Directory UMM :Data Elmu:jurnal:A:Atherosclerosis:Vol153.Issue1.Nov2000:
Atherosclerosis 153 (2000) 139 – 145
www.elsevier.com/locate/atherosclerosis
Gender difference in the influence of smoking on arterial wall
thickness
Jérôme Gariepy a, Nicolas Denarie a, Gilles Chironi a, Jean Salomon b,
Jaime Levenson a, Alain Simon a,*
a
Centre de Médecine Pré6enti6e Cardio6asculaire, Hôpital Broussais, 96 Rue Didot, 75674 Paris cedex 14, France
b
AXA FRANCE ASSURANCE, Coordination de la médecine du tra6ail, La Défense, Paris, France
Received 15 June 1999; received in revised form 26 November 1999; accepted 7 January 2000
Abstract
Background: We hypothesized that arterial wall thickening, an early atherogenic alteration, might be associated with smoking
differently according to gender, considering the cardiovascular protection of female sex hormones. Methods and results: We
measured ultrasonographically carotid and femoral intima-media thickness (IMT) in 194 men and 330 women without risk factors
other than smoking. In men: (i) current smokers had greater carotid and femoral IMT (P B 0.01, P B 0.001) and former smokers
had greater femoral IMT (PB 0.01) than never smokers; (ii) in pooled never, current and former smokers carotid and femoral
IMT correlated to current daily smoking (P B0.01) and lifelong smoking (P B0.001); and (iii) carotid and femoral IMT correlated
to age in never smokers (P B 0.001), current smokers (P B 0.01, P B 0.001) and former smokers (P B 0.01), with greater slopes in
current than in former smokers at carotid site (P B0.05) and in current than in never smokers at femoral site (P B0.05). In
women: (i) IMT did not differ by smoking status; (ii) in pooled smokers and non smokers femoral IMT correlated to current daily
smoking (P =0.01) and to lifelong smoking (P B 0.01) with a lower slope than in men (P B 0.001), while carotid IMT did not; and
(iii) carotid and femoral IMT correlated to age in never smokers (P B 0.001), current smokers (P B 0.001, P B 0.05) and former
smokers (P B0.001, P B0.01) with no different slopes. Conclusion: Smoking-related increase in IMT existed in men but not in
women, suggesting a possible protection of female gender from early structural arterial alteration of smoking. © 2000 Elsevier
Science Ireland Ltd. All rights reserved.
Keywords: Cigarette smoking; Intima-media thickness; Large artery
1. Introduction
Cigarette smoking is well recognized as a major risk
factor for atherosclerosis in men and women [1,2].
However the understanding of smoking effect on
atherogenesis remains incomplete, particularly at the
initial step of arterial disease. Large artery intima-media thickness (IMT), a marker of early arterial alteration [3], can be measured non-invasively with
considerable precision by coupling high-resolution Bmode ultrasonography with an automated, computerized system of image analysis [4,5]. Our objective was to
use this technique to describe the relationship between
IMT and cigarette smoking in a cross-sectional study of
* Corresponding author. Tel.: + 33-1-4395-9392; fax: + 33-1-45391193.
current and former smokers as compared with never
smokers. All of them were recruited among a cohort of
healthy adults, of both sexes and free from other major
cardiovascular risk factors which may have a confounding effect on the IMT/smoking association. Special
attention was given to the influence of gender and site
of IMT measurement (carotid and femoral) because
these two factors are likely to influence the response of
the arterial wall to smoking.
2. Methods
2.1. Subjects
The study population is composed of 194 men and
330 women aged 17– 65 years. They were drawn from
0021-9150/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 0 2 1 - 9 1 5 0 ( 0 0 ) 0 0 3 8 2 - 8
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J. Gariepy et al. / Atherosclerosis 153 (2000) 139–145
the cohort of the AXA study [5], a longitudinal survey
of cardiovascular risk factors involving 788 volunteers of
both sexes recruited from employees of an insurance
company (AXA, La Défense, Paris, France). The greater
number of women than in men in the study population
reflected the gender distribution existing in employees of
the tertiary sector in the ‘Ile de France’ area. The
subjects in the present work were free from cardiovascular disease including stroke, transient ischemia, coronary
heart disease, congestive heart failure and intermittent
claudication. They were also free from major risk factors
(except smoking) for cardiovascular disease: hypertension defined as an SBP ]160 mmHg and/or an DBP
]95 mmHg, the presence of antihypertensive drug
treatment or a combination of these; hypercholesterolemia defined as a total cholesterol level ] 6.2
mmol/l, the use of lipid lowering drug or both; diabetes
mellitus defined as a fasting blood glucose level ]7.8
mmol/l, the use of antidiabetic drugs or both. Lastly
information about the menopausal status was obtained
by questioning the women. A woman was classified as
postmenopausal when she reported natural menopause,
i.e. the absence of any menstruation during the 6 months
before the investigation, or hysterectomy with bilateral
oophorectomy. In addition the questionnaire elicited
information on use of hormonal replacement therapy in
postmenopausal women.
