Context Although it has been hypothesized that hypertension is in part an inflammatory
disorder, clinical data linking inflammation with incident hypertension are
scarce.
Objective To examine whether C-reactive protein levels, a marker of systemic inflammation,
are associated with incident hypertension.
Design, Setting, and Participants A prospective cohort study that began in 1992 of 20 525 female
US health professionals aged 45 years or older who provided baseline blood
samples with initially normal levels of blood pressure (BP) (systolic BP <140
mm Hg and diastolic BP <90 mm Hg, and no history of hypertension or antihypertensive
medications) and then followed up for a median of 7.8 years for the development
of incident hypertension. Plasma C-reactive protein levels were measured and
baseline coronary risk factors were collected.
Main Outcome Measure Incident hypertension, defined as either a new physician diagnosis,
the initiation of antihypertensive treatment, or self-reported systolic BP
of at least 140 mm Hg or a diastolic BP of at least 90 mm Hg.
Results During follow-up, 5365 women developed incident hypertension. In crude
models, the relative risks (RRs) and 95% confidence intervals (CIs) of developing
hypertension from the lowest (referent) to the highest levels of baseline
C-reactive protein were 1.00, 1.25 (95% CI, 1.14-1.40), 1.51 (95% CI, 1.35-1.68),
1.90 (95% CI, 1.72-2.11), and 2.50 (95% CI, 2.27-2.75) (linear trend P<.001). In fully adjusted models for coronary risk
factors, the RRs and 95% CIs were 1.00, 1.07 (95% CI, 0.95-1.20), 1.17 (95%
CI, 1.04-1.31), 1.30 (95% CI, 1.17-1.45), and 1.52 (95% CI, 1.36-1.69) (linear
trend P<.001). C-reactive protein was significantly
associated with an increased risk of developing hypertension in all prespecified
subgroups evaluated, including those with very low levels of baseline BP,
as well as those with no traditional coronary risk factors. Similar results
were found when treating C-reactive protein as a continuous variable and controlling
for baseline BP.
Conclusion C-reactive protein levels are associated with future development of
hypertension, which suggests that hypertension is in part an inflammatory
disorder.
The C-reactive protein is a marker of systemic inflammation that has
been associated with an increased risk of incident myocardial infarction and
stroke.1-5 Inflammation
has also been hypothesized to play a role in the development of hypertension,
and cross-sectional evidence demonstrates higher C-reactive protein levels
among those individuals with elevated blood pressure (BP).6-11 Higher
levels of C-reactive protein may increase BP by reducing nitric oxide production
in endothelial cells,12,13 resulting
in vasoconstriction and increased production of endothelin 1.14,15 C-reactive
protein may also function as a proatherosclerotic factor by up-regulating
angiotensin type 1 receptor expression.16
Inflammation has been shown to correlate with endothelial dysfunction17 and relate to the renin-angiotensin system.18 As a result, it has been hypothesized that hypertension
may be in part an inflammatory disorder. However, clinical data linking inflammation
with incident hypertension are scarce.19 We
therefore determined whether elevated C-reactive protein levels in normotensive
individuals are associated with an increased risk of developing hypertension.
The Women's Health Study is an ongoing randomized, double-blind, placebo-controlled
trial of low-dose aspirin and vitamin E in the primary prevention of cardiovascular
disease and cancer, which began in 1992.20 In
1992, a total of 39 876 female US health professionals aged 45 years
or older without prior myocardial infarction, stroke, transient ischemic attack,
and cancer (except nonmelanoma skin cancer) were enrolled and randomized into
the study.
