A body shape index is associated with endothelial dysfunction in both men and women

A body shape index (ABSI) was proposed for estimation of abdominal adiposity. ABSI has been reported to have associations with cardiovascular risk factors and cardiovascular events. However, there is no information on the association between ABSI and endothelial function. We examined cross-sectional associations of ABSI with endothelial function in 8823 subjects (6773 men and 2050 women). Subjects with a lower quartile of flow-mediated vasodilation (FMD) were defined as subjects having endothelial dysfunction. Pearson’s correlation coefficient analysis revealed that ABSI was negatively correlated with FMD (men, r = − 0.23, P = 0.003; women, r = − 0.32, P < 0.001). The areas under the curves of ABSI and body mass index to predict endothelial dysfunction were 0.64 (95% confidence interval [CI] 0.62–0.65) and 0.58 (95% CI 0.57–0.60) in men, and 0.68 (95% CI 0.66–0.71) and 0.59 (95% CI 0.56–0.61) in women, respectively. The cutoff values of ABSI for predicting subjects with endothelial dysfunction were 0.0796 (sensitivity, 55.2%; specificity, 65.5%) in men and 0.0823 (sensitivity, 56.2%; specificity, 73.4%) in women. Multivariate analysis revealed that an ABSI value higher than the cutoff value remained an independent predictor of endothelial dysfunction in both sexes. The results of our study suggest that ABSI calculation should be performed for evaluation of risk of cardiovascular events in both men and women. Clinical trial registration information URL for Clinical Trial: https://www.umin.ac.jp/ctr/index.htm; Registration Number for Clinical Trial: UMIN000012952 (01/05/2010).


Scientific Reports
| (2021) 11:17873 | https://doi.org/10.1038/s41598-021-97325-0 www.nature.com/scientificreports/ evaluate endothelial function [3][4][5][6] . Several investigators have reported associations between endothelial dysfunction and cardiovascular events [7][8][9][10] . Body mass index (BMI) is a simple screening tool for classifying obesity. Although an increase in BMI is known to be associated with the prevalence of cardiovascular risk factors, the effect of an increase in BMI on the incidence of cardiovascular events is still controversial 6,[11][12][13] . Numerous studies have suggested that higher BMI is associated with lower risk of mortality in patients with coronary artery disease, an association that is known as the "obesity paradox" 14 . One possible explanation for the obesity paradox is that BMI does not reflect regional body fat distribution and cannot distinguish muscle and fat mass. Indeed, several investigators have suggested that abdominal obesity and abdominal deposition of fat are more strongly associated with cardiovascular risk factors than is BMI 15,16 . It is expected that evaluation of abdominal obesity would improve the predictive value of future cardiovascular events compared with BMI. However, there are no accepted simple criteria for evaluation of abdominal obesity.
Waist circumference is one of the simple methods evaluating abdominal obesity. Since waist circumference is sensitive to body size (height, weight, and BMI), measurement of waist circumference cannot provide accurate information on the abdominal deposition of fat 17 . Krakauer et al. proposed a body shape index (ABSI) for estimation of abdominal adiposity 18 . ABSI has been shown to be associated with cardiovascular risk factors, mortality, and cardiovascular events in several ethnic groups [18][19][20][21][22][23] . However, there is no information on the association between ABSI and endothelial function. In this study, we evaluated the association between ABSI and endothelial function determined by measurement of FMD in a general population.

Relationships between ABSI and cardiovascular risk factors. The associations between ABSI and
variables by using Pearson's correlation coefficients analysis are shown in Table 2. There were significant relationships between FMD and ABSI ( Table 2). The correlation of ABSI and BMI for men was negligible (− 0.001) with a modest correlation in females of 0.042 (Table 2). Subjects were categorized into four quartile groups based on ABSI. Baseline characteristics of the subjects are summarized in online Supplementary Tables S1 and S2. FMD was significantly impaired in higher ABSI groups (Fig. 1 Table 2. Pearson's correlation coefficients analysis of relationships between a body shape index and variables. HDL high-density lipoprotein, LDL low-density lipoprotein, FMD flow-mediated vasodilation. Pearson's correlation coefficients analysis of the relations between a body shape index and variables. *P < 0.001. † P < 0.0001.

