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Articles |
1
Department of Laboratory Medicine, Children’s Hospital,
2
Center for Cardiovascular Disease Prevention, Divisions of Preventive Medicine, and
3
Cardiovascular Diseases, Brigham and Women’s Hospital, and Departments of
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Pathology and
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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; e-mail rifai{at}tch.harvard.edu.
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Abstract |
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 Top Abstract Introductionhs-CRP as a Prognostic...hs-CRP as a Predictor...Predictive Value of hs-CRP...Interpretation of hs-CRP ValuesPotential Preventive TherapiesInterrelationships with Other...Analytical Considerations in the...References |
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Approach: Findings from prospective clinical trials were examined to determine the prognostic utility of CRP in acute coronary syndromes, and observations from epidemiological studies were reviewed to determine the ability of CRP to predict future first coronary events. The analytical considerations of CRP measurement in these clinical applications were also examined.
Content: In patients with established coronary disease, CRP has been shown to predict adverse clinical events. In addition, prospective studies have consistently shown that CRP is a strong predictor of future coronary events in apparently healthy men and women. The relative risk associated with CRP is independent of other cardiovascular disease risk factors. High-sensitivity CRP (hs-CRP) assays are needed for risk assessment of cardiovascular disease. Such assays are currently available but may require further standardization because patients’ results will be interpreted using population-based cutpoints. Preventive therapies to attenuate coronary risk in individuals with increased hs-CRP concentrations include aspirin and statin-type drugs.
Summary: hs-CRP has prognostic utility in patients with acute coronary syndromes and is a strong independent predictor of future coronary events in apparently healthy subjects.
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Introduction |
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TopAbstractIntroductionhs-CRP as a Prognostic...hs-CRP as a Predictor...Predictive Value of hs-CRP...Interpretation of hs-CRP ValuesPotential Preventive TherapiesInterrelationships with Other...Analytical Considerations in the...References |
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Laboratory and clinical evidence has demonstrated that atherosclerosis
is not simply a disease of lipid deposits. Rather, systemic
inflammation also plays a pivotal role in atherothrombotic inception
and progression (1)(2)(3). Mononuclear cells, macrophages, and
T lymphocytes are prominent in atheromatous plaques in the arterial
wall (4)(5)(6)(7). Furthermore, the shoulder region of a plaque,
the most vulnerable site for rupture in acute coronary syndromes, is
heavily infiltrated with inflammatory cells (8)(9)(10).
Cytokines, which cause the de novo hepatic production of acute phase
reactants such as C-reactive protein (CRP) (11), have been
shown to increase in acute coronary syndromes even in the absence of
myocardial necrosis (12). Therefore, CRP has been examined
as a surrogate marker of other inflammatory mediators such as
interleukin-6 and tumor necrosis factor-
to better understand the
inflammatory component of atherosclerosis
(13)(14). Current knowledge, however, suggests
that the CRP concentration might reflect the vulnerability of the
atheromatous lesion and the likelihood of a plaque to rupture
(2)(3)(15). This acute phase
reactant has been studied over the last several years in a wide variety
of atherosclerotic diseases (12)(16)(17)(18)(19)(20). Its
prognostic utility in acute coronary syndromes
(12)(16)(17)(18)(19)(20) and its ability to predict future
coronary events in apparently healthy men and women (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)
have been demonstrated. The development of high-sensitivity CRP
(hs-CRP) assays has been instrumental in exploration of the role of
this acute phase reactant in predicting first cardiovascular events.
Prospective studies have consistently demonstrated a positive
association between hs-CRP and future coronary events. For hs-CRP to
make the transition from clinical research to the routine clinical
setting, however, several important issues must be satisfactorily
addressed: (a) the availability of population-based
cutpoints for interpretation and risk assessment; (b) the
existence of potential therapeutic modalities; and (c) the
reliability of the analytical systems used for measurement.
