Inflammation, Abdominal Obesity, and Smoking as

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Inflammation, Abdominal Obesity, and Smoking as
Inflammation, Abdominal Obesity, and Smoking as
Predictors of Hypertension
Leo Niskanen, David E. Laaksonen, Kristiina Nyyssönen, Kari Punnonen, Veli-Pekka Valkonen,
Ricardo Fuentes, Tomi-Pekka Tuomainen, Riitta Salonen, Jukka T. Salonen
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Abstract—Development of hypertension has been linked to chronic low-grade inflammation. However, it is not known
whether this connection is mediated by features of the metabolic syndrome or smoking, or their changes, which
themselves have been linked to inflammation. We studied the predictive value of highly sensitive C-reactive protein
(hs-CRP), smoking, and abdominal obesity to the development of hypertension in an 11-year follow-up of a
population-based study cohort comprising 379 middle-aged normotensive men. During the follow-up, 124 men (33%)
developed hypertension. Men with hs-CRP ⱖ3.0 mg/L were 2.8⫻ (95% confidence interval, 1.2 to 6.6) more likely to
develop hypertension than with hs-CRP ⬍1.0 mg/L even after adjustment for features of the metabolic syndrome,
lifestyle factors, and their changes. Cigarette smoking was also associated with development of hypertension
independently of inflammation and other confounders. Waist girth increased more in men who quit smoking than in
other men. An increase in waist girth during follow-up strongly predicted incident hypertension. The decrease in
smoking was not associated with a lower risk of hypertension in age-adjusted analyses. Hypertension is preceded by
low-grade chronic inflammation in middle-aged white men independently of smoking or features of the metabolic
syndrome. Furthermore, smoking may be a risk factor for hypertension. Although stopping smoking is beneficial with
respect to health outcomes, the subsequent increase in weight and waist girth associated with smoking cessation may
offset the decrease in the risk of hypertension that one may otherwise expect. (Hypertension. 2004;44:859-865.)
Key Words: obesity 䡲 smoking 䡲 prospective studies 䡲 insulin resistance
C
hronic low-grade inflammation seems to be an early
feature of many chronic degenerative disorders, including atherosclerosis, abdominal obesity, and type 2 diabetes.1–3
These disorders are also commonly associated with hypertension, which itself has also been linked recently to inflammation. The most compelling evidence comes from the Women’s Health Study, in which C-reactive protein (CRP) as a
marker of low-grade inflammation predicted the development
of hypertension in a cohort of 20 525 female US health
professionals during a follow-up of 7.8 years.4 This effect
was seen even in those with low baseline blood pressure
levels and in those without other conventional cardiovascular
risk factors, but no adjustment could be made for the presence
of the metabolic syndrome, a possible mediator of this
connection.5
Smoking causes an acute rise in blood pressure, whereas
the connection between chronic smoking and development
of hypertension is still unclear. Smoking in its own right
increases inflammation,6 but smoking cessation may not
reverse it.7 Furthermore, stopping smoking commonly
leads to weight gain. Weight gain is a well-established risk
factor for hypertension. Moreover, weight gain and obesity, especially abdominal, appear to not only cause
inflammation but may be preceded by inflammation.8
Complicating the picture, increased alcohol intake is
associated with hypertension and smoking but possibly
decreased abdominal fat.9
Observational studies are hampered with problems when
describing these intertwined phenomena. If we are to understand chronic low-grade inflammatory processes in relation to
the multifactorial origin of hypertension, the ideal study
setting should describe various pathways leading to hypertension by taking into account the changes in these factors. In
this study, we assessed the predictive value of low-grade
inflammation in the development of hypertension in middleaged men during an 11-year follow-up, controlling for baseline blood pressure, various lifestyle factors, features of
metabolic syndrome, and also the changes in smoking,
alcohol intake, and waist girth during follow-up. Furthermore, we evaluate the role of smoking independently of
inflammation and changes in waist girth with the development of hypertension.
Received July 1, 2004; first decision July 22, 2004; revision accepted September 22, 2004.
From the Departments of Medicine (L.N., D.E.L.) and Clinical Chemistry (K.P.), Kuopio University Hospital, Finland; Research Institute of Public
Health (K.N., V-P.V., T-P.T., J.T.S.) and Department of Public Health and General Practice (R.S.), University of Kuopio, Finland; and Jurilab Ltd (R.F.,
J.T.S.), Kuopio, Finland.
Reprint requests to Kristiina Nyyssönen, PhD, Research Institute of Public Health, University of Kuopio, PO Box 1627, FIN-70211 Kuopio, Finland.
