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European Heart Journal Advance Access originally published online on December 12, 2007
European Heart Journal 2008 29(9):1198-1206; doi:10.1093/eurheartj/ehm556
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org

Effect of age and sex on carotid intima-media thickness, elasticity and brachial endothelial function in healthy adults: The Cardiovascular Risk in Young Finns Study

Markus Juonala1,*, Mika Kähönen4, Tomi Laitinen8, Nina Hutri-Kähönen5, Eero Jokinen9, Leena Taittonen7, Matti Pietikäinen6, Hans Helenius2, Jorma S.A. Viikari1 and Olli T. Raitakari3

1 Department of Medicine, University of Turku, PO Box 52, 20521 Turku, Finland
2 Department of Biostatistics, University of Turku, Finland
3 Department of Clinical Physiology, University of Turku, Finland
4 Department of Clinical Physiology, University of Tampere, Finland
5 Department of Paediatrics, University of Tampere, Finland
6 Center of Social and Health Services, City of Kuopio, Finland
7 Department of Paediatrics, Vaasa Central Hospital, Finland
8 Department of Clinical Physiology, University of Kuopio, Finland
9 Department of Paediatrics, University of Helsinki, Finland

Received 28 February 2007; revised 8 October 2007; accepted 31 October 2007; online publish-ahead-of-print 12 December 2007.

* Corresponding author. Tel: +358 2 3130503, Fax: +358 2 3337270, Email: mataju{at}utu.fi


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Funding
 Acknowledgements
 References
 
Aims: The objective was to produce reference values and to analyse the associations of age and sex with carotid intima-media thickness (IMT), carotid compliance (CAC), and brachial flow-mediated dilatation (FMD) in young healthy adults.

Methods and results: We measured IMT, CAC, and FMD with ultrasound in 2265 subjects aged 24–39 years. The mean values (mean ± SD) in men and women were 0.592 ± 0.10 vs. 0.572 ± 0.08 mm (P < 0.0001) for IMT, 2.00 ± 0.66 vs. 2.31 ± 0.77%/10 mmHg (P < 0.0001) for CAC, and 6.95 ± 4.00 vs. 8.83 ± 4.56% (P < 0.0001) for FMD. The sex differences in IMT [95% confidence interval (CI) for sex difference –0.013 to 0.004 mm, P = 0.37] and CAC (–0.01 to 0.18%/10 mmHg, P = 0.09) became non-significant after adjustments with risk factors and carotid diameter. In FMD, the sex difference was unaltered after adjustments for risk factors, but was reversed after adjustment with brachial diameter (95% CI 0.18–1.32%, P < 0.01). With aging, IMT increased 5.7 ± 0.4 µm/year and CAC decreased 0.042 ± 0.003%/10 mmHg/year. The association of age with IMT and CAC was slightly attenuated (12 and 22%, respectively) after adjustments with risk factors, but remained significant (both P < 0.0001). Aging was not significantly related to brachial FMD (P = 0.16).

Conclusion: Reference values produced in the present study can be utilized in the cardiovascular risk stratification among young people. Sex differences in the markers of subclinical atherosclerosis were mostly explained by differences in risk factors and vessel size. This emphasizes the importance of risk factor control in the prevention of atherosclerosis in young adults.

Key Words: Endothelial function • Intima-media thickness • Arterial elasticity • Reference values


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Funding
 Acknowledgements
 References
 
To prevent manifestations of atherosclerosis, it would be important to recognize high-risk subjects with advanced pre-clinical disease. Therefore, screening for subclinical atherosclerosis has been endorsed. The AHA Prevention Conference V concluded that in asymptomatic persons >45 years, carotid intima-media thickness (IMT) measurement can add incremental information to risk factor assessment.1 In the European guidelines, carotid artery plaque detection was mentioned in risk assessment.2 In a recent summary of the SHAPE Task Force Report,3 new guidelines were introduced for cardiovascular screening in asymptomatic populations. In this report, authors expressed their opinion that primary prevention should be focused based on the assessment of subclinical atherosclerosis, not only risk factors. However, it remains uncertain how realistic this vision is. Large scale screening for subclinical atherosclerosis is not part of everyday practice. Reasons for this include uncertainty about the incremental predictive value of these measures, lack of technical standardization, complexity of non-invasive vascular measurements needing well-educated personnel, and the lack of data that interventions based on these tests improve cardiovascular outcomes. Furthermore, one important reason limiting their widespread applicability is the lack of normative values in healthy subjects.