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hs-CRP as a Prognostic Indicator in Acute Coronary Syndromes |
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TopAbstractIntroductionhs-CRP as a Prognostic...hs-CRP as a Predictor...Predictive Value of hs-CRP...Interpretation of hs-CRP ValuesPotential Preventive TherapiesInterrelationships with Other...Analytical Considerations in the...References |
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Liuzzo et al. (12) showed that in 31 patients with severe unstable angina and no evidence of myocardial necrosis, as documented by the absence of increased cardiac troponin T, hs-CRP concentrations >3 mg/L at admission were associated with an increased incidence of recurrent angina, coronary revascularization, MI, and cardiovascular death. The same group later demonstrated that hs-CRP >3 mg/L at discharge in 53 unstable angina patients was associated with increased readmission for recurrent instability and MI (16). In a similar study of unstable angina, Ferreiros et al. (18) concluded that the prognostic value of hs-CRP measured at discharge was better than that determined at admission in predicting adverse outcome at 90 days. Furthermore, hs-CRP was the strongest independent predictor of adverse events in multivariate analysis. Data from the Thrombolysis In Myocardial Infarction 11A (TIMI 11A), a study of unstable angina and non-Q-wave MI, showed that markedly increased hs-CRP (15.5 mg/L) at presentation in 437 patients was a good predictor of 14-day mortality in that population (19). Furthermore, hs-CRP helped to identify those patients with negative cardiac troponin T (qualitative rapid bedside method with cutoff of <0.2 µg/L) who were at increased risk of mortality (19). Morrow et al. (19) concluded from that study that a strategy for risk stratification using both cardiac troponin T and hs-CRP should be considered. Similar conclusions were reported in a follow-up report by the same group using serum amyloid A, another acute phase reactant, instead of hs-CRP (31). A recent report by de Winter et al. (17) showed that hs-CRP concentrations >5 mg/L at admission in 150 patients with non-ST-elevation acute coronary syndromes were associated with an increased incidence of major cardiac events within 6 months, regardless of cardiac troponin I values.
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hs-CRP as a Predictor of Future Coronary Events |
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TopAbstractIntroductionhs-CRP as a Prognostic...hs-CRP as a Predictor...Predictive Value of hs-CRP...Interpretation of hs-CRP ValuesPotential Preventive TherapiesInterrelationships with Other...Analytical Considerations in the...References |
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Perhaps of greater clinical importance is the demonstration that hs-CRP
concentrations predict first MI and stroke. To date, 10 prospective
studies, 6 in the US and 4 in Europe, have consistently shown that
hs-CRP is a powerful predictor of future first coronary event in
apparently healthy men and women (Fig. 1
). Findings from the Multiple Risk Factors Intervention Trial
(MRFIT) demonstrated a direct positive association between hs-CRP and
CHD mortality in men followed over a 17-year period (RR = 2.8;
95% CI, 1.4–5.4) (22). This relationship, however, was
evident only among smokers. A similar association between hs-CRP and
future coronary events was noted in the Cardiovascular Health Study and
Rural Health Promotion Project, which included men and women over 65
years of age with subclinical cardiovascular disease (26).
The Physicians’ Health Study (PHS) demonstrated similar positive
association between hs-CRP and future coronary events in apparently
healthy men (23). Unlike the observation in MRFIT, however,
this association was evident in both smokers and nonsmokers. This study
showed that those in the highest quartile of hs-CRP had a twofold
higher risk of future stroke (RR = 1.9; 95% CI, 1.1–3.3),
threefold higher risk of future MI (RR = 2.9; 95% CI, 1.8–4.6),
and fourfold higher risk of future peripheral vascular disease (PVD;
RR = 4.1; 95% CI, 1.2–6.0) (23)(28). The
RRs were stable over a long period of time (
6 years) and independent
of other CHD risk factors. The European MONICA (Monitoring Trends and
Determinants in Cardiovascular Disease) Augsburg study showed that an
increase of one standard deviation in the log-transformed value of
hs-CRP was associated with a 50% increase in coronary risk and that
subjects with hs-CRP concentrations in the highest quintile had a
2.6-fold higher risk of developing future coronary events
(21). A recent report from the Helsinki Heart Study
confirmed these observations and demonstrated that those in the highest
quartile of hs-CRP had a more than threefold higher risk of future MI
or cardiac death (RR = 3.56; 95% CI, 1.93–6.57) (27).
