Effect of age, gender and cardiovascular risk factors on carotid distensibility during 6-year follow-up. The cardiovascular risk in Young Finns study.
ABSTRACT Arterial elasticity decreases with aging. We evaluated the role of conventional cardiovascular risk factors in this process and studied the modifying effect of gender in a population of young adults.
6-year follow-up study that included 1711 subjects (aged 32 ± 5 years) who had carotid artery distensibility (Cdist) measured at baseline (in 2001) and at follow-up (in 2007). Risk factors measurements included waist circumference, body mass index, lipids, glucose, C-reactive protein, smoking and family history of coronary disease.
In a multivariable model, baseline age (β ± SEM = -0.024 ± 0.003, P < 0.001), waist circumference (β ± SEM = -0.005 ± 0.002, P = 0.009) and insulin (β ± SEM = -0.097 ± 0.034, P = 0.005) were associated with 6-year change in Cdist. The 6-year increase in waist circumference (β ± SEM = -0.016 ± 0.003, P < 0.001) and systolic blood pressure (β ± SEM = -0.005 ± 0.002, P = 0.006) were associated with reduced Cdist. In women, an increase in glucose was associated with reduced Cdist (β ± SEM = -0.074 ± 0.025, P = 0.004). Decreasing trend in Cdist levels was observed with increasing number of metabolic syndrome risk factors in women (P = 0.0001) but not in men (P = 0.18) (P for interaction 0.02).
In addition to age, increased adiposity and insulin levels were strong predictors for impaired arterial elasticity. Moreover, our results suggest that arterial function in women may be more vulnerable to the atherogenic effects of hyperglycemia and increased risk factor burden compared to men in young adulthood.
- SourceAvailable from: Nathalie Leone[show abstract] [hide abstract]
ABSTRACT: Arterial mechanical properties are of growing interest in the understanding of cardiovascular disease development. We aimed to determine the predictive value of carotid wall mechanics on coronary heart disease (CHD) in the Three-City study. At baseline, 3337 participants aged > or =65 years underwent a carotid B-mode ultrasonography. During a median follow-up of 43.4 months, 128 CHD occurred. Increased carotid distension (relative stroke change in lumen diameter) was significantly associated with CHD risk. Comparison of subjects in tertile 3 versus those in tertile 1 (reference) showed a hazard ratio (HR) of 1.80 (95% CI, 1.17 to 2.75). Controlling for various confounders including age, heart rate, brachial (or carotid) pulse pressure, and common carotid intima-media thickness did not alter the association between carotid distension and CHD with a HR of 1.79 (95% CI, 1.12 to 2.86; tertile 3 versus tertile 1). Brachial and carotid pulse pressures were also independently associated with CHD. No association was found between CHD and carotid distensibility coefficient, cross-sectional compliance coefficient, Young's elastic modulus, or beta stiffness index. In the elderly, increased carotid distension was independently predictive of CHD. This simple and noninvasive parameter might be of particular interest for cardiovascular risk assessment.Arteriosclerosis Thrombosis and Vascular Biology 07/2008; 28(7):1392-7. · 6.34 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Large artery mechanical properties are a major determinant of pulse pressure and cardiovascular outcome. Sex differences in these properties may underlie the variation in cardiovascular risk profile between men and women, in relation to age. To investigate sex differences in the age-related stiffening of large arteries. Cross-sectional. One hundred and twenty healthy men and women were recruited and divided equally into tertiles by age: young (mean +/- SD, 23 +/- 5 years), middle-age (47 +/- 3 years) and older (62 +/- 7 years). Lipids, mean arterial pressure and heart rate were matched within each tertile. Carotid tonometry and Doppler velocimetry were used to measure indices of large artery stiffness. There was no sex difference in systemic arterial compliance (SAC) in the young group (mean +/- SEM, 0.61 +/- 0.05 arbitrary compliance units (ACU) in women compared with 0.67 +/- 0.04 ACU in men), but in the older population women had lower SAC than men (0.27 +/- 0.03 ACU compared with 0.57 +/- 0.04 ACU respectively; P < 0.001). Measures independent of aortic geometry (distensibility index and aortic impedance) indicated that stiffness was lower in young women than in men (P < 0.05), but the reverse was true in the older population (P < 0.01). This paralleled the brachial and carotid pulse pressures, which were lower in young (P < 0.01) and higher in older women compared with those in men (P < 0.05). Follicle stimulating hormone concentrations correlated strongly (r values 0.39-0.65) with all indices of central, but not peripheral, arterial function, whereas concentrations of luteinizing hormone, progesterone and oestradiol correlated less strongly. In men and women matched for mean pressures, the age-related stiffening of large arteries is more pronounced in women, which is consistent with changes in female hormonal status.Journal of Hypertension 