Brief Rapid Communication
Prospective Study of C-Reactive Protein and the Risk of
Future Cardiovascular Events Among
Apparently Healthy Women
Paul M. Ridker, MD; Julie E. Buring, ScD; Jessie Shih, PhD;
Mathew Matias, BS; Charles H. Hennekens, MD
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
Background—C-reactive protein (CRP) predicts risk of myocardial infarction (MI) and stroke among apparently healthy
men, but in women, virtually no data are available.
Methods and Results—CRP was measured in baseline blood samples from 122 apparently healthy participants in the
Women’s Health Study who subsequently suffered a first cardiovascular event and from 244 age- and smoking-matched
control subjects who remained free of cardiovascular disease during a 3-year follow-up period. Women who developed
cardiovascular events had higher baseline CRP levels than control subjects (P50.0001), such that those with the highest
levels at baseline had a 5-fold increase in risk of any vascular event (RR54.8; 95% CI, 2.3 to 10.1; P50.0001) and a
7-fold increase in risk of MI or stroke (RR57.3; 95% CI, 2.7 to 19.9; P50.0001). Risk estimates were independent of
other risk factors, and prediction models that included CRP provided a better method to predict risk than models that
excluded CRP (all P values ,0.01). In stratified analyses, CRP was a predictor among subgroups of women with low
as well as high risk as defined by other cardiovascular risk factors.
Conclusions—In these prospective data among women, CRP is a strong independent risk factor for cardiovascular disease
that adds to the predictive value of risk models based on usual factors alone. (Circulation. 1998;98:731-733.)
Key Words: C-reactive protein n inflammation n cardiovascular diseases
C
-reactive protein (CRP) is a marker for inflammation that
appears to predict cardiovascular events among apparently healthy men. For example, in the prospective Physicians’ Health Study (PHS), high plasma concentration of
CRP was associated with a 2-fold increase in risk of stroke, a
3-fold increase in risk of myocardial infarction (MI), and a
4-fold increase in risk of developing peripheral vascular
disease.1,2 Moreover, CRP adds to the predictive value of total
and HDL cholesterol such that the risk of future MI for men
with elevated levels of CRP and hyperlipidemia appears to be
greater than the product of the risks associated with either
abnormality alone.3 Finally, CRP has been associated with
increased risks of fatal coronary events among high-risk male
smokers,4 incident coronary disease among the elderly,5 and
recurrent coronary events among those with known coronary
disease.6 – 8
In women, prospective data evaluating CRP are sparse. We
therefore sought to determine whether CRP was also an
independent predictor of future vascular disease among currently healthy women.
among 39 876 postmenopausal female health professionals with no
prior history of MI, stroke, or transient ischemic attack.9 Among
these women, 28 263 (70.9%) provided baseline blood samples
collected in EDTA, which, after cold overnight shipping, were
centrifuged and frozen at 2170°C until analysis.
Questionnaires are sent to WHS participants to elicit information
on risk factors and incident health events. For all cases of MI, stroke,
PTCA, CABG, or cardiovascular death reported after enrollment,
hospital records are obtained and reviewed. Reported MI was
confirmed if symptoms met World Health Organization criteria and
the event was associated with elevated cardiac enzymes or characteristic ECG changes. Reported stroke was confirmed if the patient
had a new neurological deficit with signs and symptoms persisting
for .24 hours; CT scans were available in most cases. Reported
revascularization procedures were confirmed by hospital records.
Coronary deaths were confirmed by autopsy reports, death certificates, and circumstances of death.
For each case subject who provided a baseline blood sample, 2
control subjects of the same age (61 year) and smoking pattern
(current, past, never) who also provided a baseline plasma sample
and who remained free of reported vascular disease during follow-up
were selected; 122 women who suffered a first cardiovascular event
during a 36-month follow-up period and 244 who remained free of
disease were included in this analysis. Plasma samples for each
subject were thawed and assayed for CRP with a high-sensitivity
ELISA (Abbott Laboratories).10
We used Student’s t test to evaluate differences in means and the
x2 statistic to evaluate differences in proportions. Because the
Methods
The study population consisted of participants in the Women’s
Health Study (WHS), a primary prevention trial being conducted
Received April 15, 1998; revision received June 15, 1998; accepted June 23, 1998.
From the Divisions of Cardiology (P.M.R.) and Preventive Medicine (P.M.R., J.E.B., C.H.H.), Brigham and Women’s Hospital, and the Department
of Ambulatory Care and Prevention (J.E.B., C.H.H.), Harvard Medical School, Boston, Mass; and Abbott Laboratories, Abbott Park, Ill (M.M., J.S.).
Correspondence to Paul M. Ridker, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail
[email protected]
© 1998 American Heart Association, Inc.
731
732
C-Reactive Protein in Women
TABLE 1.
