Subjects and study design.
The AGAHLS is an observational longitudinal study that started in 1976 with a group of 450 boys and girls. Its initial goal was to describe the natural development of growth, health, and lifestyle of adolescents, and to investigate longitudinal relationships between biological and lifestyle variables. The mean age of the subjects at the beginning of the study was 13.1 (± 0.8) yr. Since then, for each individual, measurements have been obtained two to eight times during a 24-yr follow-up period (the repeated measurements were performed at the ages of 13, 14, 15, 16, 21, 27, 29, 32, and 36 yr). At each measurement, anthropometrical (body height, weight, and skinfolds), biological (serum lipoprotein levels, blood pressure, and physical fitness), lifestyle (nutritional habits, smoking behavior, and daily PA), and psychological variables were assessed. A more detailed description of the study is provided elsewhere (16). In the most recent measurement period (in 2000), when the subjects’ mean age was 36.5 (± 0.6) yr, large artery properties were investigated for the first time. Therefore, there are no repeated data available on large artery properties, whereas there are repeated data available on the potential determinants.
For the purpose of the present study, we have selected the group of subjects who had had at least three of the four possible cardiorespiratory fitness (and covariates) measurements during adolescence (i.e., at the ages of 13, 14, 15, and 16 yr) and subsequent evaluations of these variables at age 36 (75 men and 79 women). In this group, we have analyzed the relationship between changes in cardiorespiratory fitness from adolescence to age 36 and large artery properties at age 36. From these 154 subjects, we further investigated the relationships between changes in cardiorespiratory fitness from young adulthood to age 36 and large artery properties at the age of 36. These relationships were investigated only in the individuals who had had all the three cardiorespiratory fitness (and covariates) measurements at the ages of 21, 27, and 32 yr (a subset of 56 men and 62 women). The study was approved by the medical ethical committee of the VU University Medical Center, Amsterdam, The Netherlands, and all subjects gave their written informed consent (provided by the parents when subjects were 13–16 yr of age and by themselves from age 21 onward).
Throughout the years, cardiorespiratory fitness was measured in the same laboratory with the same protocol and equipment: a maximal running test on a treadmill (Quinton 18-54) with direct measurements of oxygen uptake (Ergoanalyzer, Jaeger, Bunnik, The Netherlands). Subjects were instructed to run at a constant speed of 8 km·h−1 while the slope of the treadmill increased every 2 min in a stepwise fashion and were encouraged to continue running to their maximum. A detailed description of this measurement is given elsewhere (17). Maximal oxygen uptake (V̇O2max) was used as a measure of cardiorespiratory fitness and its values expressed per kilogram of body mass raised to the two-thirds power (mL·min−1·kg−2/3) was used in the analyses. This allometric scale approach was used due to the high dependency of V̇O2max on body size during growth (35).
Properties of the right common carotid, femoral, and brachial arteries were obtained by two trained vascular sonographers with the use of a B+M-mode ultrasound scanner equipped with a 7.5-MHz linear array probe (Pie Medical, Maastricht, The Netherlands). The ultrasound scanner was connected to a personal computer equipped with an acquisition system and vessel wall movement detector software system (Wall Track System 2, Pie Medical). This integrated device enables measurements of arterial diameter, distension, and IMT as described in detail elsewhere (7,11). None the subjects considered in the analyses were taking medications. All subjects had abstained from smoking and caffeine-containing beverages, and had light food intake (i.e., fruit, bread, and low-fat dairy products) on the day the measurements were performed. At the time of arterial properties measurements subjects had been resting in a supine position for 15 min in a quiet, temperature-controlled room. The mean diameter, distension, and, for the carotid artery, IMT, of three consecutive measurements were used in the analyses. The carotid artery was measured approximately 10 mm proximal to the beginning of the bulb, the femoral artery 20 mm proximal to the flow divider, and the brachial artery approximately 20 mm above the antecubital fossa. The interobserver and coefficients of variation for the studied measurements were carotid IMT, 11.0%; diameter, 2.9% (carotid), 4.6% (brachial), and 2.8% (femoral); and distension, 6.4% (carotid), 27.7% (brachial), and 24.2% (femoral) (11). The corresponding values for the intraobserver variability were for observer 1 and 2, respectively: carotid IMT, 8.7% and 7.4%; diameter, 2.1% and 2.3% (carotid), 5.5% and 5.2% (brachial), and 2.7% and 2.2% (femoral); and distension, 4.4% and 7.1% (carotid), 18.2% and 18.5% (brachial), and 22.7% and 18.2% (femoral). Throughout the entire period of ultrasound imaging, systolic and diastolic blood pressure were assessed in the left arm at 5-min intervals with an oscillometric device (Colin Press-Mate, model BP-8800, Komaki City, Japan). Brachial artery pulse pressure was defined as systolic minus diastolic blood pressure, and pulse pressure at the common carotid and femoral arteries was calculated by calibration of the distension wave forms (34). Diameter (D) and distension (ΔD) as described above, and the mean pulse pressure (ΔP) of three measurements obtained at approximately the same time, were used to estimate the distensibility (DC) and compliance (CC) coefficients as follows:EQUATION EQUATION