2.2. Smoking status and classification
Occupational health medicine nurse (JJ) administered
to each subject a standard oral questionnaire that included precise questions on smoking status. The subjects
were classified into three groups on the basis of their
smoking status at screening: (1) never smokers — those
who have never smoked; (2) current smokers — those
who currently smoke daily and have performed so for
the previous 3 months, regardless of the amount
smoked; and (3) former smokers — those who have
smoked, but had quit 3 months ago or more. In addition,
current smokers were asked about the average number
of cigarettes they smoked per day. Current and former
smokers were also asked about the total years
smoked and the average pack of cigarettes per day
smoked over these years and the life long smoking dose
in pack years was calculated from the total years smoked
times the average pack per day smoked. Measurement of
salivary or serum cotinine levels for validation of baseline smoking status was not available in the present
study.
2.3. Arterial in6estigation
The subjects were investigated by the same sonographic physician at the workplace with a real-time
B-mode ultrasound imager (Ultramark 4, Advanced
Technologies Laboratories) equipped with a 7.5 MHz
probe. The sonographic physician was unaware of the
smoking status of the subject investigated when the scan
was performed.
The imaging of IMT of the distal segment of the
common carotid artery and common femoral artery on
both sides was performed according to a standardized
procedure [4,5]. The IMT image, obtained in the far wall
of each artery, consisted of two parallel echogenic
lumen-intima and media-adventitia interfaces (doubleline pattern) visible on at least 1 cm of longitudinal
length. Such image did not include intrusive plaque
because its presence would disrupt the double-line pattern. Therefore, our measurement of IMT applies to wall
thickness before lesions intrude into the vessel (preintrusive IMT). Because of poor interface visualization, the
IMT image obtained was not of sufficient quality in the
femoral arteries (on both sides) of two men and of five
women. Once the optimal quality image of far wall IMT
was obtained, the image was frozen at end-diastole by
ECG-triggering, transferred to a computer equipped
with a software of digitization, and stored on disk for
central off-line reading. Off-line blind measurements of
IMT were performed by the same reader (JG), by means
of an automated computerized edge-detection program
(Iôtec, Iôdata, France) whose principles and description
have been provided elsewhere [4,5]. This program located the two interfaces defining far wall IMT and
calculated their distance every 100 mm by means of
analysis of grey level density with special tissular recognition algorithms. Average IMT was calculated as the
mean value of local IMT measures along at last 1 cm of
length of artery. For each subject a total IMT ((left +
right)/2) was taken as measure of current wall thickness
of the common carotid and common femoral arteries.
2.4. Statistical analysis
Values are expressed as mean9S.D. (or S.E. for
regression slopes). Comparisons of clinical variables and
IMT by smoking status were performed in each sex by
ANOVA and pairwise comparisons were performed by
using the Student’s t-test. Linear regressions were used
to analyze the relationships between IMT and age and
between IMT and current daily and lifelong smoking
dose. A multiple regression analysis was used for age-adjustment of IMT/smoking relationships. As the distribution of smoking dose was skewed, a logarithmic
transformation was applied. The slopes of IMT/age and
IMT/smoking relationships were compared between two
groups by means of a general linear model relating IMT
to age (or lifelong smoking), the group category, and the
product of age (or lifelong smoking) with the group
category. The statistical analysis was carried out on a
computer (Apple Macintosh) with the use of JMP (SAS)
and Excel (Microsoft) software.
J. Gariepy et al. / Atherosclerosis 153 (2000) 139–145
3. Results
Table 1 shows the clinical characteristics of the study
population by smoking status and by gender. No significant difference in any parameter existed between
never smokers, current smokers, and former smokers
except lifelong smoking dose lower in former smokers
than in current smokers in both sexes (P B0.05). In
women, the analysis of hormonal status showed that 49
were postmenopausal of whom 24 were receiving hormonal replacement therapy.
In men, carotid IMT was higher in current smokers
than in never smokers (P B 0.01) but no different between former smokers and never smokers and between
former smokers and current smokers, while in women
carotid IMT did not differ according to the smoking
status (Table 2). In men, femoral IMT was higher in
current smokers (PB 0.001) and in former smokers
(P B0.01) than in never smokers but no different between former smokers and current smokers, while in
women femoral IMT did not differ according to the
smoking status (Table 2).
In the whole population of men, carotid and femoral
IMT did correlate with the current number of cigarette
141
per day (r=0.21, r=0.19 respectively, P B0.01) and
these correlations remained significant after age-adjustment (PB 0.001, P B0.01, respectively).
In the male population carotid and femoral IMT did
correlate with smoking pack-years (r=0.37, r =0.38,
respectively, PB 0.001, Fig. 1), and these correlations
remained significant after age-adjustment (PB 0.001).
The carotid and femoral IMT/pack-years relationships
remained significant (r=0.28, r=0.35, respectively,
PB 0.001) when men who smoked more than 40 packyears were excluded, and their regression slopes were
similar to those obtained in the entire men population.
