Journal of Human Hypertension (2003) 17, 223230

& 2003 Nature Publishing Group All rights reserved 0950-9240/03 $25.00
www.nature.com/jhh

REVIEW ARTICLE

Inflammation, endothelial dysfunction,

and the risk of high blood pressure:
epidemiologic and biological evidence
LE Bautista
Department of Preventive Medicine & Biometrics, Uniformed Services University of the Health Sciences,
Bethesda, MD, USA

In spite of its high impact on cardiovascular and renal

disease, knowledge on risk factors for the development
of high blood pressure (HBP) is limited. Mild chronic
inflammation may play a significant role in the incidence
of HBP. A persistent low-grade inflammation state could
be associated with high but within the normal range
cytokine plasma concentration. By impairing the capacity of the endothelium to generate vasodilating factors,
particularly nitric oxide (NO), elevated cytokines may
lead to the development of endothelial dysfunction,
chronic impaired vasodilation, and HBP. These alterations in the L-arginine : NO pathway may play a major

role in the development of HBP in young subjects, with

inflammation-related alterations in the production of
cyclo-oxygenase-derived vasoconstrictors becoming
more prominent with advanced age. Cross-sectional
independent associations between HBP and plasma
levels of C-reactive protein, interleukin-6, and tissue
necrosis factor alpha have been reported, but no
prospective evidence of these associations is currently
available.
Journal of Human Hypertension (2003) 17, 223230.
doi:10.1038/sj.jhh.1001537

Keywords: inflammation; cytokines; C-reactive protein; interleukin-6; tumour necrosis factor alpha

Introduction
High blood pressure (HBP) is one of the most
important risk factors for cardiovascular-renal disease, because it has a high prevalence in almost all
populations; it has a large impact on disease
incidence, and can be controlled by early detection,
and treatment. Between 24.0 and 31.1% of the adult
population in the United States has HBP,1 a condition that only in 1998 accounted for $108.0 billions
in health-care spending.2 Despite its high health
impact, primary prevention of HBP is partly hampered because of a limited knowledge on risk
factors. In this article, we review the epidemiological and biological evidence of a possible link
between chronic mild inflammation (CMI) and HBP.

Epidemiologic evidence
During the last few years, several cohort studies
have shown that systemic inflammation is assoCorrespondence: LE Bautista, Department of Preventive Medicine
& Biometrics, Uniformed Services University of the Health
Sciences, Room A1039, 4301 Jones Bridge Road, Bethesda, MD
20814, USA.
E-mail: lbautista@usuhs.mil
This article is a United States Government work paper as defined
by the US copyright act.

ciated with an increased risk of acute cardiovascular

events.35 CMI has also been associated with
impaired endothelium-dependent dilatation (IEDD)
of the arterial circulation,6,7 and there is considerable cross-sectional evidence of a link between IEDD
and essential hypertension.8,9 In fact, studies in
offspring and relative of hypertensive patients
suggest that IEDD may precede the development of
HBP.10,11
Systemic inflammation is a state that involves
many pathophysiological processes and several
inflammatory markers have been used to measure
CMI. Epidemiologic data support the existence of an
association between different inflammatory markers
and HBP. A positive association between serum
level of C-reactive protein (CRP) and blood pressure
has been reported in several studies1223 (Table 1).
This association is likely confounded by other risk
factors, such as age, sex, and body mass index:
Out of the six studies with no adjustment for
potential confounders,1519,13 five1519 reported a
statistically significant association between CRP
and blood pressure (Table 1). Also, in a group of
seven studies with adjustment for potential confounders,1224 four24,2224 reported a significant association between CRP and HBP.
Most of these studies1222 were not designed to test
the CRPHBP association. We tested this hypothesis
in a random sample of free living subjects23 and

Inflammation and high blood pressure

LE Bautista
224

Table 1 Published estimates of the association between CRP and HBP

Author

Year

Sample
size

Outcome
variable

Significant association
with CRP (Po0.05)