Increased carotid IMT is a marker of structural atherosclerosis. It correlates with cardiovascular risk factors,4 the severity of coronary atherosclerosis,5 and predicts cardiovascular events.6 Decreased carotid elasticity represents early functional atherosclerosis. It has been implicated as an independent predictor for cardiovascular mortality in high-risk individuals.7 A non-invasive ultrasound technique to evaluate brachial artery flow-mediated dilatation (FMD) can be used to study endothelial function.8 Impaired FMD predicts cardiovascular events,9 and preserved endothelial function is associated with favourable cardiovascular outcome.10

In the previous reports from the Young Finns Study, we have shown that elevated LDL-cholesterol and blood pressure, obesity, smoking, and positive family history for cardiovascular disease predict increased carotid IMT and decreased elasticity.4,11,12 We have also shown that brachial FMD response is directly related with HDL-cholesterol and indirectly with blood pressure.13,14 Furthermore, there is an inverse relation between brachial FMD and carotid IMT in the Young Finns data. FMD status also seems to modify the effects of conventional risk factors on IMT.13 Therefore, these non-invasive measurements may provide valuable information on preclinical atherosclerosis in asymptomatic young adults.

To gain insight for the reference values for carotid IMT, carotid elasticity, and brachial FMD in young adults, we have analysed their distributions among 2265 men and women aged 24–39 years. In addition, we have studied the associations of sex and age with these early markers of atherosclerosis.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Funding
 Acknowledgements
 References
 
Subjects in the Young Finns Study
The Cardiovascular Risk in Young Finns Study is a follow-up study of atherosclerosis precursors in Finnish children and adolescents. The first cross-sectional study was conducted in 1980. The study has been carried out in all five Finnish university cities with medical schools (Helsinki, Kuopio, Oulu, Tampere, Turku) and their rural surroundings. In 1980, altogether 4320 children and adolescents born in 1962, 1965, 1968, 1971, 1974, and 1977, i.e. aged 3–18 years, were randomly chosen from the national population register of these areas to produce a representative sample of Finnish children. Of these subjects, a total of 3596 boys and girls participated in the cross-sectional study in 1980. In 2001, all the subjects who had taken part in the field study in 1980 and had a valid address in Finland (N = 3456) were invited to the 21-year follow-up. Altogether 2283 of these individuals, now aged 24, 27, 30, 33, 36, or 39 years, participated in the physical examination. Of these subjects, 18 subjects refused to take part in ultrasound studies. Therefore, data on carotid or brachial artery ultrasound studies were available for 2265 subjects. The study was approved by ethical committee and subjects gave their informed consent.

Clinical characteristics and risk factors
Height and weight were measured, and BMI was calculated.15 Waist circumference was measured with an accuracy of 0.1 cm. Blood pressure was measured with a random zero sphygmomanometer. Average of three measurements was used in the analysis. Smoking habits were inquired with a questionnaire. Those smoking daily were considered current smokers. For the determination of serum lipoprotein levels, venous blood samples were drawn after an overnight fast. All determinations were done using standard methods.15 Serum insulin was measured by microparticle enzyme immunoassay kit (Abbott Laboratories, Diagnostic Division, Dainabot, Japan).

Ultrasound imaging
Carotid and brachial artery ultrasound studies were performed using Sequoia512 ultrasound mainframes (Acuson, Mountain View, CA, USA) with 13.0 MHz linear array transducer, as previously described.4,13 The digitally stored scans were manually analysed by one reader blinded to subjects’ details (M.J.). To assess intra-individual reproducibility of ultrasound measurements, 57 subjects were re-examined 3 months after the initial visit (2.5% random sample).

Carotid intima-media thickness
To measure carotid IMT, the image was focused on the posterior (far) wall of the left carotid artery. At least four measurements of the far wall were taken approximately 10 mm proximal to the bifurcation to derive mean and maximum carotid IMT. The between-visit coefficient of variation (CV) of IMT measurements was 6.4%.4 Carotid artery structure was further characterized by calculating the cross-sectional area of intima-media layer using formula: {pi}*[(IMT+baseline diameter/2)2–(baseline diameter/2)2]. Carotid bulb area could be scanned in 1777 subjects. In the carotid bulb area, three far wall measurements were performed to derive mean and maximum IMT.

