ORIGINAL

PAPER

The Impact of Cigarette Smoking on 24-Hour Blood Pressure,

Inflammatory and Hemostatic Activity, and Cardiovascular Risk in
Japanese Hypertensive Patients
Yuichirou Yano, MD; Satoshi Hoshide, MD, PhD; Kazuyuki Shimada, MD, PhD; Kazuomi Kario; MD, PhD
From the Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University School of Medicine, Tochigi, Japan

The aim of the study was to assess the impact of current

smoking on 24-hour blood pressure (BP) and inflammatory
and hemostatic activity and thereby the incidence of cardiovascular disease (CVD) in Japanese hypertensive
patients. A total of 810 hypertensive patients (mean age
72 years; 38% men) were prospectively followed-up (2799
person-years). During the follow-up, 66 cases of CVD
occurred (stroke, 55; myocardial infarction, 7; both, 4). At
baseline, the current smokers (n=166) had higher levels of
high-sensitivity C-reactive protein (hs-CRP) (0.21 mg dL vs
0.14 mg dL) and plasminogen activator inhibitor-1 (PAI-1)
(46.1 ng mL vs 37.8 ng mL; both P=.001), but not of 24hour BP, compared with nonsmokers. Using a Cox regres-

sion analysis, current smoking was independently associated with an increased risk of CVD (hazard ratio [HR], 2.6;
P<.01), and the risk was substantially higher in women
(HR, 6.1; P<.001) than in men (HR, 1.4; P=.41). The CVD
risk of current smokers was magnified when it was accompanied with high hs-CRP (highest quartile range,
0.40 mg L) or PAI-1 levels (58.9 ng mL) compared with
that in smokers with low hs-CRP or PAI-1 levels (both
P<.05). Among hypertensive patients, current smokers had
increased risk of CVD events, and the increase was more
prominent when accompanied by circulatory inflammatory
and hemostatic abnormalities. J Clin Hypertens (Greenwich). 2013;15:234240. 2012 Wiley Periodicals, Inc.

There is compelling evidence of the impact of cigarette

smoking on the development of coronary artery disease (CAD), stroke, and sudden cardiac death.15 In
Japan, smoking could explain a large portion of cardiovascular disease (CVD) mortality and all-cause
mortality.5 In particular, the combined effect of smoking and hypertension on CVD and all-cause mortality
is large,3 which highlights the importance of elucidating the pathophysiological mechanisms of smoking in
hypertensive patients and identification of CVD-prone
high-risk patients.
Some studies have shown that current normotensive
or hypertensive smokers tend to have higher ambulatory blood pressure (BP), rather than higher office BP,
compared with nonsmokers.6,7 Moreover, it is increasingly recognized that low-grade inflammation as well
as alterations of coagulation and or fibrinolysis
homeostasis in the circulation or at the vascular interface can occur in current smokers.812 These abnormalities may in part explain the increased
cardiovascular risk of current smoking. However, we
are not aware of any existing data directly assessing
the impact of current smoking on the incidence of
CVD events in relation to its adverse effects on 24hour BP and inflammatory and hemostatic activity in
hypertensive patients.

Accordingly, in the present study we examined

whether current smoking is associated with abnormalities of 24-hour BP and inflammatory and hemostatic
factors, and, as a consequence, CVD events in
Japanese hypertensive patients.

Address for correspondence: Kazuomi Kario, MD, PhD, Division of

Cardiovascular Medicine, Jichi Medical University School of Medicine,
3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan
E-mail: kkario@jichi.ac.jp
Manuscript received: August 8, 2012; revised: October 4, 2012;
accepted: October 16, 2012
DOI: 10.1111/jch.12047