Before randomization, baseline blood samples were collected from 28 345
participants and stored in liquid nitrogen until analysis. Samples were then
transferred to a core laboratory facility in which they were assayed for C-reactive
protein with a validated high-sensitivity assay (Denka Seiken Co, Tokyo, Japan).5 Of the samples received, 27 939 were evaluated
and assayed for C-reactive protein. The baseline population was then restricted
to 20 525 women without hypertension, defined as having no self-reported
past or current history of hypertension, no past or current history of antihypertensive
treatment, a systolic BP of less than 140 mm Hg, and a diastolic BP of less
than 90 mm Hg at study entry. Baseline BP was reported in 1 of 9 ordinal systolic
BP categories ranging from less than 110 mm Hg to at least 180 mm Hg and 7
ordinal diastolic BP categories ranging from less than 65 mm Hg to at least
105 mm Hg. A single measurement of self-reported BP in health professionals
has been shown to be highly correlated with measured systolic BP (r = 0.72) and diastolic BP (r = 0.60).21
Incident cases of hypertension were defined by meeting at least 1 of
4 criteria: self-reports of a new physician diagnosis on follow-up questionnaires
at years 1 and 3, and all annual questionnaires thereafter; self-reports of
newly initiated antihypertensive treatment at years 1, 3, and 4; self-reported
systolic BP of at least 140 mm Hg; or self-reported diastolic BP of at least
90 mm Hg. Women reporting a new physician diagnosis of hypertension also provided
the month and year of diagnosis. A missing date for a physician diagnosis
or hypertension defined by another criterion was assigned a date of incident
hypertension by randomly selecting a date between the current and previous
annual questionnaire. Those individuals developing major concomitant diseases,
the management of which may have impact on BP, at or after baseline but before
the development of hypertension, including myocardial infarction, stroke,
pulmonary embolism, and peripheral vascular disease, were censored at that
date of diagnosis and not considered an incident case of hypertension. Based
on this definition, 5365 cases of incident hypertension developed during a
median follow-up of 7.8 years (range, 0.001-8.82 years).
Women were first compared according to level of C-reactive protein by
using mean values or proportions of baseline risk factors to assess potential
confounding. Because hormone therapy increases the level of C-reactive protein,22,23 levels were based on the quintiles
of C-reactive protein among the subset of women not taking hormone therapy.
We used Cox proportional hazards regression model analyses to compute the
relative risks (RRs) and 95% confidence intervals (CIs) of incident hypertension
for increasing plasma C-reactive protein levels, with the lowest level as
the referent. Models first included only C-reactive protein, then were adjusted
for age and randomized treatment assignment. The final multivariable model
added body mass index (calculated as weight in kilograms divided by the square
of height in meters), smoking status, exercise, alcohol consumption, parental
history of myocardial infarction before age 60 years, diabetes, postmenopausal
hormone use, and hypercholesterolemia (either any baseline history of cholesterol-lowering
medication use or a physician diagnosis of high cholesterol or a self-reported
cholesterol of at least 240 mg/dL [≥6.22 mmol/L]). Linear trend tests across
levels of plasma C-reactive protein levels were performed by using the median
value for each level as an ordinal variable.
Both stratified and joint models incorporating C-reactive protein and
either systolic BP or diastolic BP were also considered. Women in the upper
half of the prehypertension BP classification according to the Seventh Report
of the Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure (JNC 7)24 (either
systolic BP of 130-139 mm Hg or diastolic BP of 85-89 mm Hg) were excluded
from these analyses out of concern for potential misclassification and the
vast majority of these women became hypertensive during follow-up. Joint models
of C-reactive protein and BP used clinically relevant cut points for C-reactive
protein: less than 1, 1 to less than 3, and 3 or more mg/L.25 A
test for interaction between C-reactive protein, BP, and the risk of developing
hypertension was assessed with C-reactive protein as a continuous variable
and BP as an ordinal variable. All analyses were performed with SAS version
8 (SAS Institute Inc, Cary, NC), using a 2-tailed P =
.05 for significance.
Baseline characteristics of the study population according to levels
of C-reactive protein are shown in Table
1. As expected, traditional coronary risk factors were more prevalent
among those participants with elevated levels of C-reactive protein. During
a median follow-up of 7.8 years for the 20 525 women comprising the baseline
population, 5365 women developed hypertension either on the basis of newly
initiated treatment (n = 2295 [43%]) or having a systolic BP of at least 140
mm Hg or diastolic BP of at least 90 mm Hg (n = 3070 [57%]).
Overall, there was a positive association between increasing levels
of C-reactive protein and risk of developing hypertension (Table 2). In crude models, the RRs of developing hypertension increased
from the lowest (referent) to the highest level of C-reactive protein (linear
trend P<.001), such that those participants with
levels of C-reactive protein in excess of 3.5 mg/L had an RR of 2.50 (95%
CI, 2.27-2.75). In risk factor–adjusted models as well as those that
additionally adjusted for baseline BP, risks were attenuated but retained
a positive association with risk of developing hypertension (linear trend P<.001). For example, in models additionally adjusting
for baseline BP, women with increasing levels of C-reactive protein had RRs
of hypertension of 1.04 (95% CI, 0.92-1.17), 1.11 (95% CI, 0.99-1.24), 1.19
(95% CI, 1.07-1.33), and 1.34 (95% CI, 1.20-1.50; linear trend P<.001). Analyses stratified by use or nonuse of hormone therapy
showed essentially identical results. In log-transformed models that considered
C-reactive protein as a continuous variable, similar strong effects were observed
that were all statistically significant (for 1-SD increase of C-reactive protein,
adjusted RR, 1.14; 95% CI, 1.11-1.17).