01/2002; 19(12):2205-12. · 3.81 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Most epidemiologic studies of cardiovascular disease in postmenopausal women suggest that estrogen-replacement therapy has a protective effect. The effects of the use of estrogen combined with progestin are less well studied. To examine the associations of hormone-replacement therapy with concentrations of plasma lipids and hemostatic factors, fasting serum concentrations of glucose and insulin, and blood pressure, we studied 4958 postmenopausal women participating in a population-based investigation. Using cross-sectional data, we classified the women into four groups according to their use of hormone-replacement therapy: current users of estrogen alone, current users of estrogen with progestin, nonusers who had formerly used these hormones, nonusers who had never used them. Current users had higher mean levels of high-density lipoprotein cholesterol, its subfractions high-density lipoprotein2 and high-density lipoprotein3, and apolipoprotein A-I than nonusers and lower mean levels of low-density lipoprotein cholesterol, apolipoprotein B, lipoprotein(a), fibrinogen, antithrombin III, and fasting serum glucose and insulin. However, current users of estrogen alone had higher triglyceride, factor VII, and protein C levels than either nonusers or current users of estrogen with progestin. After making certain assumptions, we estimated that the findings, if causal, would translate into a reduction of 42 percent in the risk of coronary heart disease in users of hormones as compared with nonusers. Women using estrogen with progestin would have an even greater estimated benefit. A randomized trial is needed to eliminate possible selection biases in our observational study that are related to the prescription of replacement hormones. Nevertheless, hormone-replacement therapy appears to be associated with a favorable physiologic profile, which probably mediates its protective effects on cardiovascular disease. The use of estrogen combined with progestin appears to be associated with a better profile than the use of estrogen alone.New England Journal of Medicine 05/1993; 328(15):1069-75. · 51.66 Impact Factor
Effect of age, gender and cardiovascular risk factors on carotid distensibility
during 6-year follow-up. The cardiovascular risk in Young Finns study
Juha Koskinena,*, Costan G. Magnussena,b, Jorma S.A. Viikaric, Mika Kähönend, Tomi Laitinene,
Nina Hutri-Kähönenf, Terho Lehtimäkig, Eero Jokinenh, Olli T. Raitakaria,i, Markus Juonalaa,c
aResearch Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Kiinamyllynkatu 10, FI 20520 Turku, Finland
bMenzies Research Institute Tasmania, University of Tasmania, Tasmania, Australia
cDepartment of Medicine, University of Turku and Turku University Hospital, Finland
dDepartment of Clinical Physiology, Tampere University Hospital and Tampere University School of Medicine, Tampere, Finland
eDepartment of Clinical Physiology, Kuopio University Hospital, Finland
fDepartment of Pediatrics, Tampere University Hospital, Finland
gDepartment of Clinical Chemistry, Tampere University Hospital and Tampere University School of Medicine, Tampere, Finland
hHospital for Children and Adolescents, University of Helsinki, Finland
iDepartment of Clinical Physiology, Turku University Hospital, Finland
a r t i c l e i n f o
Received 8 December 2011
Received in revised form
8 March 2012
Accepted 11 April 2012
Available online 9 May 2012
Carotid artery distensibility
a b s t r a c t
Objective: Arterial elasticity decreases with aging. We evaluated the role of conventional cardiovascular
risk factors in this process and studied the modifying effect of gender in a population of young adults.
Methods: 6-year follow-up study that included 1711 subjects (aged 32 ? 5 years) who had carotid artery
distensibility (Cdist) measured at baseline (in 2001) and at follow-up (in 2007). Risk factors measure-
ments included waist circumference, body mass index, lipids, glucose, C-reactive protein, smoking and
family history of coronary disease.
Results: In a multivariable model, baseline age (b ? SEM ¼ ?0.024 ? 0.003, P < 0.001), waist circum-
ference (b ? SEM ¼ ?0.005 ? 0.002, P ¼ 0.009) and insulin (b ? SEM ¼ ?0.097 ? 0.034, P ¼ 0.005) were
associated with 6-year change in Cdist. The 6-year increase in waist circumference (b ? SEM ¼
?0.016 ? 0.003, P < 0.001) and systolic blood pressure (b ? SEM ¼ ?0.005 ? 0.002, P ¼ 0.006) were
associated with reduced Cdist. In women, an increase in glucose was associated with reduced Cdist
(b ? SEM ¼ ?0.074 ? 0.025, P ¼ 0.004). Decreasing trend in Cdist levels was observed with increasing
number of metabolic syndrome risk factors in women (P ¼ 0.0001) but not in men (P ¼ 0.18) (P for
Conclusions: In addition to age, increased adiposity and insulin levels were strong predictors for impaired
arterial elasticity. Moreover, our results suggest that arterial function in women may be more vulnerable
to the atherogenic effects of hyperglycemia and increased risk factor burden compared to men in young
? 2012 Elsevier Ireland Ltd. All rights reserved.