Variables Men Women
Age ( women. An adjusted cubic spline curve described the relationship between ABSI and odds ratio for endothelial dysfunction (Fig. 3). Figure 4 and online Supplementary Fig. S1 show the crude and multivariate-adjusted odds ratios of the low quartile of FMD according to ABSI and BMI. After adjustment of various confounders, ABSI value higher than the cutoff value remained as an independent predictor of endothelial dysfunction regardless of gender, and BMI higher than the cutoff value remained as an independent predictor of endothelial dysfunction in men.
Relationships between ABSI and history of cardiovascular disease. ROC curve analysis revealed that ABSI and BMI detect a history of cardiovascular disease with AUC values of 0.73 (95% CI 0.71-0.75) and 0.57 (95% CI 0.55-0.59), respectively, in men, and 0.73 (95% CI 0.69-0.77) and 0.58 (95% CI 0.53-0.62), respectively, in women (Fig. 5). Figure 6 shows the crude and multivariate-adjusted odds ratios for a history of cardiovascular disease according to ABSI. After adjustment of various confounders, an ABSI value higher than the cutoff value remained as an independent predictor of a history of cardiovascular disease regardless of gender.

Discussion
ABSI was derived empirically from the US NHANES population database as waist circumference divided by a power law approximation of the expected value of waist circumference for weight and height 18 . We found a negligible correlation of ABSI and BMI, indicating that ABSI should be valid as originally defined for application to our subjects. In the present study, we demonstrated that abdominal obesity evaluated by ABSI was negatively www.nature.com/scientificreports/ correlated with FMD and that ABSI had a better predictive value of endothelial dysfunction than did BMI. We also confirmed that ABSI values above the cutoff values (0.0796 for men and 0.0823 for women), which were derived from ROC curve analysis, were significantly associated with endothelial dysfunction even after adjustment for various confounders. To our knowledge, this study is the first study to show ABSI thresholds that can be used to detect patients with endothelial dysfunction. In the present study, impaired endothelial function was positively correlated with ABSI in both sexes. It is well known that abdominal obesity and endothelial dysfunction share many common risk factors. Indeed, our results support the results of previous studies showing that higher ABSI is associated with a higher prevalence of cardiovascular risk factors 20,24 . Therefore, we evaluated the associations between ABSI and endothelial function after adjustment of cardiovascular risk factors. We confirmed that ABSI values above the cutoff values were independently associated with endothelial dysfunction in men and women. These findings suggest that high ABSI is an independent risk factor for endothelial dysfunction.
Several investigators have reported an association of ABSI with risk of mortality from cardiovascular disease 22,25 . However, the cutoff value of ABSI associated with a higher risk of cardiovascular events remained unknown. Christakoudi et al. showed that cutoff values of ABSI for all-cause mortality are 0.0833 for men and 0.0762 for women in the European population 23 . In the present study, ROC curve analysis revealed that ABSI of 0.0796 for men and ABSI of 0.0823 for women were cutoff values of endothelial dysfunction. The cutoff values of ABSI for outcomes might be different between the Japanese population and European population. Nevertheless, we found that the cutoff values of ABSI for a history of cardiovascular disease were similar (0.0811 for men and  . Odds ratios and 95% confidence intervals for a low quartile of flow-mediated vasodilation (FMD) of high a body shape index (ABSI) using the low ABSI group as the reference. Low quartile of FMD indicates less than 3.6% in men and less than 3.1% in women. Low ABSI indicates less than 0.0796 in men and less than 0.0823 in women. Model 1: Adjusted for age. Model 2: Adjusted for age, body mass index, and smokers. Model 3: Adjusted for age, body mass index, presence of hypertension, dyslipidemia, and diabetes, and smokers.  Fig. 5). These findings indicate that the cutoff values of ABSI for higher risk of cardiovascular events are 0.0796 for men and 0.0823 for women in the Japanese population. The study subjects were enrolled at 22 university hospitals and affiliated clinics in Japan 26 . Height, weight, BMI, and waist circumference of the study participants were similar to nationally representative data in Japan 27 . ABSI was developed to estimate the health of body shape independently of body size (height, weight, and BMI) from a database for the American population 18 . Some researchers suggested that ABSI should be modified by age and race 28,29 . Indeed, Sato et al. reported that ABSI is significantly associated with the incidence of all-cause mortality in Japanese men, while ABSI has a weak association with the incidence of all-cause mortality in Japanese women 30 . In the present study, there was an inverse relationship between ABSI and height, especially in women. This finding suggests that ABSI is not completely appropriate for the Japanese population. However, we confirmed that ABSI was significantly correlated with waist circumference, Framingham risk score, and FMD, which are surrogate markers of cardiovascular events. Therefore, ABSI is a useful tool for assessing cardiovascular risk in the Japanese population.
There is a growing body of evidence that abdominal obesity is better predictor of cardiovascular risk than is BMI 15,16 . Some possible mechanisms by which abdominal obesity impairs endothelial function have been postulated. Abdominal obesity reflects excess subcutaneous and visceral adipose tissue. In obesity, adipose tissue becomes dysfunctional, leading to the promotion of a proinflammatory response 31 . Chronic inflammation has been shown to play a critical role in endothelial dysfunction through a decrease in nitric oxide bioavailability 32-34 . Our study showed that ABSI has a stronger association than BMI with endothelial dysfunction. ABSI had stronger correlations with waist circumference and cardiovascular risk factors. In addition, ROC curve analysis revealed www.nature.com/scientificreports/ that the AUC value of ABSI to predict a history of cardiovascular disease was superior to that of BMI (Fig. 5). ABSI in conjunction with BMI might be a useful marker for evaluating the risk of cardiovascular events in both men and women 35,36 .