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METHODS
Patients
The methods of the study have been detailed elsewhere.13,14 Briefly, we initially enrolled 821 hypertensive outpatients (clinic BP 140 90 mm Hg and age
older than 50 years) in the present study between January 1, 1992, and January 1, 1998. Patients who had
a history of stroke, coronary artery disease, chronic
heart failure, peripheral vascular disease, atrial fibrillation, and obvious present illness (eg, malignancy or
infection) at baseline were excluded from this study.
Follow-up examination was successfully conducted in
811 (99%) patients.
Clinic BP was measured after at least 5 minutes of
seated rest. Diabetes mellitus was defined as a fasting
glucose level 126 mg dL, a random nonfasting
glucose level 200 mg dL, hemoglobin A1c 6.2%, or
the use of an oral hypoglycemic agent or insulin.
Hyperlipidemia was defined as a total cholesterol
level 240 mg dL or the use of an oral lipid-lowering
agent. To estimate renal function, the glomerular
filtration rate was estimated (eGFR) by the Modification of Diet in Renal Disease study equation
modified for Japanese: 194 Cr)1.094age)0.2870.739
(for women).15 The patients were asked whether they
were currently smoking or not.
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Smoking and Cardiovascular Risk

This study was approved by the independent

research ethics committee, Jichi Medical University
School of Medicine, Japan, in 1998. All of the patients
studied were ambulatory, and all gave informed consent to participate in the study.
24-Hour ABPM
Twenty-fourhour ambulatory BP monitoring (ABPM)
was performed with an automatic oscillometric device
at 30-minute intervals.13,14 The ambulatory data used
were obtained by the oscillometric method. All
patients recorded their waking time and their bedtime.
We defined daytime and nighttime BP as the average
of values from each of these two periods.
Assay for Inflammatory and Hemostatic Factors
The methods are detailed in the Supporting Information. Briefly, in the morning (810 AM) after an overnight fast, venous blood was obtained after 10 minutes
in the supine position. Serum high-sensitivity C-reactive
protein (hs-CRP) level was measured by nephelometry
(NA Latex CRP kit; Dade Behring, Fort Lauderdale,
FL). The plasma fibrinogen level was determined using
a one-stage clotting assay kit (Dade Behring), and the
plasma levels of prothrombin fragment 1+2 (F1+2) and
plasminogen activator inhibitor-1 (PAI-1) antigen were
determined using enzyme-immunosorbent assay kits for
F1+2 (Behringwerke AG, Marburg, Germany) and PAI1 (Biopool, Umea, Sweden). The plasma level of the
von Willebrand factor (vWF) was measured using a
specific enzyme-linked immunosorbant assay (ELISA)
kit (Shield Diagnostics, Ltd, Dundee, UK). This assay
uses a monoclonal antibody against the functional epitope of vWF,16 rather than the polyclonal antibody
used by previous commercially available ELISA kits,
and the value for the commercially available pooled
plasma (CTS Standard Plasma; Behringwerke AG) was
taken as 100%. All measurements were conducted at a
single commercial laboratory (SRL Inc, Tokyo, Japan),
and the intra-assay and inter-assay coefficients of all
tests were <7%.
Follow-Up and Events
The patients medical records were intermittently
reviewed after ABPM to check on their antihypertensive drug therapy and to assess the occurrence of clinical CVD events, such as cardiac events or stroke. The
follow-up was performed during a 20-month period
from 1996 to 1998; the mean follow-up period was
4114 months, with a range of 1 to 68 months.
Among the 811 patients who were successfully followed-up, 426 patients (53%) were taking antihypertensive medication at the time of the final follow-up.
When patients failed to come to the clinic, we interviewed them by telephone: none of the cases interviewed by telephone were diagnosed as having had a
CVD event. All CVD events were diagnosed by the
physician who was caring for the patient at the time
of the event, and independent physicians reviewed the
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Yano et al.

cases and confirmed the diagnosis of CVD events.

