© 1999 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Age and Sex Differences in the Distribution and Ultrasound Morphology of Carotid Atherosclerosis
The Tromsø Study
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Abstract |
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Abstract—Atherosclerosis begins early in life and is the major underlying cause of cardiovascular morbidity and death. Yet, population-based information on age and sex differences in the extent and morphology of atherosclerosis throughout life is scarce. Carotid atherosclerosis can be visualized with B-mode ultrasound and is a marker of atherosclerosis elsewhere in the circulation. We assessed both the prevalence and the morphology of carotid atherosclerosis by B-mode ultrasound in 3016 men and 3404 women, 25 to 84 years old, who participated in a population health survey. The participation rate was 88%. Plaque morphology was graded according to whether a plaque was predominantly soft (echolucent) or hard (echogenic). Atherosclerotic plaques were found in 55.4% of the men and 45.8% of the women. In men, there was a linear increase with age in the prevalence of carotid atherosclerosis, whereas in women, there was a curvilinear age trend, with an inflection in the prevalence rate of women at
50 years of age. The male predominance in
atherosclerosis declined after the age of 50 years, the
plaque prevalence being similar in elderly men and women. Men had
softer plaques than women; this sex difference in plaque morphology
increased significantly (P=0.005) with age. The sex
difference in the prevalence of atherosclerosis and the
female age trend in atherosclerosis show significant
changes at the age of 50 years, suggesting an adverse effect of
menopause on atherosclerosis. The higher proportion of
soft plaques in men compared with women increases with age and may
partly account for the prevailing male excess risk of coronary
heart disease in the elderly despite a similar prevalence of
atherosclerosis in elderly men and women.
Key Words: ultrasonography • carotid arteries • atherosclerosis • sex
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Introduction |
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High-resolution B-mode ultrasound is a valid and reproducible method to visualize and quantify carotid atherosclerosis noninvasively. Both ultrasound and autopsy studies have found that carotid atherosclerosis correlates well with atherosclerosis elsewhere in the circulation and can be used as a marker of general atherosclerosis.1 2 3 4 Previous population-based studies on ultrasound-detected atherosclerosis are small or did not examine sex differences in the prevalence and extent of atherosclerosis from young adulthood through old age.5 6 7 8 9
Not only the extent but also the morphology of atherosclerosis is important for the development of clinical vascular disease. Soft and lipid-rich plaques in the coronary arteries seem to be particularly prone to rupture and cause occlusive thrombosis and acute coronary syndromes,10 and ultrasound morphology of stenotic carotid plaque is an independent risk factor for stroke.11 12 Dark and low-echogenicity (echolucent) plaques on ultrasound correspond with soft and lipid-rich plaques at autopsy, supporting the validity of the ultrasound method.13 14 15 The reproducibility of carotid plaque morphology is acceptable.16 No studies on age and sex differences in ultrasound-assessed plaque morphology have been published.
In this population-based ultrasound study, we examined the prevalence and morphology of carotid atherosclerosis in 6420 men and women 25 to 84 years old.
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Methods |
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Subjects
The Tromsø Study was started in 1974 and is a single-center study of inhabitants in the municipality of Tromsø, Norway. The aims of the study are to investigate, by means of epidemiological and clinical research, determinants of chronic diseases to assess etiological significance and to identify potentially modifiable determinants that may be developed into preventive or therapeutic strategies. The main focus is on cardiovascular diseases. The study design includes repeated population health surveys to which total birth cohorts and random samples of other age groups are invited.
The fourth survey of the Tromsø Study started in September 1994 and was completed in October 1995. The survey was conducted by the University of Tromsø in cooperation with the National Health Screening Service and comprised 2 screening visits 4 to 12 weeks apart. All inhabitants >24 years old were invited to the first visit, and all subjects 55 to 74 years old and random 5% to 10% samples in the other 5-year age groups >24 years old were invited to both visits. A total of 6891 subjects, 88% of the eligible population, attended both visits. The protocol for the first visit was similar to the previous surveys in this population17 and included standardized measurements of height, weight, blood pressure, and nonfasting serum lipids. The second visit also included ultrasonographic examination of the right carotid artery.16 The study was approved by the regional ethical committee.