We also considered more restrictive definitions of hypertension to address
potential misclassification. The multivariable RRs of hypertension restricted
to women initiating treatment, having a physician diagnosis, having a systolic
BP of at least 160 mm Hg, or having a diastolic BP of at least 95 mm Hg during
follow-up (4982 of 5365 women developing hypertension) for increasing levels
of C-reactive protein were 1.00, 1.06 (95% CI, 0.94-1.20), 1.18 (95% CI, 1.05-1.33),
1.30 (95% CI, 1.16-1.46), and 1.52 (95% CI, 1.36-1.70; linear trend P<.001). Alternatively, analyses of hypertension restricted
to women initiating treatment or having a physician diagnosis during follow-up
(2295 of 5365 women developing hypertension) resulted in RRs for increasing
levels of C-reactive protein of 1.00, 1.03 (95% CI, 0.87-1.22), 1.02 (95%
CI, 0.86-1.20), 1.14 (95% CI, 0.97-1.33), and 1.41 (95% CI, 1.20-1.65; linear
trend P<.001).
We next examined the age-adjusted and multivariable-adjusted associations
between C-reactive protein and the risk of developing hypertension stratified
by either systolic BP or diastolic BP. In Table 3, increasing levels of C-reactive protein were associated
with an increased risk of developing hypertension at all levels of baseline
BP in fully-adjusted models, even among women with baseline systolic BP of
less than 110 mm Hg and baseline diastolic BP of less than 65 mm Hg. Additional
adjustment for diastolic BP in models stratified by systolic BP, or for systolic
BP in models stratified by diastolic BP, did not change the RRs from our fully-adjusted
models. The consideration of log-transformed C-reactive protein as a continuous
variable also generated statistically significant results decreased to a systolic
BP of 110 mm Hg and a diastolic BP of 65 mm Hg (for 1-SD increase of C-reactive
protein among women with systolic BP 110-119 mm Hg, adjusted RR, 1.12; 95%
CI, 1.10-1.18, and for 1-SD increase of C-reactive protein among women with
diastolic BP 65-74 mm Hg, adjusted RR, 1.14; 95% CI, 1.08-1.20).
Overall, there were 7065, 6920, and 6540 women with C-reactive protein
levels of less than 1, 1 to less than 3, and 3 or more mg/L, respectively,
cut points recently set forth in clinical guidelines.25 For
these clinical cut points of C-reactive protein, the RRs of developing hypertension
in crude analyses were 1.00, 1.46 (95% CI, 1.36-1.57), and 2.11 (95% CI, 1.97-2.26;
linear trend P<.001) respectively; in risk factor–adjusted
models, the RRs were 1.00, 1.16 (95% CI, 1.08-1.25), and 1.42 (95% CI, 1.31-1.54;
linear trend P<.001) respectively. To evaluate
the robustness of the findings among women without major coronary risk factors,
we limited analyses to women who were nonsmokers, not using hormone therapy,
had a body mass index of less than 30, and did not have diabetes and hypercholesterolemia
(n = 6795; 1384 incident cases of hypertension). In this subgroup of women,
the age-adjusted RRs were 1.00, 1.26 (95% CI, 1.11-1.42), and 1.69 (95% CI,
1.47-1.94; linear trend P<.001) for corresponding
C-reactive protein levels of less than 1, 1 to less than 3, and 3 or more
mg/L, respectively. In risk factor–adjusted models, the RRs were 1.00,
1.24 (95% CI, 1.10-1.40), and 1.64 (95% CI, 1.42-1.89; linear trend P<.001) respectively.
To further explore the joint effects of C-reactive protein and BP, we
considered clinical cut points of C-reactive protein and its association with
hypertension in combination with baseline BP (Figure 1). For systolic BP, a significant statistical interaction
with C-reactive protein was observed (P<.001).