Cardiac events included fatal and nonfatal acute myocardial infarction or events requiring treatment by percutaneous coronary intervention. Stroke was
diagnosed on the basis of a sudden onset of a neurological deficit persisting for 24 hours in the absence
of any other disease that could explain the symptom.
Stroke events were categorized as ischemic stroke
(cerebral infarction and cerebral embolism) or hemorrhagic stroke; the patients whose diagnoses were
defined by clinical symptoms but not with brain computed tomography or magnetic resonance imaging
were considered to have had an undefined type of
stroke. We excluded transient ischemic attacks, ie,
those in which the neurological deficit was cleared completely within 24 hours from the onset of symptoms.
Statistical Analysis
All statistical analyses were performed with SPSS version 18.0 J software (SPSS, Chicago, IL). Variables
with normal distribution are expressed as meanstandard deviation (SD), whereas variables with skewed
distribution were logarithmically transformed before
analysis and expressed as geometric means (SD range).
Clinical parameters in patients with or without current
smoking were compared using the unpaired t test, and
categorical parameters were compared with the
chi-square test. Analysis of covariance with adjustment
for age, sex, body mass index (BMI), and a history of
diabetes or hyperlipidemia was performed to examine
the differences in 24-hour BP and inflammatory and
hemostatic risk factors in patients with or without
current smoking. The hazard ratio (HR) and 95%
confidence interval (CI) of clinical CVD events in the
current smokers were calculated using Cox regression
analyses with adjustments for significant covariates
that were determined by the differences in the baseline
clinical characteristics between the current smokers
and nonsmokers (ie, sex, BMI, history of diabetes, history of hyperlipidemia, and 24-hour pulse rate [PR]).
In that model, we also included and calculated the HR
and 95% CI of clinical CVD events for each patient
with quartiles (highest quartile vs lower quartiles) of
inflammatory and hemostatic factors.
Finally, we divided the patients according to the
presence of current smoking and the circulatory levels
of hs-CRP, another set according to the presence of
current smoking and the circulatory levels with or
without the highest quartile of F1+2, and a third set
according to the presence of current smoking and the
circulatory levels with or without the highest quartile
of PAI-1. Kaplan-Meier curves were used to compare
the unadjusted CVD events-free survival rate among
these sets of 4 groups, and the differences were
assessed by the log-rank test. The HR (95% CI) of
clinical CVD events in the groups of each set were also
calculated using Cox regression analyses with adjustments for significant covariates. Statistical significance
was defined as P<.05.
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Yano et al.

RESULTS
Clinical Characteristics
One patient with unsatisfactory blood collection was
excluded, thus 810 patients were included in the final
analysis. The mean ageSD of the 810 patients was
72.39.8 years, and 311 of the patients (38%) were
men. The baseline clinical characteristics according to
the presence of current smoking are shown Table I.
Compared with nonsmokers, current smokers were
more likely men, had lower BMI, higher prevalence
of type 2 diabetes, and lower prevalence of hyperlipidemia.
Associations of Smoking With 24-Hour BP,
Inflammation, and Hemostasis
Office and nighttime PRs were higher in patients with
current smoking than those without it, but no significant differences were found in office, daytime, or
nighttime BP levels between the two groups (Table I).

In contrast, patients with current smoking had significantly higher levels of hs-CRP, F1+2, and PAI-1 than
those without current smoking, and this difference
remained unchanged even after adjustment for age,
sex, BMI, and a history of diabetes or hyperlipidemia
(data not shown).
Smoking and CVD Risk
During an average duration of 41 months (range:
168 months, 2799 person-years), 66 CVD events
occurred (23.6 events 1000 person-years), including
59 events of clinical stroke (ischemic, 38; hemorrhagic,
9; undefined, 12) and 11 cardiac events. Among the
patients with cardiac events, 4 patients had clinical
stroke events during the follow-up period. When we
analyzed the patients according to the presence of current smoking, the crude incidence of CVD events in
current smokers was higher (50.0 events 1000 personyears) than that in noncurrent smokers (17.0
events 1000 person-years).

TABLE I. Baseline Clinical Characteristics of the Study Population According to the Presence of Current Smoking

Status
Nonsmoker (n=644)
Patient characteristics
Age, y
Men, %
Body mass index, kg m2
Type 2 diabetes, %
Hyperlipidemia, %

P Value

72.1  9.8

73.0  10.1

.29

28
24.1  3.5

78
23.1  3.6

<.001
.001

9
21

eGFR, mL min 1.73m2

Antiplatelet drugs, %

Current Smoker (n=166)

24
10

<.001
.002

56.2  13.3
27

56.3  14.3
28

164 (163 to 166)

164 (161 to 167)

.42

91 (89 to 92)
76 (75 to 77)

90 (88 to 93)
79 (77 to 81)

.95
.04

24-Hour SBP, mm Hga

24-Hour DBP, mm Hga

138 (136 to 139)

78 (77 to 79)

139 (137 to 142)

79 (77 to 80)

.30
.40

24-Hour PR, beats per mina

Daytime SBP, mm Hg

70 (70 to 71)
145 (143 to 146)

