Intima – media thickness of peripheral arteries in asymptomatic
cigarette smokers
F.W.P.J. van den Berkmortel
a,* , T.J. Smilde
a, H. Wollersheim
a, H. van Langen
b,
Th. de Boo
c, Th. Thien
aaDepartment of Medicine,Di6ision of General Internal Medicine541,Uni6ersity Hospital Nijmegen,P.O.Box9101,
6500HB Nijmegen,The Netherlands
bClinical Vascular Laboratory,Uni6ersity Hospital Nijmegen,6500HB Nijmegen,The Netherlands cDepartment of Medical Statistics,Uni6ersity Hospital Nijmegen,6500HB Nijmegen,The Netherlands
Received 12 February 1999; received in revised form 31 August 1999; accepted 10 September 1999
Abstract
Background and purpose: Although it is known that smoking is associated with an increase in arterial wall thickness, most studies have been performed in heterogeneous groups of older age, already suffering from atherosclerotic diseases or having additional cardiovascular risk factors. The purpose of this study is to assess the effect on arterial wall thickness of the carotid and femoral artery in cigarette smokers. Methods: In a cross-sectional study, intima – media thickness of the common and internal carotid artery, carotid bulb and common femoral artery was determined with the use of a B-mode ultrasound device, in 184 (44.399.0 years) cigarette smokers for whom smoking is the single cardiovascular risk factor. Comparisons were made with 56 non-smokers, matching in age and gender.Results: The posterior walls of both carotid bulbs (right:P=0.0005; left:P=0.02) and of the internal carotid arteries (right:P=0.004; left:P=0.003) as well as the posterior wall of the right common carotid artery (P=0.02) and of the right common femoral artery (PB0.0001) were thicker in smokers.Conclusions: Cigarette smoking as the single cardiovascular risk factor causes wall thickening of the carotid and femoral arteries, which indicates that early atherosclerosis is already present in smokers entering middle age. © 2000 Elsevier Science Ireland Ltd. All rights reserved.
Keywords:Cardiovascular risk factors; Carotid artery; Femoral artery; Intima – media thickness; Middle-aged cigarette smokers; Ultrasonography www.elsevier.com/locate/atherosclerosis
1. Introduction
Cigarette smoking is widely accepted as a major risk factor for cardiovascular diseases for both sexes. The precise pathophysiological mechanisms explaining this risk have not been elucidated. Changes in haemostatic factors [1], in endothelial function [2,3], in blood lipids [4,5] and accelerated atherosclerosis [4] may all play an important role.
Research has been hampered, as smoking is a dy-namic process causing variable exposure to the more than 4000 chemical compounds present in cigarette smoke. The knowledge that smoking interacts with
other classical cardiovascular risk factors, inducing syn-ergistic effects on the progression and on the develop-ment of atherosclerotic disease, further complicates the unravelling of this process [4,6].
We used ultrasonography for the non-invasive quan-titative measurements of intima – media thickness (IMT), which is associated with the presence of atherosclerotic disease elsewhere [7 – 13]. Indeed, a posi-tive association was found between IMT of the carotid artery and coronary heart disease [14], stroke [15] and peripheral artery disease [16].
The aim of our study was to determine whether only cigarette smoking, without other cardiovascular risk factors, influences the IMT of peripheral arteries. Therefore, we measured IMT of the right common femoral artery and both carotid arteries in a strictly selected group of habitual smokers entering middle-age and without cardiovascular risk factors. Smokers with
* Corresponding author. Tel.:+31-24-361-4782; fax:+ 31-24-354-1734.
E-mail address:f.vandenberkmortel@aig.azn.nl (F.W.P.J. van den Berkmortel)
other cardiovascular risk factors were excluded in order to avoid synergism or interaction.
2. Subjects and methods
2.1. Subjects
As a result of three advertisements in daily and weekly papers in the surroundings of Nijmegen, a medium-sized city (150 000 inhabitants) in The Nether-lands, 367 subjects were invited for screening; 184 smokers and 56 non-smokers out of this group met the inclusion criteria and were willing to participate.
The selected smokers had been smoking at least five cigarettes per day for at least 5 years. The non-smokers had not smoked in the previous 5 years.