Baseline Characteristics of Study Participants
Case
Subjects
(n5122)
Control
Subjects
(n5244)
P
59.368.4
59.368.4
zzz
Current
27.9
27.9
zzz
Never
42.6
42.6
Age, y
Smoking status, %
29.5
29.5
Body mass index, kg/m2
Past
27.164.8
26.065.2
0.04
Hypercholesterolemia, %
45.9
28.3
0.001
Hypertension, %
55.5
31.3
0.001
9.8
2.1
0.001
21.3
12.8
0.04
Diabetes, %
Family history of CAD, %
CRP, mg/L, median
6.45
3.75
0.0001
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
distribution of CRP levels was skewed, differences in medians were
tested with the rank sum test. Logistic regression was used to
estimate relative risks (RRs) and 95% CIs. Tests for trend were used
to assess relationships of increasing levels of CRP with risk after the
cohort was divided into quartiles defined by the distribution of the
control subjects. Likelihood ratio tests were used to determine
whether prediction models that included CRP provided a better fit
than did models limited to traditional risk factors alone. All P values
were 2-tailed.
Results
Baseline characteristics of study participants are shown in
Table 1. As expected, case subjects had higher rates of usual
cardiovascular risk factors than control subjects. Because of
matching, age and smoking status were virtually identical
between study groups.
Case subjects had higher median CRP levels at baseline
than control subjects (P50.0001). In age- and smoking-
matched analyses, the risk of future vascular events increased
with each increasing quartile of CRP (P for trend50.0001)
such that women with the highest levels had a 5-fold increase
in risk of any vascular event (RR54.8; 95% CI, 2.3 to 10.1;
P50.0001) and a 7-fold increase in risk of MI or stroke
(RR57.3; 95% CI, 2.7 to 19.9; P50.0001); estimates were
minimally altered after control for other risk factors (Table 2).
To evaluate whether CRP adds to usual risk factors in
predicting future vascular events, likelihood ratio tests were
used to compare the fit of prediction models that specifically
included or excluded log-normalized CRP. In these analyses,
the simultaneous assessment of CRP and traditional risk
factors provided an improved ability to predict risk over
models limited to traditional factors alone (all P values
,0.01). For example, models that used CRP in addition to
hyperlipidemia, hypertension, diabetes, a family history of
coronary disease, and body mass index provided a significant
improvement in prediction (P50.005) compared with models
that excluded CRP.
Baseline levels of CRP predicted risk of vascular disease
among women with and without other cardiovascular risk
factors. These effects were most striking among women who
appeared to be at low baseline risk; elevated levels of CRP
were associated with a 4-fold increase in risk in analyses
limited to nonsmokers (RR54.5, P50.001) or to those with
no history of hyperlipidemia (RR53.9, P50.002). Similarly,
elevated levels of CRP were associated with increased risk
among women with no history of hypertension (RR52.8,
P50.03), no evidence of diabetes (RR54.9, P50.001), or
those with no family history of premature atherosclerosis
(RR56.6, P50.001) (Table 3).
Discussion
These prospective data indicate that baseline CRP concentration is an independent risk factor for cardiovascular disease
TABLE 2. Relative Risks of Future Cardiovascular Events Among Apparently
Healthy Women According to Baseline Concentration of CRP
Quartile of CRP (range, mg/L)
1
(,1.5)
2
(1.5–3.7)
3
(3.8 –7.3)
4
(.7.3)
P
for Trend
Any event
RR (crude)
1.0
2.4
95% CI
zzz
1.1–5.2
1.1–5.6
2.3–10.1
P
0.03
0.02
0.0001
RR (adjusted)
zzz
1.0
95% CI
zzz
0.8–4.7
1.0–5.6
1.7–9.9
P
zzz
0.1
0.06
0.002
2.0
2.5
2.3
4.8
4.1
0.0001
0.001
MI or stroke
RR (crude)
1.0
3.5
95% CI
zzz
1.2–10.0
1.6–12.6
2.7–19.9
P
zzz
1.0
0.02
0.005
0.0001
RR (adjusted)
2.7
3.5
5.5
95% CI
zzz
0.9–8.1
P
4.5
1.1–10.4
7.3
0.0001
0.002
1.8–16.6
0.08
0.03
0.002
zzz
All models age- and smoking-matched. Adjusted models controlled for body mass index, diabetes,
hypertension, hypercholesterolemia, exercise, family history, and treatment assignment.
Ridker et al
August 25, 1998
733
TABLE 3. Relative Risks of Future Cardiovascular Events Among Low-Risk
Subgroups of Women According to Baseline Concentration of CRP
Quartile of CRP (range, mg/L)
No hyperlipidemia
1
(,1.5)
2
(1.5–3.7)
3
(3.8 –7.3)
4
(.7.3)
P
for Trend
1.0
1.7
2.0
3.9
0.002
No hypertension
1.0
1.7
2.0
2.8
0.04
No current smoking
1.0
2.0
2.3
4.5
0.0004
No diabetes
1.0
2.5
2.6
4.9
0.0001
No family history
1.0
3.3
3.2
6.6
0.0001
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
among apparently healthy middle-aged women. Moreover, in
these data, the predictive value of models that include CRP is
significantly better than those limited to usual risk factors.
Finally, these data indicate that CRP predicts vascular events
even among low-risk subgroups of women with no readily
apparent markers for disease.
Previous studies of CRP in healthy populations have
almost exclusively been limited to men.1– 4 As such, the
present data extend prior observations concerning the potential clinical utility of CRP as a marker for vascular disease.