Adjusted for

Mendall et al27
Tracy et al13
Hack et al14
Koenig et al15
Yudkin et al16
Rohde et al24
Doggen et al18
Margaglione et al19
Ford and Giles17
Festa et al20

1996
1997
1999
1999
1999
1999
2000
2000
2000
2000

279 men
400
186 women
936 men
107
1172 men
646 men
1048
8850 men
1008

SBPa/DBPa
HBPc
SBP/DBP
HBPc
SBP/DBP
HBPd
SBP/DBP
HBPe
SBP
SBP/DBP

No/no
No
No/no
Yes
Yes
Yes
Yes
Yes
Yes/no
Yes/yes

Onat et al21

2001

1046

SBP/DBP

No/no

Yamada et al22

2001

6107

SBP/DBP

Yes/no

Bautista et al23

2001

300

SBP/DBP/HBPe

Yes/yes/yes

Age, BMIb, social class

None
Age, BMI
None
Age, gender
Age
None
None
None
Age, sex, ethnicity,
smoking, BMI, insulin sensitivity
Age, waist perimeter,
fibrinogen, total cholesterol,
physical activity
Age, BMI, fibrinogen, smoking,
waist-to-hip ratio, lipid
profile, blood glucose, insulin
Age, sex, use of antihypertensive drugs,
BMI, physical activity, blood
glucose, family history of HBP,
alcohol use

SBP: systolic blood pressure; DBP: diastolic blood pressure.

Body mass index.
c
HBP, high blood pressure X160/95 mmHg.
d
Previous history of high blood pressure.
e
HBP X140/90 mmHg.
b

found a progressive increase in blood pressure

associated to higher levels of high-sensitivity CRP.
In addition, subjects in the upper quartile of CRP
were 1.56 times more likely to have HBP than those
in the lower quartile (P 0.005), even after adjustment for other risk factors. Similarly, in a group of
89 hypertensive elderly patients without diabetes,
coronary heart disease, or inflammatory disease,
Bellelli et al25 found that the proportion of nondippers (night-to-day blood pressure ratio of 100%
or higher) was 2.0 and 3.1 times higher in those from
the second and third as compared to those in the
lowest third of CRP serum levels. As a result of the
cross-sectional nature of these studies, whether the
effects of CRP are the cause or the consequence of
HBP has not been established.
CRP production by hepatocytes is regulated by
cytokines, mostly interleukin 6 (IL-6) and tumour
necrosis factor alpha (TNF-a).26 Therefore, CRP
alone is unlikely to reflect all the relevant aspects
of CMI, and its association with HBP may not be
independent of other inflammation markers. IL-6
and TNF-a levels have also been associated to HBP
in several epidemiologic studies.16,2734
IL-6 is a 26-kDa cytokine, produced by different
cells, including monocytes, lymphocytes, and endothelial cells. IL-6 stimulates the synthesis of many
acute-phase reaction proteins, including CRP, serum
amyloid A, and fibrinogen.35 In addition, IL-6 seems
to counter regulate levels of TNF-a and interleukin1b,36 so that higher IL-6 levels may reflect damage
from other cytokines. Finally, IL-6 prolongs the
Journal of Human Hypertension

IEDD associated to the administration of IL-1b and

TNF-a in human volunteers.37
Several studies show contradictory results
about the association between IL-6 and HBP
(Table 2).3,16,27,28,3032,34 Studies with adjustment for
other HBP risk factors have shown a positive
association, with only two exceptions.27,34 In the
only published study designed to test this hypothesis, Chae et al32 adjusted for all main cardiovascular risk factors and found a statistically
significant association between IL-6 levels and
blood pressure level. Unfortunately, because of the
cross-sectional nature of the data, they32 could not
sort out whether IL-6 levels were the cause or the
consequence of raised blood pressure.
TNF-a is a protein synthesized mainly by monocytes and macrophages and plays an essential role in
the initial activation of the immune system and in
lipid and glucose metabolism. Secretion of TNF-a is
significantly increased in peripheral blood monocytes from patients with HBP after stimulation with
lipopolysaccharide.38 Preactivated monocytes in
hypertensive patients could be the result or a causal
factor triggering HBP. In fact, TNF-a induces insulin
resistance,39 and is elevated in obese subjects,40 two
conditions known to be associated with essential
hypertension.
Linkage and association analyses suggest that the
TNF-a gene locus is associated to HBP in obese
subjects.41 In addition, the TNF-a-308 G/A promoter
polymorphism, a genetic variation related to tissue
TNF-a expression, has also been associated with