E-mail [email protected]
© 2004 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
DOI: 10.1161/01.HYP.0000146691.51307.84
859
860
Hypertension
December 2004
Methods
Participants
Subjects were participants of the Kuopio Ischemic Heart Disease
Risk Factor Study.10 Participants were a random age-stratified
sample of men living in Eastern Finland who were 42, 48, 54, or 60
years old at the baseline examination from 1987 to 1989. The
recruitment and study design have been described previously in
detail.10 Repeat examinations for those who had undergone carotid
ultrasound at baseline were performed from 1991 to 1994 (4-year
follow-up) and 1998 to 2001 (11-year follow-up). In all, 854 men
participated in the 11-year follow-up (90% of those alive). Men with
hypertension or diabetes at baseline were excluded, leaving 379 men
for analyses of incident hypertension during the 11-year follow-up.
The university ethics committee approved the study. All participants
gave their written informed consent.
Definition of Hypertension
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Blood pressure was measured with a random-zero mercury sphygmomanometer (Hawksley and Sons). The protocol included 3 measurements while supine, 1 while standing, and 2 while sitting, with
5-minute intervals between measurements. The mean of the 2 sitting
measurements was used as the systolic and diastolic blood pressure.
Hypertension was defined at baseline and follow-up as systolic blood
pressure ⱖ140 mm Hg, diastolic blood pressure ⱖ90 mm Hg, or use
of antihypertensive medication.11,12
multicollinearity, we adjusted fibrinogen by CRP using linear regression before including it in the logistical regression models. To
investigate the associations of CRP concentrations with hypertension, CRP concentrations were categorized using the cut-offs ⬍1.0
mg/L, 1.0 to 2.9 mg/L, and 3.0 to 9.9 mg/L.15 Cigarette smoking was
categorized as not at all, 1 to 19 cigarettes per day, and ⱖ20
cigarettes per day. Alcohol intake was converted into grams of
ethanol per week and classified as none at all, 1 to 83 g per week, and
ⱖ84 g per week (84 g of ethanol is ⬇7 drinks). Waist circumference
was categorized into thirds (only 17% and 3% of nonhypertensive
men had waist girths ⬎94 and 102 cm, values that have been
recommended as “action levels” for prevention of chronic disease).20
The variables in question were entered into logistic regression
models adjusting for age and potential mediating or confounding
variables. The association of changes in waist circumference, smoking (as cigarettes per day), and alcohol intake with incident hypertension were similarly analyzed as continuous variables in logistic
regression models. The covariates for the logistic regression models
were forced into the model. Variables are given as means⫾SD,
except for variables with a skewed distribution (CRP, insulin,
triglycerides, alcohol intake, and physical activity), which are given
as medians and interquartile ranges, and proportions, which are given
as percentages. In analyses using continuous variables, skewed
variables were log transformed. The mean was substituted for
missing values (n⫽10 to 23) of covariates. Statistical significance
was considered to be P⬍0.05. All statistical analyses were performed with SPSS 11.0 for Windows.
Anthropometric and Biochemical Measurements
Body mass index (BMI) was computed as the ratio of weight to the
square of height (kg/m2). Waist circumference was defined as the
average of 2 measurements taken at the midpoint between the lowest
rib and the iliac crest after inspiration and expiration.
Fasting blood glucose was measured using a glucose dehydrogenase method after precipitation of proteins by trichloroacetic acid.
Diabetes was defined as fasting blood glucose concentration
ⱖ6.1 mmol/L (equivalent to plasma glucose ⱖ7.0 mmol/L) or a
clinical diagnosis of diabetes with dietary, oral, or insulin treatment.13 Serum insulin was determined with a Novo Biolabs radioimmunoassay kit (Novo Nordisk). HDL fractions were separated
from fresh serum by combined ultracentrifugation and precipitation.
The cholesterol contents of lipoprotein fractions and serum triglycerides were measured enzymatically. Fibrinogen was measured
based on the clotting of diluted plasma with excess thrombin.
Measurement of Highly Sensitive CRP
Serum CRP was measured with an immunometric assay (Immulite
High Sensitivity CR Assay; DPC).14 We used CRP cut-offs of 1.0
mg/L and 3.0 mg/L, as recommended by the Center for Disease
Control and the American Heart Association.15 To limit confounding
with acute infection or occult disease, we excluded men with CRP
concentrations ⱖ10.0 mg/L.