Distensibility as defined above reflects the elastic properties of the artery, whereas the compliance reflects the buffering capacity of the artery. From IMT, diameter, and distensibility coefficient of the carotid artery, we calculated Young’s elastic modulus (Einc), an indicator of the intrinsic elastic properties of the vessel wall:EQUATION
We assessed in adolescence, young adulthood, and at age 36 the following variables: body height, body weight, body fatness, systolic (SBP) and diastolic (DBP) blood pressure, total serum cholesterol, HDL cholesterol fraction, resting heart rate, smoking status, and daily PA. Body fatness was expressed by the sum of the thickness of the biceps, triceps, subscapular, and suprailiac skinfolds (mm), measured with a Harpenden skinfold caliper (Holtain, UK). Sitting SBP and DBP (phase V) were measured twice with a sphygmomanometer (Speidl-Keller, Franken & Itallie, The Netherlands) and the lower value was recorded (mm Hg). Total and HDL cholesterol were measured from blood samples taken in the antecubital vein and expressed in millimoles per liter. Standard methods were used and external quality control took place with target samples from a World Health Organization reference laboratory. Resting heart rate was measured telemetrically (Telecust 36 and Sirecust BS1, Siemens, The Netherlands) after the subjects had been sitting on a chair for about 5 min (beats·min−1). Smoking status (yes/no) was assessed by questionnaire. Daily PA levels were assessed by a structured interview that covered the activities of the previous 3 months (17). In this interview, the intensity, frequency, and duration of all daily physical activities (at school, at work, in organized and unorganized sports, during leisure time, climbing stairs, and transportation) were assessed. Only those activities with duration of at least 5 min and intensity of more than four times the basal metabolic rate (METs) were considered. The physical activities were classified as light (4–7 METs), medium-heavy (7–10 METs), and heavy (>10 METs) based on values found in the literature. The averaged weekly time spent on the different activities was then multiplied by their intensity to calculate a total weighted activity metabolic score (expressed in metabolic equivalents—MET·wk−1).
Mean values (±SD) of V̇O2max and each covariate were calculated over the adolescence and young adulthood age periods for the subjects that met the inclusion criteria. Changes in V̇O2max (and covariates) were calculated for each individual by subtracting the mean value during adolescence or young adulthood from the value at age 36 (i.e., positive change indicates an increase and negative changes indicates a decrease in fitness or PA during the longitudinal period). We then used multiple linear regression analysis to investigate the relationships between changes in V̇O2max (main determinant) on the one hand and arterial properties (outcome variables) on the other. All relationships were analyzed first with adjustment only for gender (crude model) and second with additional adjustment for the following potential confounders: mean arterial pressure (as assessed by the oscillometric device), baseline values of V̇O2max, and absolute changes in the above-mentioned covariates (with exception for smoking status for which status at age 36 was used instead) (adjusted model). To evaluate the hypothesis that an increase in fitness (that, in turn, may have beneficial effects on arterial properties) can be caused by positive changes in PA levels, we have investigated the relationships between changes in PA on the one hand and arterial properties on the other. This was done first with adjustments as described above (adjusted model) and second with further adjustments for V̇O2max. If changes in V̇O2max are one of the mechanisms via which improvement of PA levels may have a beneficial effect on large artery properties, then this last adjustment is expected to result in a reduction of the regression coefficients. All the models described above were also adjusted for time of the day (morning/afternoon) and phase of the menstrual cycle (menstruated—yes/no, women only). As these adjustments have not materially changed any of the estimates of associations investigated herein, we have dropped these variables from of our models. We have not adjusted our analyses for food intake on the day the measurements were performed as this information was not available. After we had assessed the main effects, we added interactions between changes in V̇O2max and gender to the linear regression models. When the P value of the interaction term with gender was <0.10, stratified analyses were performed and results reported for men and women separately. All analyses were carried out with the Statistical Package of Social Sciences, 10.1 for Windows (SPSS, Inc, Chicago, IL).