In the whole population of women, carotid IMT did
not correlate with either the current number of
cigarettes per day (r =0.04) or smoking pack-years
(r=0.08, Fig. 1). In the female population, femoral
IMT did correlate with the current number of cigarettes
per day (r=0.20, P B0.01) and smoking pack-years
(r= 0.18, PB 0.01, Fig. 1) and these correlations remained significant after age-adjustment (P B0.01). The
slopes of regression between femoral IMT and either
number of cigarettes per day or smoking pack – years,
were lower in women than in men (P =0.08, PB 0.001,
respectively). In postmenopausal women, carotid and
Table 1
Clinical characteristics by smoking statusa
Men
n
Age, years
Height, m
Body mass index, kg/m2
Systolic pressure, mmHg
Diastolic pressure, mmHg
Total cholesterol, mmol/l
Blood glucose, mmol/l
Current smoking, cigarette/day
Life long smoking, pack–years
Women
NS
CS
FS
NS
CS
FS
80
40 9 9
1.75 9 0.07
24 9 3
1339 9
82 9 8
5.14 90.69
5.409 0.53
–
–
61
42 99
1.74 9 0.07
259 3
132 9 9
81 9 9
5.15 9 0.61
5.43 9 0.64
17 9 10
18 9 15
53
44 9 9
1.779 0.06
25 9 2
136 9 9
82 9 9
5.229 0.59
5.579 0.62
–
139 10*
164
40 9 8
1.62 9 0.06
23 94
130 910
79 99
4.97 9 0.66
5.19 9 0.51
–
–
114
39 9 8
1.64 90.06
23 9 3
1299 9
79 9 9
4.989 0.80
5.099 0.52
16 9 11
13 9 8
52
43 9 8*
1.62 9 0.06
23 94
129 913
779 10
4.91 9 0.82
5.12 90.60
–
10 9 10*
a
NS, never smokers; CS, current smokers; FS, former smokers; and n, number of subjects. Values are mean 9S.D.
* PB0.05 between CS and FS.
Table 2
Intima-media thickness (IMT) by smoking statusa
NS (1)
CS (2)
FS (3)
P value
(1–2)
(1–3)
(2–3)
Carotid IMT, mm
Men
Women
0.51 9 0.08
0.49 9 0.07
0.57 9 0.12
0.49 90.07
0.54 9 0.10
0.50 9 0.06
B0.01
NS
NS
NS
NS
NS
Femoral IMT, mm
Men
Women
0.45 90.08
0.42 90.05
0.52 9 0.13
0.43 90. 08
0.49 9 0.09
0.42 9 0.05
B0.001
NS
B0.01
NS
NS
NS
a
NS, never smokers; CS, current smokers; FS, former smokers; and n, number of subjects. Values are mean 9S.D. NS, non significant.
142
J. Gariepy et al. / Atherosclerosis 153 (2000) 139–145
Fig. 1. Relationships of carotid and femoral intima-media thickness (IMT) with lifelong smoking dose in the pooled populations of never smokers,
current smokers and former smokers in each sex. r= correlation coefficient.
femoral IMT did not correlate with either the current
number of cigarettes per day or smoking pack – years.
Analysis of association of IMT and age showed that
in men carotid IMT and age were correlated in never
smokers (PB 0.001), in current smokers (P B0.01), and
in former smokers (P B0.01), but the slope of the
regression line was higher (PB 0.05) in current smokers
than in former smokers (Fig. 2) and almost significantly
higher (P= 0.07) in current smokers than in never
smokers. In women, carotid IMT and age were correlated in never smokers (PB 0.001), in current smokers
(P B0.001) and in former smokers (P B0.001), but the
slopes of the regression lines were not different between
groups (Fig. 2). In men, femoral IMT and age were
correlated in never smokers (PB 0.001), in current
smokers (P B0.001) and in former smokers (P B0.01),
but the slope of the regression line was higher in
current smokers than in never smokers (P B0.05) (Fig.
2). In women, femoral IMT and age were correlated in
never smokers (PB 0.001), in current smokers (P B
0.05) and in former smokers (PB 0.01), and the slopes
of the regression lines were not different between
groups (Fig. 2).
4. Discussion
The main finding of our work was to demonstrate
that when other cardiovascular risk factors (particularly
hypertension and hypercholesterolemia) are absent,
cigarette smoking was accompanied by an increase in
carotid and femoral IMT in men but not in women.
Such a result was obtained in a sample of healthy
adults of both sexes recruited from a general population of employees in the Ile de France area and by
using a B-mode IMT measurement, highly precise
thanks to the standardization of image recording according to telediastole, the automated computerized
measure without reader dependence, and the calculation of average IMT as the mean of a great number of
local IMT measurements [5,6].