Other Assessments
Assessments of medical history and medications, smoking, alcohol
consumption, adult socioeconomic status, and moderate-to-vigorous
leisure-time physical activity have been described previously.16,17
Dietary intake of saturated fat, sodium, potassium, and fruits and
vegetables was measured with 4-day food records as grams per day
and adjusted by regression analysis for energy intake.18 Highresolution B-mode ultrasonography was used to examine a 1.0- to
1.5-cm section at the distal end of the left and right common carotid
artery proximal to the carotid bulb, as explained in detail
previously.19
Statistical Analyses
Differences in baseline characteristics between men who developed
hypertension and those who did not were assessed with Student t test,
and where indicated, the ␹ 2 test. Fibrinogen is an acute phase
reactant and as such, a marker of inflammation that has a high
correlation with CRP levels (r⫽0.50). To avoid problems with
Results
Baseline Clinical Characteristics
During the 11-year follow-up, men who developed hypertension were heavier, had a larger waist, and were more
dyslipidemic at baseline (Table 1). They also had higher
blood pressure. The prevalence of the metabolic syndrome
was uncommon in these relatively lean men without hypertension or diabetes but was more common in those who
developed hypertension during the follow-up. Smokers more
commonly developed hypertension, but the change in the
number of cigarettes smoked did not differ between men who
developed and did not develop hypertension. Alcohol intake
was similar in both groups, but increased alcohol intake at the
4-year follow-up was more common in men who developed
hypertension by the 11-year follow-up. Baseline CRP concentrations were much higher in men who later developed
hypertension.
CRP at Baseline and Hypertension
Men with CRP concentrations ⱖ3 mg/L were 3.6⫻ more
likely to develop hypertension than men with levels ⬍1.0
mg/L in age-adjusted analyses (Table 2). Adjustment for
baseline blood pressure, lifestyle factors, and cardiovascular
disease (model 2) only marginally weakened the association.
After additional adjustment for features of the metabolic
syndrome at baseline (model 3) or further for changes in waist
circumference, number of cigarettes smoked per day, or
intake of alcohol (model 4) during the first 11 years of
follow-up, men with CRP levels ⱖ3 mg/L were still 2.8⫻
more likely to develop hypertension during the 11-year
follow-up. Adjustment for changes in waist girth, smoking, or
alcohol intake over the 4-year period gave similar results as in
model 4. Adjustment for development of cardiovascular
disease during follow-up also had little effect on the results.
Inclusion of BMI in models 2 through 4 in place of or in
Niskanen et al
CRP, Smoking, and Hypertension
861
TABLE 1. Baseline Characteristics of Men Who Developed Hypertension During Follow-Up
and Those Who Did Not
Descriptive Variables
Nonhypertensive at
Follow-Up
Hypertensive at
Follow-Up
255
124
50.2 (6.6)
51.8 (6.7)
0.021
28
44
0.002
N
Age (years)
Smokers (%)
P
Change in smoking during follow-up
(for smokers)
At 4 years (n⫽133), cigarettes per day
⫺3 (11)
⫺4 (9)
0.88
At 11 years (n⫽132), cigarettes per day
⫺8 (15)
⫺4 (13)
0.14
Alcohol consumption, g/week
31 (6, 87)
28 (7, 89)
0.83
Change in alcohol intake during follow-up
(for nonabstainers)
⫺5 (119)
At 4 years (n⫽314), g/week
22 (74)
0.026
25 (112)
0.19
24
28
0.32
0.88 (0.78, 0.98)
0.91 (0.80, 1.05)
At 11 years (n⫽346), g/week
4 (150)
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Cardiovascular disease, %
Maximum carotid intima thickness, mm
0.005
Adult socioeconomic status score
6.9 (3.9)
6.8 (4.0)
Systolic blood pressure, mm Hg
121 (9)
128 (8)
⬍0.001
⬍0.001
Diastolic blood pressure, mm Hg
0.73
79 (6)
84 (6)
Body mass index, kg/m2
25.1 (2.7)
26.1 (2.9)
0.002
Waist circumference, cm
85.3 (7.9)
88.3 (8.0)
0.001
Change in waist girth during follow-up
At 4 years
4.4 (4.1)
5.3 (3.9)
0.052
At 11 years
7.1 (5.8)
8.7 (5.9)
0.015
Serum LDL cholesterol, mmol/L
3.8 (0.9)
4.0 (1.1)
0.067
Serum HDL cholesterol, mmol /L
1.40 (0.29)
1.28 (0.26)
0.001
Serum triglycerides, mmol/L
0.96 (0.75, 1.38)
1.10 (0.83, 1.64)
0.001
Fasting blood glucose, mmol /L
4.48 (0.45)
4.52 (0.47)
0.42
Fasting serum insulin, pmol/L
Fibrinogen (g/L, unadjusted)
7.9 (6.2, 10.3)
2.81 (0.50)
Metabolic syndrome (NCEP), %
1
8.9 (7.0, 11.2)
0.013
3.02 (0.50)
⬍0.001
3
0.026
Moderate and vigorous LTPA, min/week
143 (62, 256)
128 (56, 241)
0.24
Serum CRP, g/dL
0.81 (0.50, 1.46)
1.24 (0.76, 2.33)
0.002
Values are means (SD), medians (interquartile ranges), or percentages. Higher adult socioeconomic status score
means lower socioeconomic status.