Table 1 shows the mean values of V̇O2max and all covariates during adolescence and young adulthood and their respective changes to age 36. Overall, V̇O2max (mL·min−1·kg−2/3) decreased from adolescence to age 36 (in 70% of the subjects), whereas V̇O2max from young adulthood to age 36 increased (in 66% of the subjects). However, V̇O2max as expressed in absolute values (L·min−1) increased over time, particularly in men. Table 2 shows data on large artery properties at age 36. Results of the associations between changes in V̇O2max and large artery properties are further presented considering changes in V̇O2max scaled to body size (analyses with changes in V̇O2max as expressed in absolute values had similar results; data not shown).
Changes in V̇O2max and Carotid IMT
Changes in V̇O2max from adolescence to age 36 (Table 3) and from young adulthood to age 36 (Table 4) were not significantly associated with carotid IMT. To investigate whether the relationship between changes in V̇O2max and carotid IMT was or was not linear in the range of changes observed herein, we stratified changes in V̇O2max (from young adulthood to age 36) into three categories of equal size: “decrease,” “stable,” and “increase.” These categories were then included in the regression models as dummy variables, with the category “decrease” as reference, to investigate whether carotid IMT differed between these categories. We hypothesized that carotid IMT would be lower in the category “increase” as compared with the others. However, in crude analyses and also after adjustment for covariates, no differences were found among the three categories (Fig. 1).
Changes in V̇O2max and Arterial Stiffness
From adolescence to age 36 (
Changes in V̇O2max were directly and significantly associated with carotid distension (P = 0.015). This led to a positive and significant association between changes in V̇O2max and carotid distensibility (P = 0.020) and compliance (P = 0.037). However, after adjustment for potential confounders, the associations with distension and distensibility decreased and were no longer significant, whereas those with carotid compliance remained significant (P = 0.039). Changes in V̇O2max levels were inversely but not significantly associated with the carotid elastic modulus. In both crude and adjusted analyses, changes in V̇O2max were significantly associated with compliance (P < 0.001 and P = 0.005, respectively) but not distensibility (P = 0.085 and P = 0.870, respectively) of the femoral artery. This was a consequence of the net effect of positive associations with femoral diameter and distension, and negative associations with local pulse pressure. Changes in V̇O2max were directly and independently associated with brachial artery diameter (P = 0.003 for adjusted analyses) in men only (P = 0.009 for interaction with gender) but not with brachial distension, pulse pressure, and stiffness coefficients.
From young adulthood to age 36 (
Changes in V̇O2max were positively and significantly associated with compliance (P = 0.046), but not distensibility, of the carotid artery. After adjustment for potential confounders, this association was no longer significant. One must notice, however, that the estimates of the associations between changes in V̇O2max from young adulthood to age 36 and carotid distension, distensibility, and compliance were stronger than in the period of change between adolescence and age 36; the lack of significance may be explained by the relatively reduced number of subjects (i.e., less power) considered in these analyses (N = 118 vs 154). Changes in V̇O2max were not significantly associated with carotid elastic modulus. In both crude and adjusted analyses, changes in V̇O2max were positively associated with the diameter of the brachial artery (P = 0.037 and P = 0.039, respectively) in men only (P = 0.050 for interaction with gender), and with the distension of both the brachial (P = 0.012 and P = 0.008) and the femoral (P = 0.002 and P = 0.009) arteries. This resulted in a positive and significant association with distensibility of the femoral artery (P = 0.021 in adjusted analyses) and compliance of both arteries (in adjusted analyses P = 0.013 and P = 0.007, brachial and femoral arteries, respectively).
Impact of Changes in PA on Changes in V̇O2max and Large Artery Properties
We hypothesized that positive changes in V̇O2max reflect a more active lifestyle. To support this, and in the context of the present study, we first related changes in V̇O2max with concomitant changes in PA levels. The Pearson’s correlation coefficients were, for men and women, respectively, 0.22 and 0.23 (from adolescence to age 36) and 0.30 and 0.26 (from young adulthood to age 36) (P < 0.05 for all). These associations are further illustrated in Figure 2. We then investigated the relationships between changes in PA and large artery properties, and the potential mediating role of changes in V̇O2max on these relationships (Tables 5 and 6). Overall, and in both periods of change, the relationships between changes in PA and large artery properties mimic those between changes in V̇O2max and the same arterial properties (adjusted model). Moreover, the inclusion of changes in V̇O2max in the regression models resulted in a decrease of the regression coefficients in almost all the relationships investigated. This confirms our hypothesis that the impact of changes in PA on large artery properties would be, at least partially, mediated by changes in V̇O2max. However, changes in PA levels were still independently associated with arterial properties such as the distensibility of the brachial artery (in women only) (P = 0.034 and P = 0.055 from adolescence to age 36 and from young adulthood to age 36, respectively), and with the compliance of the brachial (P = 0.028) and the femoral arteries (P = 0.013), in the period of changes from young adulthood to age 36.