In men, both carotid and femoral IMT were increased in current smokers as compared with never
smokers, in agreement with previous studies showing
positive associations between arterial wall thickening,
especially in carotid arteries, and cigarette smoking
[7– 10]. Also, as compared with never smokers, male
former smokers had increased IMT. This increase
J. Gariepy et al. / Atherosclerosis 153 (2000) 139–145
reached a statistical significance at the femoral site but not
at the carotid site, supporting a higher sensitivity of the
femoral artery wall to smoking [7,11]. Another important
observation was that the difference in IMT at both sites of
measurement was smaller between former smokers and
never smokers than between current smokers and never
smokers, suggesting that the smoking effects on arterial
wall thickness may be partially reversible after cessation
of smoking, as previously mentioned [12,13]. However, it
is possible that the lower lifelong smoking dose in former
smoker men than in current smokers may have produced
a lower increase in IMT in former smokers. Indeed we
have observed a dose dependence of current daily and
lifelong smoking doses on carotid and femoral IMT in the
pooled male population of never smokers, current smokers and former smokers, which is in favour of a causative
role for smoking in arterial wall thickening. The precise
mechanisms by which smoking may produce large artery
wall thickening are unclear. A recent study of IMT in
smokeless tobacco users suggests that the pathogenesis of
arterial wall thickening in smokers seems related to
components of tobacco other than nicotine [10]. Furthermore experimental studies in cockerels have shown that
143
inhalation of sidestream cigarette smoke accelerates
development of aortic atherosclerotic plaque and the
plaque-promotion of environmental tobacco smoke may
reside in the vapor phase which may induce smooth
muscle cell proliferation [14,15]. Another result of the
present work was that current smoking in men was
associated with an acceleration of the normal age-related
increase in carotid and overall femoral IMT. Indeed the
analysis of the univariate correlations of IMT with age in
men shows that the increase in femoral IMT per year was
2-fold greater in current smokers than in never smokers,
and the same trend existed for the annual increase in
carotid IMT between current and never smokers but
without reaching statistical significance. This phenomenon of higher rate of progression of IMT was not
observed in former smokers in whom the slope of
IMT/age relationship did not differ from that of never
smokers. These cross-sectional findings are in line with the
results of a recent longitudinal study [16] showing that the
3-year progression rate of carotid IMT was 50% greater in
current smokers than in never smokers while only 25%
greater in former smokers than in never smokers.
Fig. 2. Slopes of the intima-media thickness (IMT)/age relationship with S.E. by smoking status, by site and by gender. *, †, ‡, mean P B0.05,
B 0.01, B 0.001, respectively, for the statistical significance of the regression slopes.
144
J. Gariepy et al. / Atherosclerosis 153 (2000) 139–145
Surprisingly in women unlike men, we did not find
that smoking (either current or former) was accompanied with increased IMT of both arteries examined.
This lack of association was observed in the univariate
analysis as well in multivariate model. Moreover age
was significantly associated with IMT in women, but
unlike men the slope of the IMT/age relationship did
not differ between current, former and never smokers.
Lastly, in contrast to men, current daily and lifelong
smoking doses did not correlate with carotid IMT in
women, while they were associated with femoral IMT.
However the slope of the femoral IMT/pack – years
relationships was lower in women than in men, as well
as the slope of the relation between femoral IMT and
current daily smoking but without reaching statistical
significance. The gender differences in the slopes of the
IMT/age relationships are not as a result of the fact
that several men smoked more than 40 pack – years but
no women, because they persisted when men with
greater number than 40 pack – years smoking were excluded from the analysis. These results support the
possibility that the sensitivity of the female large artery
wall to smoking is attenuated at least at the early stage
of disease. Although this finding has not been really
emphasized in the literature until now, preliminary
results of a substudy of the Monica project [17] have
already pointed to the lack of association between
cigarette smoking and ultrasonographic carotid plaque
in women. Also it has been recently shown that the
brachial artery flow-mediated dilation was not decreased in female current smokers compared with former smokers whereas it was decreased in male current
smokers compared to former smokers [18], so suggesting a gender difference in early large artery alteration
induced by smoking. The mechanisms of the relative
protection of large artery wall of women from the
thickening effect of smoking are unknown. Adverse
effects of smoking [19– 21] on endothelium, plasma
fibrinogen and oxidative stress may be blunted by
endogenous estrogens before menopause which are involved in the relative protection from cardiovascular
disease in women [22]. Indeed, women in the present
study are in a great majority premenopausal because
only 49 women (15%) are post-menopausal. However,
if the hypothesis that premenopausal female hormones
are protective as regards smoking effect on IMT is
correct, postmenopausal women would have significant
relationships between IMT and smoking, like men. The
fact that we did not observe such relationships in
postmenopausal women does not support a major role
of protective effect of female hormones on IMT. On the
other hand the number of postmenopausal women is
probably not sufficiently great to demonstrate significant correlations between IMT and smoking and the
use of hormonal replacement therapy in 50% of postmenopausal women may blunt these correlations. Fur-
thermore, the protective effect of female hormones may
partly explain the discrepancy between our work and a
previous study showing that cigarette smoking increased the development and progression of atherosclerosis in women [23]. In this study women were on
average 10 years older that in the present work and
post menopausal in the majority of cases; moreover
atherosclerosis was characterized by the presence of
radiographic calcified deposit in the aorta which is
quite different from our pre-intrusive IMT measured in
carotid and femoral arteries.
In conclusion, we have found marked differences in
the influence of smoking on IMT between men and
women. Firstly, IMT increased in the presence of smoking (current and even former) in men but not in
women. Secondly, a dose dependence of current daily
and lifelong smoking existed for IMT in men, but it
was abolished for carotid IMT and clearly attenuated
for femoral IMT in women. Thirdly, current smoking
enhanced the normal age-related increase in IMT in
men but not in women. All these findings concur for
suggesting that gender modulates the early structural
alterations of large artery walls in response to smoking.
A practical implication is that carotid and overall
femoral IMT may be a marker more appropriate in
men than in women to detect and monitor early arterial
effects of smoking.
Acknowledgements
This work was supported by grants from the AXA
insurance company (Association AXA PREVENTION) and from the Institut National de la Santé et de
la Recherche Médicale (CRI-INSERM 9610). We
gratefully acknowledge Fatiha Laskri for having performed all the ultrasonographic measurements and
Joëlle Jansens for evaluating patients and collecting
data. We also thank Maria Crichi for her assistance in
the manuscript preparation.