NCEP indicates National Cholesterol Education Program29,30; LTPA, leisure-time physical activity.
addition to waist girth had little effect on the results. CRPadjusted fibrinogen was not associated with incident hypertension, and inclusion of CRP-adjusted fibrinogen in the
models did not affect the association of CRP with incident
hypertension. The risk associated with CRP levels was
graded, and men with levels between 1.0 and 3.0 mg/L were
also at increased risk for developing hypertension.
CRP concentrations also predicted incident hypertension at
11 years even after adjustment for the average maximum
thickness of the intima carotid for the left and right carotid
arteries in addition to technical covarates (odds ratio [OR] for
CRP, ⱖ3 mg/L versus ⬍1 mg/L 2.4 to 2.9 in models 2 to 4;
P⫽0.001 to 0.017 for the trend). CRP levels ⱖ3.0 mg/L were
quite uncommon (n⫽39) in these relatively lean men without
hypertension or diabetes at baseline, but the results were very
similar when using tertiles to categorize CRP (data not
shown). CRP concentrations also predicted use of blood
pressure medication at 11 years (OR for CRP, ⱖ3 mg/L
versus ⬍1 mg/L 3.1 to 3.5 in all models; P⫽0.005 to 0.016
for the trend) and incident hypertension when defining
hypertension at the 11-year follow-up solely by systolic and
diastolic blood pressure rather than including medication in
the definition (data not shown). There was no evidence of
modification of the association of CRP with hypertension
after stratification by median systolic blood pressure, BMI, or
smoking status.
Smoking at Baseline and Hypertension
Men who smoked ⱖ20 cigarettes per day were more than
twice as likely to develop hypertension (Table 2). Additional
adjustment for features of the metabolic syndrome at baseline
(model 3) weakened the association. However, after taking
862
Hypertension
December 2004
TABLE 2. ORs (95% CI) of Developing Hypertension During the 11-Year Follow-Up According to CRP
Concentrations, Smoking, Alcohol Intake, and Waist Circumference, Respectively
Predictive Variable
Model 1
Model 2
Model 3
Model 4
CRP concentrations*
0.1–0.99 mg/L (n⫽210)
1 (reference)
1
1
1
1.0–2.99 mg/L (n⫽130)
1.82 (1.13–2.94)
1.83 (1.08–3.10)
1.66 (0.93–2.95)
1.78 (1.00–3.17)
3.0–9.99 mg/L (n⫽39)
3.55 (1.74–7.23)
3.31 (1.50–7.31)
2.87 (1.21–6.83)
2.81 (1.19–6.63)
⬍0.001
0.001
0.007
0.008
P for trend
Cigarettes per day†
0 (n⫽260)
1 (reference)
1
1
1
1–19 (n⫽41)
1.57 (0.78–3.18)
1.83 (0.84–4.01)
1.76 (0.78–3.94)
2.50 (1.04–5.97)
ⱖ20 (n⫽77)
2.38 (1.39–4.08)
2.37 (1.23–4.57)
1.95 (0.98–3.87)
3.37 (1.48–7.67)
0.001
0.007
0.046
0.003
1 (reference)
1
1
1
1–83 (n⫽232)
1.25 (0.64–2.49)
0.89 (0.41–1.93)
0.90 (0.42–1.98)
0.91 (0.40–2.07)
ⱖ84 (n⫽98)
1.46 (0.68–3.14)
0.84 (0.34–2.06)
0.94 (0.37–2.44)
0.92 (0.35–2.46)
0.34
0.71
0.96
0.90
P for trend
Alcohol, g/week‡
0 (n⫽49)
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P for trend
Waist girth at baseline§
⬍82.5 cm (n⫽127)
1 (reference)
1
1
1
82.5–88.5 cm (n⫽121)
2.23 (1.26–3.94)
1.96 (1.06–3.62)
1.43 (0.74–2.74)
1.57 (0.80–3.11)
⬎88.5 (n⫽131)
2.32 (1.34–4.04)
1.83 (1.00–3.35)
1.10 (0.53–2.26)
1.29 (0.61–2.73)
0.003
0.059
0.84
0.53
P for trend
*Model 1, Age-adjusted; model 2, adjusted for age, smoking (none, 1–19, and ⱖ20 cigarettes per day), alcohol intake (abstinent,
1– 83 g, and ⱖ84 g ethanol per week), adult socioeconomic status, leisure-time physical activity, presence of cardiovascular disease,
intake of energy-adjusted dietary factors (dietary intake of saturated fat, sodium, potassium, and fruits and vegetables), and baseline
systolic blood pressure; model 3, adjusted for variables in model 2 and waist girth (⬍82.5 cm, 82.5– 88.5 cm, and ⬎88.5 cm), and
concentrations of insulin, glucose, and HDL cholesterol; model 4, adjusted for variables in model 3 and changes in waist girth,
smoking (cigarettes per day), and alcohol intake (g/day) during the 11-year period.