Carotid elasticity
Several moving image clips of the beginning of the carotid bifurcation and the common carotid artery with duration of 5 s were acquired and stored in digital format for subsequent offline analysis. From the clip images, the best quality cardiac cycle was selected. The carotid diameter was measured at least twice (spatial measurements) in end-diastole and end-systole, respectively. The mean of the measurements was used as the end-diastolic or end-systolic diameter. Blood pressure was measured during the ultrasound study with an automated sphygmomanometer (Omron M4, Omron Matsusaka Co., Ltd, Japan). Ultrasound and concomitant brachial blood pressure measurements were used to calculate the following indices of arterial elasticity: carotid compliance (CAC) =[(Ds–Dd)/Dd]/(Ps–Pd), Young’s elastic modulus; YEM=[(Ps–Pd)*Dd]/[(Ds–Dd)/IMT] and stiffness index; SI=ln(Ps/Pd)/[(Ds–Dd)/Dd], where Dd is the diastolic diameter; Ds, the systolic diameter; Ps, systolic blood pressure; and Pd, diastolic blood pressure. The between-visit coefficient of variation was 2.7% for diastolic diameter, 16.3% for CAC, 19.5% for YEM, and 16.6% for SI.11

Brachial flow-mediated dilatation
Brachial artery ultrasound studies were performed successfully for 2109 subjects.13 A total of 147 scans were excluded due to insufficient image quality and 9 subjects with data on carotid artery studies refused to participate in the FMD test.

To assess brachial FMD, the left brachial artery diameter was measured at rest and during reactive hyperaemia. Increased flow was induced by inflation of a pneumatic tourniquet placed around the forearm to a pressure of 250 mmHg for 4.5 min, followed by a release.13 Three measurements of arterial diameter were performed at end-diastole at a fixed distance from an anatomic marker at rest and 40, 60, and 80 s after cuff release. The vessel diameter in scans after reactive hyperaemia was expressed as the percentage relative to resting scan. The average of three measurements at each time point was used to derive the maximum FMD (the greatest value between 40 and 80 s). The between-visit CV for brachial diameter was 3.2% and for FMD 26.0%.13

Statistical methods
To produce reference values for ultrasound variables, we plotted each variable against age separately for men and women. As suggested by the figures, the residuals from the regression analysis were on some occasions non-normal. Therefore, to avoid a possible bias due to asymmetry in the deviation of ultrasound variables, the sex-specific and age-dependent 95% reference limits with 95% confidence intervals (CIs) were constructed by first applying the Box-Cox transformation and then using technique described by Virtanen et al.16 More specifically, calculations were made separately for men and women. The age-dependency was solved by using simple regression model, where age was an explanatory variable and the ultrasound variable was the response variable. First, this kind of regression model was used to search for the response variable an optimal Box-Cox transformation (1/square-root transformation for IMT, square-root transformation for CAC, untransformed values for FMD), which led to the most nearly normal distribution for the residuals. This was done using procedure TRANSREG in SAS-software. The regression model with age as the explanatory variable and transformed ultrasound variable as the response variable was fitted. The 95% reference limits for each age were then calculated using fitted value of the regression value as the estimate of mean in specific age and by calculating the estimates for 95% quantile of normal distribution. Finally, the CIs for the quantile were calculated.

In group comparisons, the differences between men and women were studied using t-test or {chi}2 test. To study whether the sex differences in ultrasound variables were independent of conventional risk factors and vessel diameter, we used linear regression models. At first, we studied the impact of risk factors one by one, and finally constructed a model including all the risk factors. In these analyses, those risk factors that correlate with ultrasound variables in this cohort were included.4,11,13

The association of age with ultrasound markers was studied using linear regression analysis. Further, multivariate linear regression models were used to examine whether the associations between age and ultrasound variables were similar between men and women. The models included each ultrasound variable as the outcome variable and age, sex, and age*sex interaction term as independent variables.

The difference in FMD values measured 40, 60, or 80 s after cuff release was examined using repeated measures of analysis of variance with post hoc comparisons with Tukey’s test.

All the analyses were repeated after exclusion of subjects using antihypertensive treatments (N = 54) or cholesterol-lowering medication (N = 7) and pregnant subjects (N = 62) with essentially similar results. The statistical tests were performed with SAS version 8.1, and statistical significance was inferred at a two-tailed P-value <0.05.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Funding
 Acknowledgements
 References
 
The characteristics of study subjects are shown in Table 1.


