2024 年 31 巻 2 号 p. 171-179
Aims: Several studies have revealed an association between moderate-to-vigorous physical activity (MVPA) and arterial stiffness, which is a known risk factor for cardiovascular disease. However, a few studies have considered the difference in the longitudinal effect of its intensity in a large general population. Therefore, we examined the effect of MVPA intensity on longitudinal changes in arterial stiffness.
Methods: We conducted a prospective cohort study involving 1,982 Japanese men and women. Arterial stiffness was measured using the cardio–ankle vascular index (CAVI) at baseline and 5-year follow-up. Physical activity was quantified using the Japan Arteriosclerosis Longitudinal Study Physical Activity Questionnaire and categorized into quartiles as MVPA levels. Linear mixed models were used to examine the differences at baseline and the rate of changes in CAVI associated with MVPA levels for over 5 years.
Results: The multivariable-adjusted mean differences in CAVI at baseline were significantly lower in the third (β=−0.019 [95% confidence interval {CI}=−0.033 to −0.005]) and fourth (β=−0.018 [95% CI=−0.035 to −0.001]) quartiles of the MVPA group compared with those in the lowest quartile of MVPA, and the significant effect persisted 5 years later.
Conclusions: In summary, this study provides evidence to support the existence of a threshold for beneficial levels of MVPA in the prevention of arterial stiffness. Furthermore, this study suggests that exceeding this threshold may exert similar effects on arterial stiffness. These findings suggest that an optimal level of MVPA exists for preventing arterial stiffness, and exceeding this threshold may not engender additional benefits.
Cardiovascular diseases (CVDs) are the number one cause of death globally, taking approximately 17.9 million lives annually and 32% of all deaths worldwide1). The major risk factors for CVD include hypertension, diabetes, elevated total cholesterol level, decreased high-density lipoprotein cholesterol level, obesity, tobacco use, and physical inactivity2, 3). Because these risk factors are known to be controllable and modifiable through behavioral changes4, 5), promoting better health behavior is vital to preventing CVD.
A consensus exists that physical activity can provide many health benefits6-8) including reduction of mortality in CVD9) and attenuation of arterial stiffness10, 11). The physical activity guidelines of the World Health Organization recommended that adults should indulge in at least 150 or 75 min of moderate or vigorous physical activity throughout the week, respectively, or a combination of these activities12). Although several studies have examined the optimal intensity of physical activity for preventing CVD, the results are debatable. Although moderate-to-vigorous physical activity (MVPA) is associated with lower risks of all-cause and coronary heart disease mortality7, 13), several cohort studies have reported that longevity is significantly more associated with moderate physical activity than with vigorous physical activity14, 15). A recent meta-analysis and review disclosed a reduction in the CVD risk with increasing physical activity volumes, which plateaued at the highest levels of physical activity. This suggests the presence of a curvilinear relationship between physical activity and CVD16, 17). Although Franklin et al. discussed that this may be attributed to the relatively small sample sizes of the most active physical activity subgroups, some studies have suggested that the relationship between physical activity and CVD risk follows a U-shaped pattern, with an increased risk of CVD at the highest physical activity volumes17). Estimating the optimal intensity and amount of physical activity to prevent CVD is controversial.
Arterial stiffness is a structural change in the arteries that occurs before plaque or thrombus formation and is a risk factor for CVD and all‐cause mortality independent of other CVD risk factors18). The cardio–ankle vascular index (CAVI) is an index of arterial stiffness that measures the overall stiffness of an artery from the aorta to the ankle19). A previous study demonstrated that the degree of arterial stiffness detected reflects the progression of coronary arteriosclerosis20), and it could be a predictive factor of prognosis in CVD21-23).
As aforementioned, although several studies have revealed an association between physical activity and arterial stiffness10, 11), which is a known risk factor for CVD, a few studies have considered the difference in the longitudinal effect of its intensity in a relatively large general population24, 25). We hypothesized that the relationship between MVPA and arterial stiffness would demonstrate a curvilinear or U-shaped association similar to that observed between physical activity and CVD. Therefore, estimating the optimal amount of physical activity required to prevent arterial stiffness may be feasible. To examine the association between physical activity intensity and arterial stiffness and its longitudinal changes, we conducted a prospective cohort study involving the general Japanese population.