Study limitations.
The present study has some limitations. First, a definitive causal relationship between ABSI and endothelial function could not determine in this study since this study was a cross-sectional design.
Second, we had no information on physical activity. Physical activity is associated with both ABSI and endothelial function 37,38 . We cannot rule out the possibility that physical activity influences the association between ABSI and endothelial function. Future studies are needed to confirm the role of physical activity in the relationships between ABSI and endothelial function. Finally, the inverse association between ABSI and height might reflect the generational difference in height, since ABSI was positively correlated with age in this study. Indeed, over the past century, there has been a larger generational difference in height in Asian countries compared to American 39 . Therefore, age-specific cut-offs or some form of modification of ABSI by age will be required in future studies.
In conclusion, high ABSI is independent predictor of endothelial dysfunction. The results of our study suggest that ABSI calculation should be performed for evaluation of the risk of cardiovascular events.

Subjects.
A total of 10,247 Japanese adults (7385 subjects from the FMD-J study and 2862 subjects who underwent a health checkup at Hiroshima University Hospital between August 2010 and August 2016) were enrolled in this study 26 . The FMD-J study was a prospective multicenter study conducted at 22 university hospitals and affiliated clinics in Japan to examine the usefulness of FMD in risk stratification for cardiovascular disease in Japanese subjects 26 . The rationale and design of the FMD-J study have been described previously 26 . Subjects with unclear images of the brachial artery interfaces and subjects without information on ABSI were excluded. From this registry, 8823 subjects were recruited. ABSI was calculated by the following equation: waist circumference (m)/[BMI 2/3 (kg/m 2 ) × height 1/2 (m)] 18 . Hypertension was defined as treatment with oral antihypertensive agents or systolic blood pressure of more than 140 mm Hg or diastolic blood pressure of more than 90 mm Hg measured in a sitting position on at least three different occasions. Diabetes mellitus was defined as treatment with diabetic medication or fasting plasma glucose level ≥ 6.99 mmol/L and hemoglobin A1c level ≥ 48 mmol/mol 40 . Dyslipidemia was defined as treatment with lipid-lowering agents or low-density lipoprotein cholesterol ≥ 3.62 mmol/L or high-density lipoprotein cholesterol < 1.03 mmol/L or triglyceride ≥ 1.69 mmol/ L 41 . Smokers were defined as those who were current smokers. Coronary heart disease included angina pectoris, myocardial infarction, and unstable angina. Cerebrovascular disease included ischemic stroke, hemorrhagic stroke, and transient ischemic attack. Cardiovascular disease was defined as coronary heart disease and cerebrovascular disease. Framingham risk score was calculated by points of risk factors: age, total cholesterol level, high-density lipoprotein cholesterol level, systolic blood pressure, diabetes mellitus, and smoking status 42 .
Hiroshima University ethical committee approved the study protocol. The study was executed in accordance with the Good Clinical Practice guidelines. Informed consent for participation in the study was obtained from all subjects. The protocol was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000012952).

Figure 6.
Odds ratios and 95% confidence intervals for predicting patients with a history of cardiovascular disease of high a body shape index (ABSI) using the low ABSI group as the reference. Low ABSI indicates less than 0.0796 in men and less than 0.0823 in women. Model 1: Adjusted for age. Model 2: Adjusted for age, body mass index, and smokers. Model 3: Adjusted for age, body mass index, presence of hypertension, dyslipidemia, and diabetes, and smokers.