Background Since inflammation is believed to have a role inthe pathogenesis of cardiovascular events, measurement of markersof inflammation has been proposed as a method to improve theprediction of the risk of these events.
Methods We conducted a prospective, nested case–controlstudy among 28,263 apparently healthy postmenopausal women overa mean follow-up period of three years to assess the risk ofcardiovascular events associated with base-line levels of markersof inflammation. The markers included high-sensitivity C-reactiveprotein (hs-CRP), serum amyloid A, interleukin-6, and solubleintercellular adhesion molecule type 1 (slCAM-1). We also studiedhomocysteine and several lipid and lipoprotein measurements.Cardiovascular events were defined as death from coronary heartdisease, nonfatal myocardial infarction or stroke, or the needfor coronary-revascularization procedures.
Results Of the 12 markers measured, hs-CRP was the strongestunivariate predictor of the risk of cardiovascular events; therelative risk of events for women in the highest as comparedwith the lowest quartile for this marker was 4.4 (95 percentconfidence interval, 2.2 to 8.9). Other markers significantlyassociated with the risk of cardiovascular events were serumamyloid A (relative risk for the highest as compared with thelowest quartile, 3.0), slCAM-1 (2.6), interleukin-6 (2.2), homocysteine(2.0), total cholesterol (2.4), low-density lipoprotein (LDL)cholesterol (2.4), apolipoprotein B-100 (3.4), high-densitylipoprotein (HDL) cholesterol (0.3), and the ratio of totalcholesterol to HDL cholesterol (3.4). Prediction models thatincorporated markers of inflammation in addition to lipids weresignificantly better at predicting risk than models based onlipid levels alone (P<0.001). The levels of hs-CRP and serumamyloid A were significant predictors of risk even in the subgroupof women with LDL cholesterol levels below 130 mg per deciliter(3.4 mmol per liter), the target for primary prevention establishedby the National Cholesterol Education Program. In multivariateanalyses, the only plasma markers that independently predictedrisk were hs-CRP (relative risk for the highest as comparedwith the lowest quartile, 1.5; 95 percent confidence interval,1.1 to 2.1) and the ratio of total cholesterol to HDL cholesterol(relative risk, 1.4; 95 percent confidence interval, 1.1 to1.9).
Conclusions The addition of the measurement of C-reactive proteinto screening based on lipid levels may provide an improved methodof identifying women at risk for cardiovascular events.
Half of all myocardial infarctions occur in persons in whomplasma lipid levels are normal.1 In an effort to better identifypatients at high risk for cardiovascular events, several markersof risk have been proposed for use in screening, including homocysteineand fibrinogen levels, fibrinolytic capacity, and levels ofapolipoprotein A-I, apolipoprotein B-100, and Lp(a) lipoprotein.However, the clinical value of many of these markers has beenlimited because of inadequate standardization of assay conditions,inconsistency of prospective data, or lack of evidence of significantimprovement in the prediction of risk over that afforded bystandard lipid screening alone.2
With the recognition that atherosclerosis is an inflammatoryprocess,3 several plasma markers of inflammation have also beenevaluated as potential tools for prediction of the risk of coronaryevents. Among them are markers of systemic inflammation producedin the liver, such as high-sensitivity C-reactive protein (hs-CRP)and serum amyloid A; cytokines such as interleukin-6; and adhesionmolecules such as soluble intercellular adhesion molecule type1 (sICAM-1).4,5,6,7,8,9,10,11 However, as with other proposedpredictors of the risk of cardiovascular events, the prognosticvalue of these markers of inflammation remains uncertain. Forexample, a widely held clinical view is that levels of markersof inflammation vary too greatly over time to allow accurateprediction of risk. Furthermore, few prospective studies havemeasured all these markers of inflammation in a single groupof patients, so the relative usefulness of each marker cannotbe easily evaluated. In addition, data supporting the hypothesisthat markers of inflammation significantly increase the predictivevalue of lipid screening are scant and are limited almost exclusivelyto data from studies of hs-CRP in middle-aged men.7,12 Finally,clinical application of these findings has been limited, sincestandardized, commercial assays for most markers of inflammationare only now being developed.