This study was conducted as part of the Toon Health Study, which is a community-based prospective cohort study to characterize the risk factors for CVD in Toon City, Ehime Prefecture, Japan26-28). In this study, we recruited participants from approximately 22,000 residents of Toon City aged ≥ 30–＜80 years using direct invitations, newspaper advertisements, and posters. In the baseline survey conducted from 2009 to 2012, 2,032 participants were enrolled in this study. Of these, a history of myocardial infarction (n=17) and stroke (n=33) was excluded. Thus, the data of 1,982 individuals (men =699 and women =1,283) were included in the present analysis (Fig.1). During the follow-up survey, 1,423 individuals were in attendance, resulting in a follow-up rate of 71.8%. Throughout the baseline and follow-up surveys, identical test and measurement equipment were utilized, and the testing environment remained unchanged. The study protocol of the Toon health study conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Institutional Review Board of Ehime University Hospital and the Ethics Committee of Juntendo University. Written informed consent was obtained from each study participant.
Flow diagram of the study populations with available data
To measure arterial stiffness, participants underwent CAVI at a local health center in the morning at both baseline and 5-year follow-up. CAVI represents the degree of natural arterial stiffness, independent of blood pressure. The theoretical details of the CAVI method are described elsewhere29). CAVI was measured according to a standardized method using Vasera VS-100 (Fukuda Denshi Co., Ltd., Tokyo, Japan). All CAVI measurements were obtained during the morning hours using cuffs applied to the bilateral upper arms and ankles, with the participants lying supine and their heads held in the midline position. The examinations were performed once after the participant had rested for 5 min. In this study, CAVI was obtained on the right and left sides, and both CAVI values were calculated and analyzed using the VSS-10 software program (Fukuda Denshi Co., Ltd., Tokyo, Japan). Because the CAVI values were skewed, the variables were transformed using natural logarithms, and a higher value of either the right or left side was adopted in the analyses.
Assessment of Habitual Physical ActivityTo assess habitual physical activity, each participant completed the Japan Arteriosclerosis Longitudinal Study Physical Activity Questionnaire (JALSPAQ) to assess the metabolic equivalents of task (MET) metric. JALSPAQ is commonly used physical activity questionnaire in the Japanese setting comprising 14 detailed items of occupation, locomotion, housework, sleep time, and leisure-time physical activities, which can reflect habitual physical activities30, 31). Self-reported measures of physical activity often have weaker correlations with standard objective measures of total physical activity. Therefore, doubly labeled water (DLW) is commonly used as a stringent and physiological method to validate field methods to assess physical activity. Nonetheless, a previous study has demonstrated that the total energy expenditure assessed using the validity of JALSPAQ against DLW reveals a moderate correlation between the total physical activity calculated using the JALSPAQ and DLW values (Spearman’s correlation =0.742, P＜0.001; intraclass correlation coefficient =0.648, P＜0.001)32). The total physical activity data acquired from the questionnaire were converted and summarized into intensity-specific physical activity (MET·h/day) following the protocol by Ainsworth33). We classified the total physical activity by the intensity of habitual physical activity level: light (＜3 MET), moderate (3–5.9 MET), and vigorous (≥ 6 MET), based on a categorization defined by the Physical Activity Guidelines Advisory Committee34). In this study, we defined MVPA as the sum of intensity-specific physical activity from moderate and vigorous habitual physical activity levels and categorized it into quartile groups.