All participants filled in a questionnaire concerning their health and smoking behaviour. They underwent a thorough physical examination, including a blood sur-vey (measurement of non-fasting plasma glucose and total cholesterol concentration), electrocardiogram (ECG) and determination of ankle – arm indices (AAI) to check if they met the inclusion criteria.
The following criteria for exclusion were applied: (1) demonstrated cardiovascular diseases; (2) irregular
heart rhythm disturbances others than sporadic
(supra)ventricular extrasystoles on ECG; (3) use of anti-hypertensive, lipid or glucose-lowering medication; (4) cardiovascular risk factors, defined as obesity (body mass index \30 kg/m2), hypertension (systolic blood pressure exceeding 160 mmHg and/or diastolic blood pressure exceeding 95 mmHg; the mean of at least two readings in supine position after 5 min of rest was used), diabetes mellitus or non-fasting plasma glucose \11.1 mmol/l, hypercholesterolaemia (non-fasting to-tal plasma cholesterol \6.5 mmol/l) or a decreased AAI (AAIB0.80).
The Medical Ethics Committee of the University Hospital of Nijmegen gave their approval to this study. All participants gave written informed consent.
2.2. Methods
All scannings were performed using a Biosound Phase 2 real-time scanner equipped with a 10 MHz transducer according to a protocol described elsewhere [17]. Briefly, the procedure was as follows. Subjects were measured in supine position with their heads turned 45 degrees contralateral from the midline posi-tion. Images showing the clearest projection of inter-faces at the following measurement sites were stored on a hard disk: (1) anterior and posterior wall of the distal 1 cm of the straight part of both common carotid arteries; (2) anterior and posterior wall of the right and left carotid bulb (from 91 cm proximal to the level of
the flow divider); (3) posterior wall of the proximal 1 cm of both internal carotid arteries; and (4) the poste-rior wall of the right common femoral artery measured 1 cm proximal to the bifurcation into the deep and superficial femoral artery. All ultrasound scannings were performed by three well-trained sonographers who regularly participate in quality control measurement sessions and who perform ultrasound scannings accord-ing to the aforementioned protocol on an almost daily basis. The inter-sonographer variability that was deter-mined in a group of subjects with normal IMT ranged from 2.5 to 6.4%. The coefficient of variation for subjects with increased IMT varied between 2.5 and 8.2% [17].
Images were analysed using a semi-automatic soft-ware program (Eurequa; TSA Company, Meudon, France) as previously described [17,18]. On each scan-ning site three measurments were made. The average of the measurements was taken. The measurements were calculated by two readers with an inter-reader variabil-ity of less than 2% [17].
2.3. Data analysis
The average of three measurements at each site was used as the final outcome. Statistical differences be-tween smokers and non-smokers were tested with the Mann – WhitneyU-test and considered significant when showing P-values less than 0.05 (two-sided).
3. Results
smokers, although these differences were not statisti-cally significant. The posterior wall of the common femoral artery in smokers had a mean thickness of 1.1590.04 mm, which was significantly thicker than the mean IMT in non-smokers (0.8790.04 mm).
Comparisons of the means of posterior and anterior wall measurements of both sides for each segment (missing values were not taken into account) between smokers and non-smokers yielded no additional infor-mation, with significant differences at the level of the bulb (P=0.0007) and internal carotid artery (P= 0.0008).
Subanalyses in which the 26 subjects who had never smoked were compared to the group of smokers did not alter the results.
Fig. 1 shows the number of smoking and non-smok-ing subjects in ten clusters of 22 – 23 patients stratified to increasing IMT levels of the right femoral artery. The figure illustrates that the percentage of non-smok-ers with increasing IMT is decreasing. In contrast, the percentage of smokers with progression of IMT is increasing.
Table 2
Intima–media thickness (IMT) of several segments of the carotid and femoral arteries in smokers and non-smokersa
IMT (mm) Smokers Non-smokers
(n=56) (n=184)
Common carotid artery
0.7790.17 (183)b
Right far wall 0.7190.12 (54) Right near wall 0.8090.21 (171) 0.7990.16 (49) 0.7590.17 (183) 0.7490.13 (56) Left far wall
0.7790.17 (179)
Left near wall 0.7990.16 (52)
Bulb
Left near wall 0.8390.25 (21)
Internal carotid artery
aData are presented as mean9S.E. with the number of
observa-tions in parentheses.
