Clin. Chem., October 1, 2004; 50(10): 1733 - 1735. [Full Text] [PDF]
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U. A. Ajani, E. S. Ford, and A. H. Mokdad Prevalence of High C-Reactive Protein in Persons with Serum Lipid Concentrations within Recommended Values Clin. Chem., September 1, 2004; 50(9): 1618 - 1622. [Abstract] [Full Text] [PDF]
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 J. H. Ix, M. G. Shlipak, H. H. Liu, N. B. Schiller, and M. A. Whooley Association between Renal Insufficiency and Inducible Ischemia in Patients with Coronary Artery Disease: The Heart and Soul Study J. Am. Soc. Nephrol., December 1, 2003; 14(12): 3233 - 3238. [Abstract] [Full Text] [PDF]
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N. Khuseyinova, A. Imhof, G. Trischler, D. Rothenbacher, W. L. Hutchinson, M. B. Pepys, and W. Koenig Determination of C-Reactive Protein: Comparison of Three High-Sensitivity Immunoassays Clin. Chem., October 1, 2003; 49(10): 1691 - 1695. [Full Text] [PDF]
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T. B. Ledue and N. Rifai Preanalytic and Analytic Sources of Variations in C-reactive Protein Measurement: Implications for Cardiovascular Disease Risk Assessment Clin. Chem., August 1, 2003; 49(8): 1258 - 1271. [Abstract] [Full Text] [PDF]
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E. S. Ford, W. H. Giles, G. L. Myers, N. Rifai, P. M. Ridker, and D. M. Mannino C-reactive Protein Concentration Distribution among US Children and Young Adults: Findings from the National Health and Nutrition Examination Survey, 1999-2000 Clin. Chem., August 1, 2003; 49(8): 1353 - 1357. [Abstract] [Full Text] [PDF]
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 C.J. Malkin, P.J. Pugh, T.H. Jones, and K.S. Channer Testosterone for secondary prevention in men with ischaemic heart disease? QJM, July 1, 2003; 96(7): 521 - 529. [Full Text] [PDF]
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 I. M. van der Meer, M. P. M. de Maat, A. J. Kiliaan, D. A. M. van der Kuip, A. Hofman, and J. C. M. Witteman The Value of C-Reactive Protein in Cardiovascular Risk Prediction: The Rotterdam Study Arch Intern Med, June 9, 2003; 163(11): 1323 - 1328. [Abstract] [Full Text] [PDF]
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Y.-C. Tsen, G.-Y. Kao, C.-L. Chang, F.-Y. Lai, C.-H. Huang, S. Ouyang, M.-H. Yu, C.-P. Wang, and Y-N. Chiou Evaluation and Validation of a Duck IgY Antibody-based Immunoassay for High-Sensitivity C-reactive Protein: Avian Antibody Application in Clinical Diagnostics Clin. Chem., May 1, 2003; 49(5): 810 - 813. [Full Text] [PDF]
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C.-H. Wang, S.-H. Li, R. D. Weisel, P. W.M. Fedak, A. S. Dumont, P. Szmitko, R.-K. Li, D. A.G. Mickle, and S. Verma C-Reactive Protein Upregulates Angiotensin Type 1 Receptors in Vascular Smooth Muscle Circulation, April 8, 2003; 107(13): 1783 - 1790. [Abstract] [Full Text] [PDF]
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M. M. Kimberly, H. W. Vesper, S. P. Caudill, G. R. Cooper, N. Rifai, F. Dati, and G. L. Myers Standardization of Immunoassays for Measurement of High-Sensitivity C-reactive Protein. Phase I: Evaluation of Secondary Reference Materials Clin. Chem., April 1, 2003; 49(4): 611 - 616. [Abstract] [Full Text] [PDF]
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N. Rifai and P. M. Ridker Population Distributions of C-reactive Protein in Apparently Healthy Men and Women in the United States: Implication for Clinical Interpretation Clin. Chem., April 1, 2003; 49(4): 666 - 669. [Full Text] [PDF]