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Two reports from the Women’s Health Study (WHS) showed that hs-CRP is a strong predictor of future cardiovascular events in women (RR = 4.4; 95% CI, 2.2–8.9) (24)(25). In stratified analyses, hs-CRP continued to be a strong predictor of future cardiovascular events even among subgroups of women with no history of hyperlipidemia, hypertension, smoking, diabetes, or family history of CHD (25). The hs-CRP concentrations seen in these postmenopausal women were somewhat higher than those reported previously in men. Although no difference in hs-CRP values was noted between premenopausal women and age-matched males, recent reports showed that hormone replacement therapy (estrogen alone or estrogen and progestin) is associated with increased hs-CRP concentrations (33)(34). These findings suggest that the increased hs-CRP seen in the WHS subjects may reflect the influence of hormone replacement therapy rather than the effect of gender.
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Predictive Value of hs-CRP and Other Biochemical Markers for CHD Risk |
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TopAbstractIntroductionhs-CRP as a Prognostic...hs-CRP as a Predictor...Predictive Value of hs-CRP...Interpretation of hs-CRP ValuesPotential Preventive TherapiesInterrelationships with Other...Analytical Considerations in the...References |
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demonstrate that hs-CRP was the single strongest predictor of
risk (RR = 4.4; 95% CI, 2.2–8.9). In comparison, LDL-C, a
well-established marker of CHD, was a lesser predictor of future risk
(RR = 2.4; 95% CI, 1.3–4.6). Furthermore, in a multivariate
analysis that accounted for other CHD risk factors (obesity,
hypertension, diabetes, family history), only hs-CRP and the ratio of
TC to HDL-C had independent predictive value. In the same study of
postmenopausal women (24), hs-CRP was shown to predict risk
among those with LDL-C values <1300 mg/L, a concentration deemed
"desirable" by the current National Cholesterol Education Program
guidelines for primary prevention. In this subgroup (mean LDL-C, 1040
mg/L), the RRs of future MI, stroke, and coronary revascularization in
the lowest to the highest quartiles of hs-CRP were 1.0, 2.4, 2.9, and
4.1, respectively (95% CI for the 4th vs 1st quartile, 1.7–11.3).
After adjustment for other CHD risk factors and concentration of HDL-C,
the RR associated with hs-CRP remained highly significant (RR =
3.1; 95% CI, 1.1–8.3) and increased 
39% with each increasing
quartile of hs-CRP. This study thus demonstrated that hs-CRP can
identify individuals at increased risk of developing future coronary
events who otherwise would be missed if only lipid measurements were
used. Other examined markers of inflammation, e.g., serum amyloid A,
interleukin-6, and soluble intercellular adhesion molecule-1, showed
consistent association but a slightly weaker RR of future coronary
events.
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The predictive value of hs-CRP in men and women increased considerably
when evaluated in models that included lipid values. Data from the PHS
demonstrated that, compared with those with TC and hs-CRP below the
75th percentile, those with increased TC alone had a 2.3-fold increase
in risk (95% CI, 1.5–3.7), whereas those with increased hs-CRP alone
had a 1.5-fold increase in risk (95% CI, 0.9–2.4) (35). In
contrast, the risk of developing coronary events increased 5-fold (95%
CI, 2.5–9.8) among those with high concentrations of both TC and
hs-CRP. Therefore, the joint effects of both risk factors are greater
than the product of the individual effects of each risk factor
considered alone. Furthermore, when the study participants were
stratified according to quintile of hs-CRP and quintile of TC:HDL-C
ratio, the RR of first coronary event in those in the highest quintiles
of both hs-CRP and TC:HDL-C ratio was approximately ninefold higher
than that of men in the lowest quintiles of these analytes. Data from
the WHS demonstrated similar findings such that women in the highest
quintile of both hs-CRP and TC:HDL-C ratio had a RR more than eightfold
higher than that of women in the lowest quintiles (Fig. 3
). In all of these analyses, risk prediction models that
incorporated lipids were significantly better (P <0.001)
than those based on hs-CRP alone (24).