Inflammation and high blood pressure

LE Bautista
225

Table 2 Published estimates of the association between interleukin-6 (IL-6) and HBP
Author

Year

Sample size

Outcome
variable

Significant association
with IL-6 (Po0.05)

Adjusted for

Mendall et al27
Rifai et al28
Yudkin et al16
Ridker et al3

1997
1999
1999
2000

SBPa
HBPc
SBP/DBPa
SBP/DBP

No
No
Yes/yes
Yes/yes

Age, BMIb, smoking, occupation, alcohol

None
Age, gender
None

Volpato et al30
Chae et al32

2001
2001

198 men
100 men
107
202 with AMId
202 w/o AMI
620 women
508 Men

HBP
SBP/DBP

No
Yes/yes

Fernandez et al31
Furumoto et al34

2001
2002

226
67 HBP 52 controls

SBP/DBP
IL-6

Yes/yese
No

None
Age, AMId, BMIb, parent AMId,
diabetes, use of alcohol/aspirin, smoking,
cholesterol, physical activity
BMI
Age, sex

SBP: systolic blood pressure; DBP: diastolic blood pressure.

Body mass index.
High blood pressure: X160/95 mmHg.
d
Acute myocardial infarction.
e
Only among women.
b
c

Table 3 Published estimates of the association between tumour necrosis factor (TNF-a) and HBP
Author

Year

Sample
size

Outcome
variable

Association with
TNF-a-HBP (Po0.05)

Adjusted for

Mendall et al27

1997

198 men

SBPa

No

Age, BMI, occupation, social class,

smoking, alcohol use
Age, gender
Age, menopause
Age, sex

16

Yudkin et al
Ito et al33
Furumoto et al34

1999
2001
2002

Sheu et al29

2000

Fernandez et al45d

2002

107
82 women
67 HBPb
52 controls
85 HBPc
85 controls
258 controls
66 DM2e
46 DMIe

SBP/DBP
SBP/DBP
TNF-a

Yes/yes
Yes/no
Yes

TNF-a

No

SBP/DBP

Yes/yes

None
Age, BMI

SBP: systolic blood pressure; DBP: diastolic blood pressure.

HBP, high blood pressure X140/90 mmHg.
c
HBP X160/95 mmHg.
d
Measured sTNFRl/sTNFR2, an indicator of TNF-a activity.
e
DMI=diabetes mellitus type I; DMII=diabetes mellitus type II.
b

insulin resistance and HBP among obese people.42

Subjects homozygous for the A allele have significantly higher systolic blood pressure than those
homozygous for the G allele.42 By stimulating the
expression of the angiotensinogen gene in the
liver,43 TNF-a may also lead to high levels of
angiotensin II, a potent vasoconstrictor associated
to a chronic state of increased vascular resistance
and HBP.44 Moreover, TNF-a plays a fundamental
role in inducing IEDD,37 a condition that seems to
play a role in the pathogenesis of essential hypertension and that is also present in offspring of
hypertensive patients.11,10
Some studies in human subjects (Table 3) have
shown a positive association between TNF-a level
and HBP,16,33,34 while others have not.27,29 However,
these studies have failed to control for other risk
factors for HBP. On the other hand, Fernandez-Real
et al45 have shown that the ratio of soluble TNF-a