In a previous study, in which we used an experimental assayfor hs-CRP, we found higher levels of this marker among healthypostmenopausal women participating in the Women's Health Studywho subsequently had cardiovascular events than among thosewho did not have such events.13 On the basis of that findingand in the effort to address the clinical issues outlined above,we used a commercial assay to measure hs-CRP in the same cohortand simultaneously measured plasma levels of serum amyloid A,interleukin-6, sICAM-1, total cholesterol, low-density lipoprotein(LDL) cholesterol, high-density lipoprotein (HDL) cholesterol,the ratio of total cholesterol to HDL cholesterol, apolipoproteinA-I, and apolipoprotein B-100. In addition, to allow comparisonwith other proposed markers, we measured plasma levels of Lp(a)lipoprotein and homocysteine. We thus were able to evaluatedirectly the relative value of each of these 12 measurementsas an independent predictor of future cardiovascular eventsin a large cohort of apparently healthy women. We also soughtto determine whether the measurement of markers of inflammationin addition to standard screening of lipid levels might providea clinically useful method for improving overall predictionof the risk of cardiovascular events.
Methods
Study Participants
We designed a prospective, nested case–control study involvingparticipants in the Women's Health Study, an ongoing trial ofaspirin and vitamin E for primary prevention among postmenopausalwomen with no history of cardiovascular disease or cancer.14Blood samples were collected in tubes containing EDTA at baseline from 28,263 women (71 percent of the Women's Health Studyparticipants) and stored in liquid nitrogen until the time ofanalysis.
For this analysis, case subjects were study participants fromwhom a base-line blood sample was obtained who subsequentlyhad a cardiovascular event (defined as death from coronary heartdisease, nonfatal myocardial infarction or stroke, or a coronary-revascularizationprocedure) during a mean follow-up period of three years. Myocardialinfarction was classified as confirmed if symptoms met the criteriaof the World Health Organization15 and if the event was associatedwith abnormal levels of cardiac enzymes or diagnostic electrocardiographicchanges. Stroke was classified as confirmed if the patient hada new neurologic deficit that lasted more than 24 hours. Computedtomographic scans or magnetic resonance images were availablefor the majority of women in whom stroke occurred. Performanceof revascularization procedures was confirmed by review of hospitalrecords. Death from coronary heart disease was confirmed byreview of the autopsy report, the death certificate, medicalrecords, or information from family members regarding the circumstancesof death.
For each woman who had a confirmed cardiovascular event duringfollow-up, two control subjects of the same age (within oneyear) and smoking status (former smoker, current smoker, ornonsmoker) were selected from among the remaining study participantsfrom whom a base-line blood sample had been obtained and whoremained free of reported cardiovascular disease during follow-up.With use of these criteria, 122 case subjects and 244 controlsubjects were selected.
Procedures
Base-line plasma samples from each woman with an event and eachcontrol subject were thawed and assayed for hs-CRP, serum amyloidA, and Lp(a) lipoprotein with use of latex-enhanced immunonephelometricassays on a BN II analyzer (Dade Behring, Newark, Del.). ApolipoproteinA-I and apolipoprotein B-100 were simultaneously measured withthis device by immunoassay. Total cholesterol, HDL cholesterol,and directly obtained LDL cholesterol levels were measured ona Hitachi 911 analyzer (Roche Diagnostics, Indianapolis) withreagents from Roche Diagnostics and Genzyme (Cambridge, Mass.).Plasma levels of sICAM-1 and interleukin-6 were measured byenzyme-linked immunosorbent assay (R & D Systems, Minneapolis),and the total plasma homocysteine level was measured with anIMx homocysteine assay (Abbott Laboratories, Abbott Park, Ill.)as previously reported.16 Samples were handled in identicaland in blinded fashion throughout the study. Samples were analyzedin triplicate and in random order so as to reduce systematicbias and interassay variation.
Statistical Analysis
Means and proportions for risk factors for cardiovascular eventsat base line were calculated for women who had cardiovascularevents during follow-up and those who did not. The significanceof differences in means between the two groups was assessedwith Student's t-test, and the significance of differences inproportions was tested with use of the chi-square statistic.Analysis of trends was used to test for associations betweenincreasing levels of each plasma variable and the risk of futurecardiovascular events, after the sample was divided into quartilesaccording to the distribution of control values for that marker.Adjusted risk estimates were obtained with use of logistic-regressionmodels that, in addition to accounting for the variables usedfor matching (age and smoking status), adjusted for random assignmentto aspirin or vitamin E in the Women's Health Study; severalrisk factors for cardiovascular events, including a historyof hypertension, body-mass index, a history of diabetes, anda parental history of myocardial infarction before the age of60 years; and other measured plasma markers.