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A. Imhof, M. Frohlich, H. Loewel, N. Helbecque, M. Woodward, P. Amouyel, G. D.O. Lowe, and W. Koenig Distributions of C-reactive Protein Measured by High-Sensitivity Assays in Apparently Healthy Men and Women from Different Populations in Europe Clin. Chem., April 1, 2003; 49(4): 669 - 672. [Full Text] [PDF]
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E. S. Ford, W. H. Giles, G. L. Myers, and D. M. Mannino Population Distribution of High-Sensitivity C-reactive Protein among US Men: Findings from National Health and Nutrition Examination Survey 1999-2000 Clin. Chem., April 1, 2003; 49(4): 686 - 690. [Full Text] [PDF]
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T. C. Vukovich, S. Mustafa, H. Rumpold, and O. Wagner Evaluation of a Turbidimetric Denka Seiken C-Reactive Protein Assay for Cardiovascular Risk Estimation and Conventional Inflammation Diagnosis Clin. Chem., March 1, 2003; 49(3): 511 - 512. [Full Text] [PDF]
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M. S. Beattie, M. G. Shlipak, H. Liu, W. S. Browner, N. B. Schiller, and M. A. Whooley C-Reactive Protein and Ischemia in Users and Nonusers of {beta}-Blockers and Statins: Data From the Heart and Soul Study Circulation, January 21, 2003; 107(2): 245 - 250. [Abstract] [Full Text] [PDF]
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 N. Sattar, C. G Perry, and J. R Petrie Type 2 diabetes as an inflammatory disorder The British Journal of Diabetes & Vascular Disease, January 1, 2003; 3(1): 36 - 41. [Abstract] [PDF]
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 I. M. van der Meer, M. P.M. de Maat, A. E. Hak, A. J. Kiliaan, A. I. del Sol, D. A.M. van der Kuip, R. L.G. Nijhuis, A. Hofman, and J. C.M. Witteman C-Reactive Protein Predicts Progression of Atherosclerosis Measured at Various Sites in the Arterial Tree: The Rotterdam Study Stroke, December 1, 2002; 33(12): 2750 - 2755. [Abstract] [Full Text] [PDF]
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J. Middleton Effect of Analytical Error on the Assessment of Cardiac Risk by the High-Sensitivity C-Reactive Protein and Lipid Screening Model Clin. Chem., November 1, 2002; 48(11): 1955 - 1962. [Abstract] [Full Text] [PDF]
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S. Verma, C.-H. Wang, S.-H. Li, A. S. Dumont, P. W.M. Fedak, M. V. Badiwala, B. Dhillon, R. D. Weisel, R.-K. Li, D. A.G. Mickle, et al. A Self-Fulfilling Prophecy: C-Reactive Protein Attenuates Nitric Oxide Production and Inhibits Angiogenesis Circulation, August 20, 2002; 106(8): 913 - 919. [Abstract] [Full Text] [PDF]
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 R.J. de Winter, G.S. Heyde, K.T. Koch, J. Fischer, J.P. van Straalen, M. Bax, C.E. Schotborgh, K.J. Mulder, G.T. Sanders, J.J. Piek, et al. The prognostic value of pre-procedural plasma C-reactive protein in patients undergoing elective coronary angioplasty Eur. Heart J., June 2, 2002; 23(12): 960 - 966. [Abstract] [Full Text] [PDF]
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I. Kushner and A. R. Sehgal Is High-Sensitivity C-Reactive Protein an Effective Screening Test for Cardiovascular Risk? Arch Intern Med, April 22, 2002; 162(8): 867 - 869. [Abstract] [Full Text] [PDF]
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 S. S. Levinson High Density- and Beta-Lipoprotein Screening for Risk of Coronary Artery Disease in the Context of New Findings on Reverse Cholesterol Transport Ann. Clin. Lab. Sci., April 1, 2002; 32(2): 123 - 136. [Abstract] [Full Text] [PDF]