receptor 1 and soluble TNF-a receptor 2 (sTNFR1/

sTNFR2), a correlate of the degree of activation of
the TNF-a system, is positively and significantly
associated with systolic and diastolic blood pressure, and that lowering blood pressure decreases the
sTNFR1/sTNFR2 ratio.
Prolonged periods of low-grade systemic inflammation may explain the higher risk of HBP observed
among subjects with obesity. It is known that obesity
is independently related to higher levels of CRP,
TNF-a, and IL-6 in children46 and adults.12,14,16,27
Also, experimental studies show that TNF-a can be
produced by adipocytes under physiological conditions.40 Obesity may lead to overproduction of
TNF-a, which in turn induces the synthesis of IL-6,
the main regulator of CRP production by the liver.
Therefore, obesity may be considered as a model of
CMI, which may be the cause of the IEDD commonly
observed in these patients.47 In fact, studies in obese
Journal of Human Hypertension

Inflammation and high blood pressure

LE Bautista
226

people have led to believe that endothelial dysfunction may be the common antecedent factor in the
clustering of dyslipidaemia, impaired fibrinolysis,
and hypertension, which are attributed to insulin
resistance.16
Taken together, these findings suggest that CMI
may lead to long-term impairment of the homeostatic vasodilating mechanisms aimed to regulate
arterial blood pressure, becoming an independent
risk factor for the development of HBP. Unfortunately, most of the available reports (Tables 13) do
not provide an estimate of the magnitude of the
association between CMI and HBP. Moreover, there
is some uncertainty about the influence of environmental and genetic factors on the variability of CRP,
IL-6, and TNF-a levels in healthy subjects.42,48,49

Biological mechanisms
A chronic imbalance between endothelium-derived
relaxing and contracting factors could lead to an
abnormal vasodilating response and to HBP. Under
physiological conditions, the vascular endothelium
responds to mechanical and biochemical agonists
by producing antiplatelet, anticlotting, fibrynolitic,
vasodilating, and vasoconstricting factors.50 The
best-known endothelium-derived relaxing factors
are nitric oxide (NO),51 endothelium-derived hyperpolarizing factor (EDRF),52 and the prostanoid
prostaglandin I2(prostacyclin, PGI2).53
NO is produced during the metabolism of
L-arginine by NO synthase.50,54,55 NO induces
vasodilation, inhibits adhesion of platelets and
white blood cells to the endothelium, prevents
platelet aggregation, and inhibits growth of
smooth-muscle cells.56 Together with NO, EDHF
contributes to relaxation of large conducting arteries, and appears to be a major determinant of
vascular resistance in small arteries.57 PGI2 is a
cyclo-oxygenase (COX)-derived prostanoid. It is a
potent vasodilator53 and inhibits platelet aggregation58 and vascular smooth muscle cell growth.59
Activation of the vascular endothelium by ageing
and under pathological conditions leads to the
production of contracting factors that counteract
the relaxing activity of vasodilators, including
endothelin (ET), the prostanoid thromboxane A2
60
(TXA2), and superoxide anion (  O
Endothelial
2 ).
cells produce exclusively ET-1, the predominant
form of ET, which is the most potent vasoconstrictor
yet discovered.55 At high doses, ET1 activates ETA
receptors in endothelial cells promoting vasoconstriction, cell growth, platelet adhesion and
aggregation, and thrombosis.61,62 However, at low
doses ET1 stimulates ETB receptors in the endothelial cell and leads to increased release of NO and
PGI2 and to vasodilation.62,63 TXA2 is produced
mainly in platelets and is a potent platelet activator,
vasoconstrictor, and smooth muscle cell mitogen.64
 O
2 is an important reactive oxygen intermediate
Journal of Human Hypertension