We found that: 1) longitudinal changes in V̇O2max and PA levels from adolescence to age 36 were not associated with carotid IMT and Young’s elastic modulus; 2) changes in V̇O2max,, but not PA, were inversely associated with carotid stiffness, a relationship in part dependent on, and possibly mediated by changes in other risk factors; 3) changes in V̇O2max and PA were inversely and independently associated with brachial and femoral stiffness; and 4) the associations between changes in PA and large artery stiffness were partially explained by concomitant changes in V̇O2max.
Changes in cardiorespiratory fitness and daily PA and carotid IMT.
In a previous study within the AGAHLS, V̇O2max during adolescence and at age 36 were inversely and independently associated with carotid IMT at age 36 in men (11). In the present study, changes in V̇O2max and PA levels (either from adolescence to age 36 or from young adulthood to age 36) were not associated with smaller carotid IMT values. Shorter-term improvement of V̇O2max through physical exercise (3 months) also did not reduce carotid IMT (31). However, the same investigators had previously reported a decrease in wall thickness of the femoral artery with increased levels of V̇O2max after a physical exercise program with the same duration (9). Taken together, these and our findings suggest that a reduction of the wall thickness with increased V̇O2max levels in healthy and risk-free subjects may be site specific, i.e., evident in muscular (such as the femoral) but not elastic (such as the carotid) arteries (21). This could be partially explained by the greater number of smooth muscle cells and plasticity of the muscular as compared with elastic arteries and/or by different exercise-induced adaptations in local pulsatile blood pressure and flow velocity that would generate different shear and tensile stress forces within the arterial tree (19,21). In this line, a short-term exercise-induced decrease in IMT thus reflects a medial adaptive response rather than a decrease in atherosclerosis (a disorder of the intimal layer). Whether such a decrease in medial thickness reduces cardiovascular risk is unknown.
Despite the lack of evidence of the beneficial effects of improving V̇O2max on carotid IMT in healthy subjects, physical exercise has been a successful tool in multifactorial programs for coronary atherosclerosis reduction in patients with coronary artery disease (12). We should emphasize that we studied only 36-yr-old healthy men and women without evidence of atherosclerotic disease. It is possible that increased PA and/or V̇O2max levels have a beneficial effect on carotid IMT in older subjects and/or subjects with clinically elevated levels of IMT or cardiovascular risk factors.
Changes in cardiorespiratory fitness and daily PA and arterial diameter.
An increase in levels of V̇O2max and PA was directly and strongly associated with greater diameters of the brachial artery in men and the femoral artery in both men and women, but not with the diameter of the carotid artery. In athletes, as compared with sedentary peers, the diameter of the femoral (but not the carotid) artery is greater (9,26). We show that changes in cardiorespiratory fitness throughout the first decades of life are related to the size of muscular arteries in adults that have not undergone any special physical training intervention to modify their physical fitness other than the repeated measure of V̇O2max. It is likely that this adaptation is related to an increased blood flow (and therefore, shear stress) in arteries supplying exercising musculature (9,14,26). Such a mechanism may also explain the lack of an association between changes in V̇O2max and PA and the diameter of the carotid artery. Why gender modulates these (as well as distension) adaptations differently according to the site in the muscular arterial tree is not clear but may involve hormonal factors and differences in risk profile, habitual patterns of PA, and arterial properties (22).
Changes in cardiorespiratory fitness and daily PA and arterial stiffness.