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  		Table 1 Characteristics of study population

 
Carotid intima-media thickness
Men had significantly greater IMT in common carotid and carotid bulb area compared to women (Table 2, Figure 1). This sex difference was attenuated after adjustment with conventional risk factors and baseline carotid diameter, 95% CI for sex difference was –0.013 to 0.004 mm, P = 0.37 (Figure 2). Waist circumference had the largest diluting effect. The results were similar when only risk factors, not carotid diameter, were included to the analysis (P = 0.40), and when waist circumference was replaced with BMI (P = 0.32). IMT increased significantly with age, both in men, 6.3 ± 0.6 µm/year (P < 0.0001), and in women, 5.2 ± 0.5 µm/year (P < 0.0001). There was no significant age*sex interaction in IMT (P = 0.15). The association between age and IMT was slightly attenuated (12% reduction in the regression coefficient) after adjustment with risk factors and vessel diameter, but remained significant (P < 0.0001). The reference limits for IMT are shown in Table 3.


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  		Table 2 Mean values of carotid and brachial ultrasound measures

 

Figure 1
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  		Figure 1 Scatter-plot of mean carotid intima-media thickness. Lines represent estimated mean, and 2.5% and 97.5% reference limits.

 

Figure 2
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  		Figure 2 Carotid intima-media thickness in men and women adjusted separately with smoking, LDL-cholesterol, carotid diameter, systolic blood pressure or waist circumference, and finally with all these.

 

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  		Table 3 Reference limits (2.5% and 97.5%) and their 95% confidence intervals for ultrasound measures

 
Carotid elasticity
Men had significantly lower CAC and higher YEM and SI, compared to women (Table 2, Figure 3). The sex difference in CAC was attenuated after adjustments with risk factors and arterial diameter, 95% CI for sex difference was –0.01 to 0.18%/10 mmHg, P = 0.09 (Figure 4). CAC decreased 0.04 ± 0.004%/10 mmHg/year both in men and in women (both P < 0.0001). YEM and SI increased significantly with age (P < 0.0001). There was no significant age*sex interaction in CAC (P = 0.97). The association between age and CAC was slightly attenuated (22% reduction in the regression coefficient) after adjustment with risk factors and vessel diameter, but remained significant (P < 0.0001). The reference limits for CAC are shown in Table 3.


Figure 3
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  		Figure 3 Scatter-plot of carotid artery compliance. Lines represent estimated mean, and 2.5% and 97.5% reference limits.

 

Figure 4
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  		Figure 4 Carotid artery compliance in men and women adjusted separately with insulin, LDL-cholesterol, systolic blood pressure or carotid diameter, and finally with all these.

 
Brachial flow-mediated dilatation
Men had significantly lower FMD values compared to women, but there was no significant difference in absolute diameter change (Table 2, Figure 5). When FMD values were adjusted with baseline brachial diameter, males had significantly higher FMD values (Figure 6). To examine the sex difference in more detail, we randomly selected 224 pairs of men and women matched for identical baseline brachial diameter values and compared their FMD values. In this subgroup, FMD values (mean ± SD) in men were significantly higher compared to women (8.24 ± 4.72 vs. 7.07 ± 4.72%, respectively, P = 0.004, paired t-test). The result was similar after adjustment with risk factors.


Figure 5
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  		Figure 5 Scatter-plot of brachial flow-mediated dilatation. Lines represent estimated mean, and 2.5% and 97.5% reference limits.

 

Figure 6
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  		Figure 6 Brachial flow-mediated dilatation in men and women adjusted separately with waist circumference, HDL-cholesterol, systolic blood pressure or brachial diameter, and finally with all these.

 
Scatter-plots of brachial FMD values according to baseline brachial diameter are shown in Figure 7. Both in men and women, FMD correlated inversely with baseline diameter (P < 0.0001). Age was not significantly related with brachial FMD (β=0.03 ± 0.02%, P = 0.16). In both sexes, the highest FMD values were measured 40 s after cuff release. The difference between FMD at 40 s and FMD at 60 s was 0.13 percent units (95% CI 0.03–0.23%, P = 0.02), and the difference between FMD at 40 s and FMD at 80 s was 0.97 percent units (95% CI 0.88–1.06%, P < 0.0001). The reference limits for FMD are shown in Table 3.


Figure 7
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  		Figure 7 Scatter-plot of flow-mediated dilatation values according to baseline brachial diameter. Lines represent estimated mean, and 2.5% and 97.5% reference limits.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Funding
 Acknowledgements
 References
 
We observed that men and older subjects had increased IMT and decreased elasticity. The sex difference in IMT could be completely explained by differences in cardiovascular risk factor levels between men and women, especially by differences in obesity indices and blood pressure. Similarly, the difference in elasticity was totally attenuated after adjustment with risk factors and carotid diameter. These findings suggest that in young subjects modifiable risk factors are important in determining vascular health.