72 (71 to 73)
146 (143 to 149)

.03
.49

Daytime DBP, mm Hg
Daytime PR, beats per mina

82 (81 to 82)
76 (76 to 77)

82 (80 to 84)
77 (76 to 79)

.83
.22

Nighttime SBP, mm Hga

Nighttime DBP, mm Hga

126 (125 to 128)

72 (71 to 73)

128 (125 to 131)

73 (71 to 75)

.24
.40

Nighttime PR, beats per mina

Nocturnal SBP dipping, %a

61 (60 to 61)
)12 ()13 to )12)

BP measurements
Office SBP, mm Hga
Office DBP, mm Hga
Office PR, beats per mina

Inflammatory factors
White blood cells, 103 lLa

.93
.70

62 (61 to 64)
)12 ()13 to )10)

.02
.48

5.7 (5.6 to 5.8)

5.7 (5.5 to 6.0)

.88

0.14 (0.12 to 0.15)

0.21 (0.17 to 0.27)

.001

Fibrinogen, mg dLa
Prothrombin fragment 1+2, nmol La

267.7 (263.0 to 272.5)

1.5 (1.4 to 1.5)

277.8 (267.6 to 288.4)

1.6 (1.5 to 1.7)

.09
.02

von Willebrand factor, %a

157.4 (153.7 to 161.2)

166.0 (157.9 to 174.5)

.07

37.8 (36.0 to 39.7)

46.1 (41.6 to 51.1)

.001

High-sensitivity C-reactive protein, mg La

Hemostatic factors

Plasminogen activator inhibitor-1, ng mLa

Abbreviations: DBP, diastolic blood pressure; eGFR, glomerular filtration rate; PR, pulse rate; SBP, systolic blood pressure. Data are expressed as
meansstandard deviation. P values were obtained by an unpaired t test or chi-square test. aVariables expressed as the geometric mean (95% confidence interval) with adjustment for age, sex, body mass index, and a history of diabetes or hyperlipidemia by analysis of covariance. Statistical significance was defined as P<.05.

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Smoking and Cardiovascular Risk

The baseline clinical characteristics according to the

occurrence of clinical CVD events are shown in
Table II. At the time of final follow-up, there was no
difference in the prevalence of antihypertensive medications between patients with current smoking and
those without current smoking (calcium channel
blockers: 36% vs 34%, P=.72; diuretics: 3.0% vs
3.6%, P=1.00), except for the use of angiotensinconverting enzyme (ACE) inhibitors (34% vs 18%,
P<.01).
In Cox regression analysis (Table III), patients with
current smoking had a significantly higher incidence of
clinical CVD events than those without current smoking even after adjusting for sex, BMI, history of diabetes, history of hyperlipidemia, and 24-hour PR
(Table III, model 1). Additional adjustment for the use
of ACE inhibitors or calcium channel blockers at the

Yano et al.

time of final follow-up did not change the CVD risk of

current smoking (data not shown). When the CVD
risk of current smoking was analyzed by sex, it was
substantially high in women (HR, 6.1; 95% CI, 2.8
13.4; P<.001) rather than in men (HR, 1.4; 95% CI,
0.72.8; P=.41).
Next, we entered the highest quartile of circulatory
hs-CRP (0.40 mg L, n=201), F1+2 (1.8 nmol L,
n=202), and PAI-1 (58.9 ng mL, n=202) in model 1
in Table III. As a result, current smoking as well as
each of these inflammatory and hemostatic parameters
were significantly and independently associated with
an increased risk of CVD events (Table III, model 2).
When we entered hs-CRP, F1+2, and PAI-1 as continuous variables instead of categorical variables in
model 2, the conclusion remained unchanged (data not
shown).