The elasticity of an artery can be estimated by measuring its
distensibility. Carotid artery distensibility (Cdist), assessed non-
invasively by ultrasound, measures the ability of the arteries to
expand in response to pulse pressure caused by cardiac contraction
and relaxation . The elasticityof largearteries, such asthe carotid
artery, is the result of high elastin to collagen ratio in their walls.
The decrease in arterial elasticity that occurs with age is largely the
result of progressive calcification, elastic fiber degeneration and
increase in collagen content .
Decreased arterial elasticity has also been considered to repre-
sent the early pathophysiological changes in the arteries relevant to
the development of atherosclerosis . Several conventional risk
factors have been associated with decreased arterial elasticity in
cross-sectional studies [1,4]. Furthermore, ultrasonically measured
decreased carotid elasticity has been implicated as an independent
predictor of cardiovascular events [5e8]. These data suggest that
reduced elasticity is not only age-related but also may reflect
increased atherosclerotic burden. Although an adverse association
between cardiovascular risk factors and reduced arterial elasticity
has been demonstrated cross-sectionally among young adults, little
* Corresponding author. Tel.: þ358 40 518 3139; fax: þ358 23 337 270.
E-mail address: email@example.com (J. Koskinen).
Contents lists available at SciVerse ScienceDirect
journal homepage: www.elsevier.com/locate/atherosclerosis
0021-9150/$ e see front matter ? 2012 Elsevier Ireland Ltd. All rights reserved.
Atherosclerosis 224 (2012) 474e479
is known about the longitudinal relationship in this age group .
Even less is known about the effect of age and gender on this
association. Previous studies using a variety of indices have found
that age-related decrease in arterial function is morepronounced in
women [10e12]. Potential mechanisms may include differences in
bodysize, lengthof the vasculature , left ventricular remodeling
 and hormonal status . In addition, type 2 diabetes has been
found to relate with a greater age-related stiffening of the aorta in
women compared to men . However, longitudinal studies
examining the interplay between gender and different cardiovas-
cular risk factors in arterial elasticity are lacking.
The objective of the present analysis was to explore the role of
cardiovascular risk factors in the reduction of arterial elasticity with
increasing age and to examine whether gender modifies these
effects. The analyses were based on the longitudinal cardiovascular
risk in Young Finns study. Cdist was measured for 784 men and 927
women in 2001 (age 24e39 years) and 2007.
The cardiovascular risk in Young Finns study was launched in
1980 to assess risk factors of cardiovascular disease in 3596 chil-
dren and young adults (aged 3e18 years). Five university hospitals
in Finland (Turku, Tampere, Helsinki, Kuopio and Oulu) are taking
part in the study and the participants were randomly selected from
these areas. Cdist was measured in the follow-up studies in 2001
and 2007, at ages 24e39 and 30e45 respectively. Total of 1811
subjects participated in both follow-up studies. Subjects who had
missing Cdist data from the year 2001 or 2007 were excluded from
the present analysis. Complete Cdist data were available for 1711
non-pregnant subjects. One subject had established cardiovascular
disease, 40 subjects were currently using antihypertensive medi-
cation and 7 subjects were currently using lipid-lowering medi-
cation. Nosignificant difference in results was observedwhen these
subjects were excluded from the cohort. Total of 253 women (15%
of the total population, 27% of women) were using oral contra-
ceptives in 2001. All subjects gave written informed consent and
the study was approved by the local ethics committee.
2.2. Anthropometric and biochemical measurements
Body height, weight and waist circumferences were measured
with an accuracy of 0.1 kg and 0.5 cm. Body mass index (BMI) was
calculated using the formula: weight[kg]/(height[m])2. Blood
pressure was measured using a random zero sphygmomanometer.
Average of three measurements was used in the analyses. Venous
blood samples were drawn from the right antecubital vein after
fasting for 12 h. Serum cholesterol and triglyceride concentrations
Germany) in a clinical chemistry analyzer (AU400, Olympus).