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Interpretation of hs-CRP Values |
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TopAbstractIntroductionhs-CRP as a Prognostic...hs-CRP as a Predictor...Predictive Value of hs-CRP...Interpretation of hs-CRP ValuesPotential Preventive TherapiesInterrelationships with Other...Analytical Considerations in the...References |
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The within-person biologic variability of hs-CRP is low over a long
period of time (36). Laboratory measurements on paired
samples obtained from 236 subjects at baseline and 5 years later showed
that an individual’s log-normalized hs-CRP concentrations are highly
correlated (r = 0.60). Somewhat comparable correlation
coefficients were noted for TC (r = 0.37), LDL-C
(r = 0.32), HDL-C (r = 0.74), and
triglycerides (r = 0.49) over the 5-year follow-up
period. This finding lends further support to the fact that hs-CRP is a
good and biologically stable predictor of future MI despite the fact
that it is an acute phase reactant, providing that the patient is not
suffering from an active infection or using a drug that affects hs-CRP
concentration. hs-CRP values >15 mg/L (99th percentile of the
general population) indicate an active inflammation; patients
should be advised to have a repeat measurement in 2–3 weeks or after
the infection in resolved.
As indicated earlier, models containing both hs-CRP and TC or the
TC:HDL-C ratio were better able to predict future first coronary events
than those containing hs-CRP alone. The RRs of future first coronary
events for men and women as well as lipid concentrations were computed
in quintiles from the PHS and WHS databases, respectively, and are
presented in Fig. 3
. Because the computed RRs did not vary
significantly between men and women, a single risk assessment algorithm
is suggested for both genders (Table 1
) (37). The hs-CRP concentrations were derived from
ongoing population-based surveys. It is important to note that it is
not necessary in this case to report the actual hs-CRP concentration to
the clinician but only the patient’s RR. The clinical laboratory
should play an active role in the interpretation and implementation of
this clinical application. Providing incomplete information or just the
actual hs-CRP concentration will only frustrate and prevent the
clinician from correctly interpreting the data and managing the
patient.
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Potential Preventive Therapies |
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TopAbstractIntroductionhs-CRP as a Prognostic...hs-CRP as a Predictor...Predictive Value of hs-CRP...Interpretation of hs-CRP ValuesPotential Preventive TherapiesInterrelationships with Other...Analytical Considerations in the...References |
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Among apparently healthy men in the PHS with increased hs-CRP (>2.1 mg/L), aspirin use decreased the risk of future MI by almost 60% (23). In contrast, aspirin use was associated with a much smaller, although statistically significant, 14% decrease in future MI among men with low hs-CRP (<0.55 mg/L). Although the magnitude of reduction in future risk of MI depended on the concentration of hs-CRP, it is important to note that all subjects benefited from aspirin use. These findings suggest that aspirin was acting not only as an antiplatelet agent but also as an antiinflammatory drug.
Similar findings were also noted with pravastatin use in the CARE study (32). As indicated earlier, CARE is a prospective study of men and women with average lipid concentrations who have suffered an MI. Participants were randomized between 40 mg of pravastatin per day and placebo and followed for 5 years (38). Study participants with high hs-CRP (>9.9 mg/L or 90th percentile) at baseline experienced a reduction of 54% in the incidence of recurrent coronary events compared with a reduction of 25% in those with low hs-CRP (<9.9 mg/L or 90th percentile), although baseline lipid values were almost identical in the two groups. Moreover, during the 5-year follow-up, pravastatin lowered mean hs-CRP by almost 40%. This represented a 22% difference at 5 years in median hs-CRP between the pravastatin and placebo groups. Furthermore, the magnitude of change in hs-CRP appeared to be unrelated to that of LDL-C in both the pravastatin and placebo groups. These findings suggest that pravastatin may have antiinflammatory characteristics that are independent from its lipid-lowering property. Clinical trials are currently ongoing to further explore the interaction between pravastatin, aspirin, and the inflammatory response in primary and secondary prevention settings.