TABLE II. Baseline Clinical Characteristics of the Study Population According to the Occurrence of CVD Event
CVD Event ()) (n=744)

CVD Event (+) (n=66)

P Value

Patient characteristics
Age, y
Men, %

71.7  9.9
37

78.5  7.1
50

<.001
.05

Body mass index, kg m2

Current smoker, %

24.0  3.5
19

22.7  3.8
42

.003
<.001

Type 2 diabetes, %
Hyperlipidemia, %
eGFR, mL min 1.73 m2
Antiplatelet drugs, %

12
19

18
18

.17
1.00

56.5  13.5
26

52.3  13.5
44

137  16

148  16

<.001

78  10
71  7

82  10
72  9

.003
.29

Daytime SBP, mm Hg

144  18

153  16

<.001

Daytime DBP, mm Hg
Daytime PR, bpm

81  11
77  8

84  10
78  10

.03
.32

Nighttime SBP, mm Hg
Nighttime DBP, mm Hg

126  18
72  10

138  20
76  12

<.001
.002

Nighttime PR, beats per min

Nocturnal SBP dipping, %

61  8
)13  9

63  9
)10  11

.10
.01

Antihypertensive drug use during follow-up

Calcium channel blockers, No. (%)

53
34.4

49
33.3

.52
.89

ACE inhibitors, No. (%)

Diuretics, No. (%)

21.7
3.5

19.7
3.0

.76
1.00

1.3
1.5

1.5
0

1.00
.61

BP measurements
24-Hour SBP, mm Hg
24-Hour DBP, mm Hg
24-Hour PR, beats per min

a-Blockers, No. (%)

b-Blockers, No. (%)
Inflammatory factors
White blood cells, 103 lLa

.02
.002

5.7 (4.57.3)

5.8 (4.67.4)

.72

0.14 (0.040.57)

0.25 (0.070.88)

.001

Fibrinogen, mg dLa
Prothrombin fragment 1+2, nmol La

267.8 (213.9335.3)
1.5 (1.02.2)

293.1 (231.1371.9)
1.8 (1.12.9)

.002
<.001

von Willebrand factor, %a

Plasminogen activator inhibitor-1, ng mLa

158.1 (117.1213.5)
38.1 (20.870.0)

170.9 (126.1231.6)
56.2 (27.9113.1)

.04
<.001

High-sensitivity C-reactive protein, mg La

Hemostatic factors

Abbreviations: ACE, angiotensin-converting enzyme; BP, blood pressure; CVD, cardiovascular disease; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; PR, pulse rate; SBP, systolic blood pressure. Data are expressed as the meansstandard deviation (SD) or percentage. P values were obtained by an unpaired t test or chi-square test. Variables with skewed distributions (a) were logarithmically transformed before
analysis and expressed as geometric means (SD range). Statistical significance was defined as P<.05.

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TABLE III. Cox Regression Analysis for Cardiovascular Disease Events

Variable

Model 1 HR (95% CI)

Current smoking (0=no, 1=yes)

High-sensitivity C-reactive protein (0:<0.40 mg L, 1: 0.40 mg L)
Prothrombin fragment 1+2 (0: <1.8 nmol L, 1: 1.8 nmol L)
Plasminogen activator inhibitor-1 (0: <58.9 ng mL, 1: 58.9 ng mL)

2.6 (1.54.7)

Model 2 HR (95% CI)

2.1 (1.13.8)b
2.4 (1.43.9)a
2.2 (1.43.6)a
2.5 (1.54.1)c

Hazard ratios (HRs) and 95% confidence intervals (CIs) for cardiovascular disease (CVD) events are shown after adjustment for sex, body mass
index, history of diabetes, history of hyperlipidemia, and 24-hour pulse rate (model 1). Model 2 was adjusted by model 1 plus high levels of high-sensitivity C-reactive protein, prothrombin fragment 1+2, and plasminogen activator inhibitor-1. The analysis of each hemostatic parameter was based
on the following code: 0=the lower 3 quartiles, 1=the highest quartile. Statistical significance was defined as P<.05. aP<.01. bP<.05. cP<.001.

We divided the patients into 4 groups according to

the presence of current smoking and the highest quartile of circulatory levels of hs-CRP, F1+2, or PAI-1
levels. Kaplan-Meier curves to compare the unadjusted
CVD events-free survival rate among each set of 4
groups are shown in Figure S1S3. We also analyzed
the HR and 95% CI of the patients for each of the 4
groups calculated by Cox regression analysis with
adjustment for confounding factors (Figure, AC). The
CVD risk of current smoking was significantly higher
when it was accompanied with the highest quartile of
hs-CRP level or PAI-1 compared with when it was
accompanied with the lower quartiles of hs-CRP or
PAI-1 level, respectively (Figure, A and C).