Cardiovascular Risk Factors
Height and weight were measured with the subject in light
clothing without shoes; body mass index was calculated as weight
divided by the square of height (kg/m2). The
letter of invitation gave information about the survey and also
included questions on previous myocardial infarction or stroke,
prevalent angina pectoris or diabetes mellitus (all yes/no), treated
hypertension (never/previously/currently), and smoking habits. The
questionnaire was checked for logical inconsistencies.
Ultrasonography
High-resolution B-mode ultrasonography of the right carotid
artery was performed on 6420 persons with an ultrasound scanner (Acuson
Xp10 128 ART-upgraded) equipped with a linear-array 5-MHz color
Doppler/pulsed-wave Doppler and 7-MHz B-mode transducer. The
subjects were examined in the supine position with the head turned
slightly to the left. The common, internal, and external carotid
arteries were identified by combined B-mode and color
Doppler/pulsed-wave Doppler ultrasound. We attempted to
identify and record atherosclerotic plaques from 6 sites of the
carotid artery: the near and far walls of the internal carotid artery
as far upstream as technically possible; the bifurcation of the common
carotid artery, ie, the distal part of the common carotid artery
from the point at which the 2 parallel near and far walls start to
deviate, up to the tip of the flow divider that separates the external
carotid artery from the internal carotid artery; and the common carotid
artery from the bifurcation segment and as far downstream of the
supraclavicular region as technically possible. Frozen ultrasound
images were stored on sVHS videotapes, and a 1-minute live
recording of the carotid artery from different transducer
positions and angles was also stored to document
representative recordings of plaque thickness
and morphology.
Instrument imaging adjustments (preprocession and postprocession, persistence, transmit zones, log compression, image depth, transmit power) were set at fixed values. The gain setting (including the depth gain compensation curve), however, was adjusted according to such factors as neck thickness, subcutaneous fat, and echogenicity of the near artery wall structures to obtain optimal visualization of arterial wall morphology. The gain setting was also changed continuously during the scanning procedure on the same individual to enhance plaque detection and characterization. The gain was not set so high that structural details of the high-echogenicity far-wall media-adventitia interface were concealed.
A plaque was defined as a localized protrusion of the vessel wall into the lumen. The maximum plaque thickness was measured online on frozen B-mode images marked with electronic calipers with measurement readout in tenths of a millimeter. The measures were recorded on videotapes and on written forms by the sonographers. In the far wall, the plaque thickness was defined as the distance between the lumen-plaque interface and the media-adventitia interface. Plaques in the near wall were measured from the far edge of the periadventitia-adventitia interface to the far edge of the intima-lumen interface.18 According to the protocol, plaques were to be visualized in the full diameter of the vessel, ie, both the proximal and the distal parts of the plaque should be "attached" to the typical double-lined intima-media structure, and the double lines should also be visible on the opposite wall of the vessel lumen. Focal calcification within the vessel wall (causing echo shadowing distally) without protrusion into the lumen was not considered to indicate atherosclerotic lesions.19
Plaque morphology, in terms of ultrasound echogenicity, was graded from
1 to 4, where grade 1 denotes low echogenicity, or echolucency (defined
as a plaque appearing black or almost black, like flowing blood), and
grade 4 denotes strong echogenicity (defined as a plaque appearing
white or almost white, similar to the far-wall highly echogenic
media-adventitia interface) (Figure 1
).
In the analysis, plaques of echogenicity grades 1 and 2 were
defined as soft, echolucent plaques, and plaques of grades 3 and 4 were
defined as hard, echogenic plaques. Some plaques were difficult to
classify because of echo shadowing from calcifications within the
plaque hiding the deeper portions of the same plaque or calcium
deposits in near-wall plaques casting shadows over the vessel lumen and
far-wall plaques. Those plaques were defined as unclassifiable.
Unsatisfactory imaging quality from other causes also led to this
definition.
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We have previously reported the reproducibility of the present
ultrasound method.16 The between- and within-sonographer
agreement on plaque occurrence was substantial, with 
values (95%
CI) of 0.72 (0.60 to 0.84) and 0.76 (0.63 to 0.89), respectively.
Agreement on classification of plaque echogenicity in the 2 categories
used in the analysis was also substantial, with values
(95% CI) of 0.80 (0.61 to 0.99) and 0.79 (0.61 to 0.97) between and
within sonographers, respectively.16 A value of 0
means no agreement beyond chance, and a value of 1 means total
agreement.
Statistical Analysis
Means were compared by 2-sample Student’s t test.