†Models as above, except that CRP categories were used as a covariate in place of smoking in models 2– 4.
‡Models as above, except that CRP categories were used as a covariate in place of alcohol intake in models 2– 4.
§Models as above, except that CRP categories were used as a covariate in place of waist girth in models 3– 4.
into account the changes in waist circumference, number of
cigarettes smoked per day, or in the intake of alcohol (model
4) during the 11-year follow-up, smoking at baseline was
associated with a graded increase in the risk of hypertension
during the 11-year follow-up. The increase in risk of smoking
in model 4 compared with model 3 was a result of adjustment
for the change in smoking, alcohol intake, and waist circumference. Adjustment for the changes in waist girth, smoking,
or alcohol intake during the 4-year period gave essentially
identical results as in model 4.
Abdominal Obesity at Baseline and Hypertension
Waist girth at baseline more than doubled the likelihood of
hypertension in age-adjusted analyses (Table 2). Further adjustment for baseline systolic blood pressure and lifestyle
factors (model 2) attenuated the association, which was
mainly attributable to inclusion of CRP and baseline systolic
blood pressure into the model. Additional adjustment for
variables related to the metabolic syndrome (model 3) further
attenuated the association such that it was no longer significant. Adjustment for the changes in waist girth, smoking, or
alcohol intake during the 4-year period gave essentially
identical results as adjustment for changes during the 11-year
follow-up.
Alcohol Intake at Baseline and Hypertension
Men reporting consumption of ⱖ7 drinks per week were
1.5⫻ more likely than nondrinkers to develop hypertension
during the 11-year follow-up in age-adjusted analyses, but the
association was not significant (Table 2). The ORs attenuated
even further in multivariate analyses.
Incident Hypertension and Changes in Smoking,
Alcohol Intake, and Waist Girth
Of the changes in smoking, alcohol intake, and leisure-time
physical activity, only the changes in smoking and alcohol
intake were associated with incident hypertension. When
adjusting for only age and baseline smoking, the change in
the number of cigarettes smoked was not associated with
development of hypertension (Table 3). However, with further multivariate adjustment, the association strengthened,
which was attributable mainly to the inclusion of baseline
waist girth and HDL cholesterol levels in model 3 and to the
inclusion of the change in waist girth to model 4. The
association of the change in number of cigarettes smoked per
Niskanen et al
CRP, Smoking, and Hypertension
863
TABLE 3. ORs for Developing Hypertension According to the Change in Smoking, Alcohol
Intake, and Waist Girth During the 11-Year Follow-Up
Predictive Variable
Model 1
Model 2
Model 3
Model 4
Change in smoking (for an decrease of 10 cigarettes per day)*
4-year change
0.97 (0.76–1.25)
0.90 (0.67–1.19)
0.65 (0.43–1.01)
0.58 (0.37–0.93)
11-year change
0.88 (0.69–1.12)
0.86 (0.65–1.15)
0.56 (0.36–0.85)
0.51 (0.31–0.81)
Change in alcohol intake (for an increase of 84 g ethanol per week, equivalent to 1 drink per day)†
4-year change
1.34 (1.04–1.74)
1.37 (1.05–1.80)
1.40 (1.06–1.85)
1.34 (1.01–1.77)
11-year change
1.13 (0.98–1.31)
1.16 (0.99–1.36)
1.18 (1.00–1.39)
1.14 (0.96–1.35)
Change in waist (for a 5-cm increase during follow-up)‡
4-year change
1.38 (1.05–1.83)
1.55 (1.14–2.12)
1.57 (1.14–2.16)
1.59 (1.14–2.21)
11-year change
1.32 (1.09–1.60)
1.27 (1.03–1.58)
1.27 (1.02–1.59)
1.31 (1.04–1.66)
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*Model 1, Adjusted for age and baseline smoking (none, 1–19, and ⱖ20 cigarettes per day); model 2, adjusted for
age, baseline CRP categories, smoking, alcohol intake (abstinent, 1– 83 g, and ⱖ84 g ethanol per week), adult
socioeconomic status, leisure-time physical activity, presence of cardiovascular disease, intake of energy-adjusted
dietary factors (dietary intake of saturated fat, sodium, potassium, and fruits and vegetables), and baseline systolic
blood pressure; model 3, adjusted for variables in model 2 and waist girth (⬍82.5 cm, 82.5– 88.5 cm, and ⬎88.5
cm), and concentrations of insulin, glucose, and triglycerides; model 4, adjusted for variables in model 3 and changes
in waist girth and alcohol intake (g/day) during the 11-year period.