We evaluated the combined role of lipid levels and markers ofinflammation as predictors of the risk of future cardiovascularevents in a series of analyses in which we explored the sensitivityand robustness of our findings from a clinical perspective.First, we used the likelihood-ratio test to determine whetherlogistic-regression models that included measurements of lipidvariables and markers of inflammation provided a significantlybetter fit than did logistic-regression models limited to lipidmeasurements alone. Second, to estimate the clinical relevanceof these effects, we computed the area under receiver-operating-characteristiccurves for prediction models based on lipid measurements aloneand for models based on measurements of both lipid levels andmarkers of inflammation. Third, we divided the study participantsinto nine groups according to low, medium, and high levels oftotal cholesterol and low, medium, and high levels of each markerof inflammation. In these analyses, logistic regression wasused to evaluate simultaneously the risk of future cardiovascularevents in each of the nine groups; the group of women in thelowest third for total cholesterol and in the lowest third forthe respective marker of inflammation was considered the referencegroup. Finally, to address the clinical need for improved assessmentof risk among persons with cholesterol levels currently consideredsafe, we performed a subgroup analysis of study participantswith LDL cholesterol levels of less than 130 mg per deciliter(3.4 mmol per liter), the target level for the primary preventionof coronary heart disease according to the current guidelinesof the National Cholesterol Education Program.17
All P values were two-tailed, and values of less than 0.05 wereconsidered to indicate statistical significance. All confidenceintervals were calculated at the 95 percent level.
Results
The base-line characteristics of the women who subsequentlyhad cardiovascular events (case subjects) and those who remainedfree of reported cardiovascular disease (controls) are shownin Table 1. As expected, women who had cardiovascular eventswere heavier at base line than those who remained free of cardiovasculardisease and were more likely to have hypertension, diabetes,or a parental history of premature myocardial infarction (beforethe age of 60 years). The frequency of exercise, the frequencyof alcohol consumption, and rate of use of hormone-replacementtherapy were similar in the two groups. Because of matching,the women who had cardiovascular events and the control subjectswere virtually identical with respect to mean age and smokingstatus.
Table 1. Base-Line Clinical Characteristics of the Study Participants.
Base-line plasma levels of the inflammation markers hs-CRP (P<0.001),serum amyloid A (P=0.003), sICAM-1 (P=0.03), and interleukin-6(P=0.003) were higher among the women who subsequently had cardiovascularevents than among those who did not (Table 2). Similarly, base-lineplasma levels of total cholesterol (P=0.01), LDL cholesterol(P=0.003), apolipoprotein B-100 (P<0.001), and homocysteine(P=0.02) and the ratio of total cholesterol to HDL cholesterol(P<0.001) were significantly higher among women with subsequentevents than those without such events, whereas levels of HDLcholesterol were significantly lower among women with subsequentevents (P<0.001). Base-line levels of Lp(a) lipoprotein weresomewhat higher and levels of apolipoprotein A-I somewhat loweramong the women with events than among control subjects, butthese differences were not significant.
Table 2. Base-Line Plasma Levels of Markers of Inflammation and Lipids.
Table 3 shows the relative risks of cardiovascular events accordingto the quartile of each marker of inflammation or lipid measuredin plasma. Measurements of hs-CRP, serum amyloid A, sICAM-1,and interleukin-6 were predictive of the risk of future cardiovascularevents. Of the 12 measures, the level of hs-CRP was the mostpowerful predictor of risk in the univariate analysis (relativerisk for women in the highest quartile as compared with thelowest quartile, 4.4; 95 percent confidence interval, 2.2 to8.9; P<0.001). Of the lipid variables, the ratio of totalcholesterol to HDL cholesterol (relative risk, 3.4; P=0.001)and the apolipoprotein B-100 level (relative risk, 3.4; P=0.001)were the most powerful predictors of risk. Nonsignificant trendswere observed for apolipoprotein A-I and Lp(a) lipoprotein.As reported previously,16 increasing levels of homocysteinewere also associated with increased risk.