produced mostly by phagocytic blood-borne cell,

and also by endothelial cells.65  O
2 and other oxygen
free radicals, in and around vascular endothelial
cells, may increase vascular resistance by inactivating NO.66 In addition, free radicals catalyse the
transformation of arachidonic acid to F2-isoprostanes, a family of PGF2a-isomers.67 One of these
isomers, 8-epi PGF2a, is a potent vasoconstrictor and
mitogen67 and has been proposed as a marker of
oxidant stress in vivo.68
A possible effect of CMI on the development
of HBP may be mediated through endothelial dysfunction and alteration in the synthesis and degradation of vasodilating and vasoconstricting factors
(Figure 1).6,7,69,70 There is considerable evidence on
the effect of inflammation on endothelial dysfunction. CRP levels have been associated to IEDD in
patients with coronary heart disease.6 Also, Hingorani et al7 have shown that a mild increase in
inflammatory markers, particularly IL-6, results in
significant endothelial dysfunction in resistant and
conduit vessels, by reducing the capacity of the
endothelium to generate vasodilator factors, particularly NO. Moreover, exposure to bacterial endotoxin and inflammatory cytokines induces IEDD that
last for several days, an effect that could be
prevented by treatment with glucocorticoids70 and
aspirin.37 This finding suggests that the production
of locally generated inflammatory mediators contributes to endothelial dysfunction and that this
abnormality is not confined to the endothelial
L-arginine : NO pathway but extends to the production of COX-derived prostanoids.70,37 In addition,
COX inhibition restores NO-mediated vasodilation
in patients with essential hypertension, implying
that COX-dependent prostanoids can impair NO
production.71
Evidence from animal and clinical studies show
that the role of COX-derived vasoconstrictors and
the NO pathway on endothelial function may
depend on age. Several findings support that in
contrast to the role of the NO pathway, COX-derived
vasoconstrictors may be more important in the
incidence of HBP in older than in younger patients.
First, COX-derived vasoconstrictors do not appear to
be responsible for IEDD in normotensive offspring of
hypertensive parents,72 nor do they seem to increase
blood pressure in animal models.73 Second, ridogrel,
a combined TXA2 synthase inhibitor and TXA2
receptor blocker does not lower blood pressure in
hypertensive patients.74 Third, similar to blood
pressure, the production of COX-derived vasoconstrictors increases with age.75 Therefore, it is
possible that the development of HBP early in life
could be mostly related to abnormalities in the
L-arginine : NO pathways, and that a rising production of COX-derived vasoconstrictor prostanoids
plays a greater role in the age-related increase in
the incidence of HBP.
Although it is currently unknown how inflammation causes IEDD, several mechanisms have been

Inflammation and high blood pressure

LE Bautista
227

Figure 1 Biological mechanisms leading from chronic mild inflammation to essential hypertension.

proposed69 (Figure 1). Inflammatory cytokines may

decrease the expression of the constitutive endothelial NO synthase (cNOS), reducing NO availability, and predisposing to vasospasm.7 In fact, Yoshizumi et al76 have shown that TNF-a decreases cNOS
mRNA level by shortening its half-life. Similarly,
Verma et al77 have recently shown that CRP, at
concentrations known to predict adverse cardiovascular events, significantly reduces cNOS mRNA
stability, downregulates the expression of cNOS,
and markedly attenuates NO release and bioactivity
in endothelial cells, independently of ET receptor
blockade or IL-6 inhibition. This could reduce the
availability of NO and lead to IEDD.
On the other hand, elevated endothelial production of  O
2 and other oxygen-free radicals during
inflammation could increase the NO degradation
rate and lower its availability.66 Actually, higher
levels of oxidized LDL have been associated to
endothelial-dependent vascular dysfunction in patients with coronary heart disease6 and in patients
with cardiovascular risk factors.78 Moreover, Pleiner
et al79 have shown that IEDD induced by the
administration of lipopolysaccharide in normal
subjects can be restored by the local administration
of high doses of Vitamin C, a free-radical scavenger.
This suggests that oxidative stress may play an
important role in inflammation-induced IEDD.
IEDD could also be mediated by COX-derived
prostanoids, which are increased during inflam-