Serum HDL-cholesterol was measured by the dextran sulphate
500,000 method. LDL cholesterol was calculated using the Friede-
wald’s formula for subjects with <4 mmol/l triglycerides. Plasma
glucose concentrations were analyzed enzymatically with a clinical
chemistry analyzer (Olympus, AU400; CV 2.0%) and serum insulin
concentration was measured by microparticle enzyme immuno-
assay kit (CV 2.1%) (Abbott Laboratories, Diagnostic division, Dai-
nabot). Insulin resistancewas
homeostasis model assessment (HOMA-IR) as the product of fast-
ing glucose and insulin divided by 22.5. Serum C-reactive protein
(CRP) was analyzed by an automated analyzer (Olympus AU400)
using a latex turbidimetric immunoassay kit (CRP-UL-assay, Wako
Chemicals, Neuss, Germany).
Subjects were also asked to complete questionnaires on medi-
cation, smoking habits, family history of coronary heart disease and
climacterium status. One person reported being in the menopausal
phase of the climacterium.
2.4. Metabolic syndrome risk factors
To classify dichotomous metabolic syndrome (MetS) risk factors,
we used cut-off points proposed in a joint statement of the Inter-
national Diabetes Federation Task Force on Epidemiology and
Prevention, National Heart, Lung and Blood Institute, the American
Heart Association, the World Heart Federation, the International
Atherosclerosis Society, and the International Association for the
Study of Obesity . Three or more of the following five criteria
had to be present. For waist circumference, we used cut-points of
?102 for men and ?88 cm for women to define abdominal obesity.
Triglycerides ?1.695 mmol/l, HDL-cholesterol <1.036 mmol/l in
men or <1.295 mmol/l in women, blood pressure ?130/
?85 mmHg, fasting glucose ?5.6 mmol/l.
2.5. Cdist measurements
In the present study cohort, Cdist data was available at baseline
study in 2001 and at follow-up study in 2007. Pulse wave velocity
measurements were collected only at follow-up in 2007. Thus, to
assess the 6-year changes, we used only Cdist to assess the arterial
properties. However, Cdist correlated with pulse wave velocity
(r ¼ 0.32, P < 0.0001) and the associations between these two
methods and risk factors were similar (results available at online
supplement Table 1). An ultrasound imaging device with a high-
resolution system and 13.0-MHz linear array transducers (Sequoia
512, Acuson, CA, USA) was used. Ultrasound studies were per-
formed by trained sonographers following a standardized protocol
. Measurements were made off-line from stored digital images.
All ultrasound scans were analyzed by one reader (same reader in
2001 and 2007) blinded to subjects’ details. To assess Cdist, the best
quality cardiac cycle was selected from a continuous 5-s image file.
The common carotid diameter 10 mm from carotid bifurcation was
measured at least twice during end-diastole. The mean of the
measurements was used as the end-diastolic and end-systolic
diameter. Ultrasound and concomitant brachial blood pressure
measurements were used to calculate Cdist¼([Ds ? Dd]/Dd)/
(Ps ? Pd), where Dd is the diastolic diameter, Ds the systolic
diameter, Ps systolic blood pressure, and Pd diastolic blood pres-
sure. To assess intra-individual reproducibility of ultrasound
measurements 57 subjects were re-examined 3-months after the
initial visit in 2001 (2.5% random sample). The 3-month between
visit coefficients of variations were 2.7% for carotid artery diastolic
diameter and 14.3% for Cdist. Previously, we have shown that the
variabilityand tracking between ultrasound measurements in 2001
and 3-month re-examination as well as between measurements in
2001 and 2007 were similar . Details of these methods have
been published elsewhere .
We defined high-risk Cdist change as a ?10th percentile
decrease for age and gender specific values (N ¼ 177). In sensitivity
analyses, we had essentially similar results using standardized cut-
points corresponding to the 15th, 20th and 25th Cdist change
percentiles (data not shown).
2.6. Statistical methods
Values for triglycerides and CRP were loge-transformed to
correct for skewness. Characteristics of the study subjects were
J. Koskinen et al. / Atherosclerosis 224 (2012) 474e479
compared using t-tests and chi-square tests as appropriate. We
found an inverse correlation between baseline Cdist and change
in Cdist (r ¼ ?0.57). Therefore, to determine which risk factors
were associated with relative change in Cdist during the 6-year
follow-up, all analyses were adjusted for baseline Cdist. Pear-
son’s and Spearman’s partial correlation coefficients adjusted for
age were calculated to assess bivariate associations between Cdist
change and baseline Cdist and between Cdist change and risk
factors. To assess the independent relations between Cdist change
and risk factors, we used linear multivariable regression assessing
continuous Cdist change and logistic multivariable regression
assessing dichotomous high-risk Cdist change. To avoid high
multicollinearity, the measures of adiposity (waist circumference
and BMI), lipids (total and LDL cholesterol) and blood pressure
(systolic and diastolic) were not included in the same multivari-
able analyses simultaneously. The results were essentially similar
when waist circumference was replaced by BMI and systolic blood
pressure by diastolic blood pressure and LDL cholesterol replaced
by total cholesterol (data not shown). Analysis of covariance
(baseline Cdist and use of contraceptives as a covariate) was used
to assess Cdist change between men and women as well as to
calculate mean Cdist change between genders according to the
number of MetS components (0, 1, 2, 3 and ?4 components).