DISCUSSION
This prospective study is the first report directly demonstrating the impact of current smoking on the incidence of CVD events in relation to its influences on
24-hour BP and inflammatory and hemostatic activity
in older hypertensive patients. The main findings of
the present study were as follows: (1) current smokers
had significantly higher levels of circulatory inflammatory and hypercoagulable and hypofibrinolytic activity
than those without current smoking; (2) current smokers had a 2.6-fold increased risk of CVD events than
those without current smoking; and (3) the CVD risk
of current smokers was magnified when accompanied
with high hs-CRP (0.40 mg L) or PAI-1 levels
(58.9 ng mL).
Smoking and 24-Hour BP
In contrast with previous reports,6,7 our data indicated
that there were no significant differences in office BP,
daytime BP, and nighttime BP levels between current
smokers and nonsmokers. Despite the acute adverse
effects of smoking on BP, epidemiological studies have
shown inconsistent associations between smoking and
high BP.1,2,17,18 Weight gain, a risk factor for high BP,
may be an important confounder in such an association, since any benefit on BP from quitting smoking
could be offset by the weight gain that occurs after
smoking cessation.19 In the present study, ex-smokers
were included as nonsmokers, which might have led to
a tendency to underestimate the association between
current smoking and BP levels. Moreover, we did not
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assess the smoking dose (cigarettes day) or the nicotine content in current smokers, despite the fact that
these parameters could have influenced the association
between smoking and high BP.20,21 In contrast, an
increase in office PR or nighttime PR was observed in
current smokers. This may have been caused by an
increase in sympathetic nerve activity or impaired
parasympathetic nerve activity promoted by smoking;7
however, the CVD risk of current smoking was not
affected by the high office PR or nighttime PR levels.
Smoking, Inflammation, Hemostasis, and CVD Risk
Smoking influences the immune system (ie, neutrophils, macrophages, lymphocytes, and dendritic cells) in
many ways, including through continual exposure to
oxidative stressors.12 As a consequence, a low-grade
systemic inflammatory response is evident in smokers
as confirmed by numerous population-based studies.
Elevated levels of CRP, interleukin 6, and tumor
necrosis factor a have been reported.8,11,12 Moreover,
several studies have shown that rheological alteration
and circulatory procoagulant and hypofibrinolytic
activity occurred in current smokers.4,812 As a consequence, it has been thought that these abnormalities
may in part explain the increased cardiovascular risk
of current smoking; however, there has been no report
directly assessing whether inflammatory and hemostatic abnormalities accompanied with current smoking
are associated with clinical CVD events in hypertensive patients.
Our data indicated that the circulatory levels of hsCRP, F1+2, and PAI-1 were significantly elevated in
current smokers relative to nonsmokers (Table I).
Intriguingly, the CVD risk of current smoking can be
magnified when it is accompanied with high circulatory hs-CRP or PAI-1 levels (Figure, A and C). Circulatory hs-CRP or PAI-1 levels are determined by not
only smoking, but also other pathophysiological conditions, such as metabolic syndrome, some neurohumoral factors (eg, high sympathetic nerve activity and
renin-angiotensin-aldosterone system), and sleep
apnea,22 but we did not evaluate these factors in the
present study; therefore, further investigations are
required to examine how conditions or comorbidities
can contribute to exaggerate the CVD risk associated
with smoking in hypertensive patients.
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Smoking and Cardiovascular Risk

HR

5.3 ||

(a)

(2.5-11.0)

5
4
3

2.1*

2.1

(1.3-14.6)

(1.0-4.3)

(-)

(+)

2
1

1
0
Current smoking
Hs-CRP >0.4 mg/L

(-)
(-)

CVD patients/
total patients number

HR

(i) 22/497

(+)
(ii) 16/147

(-)
(iii) 13/112

(+)
(iv) 15/54

4.7

(b)

(2.2-10.2)

5
4

(+)

2.7**

2.6**

(1.4-5.2)

(1.3-5.3)

(-)

(-)

(+)

(+)

(-)

(+)

(-)

(+)

(iii) 16/106

(iv) 12/60

3
2
1

1
0
Current smoking
F1+2 >1.8nmol/L
CVD patients/
total patients number
HR

(i) 20/502

(ii) 18/142

4.8

(c)

(2.3-9.8)