mation (Figure 1). In hypertensive subjects, there is

an alteration of the L-arginine : NO pathway, which
coexists with an increased production of COXdependent endothelial-derived contracting factors.72
The role of inflammatory prostanoids is also
supported by the finding of an independent association between activation of circulating T-lymphocytes and NO-independent blood flow changes in
patients with coronary heart disease.6
Although I have emphasized that MCI induces
IEDD and precedes the development of HBP, it is
possible that MCI and IEDD may both precede and
follow HBP. In fact, IEDD has been considered as
one of the mechanisms by which HBP contributes
to the development of atherosclerosis80 and has been
associated to the risk of cardiovascular events in
hypertensive patients.81 Also, endothelial cells exposed to increased shear stress, as expected in HBP,
increase their production of IL-1b, IL-6, IL-8, and
TNF-a.82,83 Finally, HBP may cause intramural
hypoxia, which could increase the synthesis of free
radicals and lead to IEDD.84 However, HBP is an
unlikely major determinant of MCI, because CRP
level has been only weakly associated to prevalent
cardiovascular disease and subclinical measures of
atherosclerosis.49,85
Results from studies in subjects taking antihypertensive drugs suggest that IEDD and MCI occur
before the development of HBP. Among these
subjects, blood pressure lowering does not seem to
Journal of Human Hypertension

Inflammation and high blood pressure

LE Bautista
228

modify the IEDD that characterizes HBP,86,87,10

although some drugs may improve IEDD as a
specific effect that goes beyond blood pressure
reduction.88,80 Therefore, IEDD may act as a causative mechanism or may become irreversible once
HBP is established. Also, in an analysis of data from
a previous study23 we found that subjects with drugcontrolled HBP, without previous cardiovascular
disease, had levels of CRP similar to those in
noncontrolled subjects (P 0.58), after adjustment
for age, sex, body mass index, smoking, and physical
activity. Thus, MCI does not seem to be the
consequence of elevated blood pressure, since blood
pressure lowering does not lower CRP level. Unfortunately, no additional reports on the effect of
antihypertensive therapy on inflammatory markers
seem to be currently available.
The reduced IEDD of small and large vessel
observed in normotensive offspring and relative of
HBP patients10,11,72 suggests that a defect on the NO
pathway precedes the onset of HBP. Unfortunately,
it is not known whether inflammatory markers are
also elevated in normotensive relatives of hypertensive patients. However, the level of systemic
inflammatory markers such as CRP, white blood cell
count, and albumin levels are at least partially (35
40%) determined by genetic factors.49 A polymorphism of the gene that encodes IL-6 has been
associated to CRP levels,89 and a common polymorphism in the promoter region of the TNF-a gene
has been associated to increased TNF-a and systolic
blood pressure.42 Since heritability seems to be an
important independent determinant of the level of
inflammatory markers in normal subjects, it is
reasonable to argue that MCI could precede the
development of HBP, even if the vascular wall also
contributes to the inflammation process as a response to the blood pressure elevation.

Conclusion
Epidemiologic and biological evidence suggest that
CMI may be an independent risk factor for the
development of HBP. Elevated plasma levels of CRP,
TNF-a and IL-6, within the normal range, have been
associated to HBP. There is cross-sectional evidence
of an independent association between CRP plasma
levels and HBP.23 IL-6 also seems to be significantly
and independently correlated with systolic and
diastolic blood pressure,32 and with IEDD.7 TNF-a
appears to be the critical cytokine in the process of
endothelial stunning,37 and has been associated to
the insulin-resistant syndrome16,40 and to HBP.34,45
However, prospective cohort studies are needed to
elucidate whether cytokine elevation predicts the
development or is just a consequence of HBP.
Knowledge of the contribution of CMI to HBP
development could facilitate current efforts on
detection, evaluation, and treatment of hypertension.
Journal of Human Hypertension

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