Statistical analyses were performed with SAS version 9.1 and
statistical significance inferred as a two-tailed P value ? 0.05.
3.1. Clinical characteristics
in 2001 ? 2007) of study subjects are shown in Table 1. Women had
higher Cdist compared to men in both study years. Decrease in Cdist
was similar between men and women (P ¼ 0.29). As shown in Fig.1,
Cdist decreased with age (P < 0.0001) in both genders. Cdist
decreased during 6-years in high-risk Cdist change individuals
vs. ?0.14 ? 0.02%/10 mmHg respectively).
3.2. Risk factors predicting 6-year change in Cdist
Correlation coefficients between risk factors and Cdist are
shown in online supplement Table 2. Increased adiposity measures,
blood pressure, glucose, triglycerides and insulin were associated
with reduced Cdist (all P values < 0.01). Fig. 1 (available in the
online supplement) shows graphically the association between
Cdist change and baseline waist circumference (P < 0.00001).
To assess the independent determinants of Cdist change, a multi-
variable regression model was constructed. The model included
triglycerides, LDL cholesterol, HDL cholesterol, CRP, insulin, smoking
waist circumference (b ? SEM ¼ ?0.005 ? 0.002, P ¼ 0.009) and
in Table 3 (available in online supplement). Further, all risk factors
were regressed simultaneously against dichotomous high-risk Cdist
change (age and gender specific 6-year change in Cdist ?10th
percentile). Only waist circumference (odds ratio, 95% confidence
interval ¼ 1.05,1.03e1.07, P < 0.0001) remained significantly associ-
ated with high-risk Cdist change (results available in online supple-
ment Table 4).
Finally, we assessed whether the 6-year changes in risk factors
were associated with continuous Cdist change in a multivariable
model. Increase inwaist circumference (b ? SEM ¼ ?0.016 ? 0.003,
(b ? SEM ¼ ?0.005 ? 0.002, P ¼ 0.006) remained independently
associated with decreased Cdist during 6-year follow-up. Results
for HOMA-IR were essentially similar with insulin. Correlation
coefficient between HOMA-IR and insulin was 0.92, P > 0.0001.
3.3. Differences in Cdist change between men and women
No age*gender interaction was observed in Cdist change
(P ¼ 0.11). As shown in Fig. 2, a significant decreasing trend in Cdist
was observed with increasing number of MetS risk factors in
women but not in men (P for interaction 0.02). In addition, we
cardiovascular risk factors (age, waist circumference, BMI, blood
pressure, total-, LDL- and HDL cholesterol, triglycerides, glucose,
insulin, CRP, smoking and family history of CVD) and Cdist change.
Baseline characteristics and Cdist data of the study population.
Number of subjects
Waist circumference (cm)
Body mass index (kg/m2)
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg) 73 ? 11
Total cholesterol (mmol/l)
LDL cholesterol (mmol/l)
Apolipoprotein B (g/l)
Apolipoprotein A1 (g/l)
Plasma glucose (mmol/l)
C-reactive protein (mg/l)
Daily smoking (%)
Metabolic syndrome (%)
Cdist 2001 (%/10 mmHg)
Cdist 2007 (%/10 mmHg)
Cdist change (%/10 mmHg)
31.9 ? 5.0
90 ? 11
25.7 ? 4.0
121 ? 12
32.0 ? 4.9
79 ? 11
24.4 ? 4.5
112 ? 12
69 ? 10
5.08 ? 0.93
3.16 ? 0.76
1.41 ? 0.31
5.24 ? 1.03
3.43 ? 0.92
1.15 ? 0.27
1.29(0.90e1.80) 1.05(0.80e1.35) <0.0001
1.13 ? 0.29
1.39 ? 0.21
0.99 ? 0.24
1.55 ? 0.26
2.00 ? 0.02
1.73 ? 0.02
?0.26 ? 0.02
2.33 ? 0.03
2.03 ? 0.02
?0.31 ? 0.03
Data are mean ? SD or median (interquartile range) for continuous variables, and
percentages for dichotomous variables.