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www.elsevier.com/locate/atherosclerosis
Gender difference in the influence of smoking on arterial wall
thickness
Jérôme Gariepy a, Nicolas Denarie a, Gilles Chironi a, Jean Salomon b,
Jaime Levenson a, Alain Simon a,*
a
Centre de Médecine Pré6enti6e Cardio6asculaire, Hôpital Broussais, 96 Rue Didot, 75674 Paris cedex 14, France
b
AXA FRANCE ASSURANCE, Coordination de la médecine du tra6ail, La Défense, Paris, France
Received 15 June 1999; received in revised form 26 November 1999; accepted 7 January 2000
Abstract
Background: We hypothesized that arterial wall thickening, an early atherogenic alteration, might be associated with smoking
differently according to gender, considering the cardiovascular protection of female sex hormones. Methods and results: We
measured ultrasonographically carotid and femoral intima-media thickness (IMT) in 194 men and 330 women without risk factors
other than smoking. In men: (i) current smokers had greater carotid and femoral IMT (P B 0.01, P B 0.001) and former smokers
had greater femoral IMT (PB 0.01) than never smokers; (ii) in pooled never, current and former smokers carotid and femoral
IMT correlated to current daily smoking (P B0.01) and lifelong smoking (P B0.001); and (iii) carotid and femoral IMT correlated
to age in never smokers (P B 0.001), current smokers (P B 0.01, P B 0.001) and former smokers (P B 0.01), with greater slopes in
current than in former smokers at carotid site (P B0.05) and in current than in never smokers at femoral site (P B0.05). In
women: (i) IMT did not differ by smoking status; (ii) in pooled smokers and non smokers femoral IMT correlated to current daily
smoking (P =0.01) and to lifelong smoking (P B 0.01) with a lower slope than in men (P B 0.001), while carotid IMT did not; and
(iii) carotid and femoral IMT correlated to age in never smokers (P B 0.001), current smokers (P B 0.001, P B 0.05) and former
smokers (P B0.001, P B0.01) with no different slopes. Conclusion: Smoking-related increase in IMT existed in men but not in
women, suggesting a possible protection of female gender from early structural arterial alteration of smoking. © 2000 Elsevier
Science Ireland Ltd. All rights reserved.
Keywords: Cigarette smoking; Intima-media thickness; Large artery
1. Introduction
Cigarette smoking is well recognized as a major risk
factor for atherosclerosis in men and women [1,2].
However the understanding of smoking effect on
atherogenesis remains incomplete, particularly at the
initial step of arterial disease. Large artery intima-media thickness (IMT), a marker of early arterial alteration [3], can be measured non-invasively with
considerable precision by coupling high-resolution Bmode ultrasonography with an automated, computerized system of image analysis [4,5]. Our objective was to
use this technique to describe the relationship between
IMT and cigarette smoking in a cross-sectional study of
* Corresponding author. Tel.: + 33-1-4395-9392; fax: + 33-1-45391193.
current and former smokers as compared with never
smokers. All of them were recruited among a cohort of
healthy adults, of both sexes and free from other major
cardiovascular risk factors which may have a confounding effect on the IMT/smoking association. Special
attention was given to the influence of gender and site
of IMT measurement (carotid and femoral) because
these two factors are likely to influence the response of
the arterial wall to smoking.
2. Methods
2.1. Subjects
The study population is composed of 194 men and
330 women aged 17– 65 years. They were drawn from
0021-9150/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 0 2 1 - 9 1 5 0 ( 0 0 ) 0 0 3 8 2 - 8
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J. Gariepy et al. / Atherosclerosis 153 (2000) 139–145
the cohort of the AXA study [5], a longitudinal survey
of cardiovascular risk factors involving 788 volunteers of
both sexes recruited from employees of an insurance
company (AXA, La Défense, Paris, France). The greater
number of women than in men in the study population
reflected the gender distribution existing in employees of
the tertiary sector in the ‘Ile de France’ area. The
subjects in the present work were free from cardiovascular disease including stroke, transient ischemia, coronary
heart disease, congestive heart failure and intermittent
claudication. They were also free from major risk factors
(except smoking) for cardiovascular disease: hypertension defined as an SBP ]160 mmHg and/or an DBP
]95 mmHg, the presence of antihypertensive drug
treatment or a combination of these; hypercholesterolemia defined as a total cholesterol level ] 6.2
mmol/l, the use of lipid lowering drug or both; diabetes
mellitus defined as a fasting blood glucose level ]7.8
mmol/l, the use of antidiabetic drugs or both. Lastly
information about the menopausal status was obtained
by questioning the women. A woman was classified as
postmenopausal when she reported natural menopause,
i.e. the absence of any menstruation during the 6 months
before the investigation, or hysterectomy with bilateral
oophorectomy. In addition the questionnaire elicited
information on use of hormonal replacement therapy in
postmenopausal women.