Basic characteristics of smokers and non-smokersa
Smokers
Systolic blood pressure 128914 130915 (mmHg)
Heart rate (beats/min)
Non-fasting plasma 5.190.8 4.991.0 cholesterol (mmol/l)
5.190.9
Non-fasting plasma glucose 4.990.8 (mmol/l)
Alcohol intake (U/week)
Percentage of subjects with:
Use of vitamins and/or 22 27 supplements
34 46
Smoking housemate(s)
At least one family member 14 13 with cardiovascular
disease
aData are presented as mean9S.D.
bCalculations are performed with the assumption that one pack
contains 25 cigarettes.
cLife-long smoking dose of ex-smokers. dPB0.01.
ePB0.0001.
Fig. 1. The number of smoking and non-smoking subjects in ten clusters of 22 – 23 participants (expressed in percentage of the total smoking and non-smoking groups) stratified to increasing intima – media thickness (IMT) of the right femoral artery.
4. Discussion
In this study we evaluated the effects of cigarette smoking as the single cardiovascular risk factor, and we found an increase of carotid and femoral wall thicken-ing. These findings indicate that early atherosclerosis is already present in cigarette smokers without other crite-ria for increased cardiovascular risk.
An association between smoking and carotid artery wall thickening has been reported in large population-based [19 – 21] or hospital-population-based cross-sectional [22,23] studies.
com-mon carotid artery wall thickening, most studies did not discriminate between different segments of the carotid artery. Moreover, data concerning femoral artery wall thickness are scarce, despite the described stronger association of smoking with femoral IMT [24]. Frequently, the examined study populations were older and affected by atherosclerotic diseases or by multiple cardiovascular risk factors.
The results concerning progression of intima – media thickening are conflicting. Salonen et al. [7] described augmented progression of intima – media thickening in smokers over a period of 2 years, while Belcaro et al. [11] could not confirm this in a 6-year follow-up study. Recently Howard et al. [25] published a large 3-year follow-up study describing a two-fold increase in IMT in current smokers.
Our study population was well-defined and consisted of an equal number of males and females who were positively selected because of the absence of concomi-tant cardiovascular risk factors or manifest atheroscle-rotic disease. There were no differences in basic characteristics concerning age, gender, body mass in-dex, blood pressure and plasma total cholesterol and glucose concentrations. The increased heart rate [26 – 28] and higher weekly alcohol intake [29,30] are well-known characteristics in a smoking population.
Common carotid artery wall thickness was not differ-ent between smokers and non-smokers except for the posterior wall of the right common carotid artery. The largest differences in IMT were seen at the carotid bulb, the internal carotid artery and the common femoral artery. These findings are in accordance with the litera-ture [21,24,31,32], which indicates that there are differ-ent risk patterns for early atherosclerosis of various arteries and even for arterial segments. Smoking mainly affects the carotid bulb and femoral artery. Therefore it can be recommended in an early stage to measure the common femoral artery or carotid bulb of smokers in order to detect atherosclerosis. Since the group of non-smokers partly consisted of former non-smokers, our results may be smoothed. However, in-depth comparison of the 26 ‘never-smokers’ with the smoking group yielded similar results.
As already suggested by Salonen et al. [33] and Smilde et al.[17], the amount of missing data limits the usefulness of the applied ultrasound technique. It is assumed that anatomical variations are the major cause of the missing values. Especially at the site of the carotid bulb and internal carotid artery, two known predilection sites for atherosclerosis, the amount of missing values may rise up to 60 – 70%. Although the number of missing values in our study population (Table 2; 3% for the common carotid arteries, 49% for the bulbs, 33% for the internal carotid arteries and 7% for the common femoral arteries) does not exceed the amount of missing data described earlier [17], this may
have influenced the results. However, the high number of missing values underlines the importance of our results, finding significant differences in relatively small numbers of observations. Since the common femoral artery can reliably be measured in more than 90%, measurements of this artery are preferred to detect early atherosclerosis in smokers.
We conclude that asymptomatic middle-aged subjects with cigarette smoking as the single cardiovascular risk factor already suffer from early atherosclerosis, explain-ing at least in part their increased cardiovascular risk. IMT of the femoral artery may be of major importance in future research regarding early atherosclerosis in smokers.
Acknowledgements
This research project was financially supported by grant NHS 94.035 from the Dutch Heart Foundation, The Netherlands.
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