Logistic regression was used to calculate age-adjusted odds ratios of
having soft plaques according to sex and age. Descriptive statistics,
t tests, and regression analyses were performed with
the SAS software package.20 The probability values
are 2-sided, and a value of P<0.05 was considered
statistically significant.
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Results |
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Selected characteristics of the 3016 men and 3404 women are presented in Table 1
. Men
were slightly younger than women and had a higher prevalence of carotid
plaque (P<0.001). Approximately 32% of both men and women
were smoking cigarettes daily. The mean cholesterol level
was relatively high, females having significantly higher levels than
men (P<0.001).
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A total of 1670 men (55.4%) and 1558 women (45.8%) had carotid
plaques. The prevalence of plaque increased with age in both men and
women (Table 2). The age-adjusted odds
ratios (95% CI) for plaque prevalence in men compared with women were
1.85 (1.24, 2.76), 1.65 (1.41, 1.91), 1.46 (1.24, 1.73), 0.76 (0.38,
1.55), and 1.56 (1.41, 1.74) among subjects <55 years old, 55 to 64
years, 65 to 74 years, >74 years, and for all subjects, respectively.
The odds ratios did not change notably with control for age, body mass
index, total cholesterol, HDL cholesterol,
current smoking, treated hypertension, and diabetes mellitus: 1.77
(1.10, 2.84), 1.70 (1.44, 2.00), 1.59 (1.32, 1.91), 0.87 (0.37, 1.22),
and 1.66 (1.47, 1.86) among the same subject groups, respectively. In
men, there was a nearly linear increase until the age of 65 years;
thereafter, the age-related increase leveled off (Figure 2). Compared with men, women had a less
steep increase in plaque prevalence between the ages of 35 and 49
years. After this age, atherosclerosis accelerated more
rapidly in women than in men. In the age group of 75 to 84 years, more
women (81.2%) than men (76.5%) had carotid
atherosclerosis. The difference, however, was not
statistically significant. The male-to-female ratio of plaque
prevalence was highest in the age group of 45 to 49 years (Figure 3) and declined thereafter. Table 2 also shows that the number of atherosclerotic lesions and the
thickness of plaques increased with age in both sexes. The predilection
site of atherosclerosis seems to be in the bifurcation
segment of the carotid artery, where the number of plaques is highest
for both sexes at any age. Figure 4 shows
that only 15% of the plaques were located entirely outside the
bifurcation segment. There was no sex difference in the within-artery
distribution of carotid atherosclerosis.
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1 carotid plaques.
Soft carotid plaques were present in 37.7% of the 3100 subjects
with morphologically classifiable plaques. In all age groups, there was
a greater proportion of soft plaques in men than in women (Table 3). The proportion of soft plaques
declined with age in both sexes, but more in women than in men; the
odds ratio for soft plaques in men compared with women increased by age
(Table 3). In a multiple logistic regression analysis
with age and sex, there was a statistically significant age-by-sex
interaction (P=0.005). The prevalence of soft plaques
increased with age until 60 years for both sexes (Figure 5). After this age, there was no further
increase in prevalence of soft plaques for either sex. In all age
groups, more men than women had soft plaques. This sex difference in
soft plaque prevalence remained fairly constant from the age of 40
years and throughout old age (Figure 5). The odds ratios did not
change notably with control for age, body mass index, total
cholesterol, HDL cholesterol, current smoking,
treated hypertension, and diabetes mellitus: 1.17 (0.50, 2.74), 1.00
(0.79, 1.26), 1.35 (1.07, 1.71), 2.26 (0.90, 5.65), and 1.14 (0.97,
1.34) among subjects <55 years old, 55 to 64 years, 65 to 74 years,
>74 years, and for all subjects, respectively. The interaction between
age and sex was now nonsignificant (P=0.21). When the 153
women who had ever used postmenopausal hormone replacement therapy were
excluded from the analysis, the risk estimates for plaque
prevalence and plaque morphology did not change notably even after
adjustment for cardiovascular risk factors (data not
shown).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This population-based ultrasound study demonstrates a strong relationship between age and prevalence of carotid atherosclerosis in both sexes. Similar findings have been reported from other population-based studies (Table 4
), but previous studies were small or
did not include subjects throughout a broad age range.5 6 7 8 9
Differences in study designs, including various ultrasound imaging
methods, inclusion criteria, and definition of
atherosclerosis, make direct comparisons between
studies difficult. However, the prevalence of ultrasound-detected
carotid atherosclerosis, with a few exceptions, seems
to be fairly similar in studies from Europe and the United States
(Table 4).