Total of 253 women (27% of women) were using oral contraceptives in 2001.
24 2730333639 4245
Carotid artery distensibility (%/10mmHg)
Women in 2001
Women in 2007
Men in 2001
Men in 2007
Fig. 1. Carotid artery distensibility values (Mean ? SEM) in 2001 and 2007.
J. Koskinen et al. / Atherosclerosis 224 (2012) 474e479
In these analyses, a significant gender*glucose interaction was
observed (P ¼ 0.03). In women, increase in glucose was associated
with decrease in Cdist (b ¼ ?0.074 ? 0.025, P ¼ 0.004), whereas in
men the association was non-significant (b ¼ 0.008 ? 0.028,
P ¼ 0.78). The glucose levels increased during the 6-year follow-up
among both genders (mean [mmol/l] ? SE: 0.29 ? 0.03 and
0.27 ? 0.03 respectively, P for difference 0.44).
contribute to the impairment of arterial properties assessed by
Cdist in young adults. In this cohort, baseline and 6-year change in
waist circumference, baseline insulin and change in systolic blood
pressure were independently associated with 6-year decrease in
Cdist. We could also demonstrate that gender modified the asso-
ciation between glucose and Cdist change as well as the association
between increasing number of MetS risk factors and Cdist change.
Decreased Cdist is associated with cardiovascular risk factors
and has been implicated as a predictor forcardiovascular events .
In the present study, we demonstrate that baseline and 6-year
change in waist circumference had a strong association with
impaired Cdist in multivariable models. In line, we have previously
shown cross-sectional association between central obesity and
Cdist  and that childhood adiposity was associated with
decreased Cdist in adulthood . Central obesity in particular may
predispose to hypertension, development of insulin resistance,
systemic inflammation and several other cardio-metabolic risk
factors . Further, central obesity is a strong predictor for
increased risk of atherosclerosis, myocardial infarction and death.
These observations maysuggest that increased waist circumference
is a risk marker that reflects long-term deviations in several cardio-
metabolic risk variables. Further, we have previously shown that
beneficial changes in Cdist were associated with weight loss which
in turn independently correlated with increased physical activity
and increased attention paid to health habits . Our data suggest
that intervention against adverse lifestyle in young adulthood
might limit atherosclerosis.
An increase in systolic blood pressure was associated with
decrease in Cdist, suggesting that intrinsic changes of the carotid
artery maybe modified byhypertension. However, several previous
studies have concluded than the decrease in large artery distensi-
bility observed in hypertensive patients is due primarily to
a mechanical responseof the arterial walls tothe pressure elevation
rather than structural changes [17,18]. In line with these data, we
found no significant association between baseline blood pressure
or change in diastolic blood pressure and Cdist change.
We also demonstrated that plasma insulin predicted impaired
Cdist during the 6-year follow-up period. In line, we have previ-
ously shown that insulin predicted accelerated subclinical athero-
sclerosis assessed by carotid intima-media thickness that may also
accompany impaired arterial elasticity . Further, evidence from
large scale meta-analyses examining longitudinal relationship
between plasma insulin and cardiovascular disease suggest that
hyperinsulinemia is associated with increased cardiovascular
morbidity, independently of other cardiovascular risk factors
[20,21]. Insulin resistance leads to hyperinsulinemia to maintain
euglycemia, thus, hyperinsulinemia may be a surrogate marker of
insulin resistance which we were not able to measure. Various
mechanisms have been hypothesized by which hyperinsulinemia
could promote atherosclerosis . However, it has been suggested
that the association of hyperinsulinemia with cardiovascular
disease is at least partly mediated by the clustering of several risk
factors caused by insulin resistance .
We found that an increase in glucose was associated with Cdist
regression only in women in multivariable models. This strong
association in women is of interest due to previous studies
reporting that type 2 diabetes increases the risk for stroke and
coronary heart disease in women to a greater extent than in men
[24,25]. This association may be explained by the concomitant
disorders that are more common in diabetic women than in men
[24,25]. Possible mechanisms may also include decreased heart-
rate variability due to impaired Cdist that has been found to be
more pronounced in women in the presence of multiple cardio-
metabolic risk factors. In line, we observed accelerated decrease
in Cdist according to increasing number of metabolic risk factors in
women but not in men . Results in previous cross-sectional
studies have shown significant associations between MetS and
decreased arterial elasticity in women but not in men [27,28]. Our
observations suggest that women may be more vulnerable to the
atherogenic effects of cardio-metabolic risk factor clustering and
especially to hyperglycemia already in young adulthood compared
to men. Both insulin resistance and obesity have been associated
with lower estrogen concentrations and hyperandrogenicity thus
decreasing their protective effect on the vasculature inwomen .