Table 3. Relative Risk of Cardiovascular Events According to Base-Line Plasma Levels of Markers of Inflammation and Lipids.
Levels of several markers of inflammation were highly correlated.For example, the correlation coefficient for the relation betweenhs-CRP and serum amyloid A was 0.81 (P<0.001). In contrast,correlations between markers of inflammation and lipid measureswere low; less than 10 percent of the variance in any markerof inflammation was explained by any of the lipid measures.
To determine the independent predictive value of each of the12 measures, we performed a series of logistic-regression analysesthat simultaneously controlled for increasing quartiles of hs-CRP,serum amyloid A, sICAM-1, interleukin-6, homocysteine, and Lp(a)lipoprotein and the ratio of total cholesterol to HDL cholesterol(because of colinearity with this ratio, levels of apolipoproteinA-I, apolipoprotein B-100, and LDL cholesterol were not includedin these analyses). As shown in Table 4, only the level of hs-CRPand the ratio of total cholesterol to HDL cholesterol were foundto be independent predictors of risk in models in which womenwere matched for smoking status and age or in models that includedfurther adjustments for body-mass index, hypertension, diabetes,and parental history of premature coronary artery disease. Insimilar models that were limited to markers of inflammation,hs-CRP remained an independent predictor of the risk of futurecardiovascular events. In contrast, the beta coefficients associatedwith serum amyloid A, sICAM-1, and interleukin-6 decreased substantiallyand were no longer statistically significant in analyses thatincluded control for the quartile of hs-CRP.
Table 4. Adjusted Relative Risk of Cardiovascular Events Associated with an Increase of One Quartile in the Concentration of Each Plasma Marker.
To explore whether any of the markers of inflammation addedto the predictive value of lipid-based screening, several additionalanalyses were performed. First, we computed the relative riskof cardiovascular events in analyses in which study participantswere stratified into nine groups according to total cholesterollevel as well as each marker of inflammation. As shown in Figure 1,for each marker of inflammation included in this analysis,the risk of cardiovascular events was lowest among women withlow total cholesterol levels and low levels of the marker inquestion. In contrast, the risk tended to be highest among womenwith high total cholesterol levels and high levels of a markerof inflammation. However, even among the women with low totalcholesterol levels, the risk of cardiovascular events was significantlyhigher among those with high levels of hs-CRP and serum amyloidA than among those with low levels of these markers (Figure 1).These associations were also evident, but to a lesser extent,for interleukin-6 and sICAM-1. In all of the analyses, theseadditive effects were robust with respect to the choice of cutoffpoint and the choice of the lipid variable analyzed. For example,the addition of hs-CRP to lipid screening produced a significantand additive predictive effect when regression analyses werebased on cutoff points for quartiles (rather than cutoff pointsfor the division of the study group into thirds) and on analysisof the ratio of total cholesterol to HDL cholesterol (ratherthan on total cholesterol alone).
Figure 1. Relative Risk of Cardiovascular Events among Apparently Healthy Postmenopausal Women According to Base-Line Levels of Total Cholesterol and Markers of Inflammation.
Each marker of inflammation improved risk-prediction models based on lipid testing alone, an effect that was strongest for hs-CRP and serum amyloid A.
Second, likelihood-ratio tests were used to compare the fitof predictive models that were based on measurement of a markerof inflammation in combination with lipids to the fit of modelsbased on lipid measurements alone. In these analyses, each ofthe markers of inflammation significantly improved the usefulnessof lipid screening in predicting risk. For example, models includingboth hs-CRP and total cholesterol were significantly betterin the prediction of the risk of cardiovascular events thanwere models including only total cholesterol (P<0.001). Likewise,models involving both hs-CRP and the ratio of total cholesterolto HDL cholesterol allowed significantly better prediction ofrisk than did models based solely on this lipid ratio alone(P<0.001). Similar additive effects were seen for serum amyloidA, sICAM-1, and interleukin-6 when these markers were addedto models based on total cholesterol or the ratio of total cholesterolto HDL cholesterol alone (P<0.01 for all comparisons).