2.2. Smoking status and classification
Occupational health medicine nurse (JJ) administered
to each subject a standard oral questionnaire that included precise questions on smoking status. The subjects
were classified into three groups on the basis of their
smoking status at screening: (1) never smokers — those
who have never smoked; (2) current smokers — those
who currently smoke daily and have performed so for
the previous 3 months, regardless of the amount
smoked; and (3) former smokers — those who have
smoked, but had quit 3 months ago or more. In addition,
current smokers were asked about the average number
of cigarettes they smoked per day. Current and former
smokers were also asked about the total years
smoked and the average pack of cigarettes per day
smoked over these years and the life long smoking dose
in pack years was calculated from the total years smoked
times the average pack per day smoked. Measurement of
salivary or serum cotinine levels for validation of baseline smoking status was not available in the present
study.
2.3. Arterial in6estigation
The subjects were investigated by the same sonographic physician at the workplace with a real-time
B-mode ultrasound imager (Ultramark 4, Advanced
Technologies Laboratories) equipped with a 7.5 MHz
probe. The sonographic physician was unaware of the
smoking status of the subject investigated when the scan
was performed.
The imaging of IMT of the distal segment of the
common carotid artery and common femoral artery on
both sides was performed according to a standardized
procedure [4,5]. The IMT image, obtained in the far wall
of each artery, consisted of two parallel echogenic
lumen-intima and media-adventitia interfaces (doubleline pattern) visible on at least 1 cm of longitudinal
length. Such image did not include intrusive plaque
because its presence would disrupt the double-line pattern. Therefore, our measurement of IMT applies to wall
thickness before lesions intrude into the vessel (preintrusive IMT). Because of poor interface visualization, the
IMT image obtained was not of sufficient quality in the
femoral arteries (on both sides) of two men and of five
women. Once the optimal quality image of far wall IMT
was obtained, the image was frozen at end-diastole by
ECG-triggering, transferred to a computer equipped
with a software of digitization, and stored on disk for
central off-line reading. Off-line blind measurements of
IMT were performed by the same reader (JG), by means
of an automated computerized edge-detection program
(Iôtec, Iôdata, France) whose principles and description
have been provided elsewhere [4,5]. This program located the two interfaces defining far wall IMT and
calculated their distance every 100 mm by means of
analysis of grey level density with special tissular recognition algorithms. Average IMT was calculated as the
mean value of local IMT measures along at last 1 cm of
length of artery. For each subject a total IMT ((left +
right)/2) was taken as measure of current wall thickness
of the common carotid and common femoral arteries.
2.4. Statistical analysis
Values are expressed as mean9S.D. (or S.E. for
regression slopes). Comparisons of clinical variables and
IMT by smoking status were performed in each sex by
ANOVA and pairwise comparisons were performed by
using the Student’s t-test. Linear regressions were used
to analyze the relationships between IMT and age and
between IMT and current daily and lifelong smoking
dose. A multiple regression analysis was used for age-adjustment of IMT/smoking relationships. As the distribution of smoking dose was skewed, a logarithmic
transformation was applied. The slopes of IMT/age and
IMT/smoking relationships were compared between two
groups by means of a general linear model relating IMT
to age (or lifelong smoking), the group category, and the
product of age (or lifelong smoking) with the group
category. The statistical analysis was carried out on a
computer (Apple Macintosh) with the use of JMP (SAS)
and Excel (Microsoft) software.
J. Gariepy et al. / Atherosclerosis 153 (2000) 139–145
3. Results
Table 1 shows the clinical characteristics of the study
population by smoking status and by gender. No significant difference in any parameter existed between
never smokers, current smokers, and former smokers
except lifelong smoking dose lower in former smokers
than in current smokers in both sexes (P B0.05). In
women, the analysis of hormonal status showed that 49
were postmenopausal of whom 24 were receiving hormonal replacement therapy.
In men, carotid IMT was higher in current smokers
than in never smokers (P B 0.01) but no different between former smokers and never smokers and between
former smokers and current smokers, while in women
carotid IMT did not differ according to the smoking
status (Table 2). In men, femoral IMT was higher in
current smokers (PB 0.001) and in former smokers
(P B0.01) than in never smokers but no different between former smokers and current smokers, while in
women femoral IMT did not differ according to the
smoking status (Table 2).
In the whole population of men, carotid and femoral
IMT did correlate with the current number of cigarette
141
per day (r=0.21, r=0.19 respectively, P B0.01) and
these correlations remained significant after age-adjustment (PB 0.001, P B0.01, respectively).
In the male population carotid and femoral IMT did
correlate with smoking pack-years (r=0.37, r =0.38,
respectively, PB 0.001, Fig. 1), and these correlations
remained significant after age-adjustment (PB 0.001).
The carotid and femoral IMT/pack-years relationships
remained significant (r=0.28, r=0.35, respectively,
PB 0.001) when men who smoked more than 40 packyears were excluded, and their regression slopes were
similar to those obtained in the entire men population.