The adverse effects of low estrogen in turn include alterations in
circulating lipoproteins, glucose, insulin and blood pressure . In
addition, follicle stimulating hormone has been found to correlate
inversely with arterial elasticity  by increasing vascular smooth
muscle tone and growth . However, in the present study cohort
only one woman reported being in the menopausal phase of the
climacterium. It is also possible that part of the risk associated with
decreased Cdist in women is mediated by some unmeasured
factors. Potential candidates may include the loss of gluteofemoral
fat by increasing age. Population studies have shown that an
increased gluteofemoral fat is independently associated with
a protective lipid and glucose profile, as well as a decrease in
cardiovascular and metabolic risk .
Common carotid artery distensibility measured by B-mode
ultrasound have been studied and relatedtoall-cause mortalityand
cardiovascular events [6e8,33e35]. Blacher et al. related carotid
stiffness to total mortality in a study of hemodialysis patients 
and Barenbrock et al. reported an independent association with
Change in Cdist 2001-2007 (%/10mmHg)
P for trend 0.18
P for trend 0.0001
P for interaction 0.02
Number of metabolic syndrome components in 2001
Fig. 2. Changeincarotid arterialdistensibility(Cdist) inmen andwomenbetween2001
and 2007 according to increasing number of metabolic syndrome components: waist
circumference ?102 for men and ?88 cm for women, triglycerides ?1.695 mmol/l,
HDL-cholesterol <1.036 mmol/l in men or <1.295 mmol/l in women, blood pressure
?130/?85 mmHg, fasting glucose ?5.6 mmol/l.
J. Koskinen et al. / Atherosclerosis 224 (2012) 474e479
cardiovascular events in a study of 68 renal transplant recipients
. With respect to aortic distensibility, Stefanidis et al. studied 54
patients with coronary artery disease and reported that increased
aortic distensibility was associated with reduced coronary risk .
SMART study reported an inverse relationship between carotid
distension and prevalent ischemic stroke and transient ischemic
attack in patients with internal carotid artery stenosis . Haluska
et al. showed that measuring carotid artery distensibility is inde-
pendently correlated with fatal and non-fatal events in patients
with varying degrees of cardiovascular risk. Findings in a large
population-based elderly cohort showed that the increase in
carotid distension was significantly predictive of CHD occurrence.
These data suggest that reduced arterial elasticity is not only age-
related, but also reflects increased atherosclerotic burden. The
implications of Cdist inpopulation-based samples, however,arenot
entirely clear, and more studies are needed to confirm the role of
Cdist change as an indicator of a clinical atherosclerotic disease. In
addition the relatively high CV of the technique may preclude its
use for longitudinal assessmentof individual patients in the routine
clinic setting. Another widely used method assessing arterial
function in the measurement of pulse wave velocity (PWV). The
relationship between PWV and Cdist observed in recent study by
Koivistoinen et al. suggests that these two independent methods
for estimating arterial elasticity are, at least to a degree, represen-
tatives of a similar adverse process in the vascular wall . It is
suggested, that PWV reflects a different aspect of vascular damage
than flow-mediated dilatation or intima-media thickness in young
adults, whereas in older adults the information provided by PWV
and IMT may be, to some extent, similar as regards subclinical
vascular damage . In line, in the present study cohort pulse
wave velocity and Cdist correlated strongly and the associations
between these two methods and risk factors were similar.
Our study has limitations. Accurate assessment of Cdist requires
the determination of several variables, including arterial diameter
and blood pressure measurements. Therefore, long-term variation
for Cdist was somewhat high (CV ¼ 14.3%) and the non-significant
associations in Cdist change when assessing risk factors should be
interpreted cautiously. Similar variations are also observed in
previous reports . For comparison, the coefficient of variations
was better for intima-media thickness (6.5%) but worse for flow-
mediated dilatation (26.0%) in the present study cohort. The
reproducibility of distensibility measurements may be improved by
the use of computerized edge-detection analysis of sequential
image frames . However, small variation in the carotid artery
diameter measurements suggests that much of the long-term
variation in Cdist is due to physiological fluctuation and not to
measurementerror . Anotherlimitation in measuring Cdist is the
lack of a method to determine blood pressure i.e. pulse pressure at
the site of measurement. The use of brachial pressures may over-
estimate pulse pressure in central arteries. This increase is
a consequence of pulse-wave reflection from the periphery, which
amplifies the peak of the pressure wave in peripheral arteries close
to the reflection sites. Pulse-wave reflection is closely related to age
and therefore, the difference between central and peripheral pulse
pressure is likely to be similar between study subjects within
a narrow age range, as in the present study .