Third, as a measure of clinical usefulness, we computed thearea under the receiver-operating-characteristic curve associatedwith risk-prediction models based on lipid screening alone andcompared it with those based on a combination of lipids andmarkers of inflammation. In these analyses, the use of hs-CRPlevels in addition to total cholesterol increased the area underthe receiver-operating-characteristic curve from 0.59 to 0.66(P<0.001) and in addition to the ratio of total cholesterolto HDL cholesterol increased the area under the curve from 0.64to 0.68 (P<0.001). Similar effects were observed for analysesthat included serum amyloid A, sICAM-1, and interleukin-6: theaddition of these markers to screening based on total cholesterolincreased the area under the curve from 0.59 to 0.63, 0.63,and 0.64, respectively (P<0.003 for all three comparisons).Use of the serum amyloid A level in addition to the ratio oftotal cholesterol to HDL cholesterol increased the area underthe curve from 0.64 to 0.67 (P=0.007); the use of sICAM-1 inaddition to this ratio led to a smaller change (area under thecurve, 0.65; P=0.01), as did the use of interleukin-6 (areaunder the curve, 0.65; P=0.01).
Finally, to address the clinical observation that many personswith "safe" lipid levels nonetheless have cardiovascular events,we performed a subgroup analysis limited to women whose levelsof LDL cholesterol were less than 130 mg per deciliter, thetarget level currently recommended for primary prevention ofcoronary heart disease by the National Cholesterol EducationProgram.17 In this analysis, women with increased base-linelevels of hs-CRP, serum amyloid A, interleukin-6, or sICAM-1were found to be at increased risk for future cardiovascularevents. This effect was strongest for hs-CRP and serum amyloidA. In this subgroup, the relative risks of cardiovascular eventsfor women in the lowest to the highest quartiles of hs-CRP were1.0, 2.4, 2.9, and 4.1 (95 percent confidence interval for womenin the highest as compared with the lowest quartile, 1.7 to11.3; P=0.002; P for trend across quartiles, 0.005). After adjustmentfor body-mass index, the presence or absence of hypertension,diabetes, or a parental history of premature myocardial infarction,and the level of HDL cholesterol, the increased risk for womenin the highest quartile of hs-CRP at base line remained statisticallysignificant (relative risk, 3.1; 95 percent confidence interval,1.1 to 8.3; P=0.03). Thus, even among women with "safe" levelsof LDL cholesterol, the adjusted relative risk of cardiovascularevents increased approximately 39 percent with each increasingquartile for hs-CRP (95 percent confidence interval, 13 to 89percent; P=0.03). The mean LDL cholesterol level in this subgroupanalysis was 104 mg per deciliter (2.7 mmol per liter).
Discussion
In this prospective study of apparently healthy postmenopausalwomen, four markers of inflammation — hs-CRP, serum amyloidA, interleukin-6, and sICAM-1 — were found to be significantpredictors of the risk of future cardiovascular events. In addition,measurement of these markers increased the predictive valueof models based only on standard lipid screening. Of the 12plasma measures evaluated in this study, hs-CRP was the mostsignificant predictor of the risk of cardiovascular events;when measured with a widely available, standardized commercialassay,18 this marker distinguished between women at high riskand those at low risk, even in the subgroup of women with LDLcholesterol levels below 130 mg per deciliter (mean, 104 mgper deciliter), the target considered safe in the current guidelinesof the National Cholesterol Education Program.17
The results of the current study have several important implications.First, the findings confirm that in women, markers of inflammationare important predictors of the risk of cardiovascular events.Previous data on this issue have been derived largely from studiesof middle-aged men.4,5,6,7,8,9,10,11 Thus, from a pathophysiologicperspective, the current data support the hypothesis that atherosclerosisis, in part, an inflammatory disease.3
Second, because we used a commercially available assay to measureplasma hs-CRP,18 our results provide clinically relevant confirmationof previous findings in this cohort, which were obtained withuse of an experimental assay.13 The commercial assay is inexpensiveand can be used with standard hospital and outpatient laboratoryequipment; thus, screening for this predictor of cardiovascularrisk would be practical in many clinical settings.