In the whole population of women, carotid IMT did
not correlate with either the current number of
cigarettes per day (r =0.04) or smoking pack-years
(r=0.08, Fig. 1). In the female population, femoral
IMT did correlate with the current number of cigarettes
per day (r=0.20, P B0.01) and smoking pack-years
(r= 0.18, PB 0.01, Fig. 1) and these correlations remained significant after age-adjustment (P B0.01). The
slopes of regression between femoral IMT and either
number of cigarettes per day or smoking pack – years,
were lower in women than in men (P =0.08, PB 0.001,
respectively). In postmenopausal women, carotid and
Table 1
Clinical characteristics by smoking statusa
Men
n
Age, years
Height, m
Body mass index, kg/m2
Systolic pressure, mmHg
Diastolic pressure, mmHg
Total cholesterol, mmol/l
Blood glucose, mmol/l
Current smoking, cigarette/day
Life long smoking, pack–years
Women
NS
CS
FS
NS
CS
FS
80
40 9 9
1.75 9 0.07
24 9 3
1339 9
82 9 8
5.14 90.69
5.409 0.53
–
–
61
42 99
1.74 9 0.07
259 3
132 9 9
81 9 9
5.15 9 0.61
5.43 9 0.64
17 9 10
18 9 15
53
44 9 9
1.779 0.06
25 9 2
136 9 9
82 9 9
5.229 0.59
5.579 0.62
–
139 10*
164
40 9 8
1.62 9 0.06
23 94
130 910
79 99
4.97 9 0.66
5.19 9 0.51
–
–
114
39 9 8
1.64 90.06
23 9 3
1299 9
79 9 9
4.989 0.80
5.099 0.52
16 9 11
13 9 8
52
43 9 8*
1.62 9 0.06
23 94
129 913
779 10
4.91 9 0.82
5.12 90.60
–
10 9 10*
a
NS, never smokers; CS, current smokers; FS, former smokers; and n, number of subjects. Values are mean 9S.D.
* PB0.05 between CS and FS.
Table 2
Intima-media thickness (IMT) by smoking statusa
NS (1)
CS (2)
FS (3)
P value
(1–2)
(1–3)
(2–3)
Carotid IMT, mm
Men
Women
0.51 9 0.08
0.49 9 0.07
0.57 9 0.12
0.49 90.07
0.54 9 0.10
0.50 9 0.06
B0.01
NS
NS
NS
NS
NS
Femoral IMT, mm
Men
Women
0.45 90.08
0.42 90.05
0.52 9 0.13
0.43 90. 08
0.49 9 0.09
0.42 9 0.05
B0.001
NS
B0.01
NS
NS
NS
a
NS, never smokers; CS, current smokers; FS, former smokers; and n, number of subjects. Values are mean 9S.D. NS, non significant.
142
J. Gariepy et al. / Atherosclerosis 153 (2000) 139–145
Fig. 1. Relationships of carotid and femoral intima-media thickness (IMT) with lifelong smoking dose in the pooled populations of never smokers,
current smokers and former smokers in each sex. r= correlation coefficient.
femoral IMT did not correlate with either the current
number of cigarettes per day or smoking pack – years.
Analysis of association of IMT and age showed that
in men carotid IMT and age were correlated in never
smokers (PB 0.001), in current smokers (P B0.01), and
in former smokers (P B0.01), but the slope of the
regression line was higher (PB 0.05) in current smokers
than in former smokers (Fig. 2) and almost significantly
higher (P= 0.07) in current smokers than in never
smokers. In women, carotid IMT and age were correlated in never smokers (PB 0.001), in current smokers
(P B0.001) and in former smokers (P B0.001), but the
slopes of the regression lines were not different between
groups (Fig. 2). In men, femoral IMT and age were
correlated in never smokers (PB 0.001), in current
smokers (P B0.001) and in former smokers (P B0.01),
but the slope of the regression line was higher in
current smokers than in never smokers (P B0.05) (Fig.
2). In women, femoral IMT and age were correlated in
never smokers (PB 0.001), in current smokers (P B
0.05) and in former smokers (PB 0.01), and the slopes
of the regression lines were not different between
groups (Fig. 2).
4. Discussion
The main finding of our work was to demonstrate
that when other cardiovascular risk factors (particularly
hypertension and hypercholesterolemia) are absent,
cigarette smoking was accompanied by an increase in
carotid and femoral IMT in men but not in women.
Such a result was obtained in a sample of healthy
adults of both sexes recruited from a general population of employees in the Ile de France area and by
using a B-mode IMT measurement, highly precise
thanks to the standardization of image recording according to telediastole, the automated computerized
measure without reader dependence, and the calculation of average IMT as the mean of a great number of
local IMT measurements [5,6].
In men, both carotid and femoral IMT were increased in current smokers as compared with never
smokers, in agreement with previous studies showing
positive associations between arterial wall thickening,
especially in carotid arteries, and cigarette smoking
[7– 10]. Also, as compared with never smokers, male
former smokers had increased IMT. This increase
J. Gariepy et al. / Atherosclerosis 153 (2000) 139–145
reached a statistical significance at the femoral site but not
at the carotid site, supporting a higher sensitivity of the
femoral artery wall to smoking [7,11]. Another important
observation was that the difference in IMT at both sites of
measurement was smaller between former smokers and
never smokers than between current smokers and never
smokers, suggesting that the smoking effects on arterial
wall thickness may be partially reversible after cessation
of smoking, as previously mentioned [12,13]. However, it
is possible that the lower lifelong smoking dose in former
smoker men than in current smokers may have produced
a lower increase in IMT in former smokers. Indeed we
have observed a dose dependence of current daily and
lifelong smoking doses on carotid and femoral IMT in the
pooled male population of never smokers, current smokers and former smokers, which is in favour of a causative
role for smoking in arterial wall thickening. The precise
mechanisms by which smoking may produce large artery
wall thickening are unclear. A recent study of IMT in
smokeless tobacco users suggests that the pathogenesis of
arterial wall thickening in smokers seems related to
components of tobacco other than nicotine [10]. Furthermore experimental studies in cockerels have shown that
143
inhalation of sidestream cigarette smoke accelerates
development of aortic atherosclerotic plaque and the
plaque-promotion of environmental tobacco smoke may
reside in the vapor phase which may induce smooth
muscle cell proliferation [14,15]. Another result of the
present work was that current smoking in men was
associated with an acceleration of the normal age-related
increase in carotid and overall femoral IMT. Indeed the
analysis of the univariate correlations of IMT with age in
men shows that the increase in femoral IMT per year was
2-fold greater in current smokers than in never smokers,
and the same trend existed for the annual increase in
carotid IMT between current and never smokers but
without reaching statistical significance. This phenomenon of higher rate of progression of IMT was not
observed in former smokers in whom the slope of
IMT/age relationship did not differ from that of never
smokers. These cross-sectional findings are in line with the
results of a recent longitudinal study [16] showing that the
3-year progression rate of carotid IMT was 50% greater in
current smokers than in never smokers while only 25%
greater in former smokers than in never smokers.