There is controversy regarding the effect of measurement error
bias in analysesevaluating change invariablewith baseline variable
used as a covariate . However, we have previously shown that
the results from analyses correcting for measurement error bias
were quite similar to those obtained from the models adjusted for
baseline variable . Another potential limitation of our study was
selection bias due to lost-to follow-up. However, baseline charac-
teristics in 1980 were virtually similar between participants and
non-participants, and study cohort seems to be representative of
the original study population . Because our study cohort was
racially homogenous, the generalizability of our results is limited to
white European subjects.
In conclusion, we found that conventional risk factors are
associated with accelerated decrease in Cdist independent of age.
Our observations suggest an important pathophysiological role for
adiposity in predicting decreased arterial function development in
young adults. Moreover, our data suggests that women may be
more vulnerable to the atherogenic effects of glucose and increased
risk factor burden already at relatively young age.
No conflict of interest declared.
Sources of funding: This study was financially supported by the
Academy of Finland (grant no. 126925, 121584, 124282, 129378,
117797, 41071), the Social Insurance Institution of Finland, Kuopio,
Tampere and Turku University Hospital Medical Funds, the Finnish
Foundation of Cardiovascular Research, the Turku University
Foundation, Turku University, Juho Vainio Foundation, the Lydia
Maria Julin Foundation, Aarne and Aili Turunen Foundation, Finnish
Medical Foundation, Paavo Nurmi Foundation, Finnish Cultural
Foundation, Emil Aaltonen Foundation, Sigrid Juselius Foundation
and Tampere Tuberculosis Foundation, Orion-Farmos Research
Appendix A. Supplementary data
Supplementary data related tothis article can be found online at
 Juonala M, Järvisalo MJ, Mäki-Torkko N, Kähönen M, Viikari JS, Raitakari OT.
Risk factors identified in childhood and decreased carotid artery elasticity in
adulthood: the cardiovascular risk in young Finns study. Circulation 2005;
 Avolio A, Jones D, Tafazzoli-Shadpour M. Quantification of alterations in
structure and function of elastin in the arterial media. Hypertension 1998;32:
 Oliver JJ, Webb DJ. Noninvasive assessment of arterial stiffness and risk of
atherosclerotic events. Arterioscler Thromb Vasc Biol 2003;23:554e66.
 Mattsson N, Rönnemaa T, Juonala M, Viikari JS, Jokinen E, Hutri-Kähönen N,
et al. Arterial structure and function in young adults with the metabolic
syndrome: the cardiovascular risk in young Finns study. Eur Heart J 2008;29:
 Mitchell GF, Hwang SJ, Vasan RS, Larson MG, Pencina MJ, Hamburg NM, et al.
Arterial stiffness and cardiovascular events: the Framingham heart study.
 Leone N, Ducimetiere P, Gariepy J, Courbon D, Tzourio C, Dartigues JF, et al.
Distension of the carotid artery and risk of coronary events: the three-city
study. Arterioscler Thromb Vasc Biol 2008;28:1392e7.
 Blacher J, Pannier B, Guerin AP, Marchais SJ, Safar ME, London GM. Carotid
arterial stiffness as a predictor of cardiovascular and all-cause mortality in
end-stage renal disease. Hypertension 1998;32:570e4.
 Haluska BA, Jeffries L, Carlier S, Marwick TH. Measurement of arterial
distensibility and compliance to assess prognosis. Atherosclerosis 2010;209:
 Koskinen J, Magnussen CG, Taittonen L, Räsänen L, Mikkilä V, Laitinen T, et al.
Arterial structure and function after recovery from the metabolic syndrome:
the cardiovascular risk in young Finns study. Circulation 2010;121:392e400.
 De Angelis L, Millasseau SC, Smith A, Viberti G, Jones RH, Ritter JM, et al. Sex
differences in age-related stiffening of the aorta in subjects with type 2 dia-
betes. Hypertension 2004;44:67e71.
 Redfield MM, Jacobsen SJ, Borlaug BA, Rodeheffer RJ, Kass DA. Age- and
gender-related ventricular-vascular stiffening: a community-based study.
 Waddell TK, Dart AM, Gatzka CD, Cameron JD, Kingwell BA. Women exhibit
a greater age-related increase in proximal aortic stiffness than men. J Hyper-
J. Koskinen et al. / Atherosclerosis 224 (2012) 474e479