Assessment of CovariatesBlood samples were collected at baseline after at least 10 h of fasting. Then, an oral glucose tolerance test was performed. Overnight fasting blood samples were drawn from the antecubital vein into vacuum tubes containing a serum separator gel. The serum tube was centrifuged immediately at 3,000 g for 15 min at 4℃, and the separated serum was sent to a laboratory for analysis. Enzymatic methods were used to measure serum total cholesterol and triglyceride levels. Low- and high-density lipoprotein cholesterol levels were measured using the direct homogeneous method. Lipid measurements were standardized using the CDC NHLBI Lipid Standardization Program provided by the Centers for Disease Control and Prevention (Atlanta, GA, USA). Serum glucose levels were measured with the hexokinase method (Sysmex, Kobe, Japan) using an automatic chemistry analyzer (7600-D; Hitachi Co., Tokyo, Japan), and participants with fasting serum glucose levels of ≥ 7.0 mmol/L and 2-h postprandial glucose levels of ≥ 11.0 mmol/L or are currently using antihyperglycemic agents were diagnosed with diabetes mellitus. A self-administered questionnaire was used to assess medication use for hypertension, dyslipidemia, diabetes mellitus, and smoking habits. Their height in stocking feet and weight in light clothing were measured by physicians or public health nurses. The weight was calculated by subtracting 500 g as the weight of the clothing from the actual weight. Body mass index was calculated as weight (kg) divided by height in meters squared (m2). The total amount of physical activity (MET·h/day) was evaluated using JALSPAQ, as described in the section on assessment of habitual physical activity.
Statistical AnalysisTo show the baseline characteristics of the participants, chi-squared tests for proportions and analysis of variance for mean values were used. Linear mixed models were used to examine the effect of habitual physical activity intensity on baseline differences (2009–2012) and 5-year changes in CAVI (2014–2018). These models use all available data over the follow-up period, handle differences in the length of the follow-up period, and consider the correlation between repeated measures on the same participant. This statistical method is commonly used to analyze longitudinal data, considering the correlation that exists between multiple measurements obtained from the same individual over time. The fixed effect in this study was specified as MVPA, whereas the random effect was specified as time. By utilizing mixed-effects modeling, we effectively accounted for within-individual variability in the data and obtained robust estimates of the effect of MVPA over time. The linear mixed models included a term for time (participant follow-up in years divided by five to yield effects on changes in CAVI over 5 years). The main effect estimates the effect of MVPA on CAVI at baseline, whereas the habitual physical activity×time interaction term estimates the mean difference in the 5-year changes in CAVI. On the basis of this analysis, the least-squares means and 95% confidence intervals (CIs) of CAVI were calculated for each quartile group and subsequently plotted on the graph. The covariates in all multivariable analyses were age (years), sex (male or female), diabetes mellitus (yes or no), body mass index (kg/m2), serum high-density lipoprotein cholesterol level (mmol/L), serum total cholesterol level (mmol/L), hypertension medication use (yes or no), dyslipidemia medication use (yes or no), smoking habits (yes or no), and total physical activity (MET·h/day) at baseline. The linear trends were assessed using the continuous value of MVPA. The interaction of MVPA with sex in relation to CAVI was tested using the cross-product terms of these variables in the linear mixed model. All analyses were performed using SAS statistical package (version 9.4; SAS Institute Inc., Cary, NC, USA). Statistical significance was defined as P＜0.05.
The characteristics of the participants at baseline according to MVPA categories are shown in Table 1. Participants in the higher MVPA group tended to be older and have higher CAVI and high high-density lipoprotein cholesterol levels and total physical activity than those in the lowest MVPA group. The proportion of men and those who were taking dyslipidemia and hypertension medications and were diagnosed with diabetes mellitus tended to be higher in the higher MVPA group than in the lowest MVPA group. The proportion of smokers was significantly lower in the highest MVPA group than in the lowest MVPA group.