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Atherosclerosis occurs more frequently in men than in
women. The present study shows, however, that the sex gap in plaque
prevalence is strongly influenced by age. The male-to-female ratio in
prevalence peaks at age 45 to 49 years and then declines steadily
(Figure 2
). For subjects >75 years old, the total plaque
prevalences in men and women do not differ. The curvilinear shape of
the atherosclerosis prevalence curve for women suggests
that the incidence of new atherosclerotic plaques is lower for women
than for men before the age at which the majority of women experience
menopause and higher thereafter. Some of the declining prevalence of
atherosclerosis with age among older male subjects may
be due to a survival selection bias causing an
overrepresentation of atherosclerosis-free male
survivors.
The overall rate of attendance in our study was high (88%), but lower
(70%) among the youngest (<35 years old) and oldest (>80 years
old) participants. It is likely that this has resulted in a lower
prevalence of plaques in the oldest age group, because one must expect
subjects with the lowest burden of
atherosclerosis-related disease to be
overrepresented among the attenders (and survivors). The
effect of the lower attendance rate is more unpredictable among younger
participants but is probably marginal. The ultrasound examination was
conducted without any clinical interview and was blinded with regard to
symptoms of atherosclerosis. Some subjects, however,
revealed symptoms and fragments of their medical history to the
sonographers during the examination. We find it unlikely that this
information has influenced our results with regard to plaque prevalence
to any significant degree.
No previous large, population-based study has compared the prevalence of carotid plaque in men and women from early adulthood through old age. Prati and colleagues7 examined a total of 1348 subjects between the ages of 18 and 99 years and did not find plaque before the age of 40 years in either sex. In the MONICA Project Augsburg,8 a curvilinear relationship between age and carotid atherosclerosis in women seemed to appear but was not discussed by the authors. A direct comparison with our results is difficult, because the analysis in that study was done in 10-year age groups and none of the participants were >65 years old. The Bruneck Ischemic Heart Disease and Stroke Prevention Study,9 which included 909 subjects >40 years old, also performed analyses on 10-year age groups, and their data on prevalence of atherosclerosis are therefore difficult to compare with our findings. That study showed a declining sex difference in plaque prevalence at high ages similar to those we found. Apart from ultrasound-based studies, information on the prevalence of atherosclerosis and sex differences in the prevalence of atherosclerosis in the general population is scarce. In an autopsy survey, Sternby21 found age-related prevalence curves for coronary atherosclerosis in men and women similar to those we found for carotid atherosclerosis, with convergence of the prevalence of atherosclerosis in all 3 main coronary arteries in the youngest (<35 years) and oldest (>75 years) age groups.
It has been discussed whether coronary morbidity and mortality in women is affected by menopause and whether there is an acceleration in the risk of coronary disease and death after menopause. Recently, Tunstall-Pedoe22 described it as a myth of menopause that risk in women is held low until menopause, when it rebounds, becomes equal, and later surpasses that in men. He showed that the male excess in risk of coronary death continues to rise with age and that the sex gap never closes. Similar findings were reported by Barrett-Connor.23 Our findings of a premenopausally increasing sex gap in the prevalence of atherosclerosis and a postmenopausal decrease and ultimately closure of the gap at higher ages are not at variance with their findings, because clinical manifestations of vessel wall atherosclerotic lesions may be delayed by many years.
In addition, sex differences in plaque morphology may account for the
prevailing male excess risk of coronary death in older age,
despite a similar prevalence of atherosclerosis in
elderly men and women. Our study shows, to the best of our knowledge
for the first time in a general population, that men have softer
plaques than women and that the male excess prevalence of soft plaques
remains high in old age. One previous clinical study on
ultrasound-assessed plaque morphology of stenotic
plaques12 also found that women had harder plaques than
men, but that study has limitations because the subjects were selected
for carotid endarterectomy. Most myocardial
infarctions and sudden coronary deaths are caused by the
rupture of soft, lipid-rich plaques.10 24 If carotid and
coronary plaques share common morphological characteristics
within individuals, our finding may provide for the continued male
excess risk of coronary death in older age. Sex differences in
plaque morphology may also partly account for the substantially greater
male-to-female ratio for coronary mortality23 25
than the male-to-female ratio for atherosclerosis
throughout life (Figure 3).