As in other studies, FMD values were significantly higher in women.17,18 However, the absolute diameter change during the test did not significantly differ between sexes. When the FMD values were adjusted with baseline diameter, men actually had significantly higher values. This result remained the same when we compared pairs of men and women with identical baseline diameters. Whether this observation reflects possible sex differences in nitric oxide production remains to be established. The practical implication is that the higher FMD (%) values observed in women are mostly due to smaller baseline diameters, so that only the relative change in arterial diameter is higher in women.18 In line, our present results and previous reports18–20 have shown that brachial FMD correlates highly significantly with baseline diameter. Therefore, brachial size and sex-specific reference values should be used for brachial FMD in young adults.

We observed that FMD values were the highest at 40 s after cuff release. In previous studies, the peak FMD has been detected at about 70 s after cuff release.21–23 However, study populations and sample sizes have been different in these studies. Altogether, instead of measuring only 60 s after cuff release, as has been conducted in several studies,8 the need for several diameter measurements during post-occlusion period should be emphasized in order to capture the maximal response.

Carotid IMT, elasticity, and brachial FMD are markers of subclinical atherosclerosis that predict cardiovascular events independent on conventional risk factors.7,9,24 Especially, the relationship between carotid IMT and cardiovascular events has been studied extensively. However, the relationship between carotid elasticity, brachial FMD, and cardiovascular events is much less clear, and thus their clinical use is still controversial. Although the measurements of carotid IMT have been recommended as a tool in primary prevention in consensus statements, no guidelines have called for use of these tests in clinical practice.3,25 In addition, there is no consensus concerning what is an abnormal finding in the assessment of subclinical atherosclerosis. Therefore, reference values produced in the present large population-based cohort of young adults are useful in determining the cut-off points between normal and abnormal IMT.

In addition to screening for abnormal values, an alternative way to utilize the reference values in cardiovascular risk stratification is using the vascular age concept.26 This means that risk assessment using algorithms could be calculated using individual’s vascular age derived from the carotid IMT measurements instead of biological age. For example, in the present study population, a 27-year-old man with IMT of 0.63 mm is actually at the mean level for 39-year-old subjects—therefore, his vascular age is 39 years.

Study limitations
One limitation of the present study is the narrow age range of our population. Our data consists of white European subjects, and therefore the results may not be generalized to other ethnic groups. However, comparable to our results, in the Bogalusa Heart Study mean IMT in white Bogalusa women aged 27–43 years was 0.644 mm and in men 0.668 mm.27 Ultrasound measurements were performed manually, and not with automated systems, but the reproducibility values from our laboratory are comparable with other reports.28–30 Due to logistic reasons, we measured carotid IMT only in the common carotid artery and in the carotid bulbus, and not in the internal carotid artery, which may be more sensitive to develop atherosclerosis.6 Furthermore, endothelium independent nitrogen-mediated dilation responses were not measured in the brachial artery test.

The reproducibility of IMT measurements was good (CV 6%). We found relatively large within-subject long-term variation in CAC11 and FMD measurements,13 which are, however, in agreement with previous reports.31–33 Large variation in CAC is, in part, due to the fact that several variables including arterial diameter and blood pressure measurements are used to derive this index. Nevertheless, the long-term reproducibility of the carotid and brachial diameter measurements was excellent. This suggests that much of the variation of CAC and FMD is due to physiological fluctuation and not to measurement error. In line, several factors may affect FMD variation.8 Finally, one potential limitation is the non-participation in the follow-up study. We have previously shown, however, that baseline risk factors (in 1980) are similar among participants and dropouts in the 21-year follow-up.15 Thus, the present study cohort seems to be representative of the original study population.

Conclusions
The evaluation of structural and functional changes in arteries might be helpful in identifying individuals being at risk for developing clinical cardiovascular disease. Therefore, the reference values produced in the present study may have value in primary prevention of atherosclerotic diseases. We observed that sex differences in the markers of subclinical atherosclerosis were mostly explained by differences in conventional risk factors and vessel size. This points out to the importance of risk factor control in the prevention of atherosclerotic diseases in young adults.


   Funding
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
Acknowledgements
 References
 
This study was financially supported by the Academy of Finland (grants no. 77841, 210283, 121584, and 34316), the Social Insurance Institution of Finland, the Turku University Foundation, the Juho Vainio Foundation, Finnish Foundation for Cardiovascular Research, Research funds from the Tampere and Turku University Hospitals, the Research Foundation of Orion Corporation, and the Finnish Cultural Foundation.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
 Acknowledgements
References
 
We thank Irina Lisinen for skillful statistical assistance.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
 Acknowledgements
 References
 

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