| Moderate-to-vigorous physical activity levels | P value | ||||
|---|---|---|---|---|---|
| Quartile 1 | Quartile 2 | Quartile 3 | Quartile 4 | ||
| Median (range), METs·h/day | 1.79 (0.00-3.00) | 4.17 (3.00-5.49) | 7.12 (5.50-9.70) | 14.88 (9.72-61.38) | |
| N | 495 | 496 | 496 | 495 | - |
| CAVI at baseline | 8.06 | 8.21 | 8.28 | 8.24 | ＜0.001 |
| CAVI at follow-up | 8.12 | 8.43 | 8.48 | 8.36 | ＜0.001 |
| Age, years | 54.3 | 58.0 | 60.0 | 58.4 | ＜0.001 |
| Sex (men), % | 34.8 | 29.2 | 33.1 | 39.3 | ＜0.001 |
| TCH, mmol/L | 5.28 | 5.32 | 5.35 | 5.31 | 0.30 |
| HDLC, mmol/L | 1.57 | 1.61 | 1.61 | 1.58 | 0.04 |
| LDLC, mmol/L | 3.10 | 3.10 | 3.11 | 3.12 | 0.93 |
| Smoking habits, % | 8.5 | 6.7 | 3.8 | 6.9 | ＜0.001 |
| BMI, kg/m2 | 23.2 | 23.0 | 23.1 | 23.2 | 0.28 |
| Hypertension medication use, % | 17.7 | 22.5 | 22.6 | 20.2 | 0.03 |
| Dyslipidemia medication use, % | 12.9 | 14.7 | 18.2 | 13.4 | 0.02 |
| Diabetes mellitus, % | 9.5 | 12.2 | 10.4 | 13.3 | 0.02 |
| Total physical activity, METs·h/day | 32.8 | 33.7 | 35.4 | 40.8 | ＜0.001 |
ANOVA for continuous variables, chi-squared test for categorical variables. Continuous variables are listed with mean values. CAVI, cardio-ankle vascular index; TCH, total cholesterol; HDLC, high-density lipoprotein cholesterol; LDLC, Low-density lipoprotein cholesterol; BMI, body mass index; mmol/L, millimole per liter; METs, metabolic equivalents.
The multivariable-adjusted mean differences in CAVI according to MVPA levels at baseline and 5-year follow-up are shown in Table 2. At baseline, CAVI was significantly lower in the third quartile of the MVPA group (β=−0.019 ([95% CI=−0.033 to −0.005])) than in the lowest quartile of the MVPA group. Also, CAVI was significantly lower in the fourth quartile of the MVPA group (β=−0.018 ([95% CI−0.035 to −0.001])) than in the lowest quartile of the MVPA group. There was no significant association between MVPA and the rate of change in CAVI at the 5-year follow-up in the second to fourth vs. lowest quartile groups, suggesting that the effect of MVPA in the third and fourth quartile groups vs. lowest quartile group on CAVI persisted 5 years later. The linear trend of the continuous value of MVPA in relation to CAVI was borderline significant (P for trend=0.05). The interaction of MVPA with sex in relation to CAVI was not significant (P for interaction =0.46). The lower parts of Table 2 and Fig.2 show the least-squares means and 95% CIs for CAVI for each quartile group. Compared with the first quartile group with mean (95% CI)=8.21 (8.12–8.29), the third, 8.05 (7.97–8.12), and fourth, 8.06 (7.96–8.15), quartile groups exhibited a statistically significant decrease in CAVI at baseline.
| Q1 | Q2 | Q3 | Q4 | ||
|---|---|---|---|---|---|
| Model 1 | β (95% CI) | β (95% CI) | β (95% CI) | P for trend | |
| Baseline | Reference | -0.005 (-0.019 to 0.009) | -0.015 (-0.029 to -0.001) | -0.009 (-0.023 to 0.005) | 0.06 |
| Follow-up | Reference | 0.010 (-0.004 to 0.026) | 0.011 (-0.004 to 0.026) | 0.002 (-0.013 to 0.017) | 0.58 |
| Model 2 | β (95% CI) | β (95% CI) | β (95% CI) | P for trend | |
| Baseline | Reference | -0.010 (-0.023 to 0.004) | -0.019 (-0.033 to -0.005) | -0.018 (-0.035 to -0.001) | 0.05 |
| Follow-up | Reference | 0.008 (-0.006 to 0.023) | 0.012 (-0.002 to 0.027) | 0.003 (-0.011 to 0.018) | 0.61 |
| Mean (95% CI) | Mean (95% CI) | Mean (95% CI) | Mean (95% CI) | ||
| The mean CAVI for Baseline | 8.21 (8.12-8.29) | 8.13 (8.05-8.20) | 8.05 (7.97-8.12) | 8.06 (7.96-8.15) | |
| The mean CAVI for Follow-up | 8.27 (8.19-8.36) | 8.25 (8.18-8.33) | 8.20 (8.12-8.27) | 8.16 (8.07-8.25) |
Linear mixed models were used to examine the effect of MVPA on baseline differences and 5-year changes in CAVI. Linear trends were assessed using the continuous value of MVPA.