Other lines of evidence support our findings that atherosclerosis in women may be qualitatively different from atherosclerosis in men. Coronary bypass surgeons have reported that atherosclerotic tissues in female patients often are more friable and difficult to work with than atherosclerotic tissues in male patients.26 Furthermore, results from 3 major carotid surgery trials27 28 29 showed greater benefit from operations in men than in women. Finally, histological characterization of stenotic plaques studied after carotid endarterectomy,30 and of plaques in coronary arteries or saphenous vein bypass grafts on autopsy,31 have shown significant sex differences in plaque morphology.
We conclude that the male-to-female ratio of carotid atherosclerosis increases until the age of 50 years and thereafter declines so that the prevalence of atherosclerosis is similar in elderly men and women. These findings may suggest that events related to menopause may promote atherosclerosis in women. The present study indicates that men have softer plaques than women. We hypothesize that sex differences in plaque morphology may partly account for the prevailing male excess risk of coronary heart disease in the elderly.
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Acknowledgments |
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This study was supported by grants from the Norwegian Research Council and was conducted in collaboration with the National Health Screening Service, Oslo, Norway. We thank our ultrasound technician, Jon T. Moe Joakimsen, for skillful contributions to the data collection and analysis of plaque morphology.
Received January 22, 1999; accepted July 8, 1999.
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H. Yamagami, K. Kitagawa, Y. Nagai, H. Hougaku, M. Sakaguchi, K. Kuwabara, K. Kondo, T. Masuyama, M. Matsumoto, and M. Hori Higher Levels of Interleukin-6 Are Associated With Lower Echogenicity of Carotid Artery Plaques Stroke, March 1, 2004; 35(3): 677 - 681. [Abstract] [Full Text] [PDF]
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 P. Prandoni, F. Bilora, A. Marchiori, E. Bernardi, F. Petrobelli, A. W.A. Lensing, M. H. Prins, and A. Girolami An Association between Atherosclerosis and Venous Thrombosis N. Engl. J. Med., April 10, 2003; 348(15): 1435 - 1441. [Abstract] [Full Text] [PDF]
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 M. Zureik, J.-M. Bureau, M. Temmar, C. Adamopoulos, D. Courbon, K. Bean, P.-J. Touboul, A. Benetos, and P. Ducimetiere Echogenic Carotid Plaques Are Associated With Aortic Arterial Stiffness in Subjects With Subclinical Carotid Atherosclerosis Hypertension, March 1, 2003; 41(3): 519 - 527. [Abstract] [Full Text] [PDF]
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 J. B. Chang and T. A. Stein Ten-Year Outcome After Saphenous Vein Patch Angioplasty in Males and Females After Carotid Endarterectomy Vascular and Endovascular Surgery, January 1, 2002; 36(1): 21 - 27. [Abstract] [PDF]
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A.J.C. Slooter, M. L. Bots, L. M. Havekes, A. I. del Sol, M. Cruts, D. E. Grobbee, A. Hofman, C. Van Broeckhoven, J.C.M. Witteman, and C. M. van Duijn Apolipoprotein E and Carotid Artery Atherosclerosis: The Rotterdam Study Stroke, September 1, 2001; 32(9): 1947 - 1952. [Abstract] [Full Text] [PDF]
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E. B. Mathiesen, K. H. Bonaa, and O. Joakimsen Low Levels of High-Density Lipoprotein Cholesterol Are Associated With Echolucent Carotid Artery Plaques: The Tromso Study Stroke, September 1, 2001; 32(9): 1960 - 1965. [Abstract] [Full Text] [PDF]
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 M. Zureik, F. Kauffmann, P.-J. Touboul, D. Courbon, and P. Ducimetiere Association Between Peak Expiratory Flow and the Development of Carotid Atherosclerotic Plaques Arch Intern Med, July 9, 2001; 161(13): 1669 - 1676. [Abstract] [Full Text] [PDF]
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U. G.R. Schulz and P. M. Rothwell Sex Differences in Carotid Bifurcation Anatomy and the Distribution of Atherosclerotic Plaque Stroke, July 1, 2001; 32(7): 1525 - 1531. [Abstract] [Full Text] [PDF]
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