Third, we believe the current results have public health implicationsboth in terms of the prediction of the risk of cardiovascularevents and in terms of the use of inhibitors of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase for primary prevention. Althoughthe results of large-scale randomized trials have indicatedthat HMG-CoA reductase inhibition is effective even among personsat low-to-moderate risk as defined by standard lipid screening,19,20the large number of patients who would need to be treated andthe high cost of this approach have limited the clinical applicationof those findings. Thus, our observation that measurement ofmarkers of inflammation such as hs-CRP can significantly improvemodels for the prediction of cardiovascular risk may lead tobetter clinical identification of patients who might benefitfrom primary prevention and for whom the cost-to-benefit ratiofor long-term use of statins would be improved. This issue isparticularly intriguing because recent data from the Cholesteroland Recurrent Events trial indicate that long-term therapy withpravastatin significantly lowers plasma levels of hs-CRP21 andthat the efficacy of pravastatin in lowering the rate of cardiovascularevents is greatest in those with increased levels of hs-CRP.22As in the current findings, which indicate that hs-CRP is apotent predictor of risk regardless of the LDL cholesterol level,data from the Cholesterol and Recurrent Events trial indicatethat use of pravastatin resulted in decreased levels of hs-CRPin a manner largely independent of LDL cholesterol.21
Several limitations of these analyses merit consideration. First,our cohort comprised apparently healthy postmenopausal women,and thus the results may not apply to younger women, who mayalso be at increased risk for cardiovascular events. Second,we measured each marker of inflammation at study entry and thuscould not evaluate the effects of changes in the levels of thesemarkers over time. However, follow-up studies have found thatlevels of hs-CRP are stable over long periods, as long as measurementsare not made within two to three weeks of an acute infection.21,23Moreover, with respect to the current results, variation overtime in levels of these markers and regression dilution biaswould tend, if anything, to lead to an underestimation of neteffects. Finally, although base-line levels of several markersof inflammation were greater than normal among women at riskfor future cardiovascular events, the mechanisms underlyingthese elevations remain uncertain. In this study, we did notfind significant associations between cardiovascular risk andtiters of IgG antibodies against Chlamydia pneumoniae,Helicobacterpylori, herpes simplex virus, or cytomegalovirus or betweentiters of these antibodies and plasma levels of hs-CRP.24 Onthe other hand, markers of inflammation, including hs-CRP, interleukin-6,and interleukin-1–receptor antagonist,25,26,27,28,29,30,31have proved to have predictive value among persons with unstableangina or acute coronary syndromes. Thus, it is also possiblethat the inflammation that we detected in apparently healthywomen who were at risk for future cardiovascular events maybe an indirect marker of an enhanced cytokine response to avariety of inflammatory stim-uli that ultimately prove criticalat the time of acute plaque rupture.32
In conclusion, in this prospective evaluation of 12 plasma variables,hs-CRP proved to be the strongest and most significant predictorof the risk of future cardiovascular events. As in previouspopulation-based epidemiologic studies, half of all cardiovascularevents in our cohort occurred among women without overt hyperlipidemia.Thus, these data raise the possibility that the addition ofhs-CRP to standard lipid screening will generate an improvedmethod for identifying persons at high risk for future cardiovascularevents, who would thus be candidates for primary-preventioninterventions such as the use of HMG-CoA reductase inhibitors.
Drs. Ridker and Hennekens are named as coinventors on a pendingpatent application filed by Brigham and Women's Hospital onthe use of markers of inflammation in coronary artery disease.
Supported by grants (HL58755 and HL43851) from the NationalHeart, Lung, and Blood Institute, by a grant (CA47988) fromthe National Cancer Institute, and by an Established InvestigatorAward from the American Heart Association (to Dr. Ridker).
Source Information
From the Center for Cardiovascular Disease Prevention (P.M.R.) and the Divisions of Cardiology (P.M.R.) and Preventive Medicine (P.M.R., C.H.H., J.E.B.), Brigham and Women's Hospital and Harvard Medical School, Boston; and the Department of Pathology, Children's Hospital Medical Center and Harvard Medical School, Boston (N.R.).
Address reprint requests to Dr. Ridker at Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115, or at pridker{at}rics.bwh.harvard.edu.
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A correction has been published: N Engl J Med 2000;343(7):512.
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