†Models as above, except that alcohol categories were used as a covariate in place of smoking in model 1, and
the change in smoking (cigarettes per day) during follow-up was used as a covariate in place of change in alcohol
intake in model 4.
‡Models as above, except that baseline waist categories were used as a covariate in place of baseline smoking
in model 1, baseline waist circumference was also included in place of CRP categories in model 2, and adjustment
for changes in alcohol intake and smoking was made in model 4.
day during the 11-year follow-up with incident hypertension
was significant also in analyses confined to smokers (eg, in
models 2 to 4; OR, 0.42 to 0.56 for a 10-cigarette decrease;
P⫽0.021 to 0.006). The relevance of taking into account the
change in waist girth in the association of the change in
smoking with development of hypertension is also illustrated
by the increase in waist circumference with smoking cessation. The waist girth of nonsmokers who remained nonsmokers increased 7.3 cm (95% confidence interval [CI], 6.6 to
8.1), and that of smokers at baseline who remained smokers
increased 7.0 cm (95% CI, 5.7 to 8.3) during the 11-year
follow-up. In contrast, the waist girth of men who quit during
the follow-up increased by 10.4 cm (95% CI, 8.7 to 12.2;
P⫽0.003 for the difference between groups after adjustment
for age and baseline waist girth). An increase in alcohol
intake also increased the risk of hypertension during the
11-year follow-up. Of the changes during follow-up in the
metabolic variables shown in model 3, only the change in
waist girth was associated with development of hypertension
(Table 3). Multivariate adjustment had little effect on the
association.
Discussion
This study extends the findings of Women’s Health Study4 of
chronic low-grade inflammation as a predictor of hypertension in men. Moreover, this association is not explained by
various lifestyle factors or features of the metabolic
syndrome.
Although hypertension is another member of a long list of
disorders preceded by low-grade inflammation, the mechanisms of the mediating factors remain elusive. Based on the
results of this study, inflammation as measured by highly
sensitive CRP concentrations is clearly more than a marker of
abdominal obesity or the metabolic syndrome and is not
explained by smoking or presence of cardiovascular disease.
There could well be an underlying genetic propensity, although little data currently exist to support this conviction.
On the other hand, low-grade inflammation as measured by
CRP levels could still be a marker of highly active cytokineproducing adipose tissue infiltrated by macrophages and
leading to complement activation and release of vasoactive
cytokines and subsequent endothelial dysfunction;8,21 and any
increase in the amount of fat tissue, especially in the abdominal area, could lead to more active function and development
of hypertension. This mechanism is unlikely to explain a
major part of the association of CRP levels with incident
hypertension because adjustment for waist girth and other
variables related to the metabolic syndrome only slightly
attenuated the association. Elevated CRP concentrations may
also be secondary to artery wall thickening and atherosclerotic burden, but adjustment for carotid intima thickness did
not alter the predictive value of CRP. CRP itself may cause
endothelial dysfunction.22 Furthermore, CRP may upregulate
angiotensin type 1 receptors, leading to proliferation of
vascular smooth muscle cells 23 and subsequently to
hypertension.
In this study, the predictive role of smoking with development of hypertension was somewhat surprising. Middle-aged
men who decreased the number of cigarettes smoked daily by
10 were not less likely to develop hypertension in ageadjusted analyses. However, when taking into account waist
at baseline and the increase in waist girth in addition to other
variables, decreasing the number of cigarettes smoked by 10
halved their adjusted risk of hypertension. Thus, even smok-
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ing cessation did not seem to protect from hypertension, most
likely because of the associated increase in abdominal obesity. There are previous reports suggesting that smoking or
smoking cessation24 –27 may indeed be a harbinger for development of hypertension, but generally, smoking has not been
considered a causative factor of hypertension. One of the
mechanisms may be smoking-induced renal damage.28
Alcohol intake was weakly associated with development of
hypertension, and after multivariate adjustment, the connection was abolished. On the other hand, an increase in alcohol
intake during the follow-up was clearly associated with a
higher incidence of hypertension. The overall weak association of alcohol intake with incident hypertension may be
attributable to the difficulty in the reliable recording of
alcohol intake.