5
4
2.3**

(1.2-4.5)

2.1
(0.9-4.6)

2
1
0
Current smoking
PAI-1 >58.9ng/ml
CVD patients/
total patients number

(-)
(-)
(i) 21/504

(-)
(+)
(ii) 17/140

(+)

(+)

(-)

(+)

(iii) 10/104

(iv) 18/62

FIGURE. Cox regression analysis of cardiovascular disease (CVD)

events. The hazard ratio (HR) (95% confidence interval [CI]) of CVD
events in patients with or without current smoking and high or low levels of high-sensitivity C-reactive protein (hs-CRP) (a), prothrombin fragment 1+2 (F1+2) (b), and plasminogen activator inhibitor-1 (PAI-1) (c)
are shown. The analysis was adjusted for age, sex, body mass index,
a history of diabetes, estimated glomerular filtration rate, a use of antiplatelet drugs, antihypertensive medication at the time of final followup, and 24-hour systolic blood pressure level. *P<.05 vs group (i),
**P<.01 vs group (i), P<.001 vs group (i), ||P<.05 vs group (ii), P<.05
vs group (iii).

Sex Difference of Cardiovascular Risk in Current

Smoking
As in previous Japanese and Western reports,1,4 the
cardiovascular risk of smoking was found to be
greater in women than in men. The mechanism is
unclear, but possible biological aspects have been
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Yano et al.

suggested. A previous study showed that the CVD

risk of smoking was exaggerated by the absence of
estrogen status.23 This may be in part due to the
fact that estrogen exerts beneficial effects on the hemostatic system, eg, it increases fibrinolytic potential
and decreases procoagulant factors.24 Although we
could not assess the presence of menopause in the
present study, our female patients were sufficiently
advanced in age to be postmenopausal, suggesting
that they may have lost some of the protection conferred by estrogen. Moreover, unmeasured factors,
such as participants characteristics, may have been
important contributors to this phenomenon. Female
smokers may be significantly different from nonsmoking women in terms of their health-related
behaviors and social activities, both of which could
confound the association between smoking and CVD
risk.4,25 In spite of these findings, the result that the
Cox regression showed an HR with a wide range of
95% CI values for the CVD risk of female smokers
may have been a result of the small sample size,
and thus our data should be interpreted with
caution.
Study Limitations
There were several limitations in the present study.
First, as mentioned above, we did not assess the number of ex-smokers who were categorized as nonsmokers in the present study. Certain adverse reactions,
such as high CRP levels, remain elevated for longer
periods after smoking cessation,8 and this phenomenon
could lead to underestimation of the CVD risk conferred by current smoking. Second, we did not collect
any data on the smoking dose or duration (years), or
on the lifelong smoking dose (pack-years), which
would be of interest to refine the potential dose effect
of smoking on inflammatory hemostatic biomarker
levels and CVD risk. Third, the hemostatic factors
measured in the present study, in particular PAI-1,
showed diurnal variation (ie, they rose in the
morning).26 Although all blood sampling was conducted in the morning, there may be intra-individual
and inter-individual variation in hemostatic factors,
which may lead to an underestimation of the true
association between cigarette smoking, hemostatic factors, and CVD events. Lastly, our findings were
derived from hypertensive patients, and thus generalization to the general population or other ethnicities is
not appropriate.

CONCLUSIONS
This study has clearly shown an increased risk of CVD
events conferred by current smoking in Japanese
hypertensive patients, and this risk was more prominent when accompanied by circulatory inflammatory
and hemostatic abnormalities. These results need to be
confirmed in larger studies, and interventional studies
will also be needed to establish the precise values of
our data.
The Journal of Clinical Hypertension

Vol 15 | No 4 | 2013

239

Smoking and Cardiovascular Risk

Yano et al.

Acknowledgments: This study was supported by a research grant for

cardiovascular medicine (14-6) from the Ministry of Health, Labor, and
Welfare (K.K.) and a research grant (C-2) from the Ministry of Education,
Culture, Sports, Science, and Technology (K.K.) of Japan.
Disclosure: None.

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Supporting Information

Additional Supporting Information may be found in

the online version of this article:
Data S1. Methods.
Figure S1S3. Kaplan-Meier cumulative incidence of
cardiovascular disease.

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