C-reactive protein levels of 1 to 3 and more than 3 mg/L conferred an additional
risk of developing hypertension in women in which systolic BP levels were
classified as normal (<120 mm Hg) or prehypertension (<130 mm Hg) by
the JNC 7 guidelines, with significant RRs compared with women with a systolic
BP of less than 110 mm Hg and C-reactive protein level of less than 1 mg/L
(all P<.001). For diastolic BP, a similar additive
effect was observed, although the interaction did not reach statistical significance
(P = .11).
This study provides evidence that baseline levels of C-reactive protein
are modestly but independently associated with an increased risk of incident
hypertension, even among those with very low initial systolic BP and diastolic
BP as classified by the JNC 7.24 This finding
for C-reactive protein was independent of baseline levels of systolic BP and
diastolic BP. Similar effects were observed among those participants without
baseline coronary risk factors and in analyses where C-reactive protein was
considered as a continuous variable. These data suggest that inflammation
may have a potentially important role in the development of hypertension.
Despite the fact that up to 50 million US individuals are affected,24 the etiology of hypertension often remains unclear.
These data from the Women's Health Study represent the first major prospective
analysis of the association between C-reactive protein and incident hypertension
and are consistent with the findings for other inflammation-sensitive plasma
proteins, including fibrinogen, α1-antitrypsin, haptoglobin,
orosomucoid, and ceruloplasmin.19 Previous
evidence of an association between C-reactive protein and BP has been derived
solely from cross-sectional studies in which no causal link can be established.6-9 In those
studies, C-reactive protein has been more strongly associated with systolic
BP than diastolic BP, which is consistent with the emerging importance of
systolic BP as a means of cardiovascular risk prediction.26
Although the current data provide evidence for a critical role of inflammation
in the development of hypertension, the mechanisms of this effect are uncertain
and require further evaluation. C-reactive protein has been reported to decrease
production of nitric oxide by endothelial cells12,13 and
thus might indirectly promote vasoconstriction, leukocyte adherence, platelet
activation, oxidation, and thrombosis.14,15,27 C-reactive
protein also has been reported to have proatherosclerotic properties by upregulating
angiotensin type-1 receptor expression,16 affecting
the renin-angiotensin system and contributing to the pathogenesis of hypertension.
These changes are all indicative of progressive atherosclerosis and endothelial
dysfunction,28 with structural and functional
changes in the endothelium ultimately leading to the development of hypertension.29 These findings are supported by cross-sectional associations
not only for C-reactive protein but also IL-6, intercellular adhesion molecule
1, and tumor necrosis factor α with either BP or hypertension.8,9,30
Higher levels of C-reactive protein also play an important role in the
induction of plasminogen activator inhibitor 1 (PAI-1), a marker of impaired
fibrinolysis and atherothrombosis.15,31 The
recent novel finding that C-reactive protein increases PAI-1 expression and
activity in human aortic endothelial cells15 supports
a possible mechanism by which the association between C-reactive protein and
the development of hypertension is mediated. Patients with hypertension have
markedly higher levels of PAI-1 than normotensive patients,32 and
both systolic and diastolic BP were significantly (P<.001)
and positively associated with PAI-1 levels in the Framingham offspring cohort.33
Potential limitations of our study warrant discussion. As in any epidemiologic
study, residual confounding is of concern. After controlling for other known
risk factors for both hypertension and atherothrombosis, as well as baseline
BP, our results remained significant. We observed similar results in subgroup
analyses limited to those participants without baseline coronary risk factors.
We relied on a single baseline measurement of C-reactive protein. However,
C-reactive protein has been shown to be stable over long periods of follow-up,
with little or no diurnal variation.34,35
In our study, incident hypertension was based on self-reported BP, treatment,
physician diagnosis, or all 3 combined. To address this potential limitation,
we performed a separate study in which an 86% validation rate for self-reported
hypertension was observed, consistent with other studies.36,37 For
example, in a comparable population in the Nurses' Health Study, 99% of women
who reported high BP confirmed their diagnosis based on medical records.37 Sensitivity analyses considering various definitions
of hypertension also yielded consistent and significant linear trends across
increasing levels of C-reactive protein. Any impact of misclassification would
likely be random, biasing our observed RRs toward the null hypothesis.
Although hypertension awareness, treatment, and control rates have increased
during the past 3 decades, the identification of individuals at risk for hypertension
remains a high priority.24 These data provide
evidence that inflammation may be an important mechanism through which hypertension
develops.
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