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Interrelationships with Other CHD Risk Factors |
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TopAbstractIntroductionhs-CRP as a Prognostic...hs-CRP as a Predictor...Predictive Value of hs-CRP...Interpretation of hs-CRP ValuesPotential Preventive TherapiesInterrelationships with Other...Analytical Considerations in the...References |
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Analytical Considerations in the Measurement of hs-CRP |
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TopAbstractIntroductionhs-CRP as a Prognostic...hs-CRP as a Predictor...Predictive Value of hs-CRP...Interpretation of hs-CRP ValuesPotential Preventive TherapiesInterrelationships with Other...Analytical Considerations in the...References |
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90th percentile of the general population) to
well over 200 mg/L. Such traditional assays, however, do not have
appropriate sensitivity in the range required for the determination of
cardiovascular risk in apparently healthy men and women. To achieve the desired limit of quantification, manufacturers and investigators have continued to use immunochemical techniques in their attempts to measure hs-CRP, but with modifications to increase the detectable signal. Several approaches have been used, including the labeling of anti-CRP antibodies with either an enzyme (ELISA) or a fluorescent compound, and attaching the antibodies, either monoclonal or polyclonal, to polystyrene beads (50)(51)(52)(53)(54)(55). The latter approach was popular among manufacturers because it enabled the adaptation to commonly used automated analyzers in clinical chemistry laboratories. Currently, hs-CRP concentrations as low as 0.15 mg/L (<2.5th percentile of the general population) can be reliably measured. It is important to note, however, that not all hs-CRP assays possess a similar sensitivity or lower limit of quantification (56). For practical considerations, it is advisable to have a single CRP assay in the clinical laboratory that is capable of measuring low and high concentrations. However, if that is impossible, clinicians should be aware of the availability of two different CRP assays and request hs-CRP for cardiovascular risk prediction purpose.
Because the hs-CRP value of an individual patient is interpreted in the context of cutpoints established by prospective clinical studies, standardization of hs-CRP assays is crucial. Poor agreement among methods will lead to misclassification and mismanagement of patients. Recent reports have indicated that the measurement of low hs-CRP concentrations is not consistent among various methods, suggesting that standardization efforts are needed (51)(56). In one case where a significant bias was noted between two methods (51), the manufacturers of both reagent systems claimed to have their calibrators traceable to the WHO reference materials. Unfortunately, this is not an unusual occurrence. Although manufacturers attempt to standardize their assays using the WHO calibrators, they often fail to follow the appropriate value transfer protocol from the reference materials to their own calibrators (57). Invariably, this leads to suboptimal standardization.
An in-house hs-CRP ELISA method (52), utilizing polyclonal antibodies from Calbiochem, was used in MRFIT, the Cardiovascular Health Study, and the Rural Health Promotion Project as well as in the early work from the PHS. The analytical performance and clinical efficacy of the ELISA assay were compared with those of an automated and commercially available latex-enhanced method (Dade Behring) (51) used at present in several prospective studies, including the PHS, WHS, Women’s Health Initiative, Nurses’ Health Study, Health Professionals’ Study, and Texas/Air Force Coronary Atherosclerosis Prevention Study (58). The two assays were evaluated using plasma samples from the PVD cohort of the PHS in a nested case-control design. Excellent analytical agreement between the two methods was reported (slope = 0.99; intercept = 0.36 mg/L; r = 0.95) (58). In addition, for both methods, the calculated RRs of developing future PVD increased significantly with each increasing quartile of hs-CRP. The calculated interquartile increase in RR of PVD was 31% (95% CI, 5.2–62.2) for the ELISA and 34% (95% CI, 8.2–66.1) for the latex-enhanced method. Furthermore, all but two participants were classified into concordant quartiles or varied by only one quartile. This study demonstrated comparable clinical efficacy of the two methods and linked the earlier and the current data, thus assuring consistency among reported hs-CRP values. On the basis on this report, the US Food and Drug Administration approved the use of this latex-enhanced method in the risk assessment of cardiovascular disease. Therefore, this latex-enhanced method is usually used as the reference procedure when comparison studies of various hs-CRP assays are conducted. At present, only a few hs-CRP methods are commercially available. However, several assays are currently under development or evaluation and are expected to be available for routine clinical use in the very near future.
conclusion
hs-CRP is a very promising novel biochemical marker for the
prediction of future first or recurrent coronary events. American and
European prospective studies have been highly consistent regarding the
ability of hs-CRP to predict future CHD risk in both men and women.
Potential preventive therapeutic modalities to attenuate coronary risk
in those with increased hs-CRP concentrations have been suggested. The
potential use of hs-CRP as a means to improve the cost-to-benefit ratio
in statin therapy is currently under investigation. Although
standardization of hs-CRP measurement at the lower concentration range
among various methods should be addressed, a robust and Food and Drug
Administration-approved method is currently available. Several other
sensitive assays are under development and are expected to be
commercially available soon.
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Footnotes |
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References |
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) and 95% CIs (lines) are
computed for those in the top compared with the bottom quartile. Data
from Refs. (