Model 1=adjusted for age and sex. Model 2=adjusted for age, sex, diabetes mellitus, body mass index, serum high-density lipoprotein cholesterol, serum total cholesterol, hypertension medication use, dyslipidemia medication use, smoking habit, and total physical activity. CAVI; cardio-ankle vascular index. MVPA; moderate-to-vigorous physical activity.
Linear mixed models were used to estimate the least-squares means on baseline differences and 5-year changes in CAVI.
Adjusted for age, sex, diabetes mellitus, body mass index, serum high-density lipoprotein cholesterol, serum total cholesterol, hypertension medication use, dyslipidemia medication use, smoking habit, and total physical activity. CAVI; cardio-ankle vascular index. MVPA; moderate-to-vigorous physical activity.
In this study, arterial stiffness measured using the CAVI level was significantly lower in the third quartile of the MVPA group than in the lowest quartile at baseline. The third quartile, which has a range of 5.50–9.70 MET·h/day of physical activity according to MVPA, benefited most from preventing arterial stiffness and may be classified as the optimal amount of MVPA to prevent arterial stiffness. Additionally, arterial stiffness decreased significantly in the fourth quartile (9.72–61.38 MET·h/day), comparable with the reduction observed in the third quartile from the lowest quartile. The findings of this study suggest that the third and fourth quartiles of MVPA exert analogous effects on arterial stiffness. These results indicate that an increase in MVPA beyond the third quartile does not confer any additional benefit on arterial stiffness. Furthermore, MVPA was not significantly associated with the rate of change in CAVI at the 5-year follow-up, suggesting that the significant association between the third and fourth quartile of the MVPA group and CAVI at baseline persisted 5 years later. The absence of a significant difference in the rate of change over the follow-up period suggests that the slope generated by the passage of time remained consistent, thereby preserving the degree of the initial association. In other words, the statistically significant association observed at baseline persisted after five years. To the best of our knowledge, this study represents the first attempt to examine the longitudinal effects of habitual physical activity intensity on arterial stiffness and to estimate the optimal threshold of MVPA required to prevent arterial stiffness in a relatively large sample of the general population. The most important findings of the study were that an appropriate level of MVPA for preventing arterial stiffness exists and exceeding this level may not confer additional benefits.
Endes et al.24) investigated these longitudinal associations in a relatively large general population. The findings of the study suggest that maintaining or adopting a physically active lifestyle is linked to reduced arterial stiffness in older adults, which is congruent with the present study. However, this study used a 4-item questionnaire to assess physical activity and stratification into active and inactive groups. Therefore, this hinders the estimation of an appropriate threshold for the physical activity dose. Moreover, arterial stiffness was assessed solely at follow-up, precluding the evaluation of its progression from baseline. Aoyagi et al.25) examined the longitudinal associations between physical activity and central arterial stiffness. Physical activity levels were categorized by quartiles, and the indices of central arterial stiffness tended to be higher for participants in the lowest quartile than for those in the two highest quartiles. This finding is consistent with that of this study. The study utilized standardized and physiological assessments, such as electronic pedometer/accelerometer measurements for physical activity and PWV, to assess arterial stiffness, which strengthen the validity of their findings. However, the sample size was limited to 198 participants, which resulted in relatively weak correlations. Additionally, the assessment of arterial stiffness was only conducted at follow-up, which prevented the evaluation of its progression from baseline. Overall, the findings of these studies support the notion that physical activity may play a role in mitigating arterial stiffness and provide valuable insight into the underlying mechanisms of this relationship. However, the limitations of this study highlight the requirement for further research with larger and more diverse samples and longitudinal assessments of arterial stiffness to better understand its progression over time.
The importance and novelty of this study lie in its demonstration that the optimal level of MVPA exerts a beneficial effect on arterial stiffness and its progression, whereas exceeding this level of MVPA does not offer further benefits in this regard. Moreover, this study estimates the optimal threshold of MVPA required to prevent arterial stiffness. Although physical activity is crucial for preventing CVD and arterial stiffness10, 11) and is recommended for the primary prevention of CVD2, 3), there is an elevated risk of musculoskeletal injury associated with excessive physical activity35, 36). Therefore, it is essential to establish an upper limit by estimating the threshold of physical activity, which can provide important guidance for maintaining physical health while minimizing the risk of injury. On the basis of the median value of the third quartile (7.12 MET·h/day), the equivalent duration of moderate physical activity (3–5.9 MET) was 506–997 min/week. These findings suggest that the plateau effect is achieved at approximately 3–6 times the recommended exercise volume of at least 150 min/week of moderate physical activity according to the physical activity guidelines of the World Health Organization12). Particularly, engaging in MVPA through activities such as walking approximately 2 h/day (3 MET) or jogging 1 h/day (7 MET) may be the most effective in preventing arterial stiffness, and exceeding this level may not provide additional benefits.