The strengths of this study are the population-based prospective design, high participation rate, detailed assessment
of variables related to lifestyle, and the metabolic syndrome
and use of a uniform and constant definition of hypertension
with careful measurement of blood pressure according to a
standard protocol. Importantly, the changes of major variables related to lifestyle and the metabolic syndrome during
follow-up were determined. The limitations are that of the
various inflammatory markers, only a single baseline measurement of CRP was taken into account. However, this, if
anything, leads to conservative estimate of the association in
question. The study was performed in middle-aged white
men, and generalization to other groups should be viewed
with caution.
Perspectives
We have demonstrated that hypertension is preceded by
low-grade chronic inflammation as assessed by CRP in
middle-aged white men. This connection was not explained
by smoking, baseline systolic blood pressure, or features of
metabolic syndrome. Furthermore, smoking may be a risk
factor for hypertension. Although stopping smoking is extremely beneficial with respect to cardiovascular risk and
other health outcomes, the subsequent weight gain and
increase in waist girth associated with smoking cessation may
offset the decrease in risk of hypertension that one may
otherwise expect. Therefore, efforts to curtail smoking should
also take more seriously into account the consequences of the
subsequent weight gain because the early prevention of
abdominal obesity may be easier than later attempts at weight
loss and control of hypertension. This study illustrates that
multiple pathways seem to lead to hypertension independently of inflammation, including an increase in waist girth
and smoking, even when the relevant changes during the
follow-up are taken into account.
Acknowledgments
The Kuopio Ischemic Heart Disease Risk Factor Study was supported by grants from the Academy of Finland (grants 41471, 45155,
1041086, and 2041022), the Ministry of Education of Finland (grants
167/722/96, 157/722/97, and 156/722/98), and the National Heart,
Lung, and Blood Institute of the United States (grant HL44199). We
thank the staff of the Research Institute of Public Health, University
of Kuopio, and Kuopio Research Institute of Exercise Medicine for
data collection in the Kuopio Ischemic Heart Disease Risk
Factor Study.
References
1. Ridker PM, Buring JE, Shih J, Matias M, Hennekens CH. Prospective
study of C-reactive protein and the risk of future cardiovascular events
among apparently healthy women. Circulation. 1998;98:731–733.
2. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive
protein, IL 6, and risk of developing type 2 diabetes mellitus. J Am Med
Assoc. 2001;286:327–334.
3. Laaksonen DE, Niskanen L, Nyyssönen K, Punnonen K, Tuomainen TP,
Valkonen VP, Salonen R, Salonen JT. C-reactive protein and the development of the metabolic syndrome and diabetes in middle-aged men.
Diabetologia. 2004;47:1403–1410.
4. Sesso HD, Buring JE, Rifai N, Blake GJ, Gaziano JM, Ridker PM.
C-reactive protein and the risk of developing hypertension. J Am Med
Assoc. 2003;290:2945–2951.
5. Grundy SM. Inflammation, hypertension, and the metabolic syndrome.
J Am Med Assoc. 2003;290:3000 –3002.
6. Bazzano LA, He J, Muntner P, Vupputuri S, Whelton PK. Relationship
between cigarette smoking and novel risk factors for cardiovascular
disease in the United States. Ann Intern Med. 2003;138:891– 897.
7. Crook MA, Scott DA, Stapleton JA, Palmer RM, Wilson RF, Sutherland
G. Circulating concentrations of C-reactive protein and total sialic acid in
tobacco smokers remain unchanged following one year of validated
smoking cessation. Eur J Clin Invest. 2000;30:861– 865.
8. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante
AW Jr. Obesity is associated with macrophage accumulation in adipose
tissue. J Clin Invest. 2003;112:1796 –1808.
9. Greenfield JR, Samaras K, Jenkins AB, Kelly PJ, Spector TD, Campbell
LV. Moderate alcohol consumption, dietary fat composition, and
abdominal obesity in women: evidence for gene-environment interaction.
J Clin Endocrinol Metab. 2003;88:5381–5386.
10. Salonen JT. Is there a continuing need for longitudinal epidemiologic
research? The Kuopio Ischaemic Heart Disease Risk Factor Study. Ann
Clin Res. 1988;20:46 –50.
11. Joint National Committee. The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood
pressure. Arch Intern Med. 1997;157:2413–2446.
12. World Health Organization-International Society of Hypertension. 1999
World Health Organization-International Society of Hypertension
Guidelines for the Management of Hypertension. Guidelines Subcommittee. J Hypertens. 1999;17:151–183.
13. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of
diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional report of a WHO consultation.
Diabet Med. 1998;15:539 –553.