Our primary prevention data in women are also consistent
with subgroup observations from the Cardiovascular Health
Study, in which CRP levels were found to predict risk among
41 elderly women with evidence of subclinical cardiovascular
disease, as well as observations from the Rural Health
Promotion Project, in which CRP levels were higher among
65 elderly women at risk for vascular events.5 In both of these
prior subgroup analyses, the risks of vascular disease associated with CRP were greater for women than for men. This
also appears to be the case for our data, in which the adjusted
RR of either MI or stroke for women with CRP levels in the
highest quartile was 5.5, compared with 2.8 for men participating in the PHS.1 Whether these differences reflect chance
or effect modification by sex requires investigation.
It is also of interest that median levels of CRP in the
present study of women are higher overall than levels
observed in previous studies of men.1–3 Although this may
further reflect sex-specific effects, it is important to recognize
that the CRP assay techniques and the methods of blood
collection and storage in the present study are somewhat
different from those used in previous studies. The higher
median CRP levels observed in the present data may also
reflect the fact that, at least compared with men evaluated in
the PHS,1–3 women in the present analysis were more likely to
be current smokers, were heavier, and had a higher prevalence of hypertension, hyperlipidemia, and family history of
premature atherosclerosis; all of these factors are associated
with increased CRP levels1–7 and thus might contribute to a
higher overall distribution of baseline values.
These data support the hypothesis that low-grade inflammation is a marker for subsequent cardiovascular disease.
Whether CRP has direct vascular or prothrombotic effects,
reflects underlying endothelial dysfunction due to prevalent
atherosclerosis, leads to increased lipid peroxidation, or is
simply a marker resulting from an as yet undetermined
environmental and/or infectious stimulus remains to be
elucidated.11,12
Acknowledgments
This study was supported by grants from the National Institutes of
Health and by an Established Investigator Award from the American
Heart Association (Dr Ridker).
References
1. Ridker PM, Cushman M, Stampfer MJ, Tracy R, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently
healthy men. N Engl J Med. 1997;336:973–979.
2. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH.
Plasma concentration of C-reactive protein and risk of developing peripheral vascular disease. Circulation. 1998;97:425– 428.
3. Ridker PM, Glynn RJ, Hennekens CH. C-reactive protein adds to the
predictive value of total and HDL cholesterol in determining risk of first
myocardial infarction. Circulation. 1998;97:2007–2011.
4. Kuller LH, Tracy RP, Shaten J, Meilahn EN, for the MRFIT Research
Group. Relationship of C-reactive protein and coronary heart disease in
the MRFIT nested case-control study. Am J Epidemiol. 1996;144:
537–547.
5. Tracy RP, Lemaitre RN, Psaty BM, Ives DG, Evans RW, Cushman M,
Meilahn EN, Kuller LH. Relationship of C-reactive protein to risk of
cardiovascular disease in the elderly: results from the Cardiovascular
Health Study and the Rural Health Promotion Project. Arterioscler
Thromb Vasc Biol. 1997;17:1121–1127.
6. Liuzzo G, Biasucci LM, Gallimore JR, Grillo RL, Rebuzzi AG, Pepys
MB, Maseri A. The prognostic value of C-reactive protein and serum
amyloid A protein in severe unstable angina. N Engl J Med. 1994;331:
417– 424.
7. Thompson SG, Kienast J, Pyke SDM, Haverkate F, van de Loo JCW,
European Concerted Action on Thrombosis and Disabilities Angina
Pectoris Study Group. Hemostatic factors and the risk of myocardial
infarction or sudden death in patients with angina pectoris. N Engl J Med.
1995;332:635– 641.
8. Ridker PM, Rifai N, Pfeffer MA, Sacks FM, Moye LA, Goldman S,
Flaker GC, Braunwald E, for the Cholesterol, and Recurrent Events
(CARE) Investigators. Inflammation, pravastatin, and the risk of coronary
events after myocardial infarction in patients with average cholesterol
levels. Circulation. In press.
9. Buring JE, Hennekens CH, for the Women’s Health Study Research
Group. The Women’s Health Study: summary of the study design. J
Myocard Ischemia. 1992;4:27–29.
10. Wilkins J, Gallimore R, Moore EG, Pepys MB. Rapid automated high
sensitivity enzyme immunoassay of C-reactive protein. Clin Chem. 1998;
44:1358 –1361.
11. Ridker PM. Inflammation, infection, and cardiovascular risk: how good is
the clinical evidence? Circulation. 1998;98:1671–1674.
12. Tracy RP. Inflammation in cardiovascular disease: cart, horse, or both?
Circulation. 1998;97:2000 –2002.
Prospective Study of C-Reactive Protein and the Risk of Future Cardiovascular Events
Among Apparently Healthy Women
Paul M. Ridker, Julie E. Buring, Jessie Shih, Mathew Matias and Charles H. Hennekens
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
Circulation. 1998;98:731-733
doi: 10.1161/01.CIR.98.8.731
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1998 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circ.ahajournals.org/content/98/8/731
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about
this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation is online at:
http://circ.ahajournals.org//subscriptions/