Numerous previous studies have consistently demonstrated that adopting healthy lifestyle behaviors, such as regularly engaging in aerobic exercise and adhering to certain dietary practices, represent the most established approaches for improving vascular function in the context of aging. The consensus is that aerobic exercise impedes the progression of arterial stiffness37). Aerobic exercise training promotes the preservation of endothelial function and can reverse the age-related increase in inflammation38). The mechanisms by which physical activity prevents vascular dysfunction in aging individuals are complex and multifaceted. Oxidative stress is a primary mechanism underlying age-related vascular dysfunction, which is mitigated by physical activity, and it contributes to the sustained impairment of endothelial function. Some studies have suggested that physical activity affects the vascular endothelium by modifying oxidative stress and low-grade inflammation39, 40) and that people who perform regular aerobic exercise have lower C-reactive protein and inflammatory cytokine levels and higher anti-inflammatory cytokine levels41, 42). However, excessive physical activity can negatively affect arterial stiffness due to the accumulation of oxidative stress. A study has pointed out that oxidative stress and the production of free radicals by prolonged exercise may damage tissues43). Several studies have found that, although appropriate physical activity promotes health benefits6-8), excessive physical activity increases the production of excessive reactive oxygen species, which are elevated biomarkers of oxidative stress in both skeletal muscles and blood44). This study suggests that a curvilinear association between physical activity and arterial stiffness is attributed to reverse causality resulting from the accumulation of oxidative stress resulting from prolonged MVPA in the fourth quartile.
This study has several strengths. First, this was a prospective cohort study involving a relatively large sample size of community residents, with a 5-year follow-up to examine the association of physical activity with longitudinal changes in arterial stiffness after adjusting for potential confounding factors. However, this study has several limitations. First, CAVI is not the international gold standard measurement for arterial stiffness. Although CAVI is common in clinical settings in Japan, the international gold standard is PWV in both clinical and research settings11). However, CAVI has high reproducibility19) and may be used to measure the progression of coronary arteriosclerosis20). Moreover, compared with PWV, CAVI is not directly affected by blood pressure at the measuring time due to the measurement mechanism, which is an advantage45). In addition, the observation of JALSPAQ was limited to the baseline measurement and did not continue for the subsequent 5-year follow-up. Thus, the study’s findings did not establish a causal relationship between physical activity and arterial stiffness. Further, longitudinal studies are required to fully understand the potential impact of JALSPAQ on CAVI.
Finally, although we adjusted for possible confounding factors in this study, residual confounders by unmeasured variables, such as genetic factors, may have existed46). However, genetic effects on arterial stiffness are not obvious, and genetic risk and intergenerational studies are sparse46).
In summary, this study provides evidence to support the existence of a threshold for beneficial levels of MVPA in the prevention of arterial stiffness. Furthermore, this study suggests that exceeding this threshold exerts similar effects on arterial stiffness. These findings suggest that an optimal level of MVPA exists for preventing arterial stiffness, and exceeding this threshold may not engender additional benefits.
We thank the staff and participants of the Toon Health Study and the municipal authorities, officers, and health professionals of Toon City for their valuable contributions.
This study was supported in part by Grants-in-Aid for Scientific Research (Grants-in-Aid for Research B, #22390134 for 2010-2012, #25293142 for 2013-2015, and #18H03056 for 2018–2022) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and Health and Labor Sciences Research Grants (Comprehensive Research on Lifestyle Related Diseases including Cardiovascular Diseases and Diabetes Mellitus, #201021038A for 2010-2012) from the Ministry of Health, Welfare and Labor, Japan. Also, this research was supported by AMED under Grant Number JP22rea522104.
The authors have no conflicts of interest to declare.