Fig. 2. Slopes of the intima-media thickness (IMT)/age relationship with S.E. by smoking status, by site and by gender. *, †, ‡, mean P B0.05,
B 0.01, B 0.001, respectively, for the statistical significance of the regression slopes.
144
J. Gariepy et al. / Atherosclerosis 153 (2000) 139–145
Surprisingly in women unlike men, we did not find
that smoking (either current or former) was accompanied with increased IMT of both arteries examined.
This lack of association was observed in the univariate
analysis as well in multivariate model. Moreover age
was significantly associated with IMT in women, but
unlike men the slope of the IMT/age relationship did
not differ between current, former and never smokers.
Lastly, in contrast to men, current daily and lifelong
smoking doses did not correlate with carotid IMT in
women, while they were associated with femoral IMT.
However the slope of the femoral IMT/pack – years
relationships was lower in women than in men, as well
as the slope of the relation between femoral IMT and
current daily smoking but without reaching statistical
significance. The gender differences in the slopes of the
IMT/age relationships are not as a result of the fact
that several men smoked more than 40 pack – years but
no women, because they persisted when men with
greater number than 40 pack – years smoking were excluded from the analysis. These results support the
possibility that the sensitivity of the female large artery
wall to smoking is attenuated at least at the early stage
of disease. Although this finding has not been really
emphasized in the literature until now, preliminary
results of a substudy of the Monica project [17] have
already pointed to the lack of association between
cigarette smoking and ultrasonographic carotid plaque
in women. Also it has been recently shown that the
brachial artery flow-mediated dilation was not decreased in female current smokers compared with former smokers whereas it was decreased in male current
smokers compared to former smokers [18], so suggesting a gender difference in early large artery alteration
induced by smoking. The mechanisms of the relative
protection of large artery wall of women from the
thickening effect of smoking are unknown. Adverse
effects of smoking [19– 21] on endothelium, plasma
fibrinogen and oxidative stress may be blunted by
endogenous estrogens before menopause which are involved in the relative protection from cardiovascular
disease in women [22]. Indeed, women in the present
study are in a great majority premenopausal because
only 49 women (15%) are post-menopausal. However,
if the hypothesis that premenopausal female hormones
are protective as regards smoking effect on IMT is
correct, postmenopausal women would have significant
relationships between IMT and smoking, like men. The
fact that we did not observe such relationships in
postmenopausal women does not support a major role
of protective effect of female hormones on IMT. On the
other hand the number of postmenopausal women is
probably not sufficiently great to demonstrate significant correlations between IMT and smoking and the
use of hormonal replacement therapy in 50% of postmenopausal women may blunt these correlations. Fur-
thermore, the protective effect of female hormones may
partly explain the discrepancy between our work and a
previous study showing that cigarette smoking increased the development and progression of atherosclerosis in women [23]. In this study women were on
average 10 years older that in the present work and
post menopausal in the majority of cases; moreover
atherosclerosis was characterized by the presence of
radiographic calcified deposit in the aorta which is
quite different from our pre-intrusive IMT measured in
carotid and femoral arteries.
In conclusion, we have found marked differences in
the influence of smoking on IMT between men and
women. Firstly, IMT increased in the presence of smoking (current and even former) in men but not in
women. Secondly, a dose dependence of current daily
and lifelong smoking existed for IMT in men, but it
was abolished for carotid IMT and clearly attenuated
for femoral IMT in women. Thirdly, current smoking
enhanced the normal age-related increase in IMT in
men but not in women. All these findings concur for
suggesting that gender modulates the early structural
alterations of large artery walls in response to smoking.
A practical implication is that carotid and overall
femoral IMT may be a marker more appropriate in
men than in women to detect and monitor early arterial
effects of smoking.
Acknowledgements
This work was supported by grants from the AXA
insurance company (Association AXA PREVENTION) and from the Institut National de la Santé et de
la Recherche Médicale (CRI-INSERM 9610). We
gratefully acknowledge Fatiha Laskri for having performed all the ultrasonographic measurements and
Joëlle Jansens for evaluating patients and collecting
data. We also thank Maria Crichi for her assistance in
the manuscript preparation.
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