14. Laaksonen DE, Niskanen L, Punnonen K, Nyyssönen K, Tuomainen T-P,
Salonen R, Rauramaa R, Salonen JT. Sex hormones, inflammation and
the metabolic syndrome: a population-based study. Eur J Endocrinol.
2003;149:601– 608.
15. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO III,
Criqui M, Fadl YY, Fortmann SP, Hong Y, Myers GL, Rifai N, Smith SC
Jr, Taubert K, Tracy RP, Vinicor F. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a
statement for healthcare professionals from the Centers for Disease
Control and Prevention and the American Heart Association. Circulation.
2003;107:499 –511.
16. Lynch JW, Kaplan GA, Cohen RD, Kauhanen J, Wilson TW, Smith NL,
Salonen JT. Childhood and adult socioeconomic status as predictors of
mortality in Finland. Lancet. 1994;343:524 –527.
17. Laaksonen DE, Lakka HM, Salonen JT, Niskanen LK, Rauramaa R,
Lakka TA. Low levels of leisure-time physical activity and cardiorespiratory fitness predict development of the metabolic syndrome. Diabetes
Care. 2002;25:1612–1618.
18. Laaksonen DE, Nyyssonen K, Niskanen L, Rissanen TH, Salonen JT.
Dietary and serum linoleic and polyunsaturated fatty acids predict
cardiovascular mortality in middle-aged men. Arch Intern Med. In
press.
19. Salonen JT, Salonen R. Ultrasound B-mode imaging in observational
studies of atherosclerotic progression. Circulation. 1993;87:II56 –II65.
20. Lean ME, Han TS, Seidell JC. Impairment of health and quality of life in
people with large waist circumference. Lancet. 1998;351:853– 856.
Niskanen et al
21. Wellen KE, Hotamisligil GS. Obesity-induced inflammatory changes in
adipose tissue. J Clin Invest. 2003;112:1785–1788.
22. Verma S, Yeh ET. C-reactive protein and atherothrombosis– beyond a
biomarker: an actual partaker of lesion formation. Am J Physiol Regul
Integr Comp Physiol. 2003;285:R1253–R1256.
23. Wang CH, Li SH, Weisel RD, Fedak PW, Dumont AS, Szmitko P, Li
RK, Mickle DA, Verma S. C-reactive protein upregulates angiotensin
type 1 receptors in vascular smooth muscle. Circulation. 2003;107:
1783–1790.
24. Rywik SL, Williams OD, Pajak A, Broda G, Davis CE, Kawalec E,
Manolio TA, Piotrowski W, Hutchinson R. Incidence and correlates of
hypertension in the Atherosclerosis Risk in Communities (ARIC) Study
and the Monitoring Trends and Determinants of Cardiovascular Disease
(POL-MONICA) Project. J Hypertens. 2000;18:999 –1006.
25. Lee DH, Ha MH, Kim JR, Jacobs DR Jr. Effects of smoking cessation on
changes in blood pressure and incidence of hypertension: a 4-year
follow-up study. Hypertension. 2001;37:194 –198.
CRP, Smoking, and Hypertension
865
26. Janzon E, Hedblad B, Berglund G, Engstrom G. Changes in blood
pressure and body weight following smoking cessation in women.
J Intern Med. 2004;255:266 –272.
27. Schut AF, Sayed-Tabatabaei FA, Witteman JC, Avella AM, Vergeer JM,
Pols HA, Hofman A, Deinum J, van Duijn CM. Smoking-dependent
effects of the angiotensin-converting enzyme gene insertion/deletion
polymorphism on blood pressure. J Hypertens. 2004;22:313–319.
28. Orth SR. Effects of smoking on systemic and intrarenal hemodynamics:
influence on renal function. J Am Soc Nephrol. 2004;15(suppl 1):S58–S63.
29. National Cholesterol Education Program. Executive Summary of the
Third Report of the National Cholesterol Education Program (NCEP)
Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults (Adult Treatment Panel III). J Am Med Assoc.
2001;285:2486 –2497.
30. Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E,
Tuomilehto J, Salonen JT. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. J Am Med Assoc. 2002;
288:2709 –2716.
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Inflammation, Abdominal Obesity, and Smoking as Predictors of Hypertension
Leo Niskanen, David E. Laaksonen, Kristiina Nyyssönen, Kari Punnonen, Veli-Pekka
Valkonen, Ricardo Fuentes, Tomi-Pekka Tuomainen, Riitta Salonen and Jukka T. Salonen
Downloaded from http://hyper.ahajournals.org/ by guest on August 11, 2017
Hypertension. 2004;44:859-865; originally published online October 18, 2004;
doi: 10.1161/01.HYP.0000146691.51307.84
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2004 American Heart Association, Inc. All rights reserved.
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