Changes in V̇O2max from adolescence to age 36 were independently associated with compliance (i.e., buffering capacity) of the elastic carotid and the muscular femoral arteries but not distensibility (i.e., elastic properties) of these arteries. However, in a shorter period (i.e., from young adulthood to age 36), where stronger estimates of association were found for almost all the studied variables (Table 4 vs Table 3), changes in V̇O2max were not only independently associated with compliance but also with the distensibility of both the brachial and the femoral arteries. This suggests that these arteries underwent adaptations toward a more elastic wall constitution, due to the relatively stronger association of changes in V̇O2max with distension than with diameter. Results of analyses of changes in PA levels were, in general, quite similar to those of analyses of changes in V̇O2max. The lack of association between changes in PA and stiffness of the carotid artery agrees with the ARIC study (28), in which only vigorous activities (in that study >5 METs), i.e., the type of activities that might result in changes in V̇O2max levels, were positively but weakly associated with distensibility of this artery. Nevertheless, the associations between changes in V̇O2max and arterial stiffness properties of the carotid artery were not independent of changes in covariates, as the regression coefficients changed considerably after adjustments. In additional analyses, mean blood pressure and changes in HDL cholesterol and body weight were the main “confounders” in the associations with carotid distension, distensibility, and compliance. Mean blood pressure is a true confounder in the associations investigated herein because these stiffness estimates are dependent on distending pressure, an aspect that we wished to adjust for. However, HDL cholesterol and body weight are variables that can be also in the pathway between V̇O2max and arterial stiffness, suggesting that the beneficial effects of V̇O2max on the carotid artery are mediated by changes in other risk factors. The adjusted estimates presented here may thus underestimate the true associations between changes in V̇O2max and carotid stiffness properties. Overall our study, as do others (8,30), supports the concept that improving V̇O2max and PA levels reduces arterial stiffness and might attenuate the age-related reduction in arterial stiffness. However, a fact of major importance for public health recommendations that has emerged from recent studies (20,27) is that this beneficial effects may be achieved with aerobic exercise but not resistance training.
Cardiorespiratory fitness and a physical active lifestyle have a favorable impact on cardiovascular health, either via the reduction of other risk factors (e.g., hypertension, dyslipidemia, Type 2 diabetes, obesity) or via direct effects on the cardiovascular system (29). In our study, we confirm that the salutary associations of cardiorespiratory fitness with the properties of the elastic carotid artery are most likely mediated by the preservation of a more favorable body composition and HDL levels throughout age in the fitter individuals. We also show that an increase in cardiorespiratory fitness and daily PA levels are inversely and independently associated with arterial stiffness, especially in the muscular vasculature. An explanation for these direct effects of training-induced improvements of cardiorespiratory fitness, either acutely or chronically, is an adaptation to shear stress forces (14,29). During exercise, blood flow increases, leading to higher intraluminal shear forces, which stimulate the endothelium to release relaxing factors, mainly believed to be nitric oxide (NO), resulting in arterial vasodilation. In response to chronic increases in blood flow, arterial remodeling occurs (larger vessel diameter) in order to restore basal shear stress, a phenomenon that was shown to be endothelium dependent (3). Other mechanisms might be involved, such as a decrease in vascular smooth muscle tone due not only to an improved local and basal production of NO but also to an exercise-induced reduction in sympathetic tone and/or renin-angiotensin system activity (15). Moreover, emerging evidence suggests that PA and cardiorespiratory fitness may have anti-inflammatory (1) and antithrombotic (29) effects that, in turn, affect vascular structure and function.
Role of PA and implications for public health.
The results found in this study suggest that improving V̇O2max may be an important tool for the prevention of cardiovascular disease and that improvement of V̇O2max levels can be achieved by engaging a more physically active lifestyle. Although V̇O2max has a genetic component, it is primarily determined by PA. This has been also previously reported in the same population of the present study (17). Moreover, PA, as compared with other lifestyles (nutrient intake, smoking, and alcohol consumption), is a strong correlate of cardiovascular risk factors (e.g., body fatness) (32), a pathway via which one may also expect healthy effects on arterial properties. Nevertheless, changes in PA levels were also inversely associated with arterial stiffness (especially in the muscular arteries) independently of changes in V̇O2max. Again, this suggests that other mechanisms than a change in V̇O2max are involved. In addition, it also suggests that any change in PA, even not reflected in changes in V̇O2max (that usually occur with moderate-heavy intensities) may be sufficient for a salutary impact on arterial stiffness. In this line, the low-intensity activities (i.e., 4–7 METs) had the highest frequency and duration, and have contributed the most (about 2/3) for the total PA score calculated at age 36 in the AGAHLS (data not shown). This is important information for public health policies directed to the general population, in the sense that increases in these kinds of activities may be easier to achieve. Therefore, from a public health point of view, our results support the promotion of a more physical active lifestyle, either starting during adolescence or later during young adult life, as a tool for primary prevention of cardiovascular disease.
The first author of this paper was supported by a research grant from the Foundation for Science and Technology–Portuguese Ministry of Science and Technology (grant PRAXIS XXI/BD/19760/99). The AGALHS has, since 1974, been supported by major grants from the Foundation for Educational Research, the Dutch Prevention Fund, the Netherlands Heart Foundation, the Dutch Ministry of Public Health, Well Being and Sport, the Dairy Foundation on Nutrition and Health, the Netherlands Olympic Committee/Netherlands Sports Federation, Heineken BV, and the Scientific Board on Smoking and Health.
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