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 G. Sesmilo, W. P. Fairfield, L. Katznelson, K. Pulaski, P. U. Freda, V. Bonert, E. Dimaraki, S. Stavrou, M. L. Vance, D. Hayden, et al. Cardiovascular Risk Factors in Acromegaly before and after Normalization of Serum IGF-I Levels with the GH Antagonist Pegvisomant J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1692 - 1699. [Abstract] [Full Text] [PDF]
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S. S. Levinson and R. J. Elin What Is C-Reactive Protein Telling Us About Coronary Artery Disease? Arch Intern Med, February 25, 2002; 162(4): 389 - 392. [Full Text] [PDF]
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P. Tarkkinen, T. Palenius, and T. Lovgren Ultrarapid, Ultrasensitive One-Step Kinetic Immunoassay for C-Reactive Protein (CRP) in Whole Blood Samples: Measurement of the Entire CRP Concentration Range with a Single Sample Dilution Clin. Chem., February 1, 2002; 48(2): 269 - 277. [Abstract] [Full Text] [PDF]
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G. Sesmilo, K. K. Miller, D. Hayden, and A. Klibanski Inflammatory Cardiovascular Risk Markers in Women with Hypopituitarism J. Clin. Endocrinol. Metab., December 1, 2001; 86(12): 5774 - 5781. [Abstract] [Full Text] [PDF]
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A. Hamwi, T. Vukovich, O. Wagner, H. Rumpold, R. Spies, M. Stich, and C. Langecker Evaluation of Turbidimetric High-Sensitivity C-Reactive Protein Assays for Cardiovascular Risk Estimation Clin. Chem., November 1, 2001; 47(11): 2044 - 2046. [Full Text] [PDF]
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 R. P. Tracy Is Visceral Adiposity the "Enemy Within"? Arterioscler Thromb Vasc Biol, June 1, 2001; 21(6): 881 - 883. [Full Text] [PDF]
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U.-H. Stenman Immunoassay Standardization: Is It Possible, Who Is Responsible, Who Is Capable? Clin. Chem., May 1, 2001; 47(5): 815 - 820. [Full Text] [PDF]
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N. Rifai and P. M. Ridker High-Sensitivity C-Reactive Protein: A Novel and Promising Marker of Coronary Heart Disease Clin. Chem., March 1, 2001; 47(3): 403 - 411. [Abstract] [Full Text] [PDF]
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W. L. Roberts, L. Moulton, T. C. Law, G. Farrow, M. Cooper-Anderson, J. Savory, and N. Rifai Evaluation of Nine Automated High-Sensitivity C-Reactive Protein Methods: Implications for Clinical and Epidemiological Applications. Part 2 Clin. Chem., March 1, 2001; 47(3): 418 - 425. [Abstract] [Full Text] [PDF]
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H. K. Meier-Ewert, P. M. Ridker, N. Rifai, N. Price, D. F. Dinges, and J. M. Mullington Absence of Diurnal Variation of C-Reactive Protein Concentrations in Healthy Human Subjects Clin. Chem., March 1, 2001; 47(3): 426 - 430. [Abstract] [Full Text] [PDF]
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W. Koenig C-Reactive Protein and Cardiovascular Risk: Has the Time Come for Screening the General Population? Clin. Chem., January 1, 2001; 47(1): 9 - 10. [Full Text] [PDF]
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S. Verma, S.-H. Li, M. V. Badiwala, R. D. Weisel, P. W.M. Fedak, R.-K. Li, B. Dhillon, and D. A.G. Mickle Endothelin Antagonism and Interleukin-6 Inhibition Attenuate the Proatherogenic Effects of C-Reactive Protein Circulation, April 23, 2002; 105(16): 1890 - 1896. [Abstract] [Full Text] [PDF]
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