Normal-Weight Obesity and Subclinical Atherosclerosis Risk
Clinical and biochemical characteristics of the study subjects are presented in Table 1 . In total, 52.5 % (n = 1795) and 8.3 % (n = 283) of the whole study population (n = 3546) were categorized as NWL and NWO, respectively, after excluding the subjects who did not meet the inclusion criteria. Because NWO subjects were older (p < 0.001) and NWO were less likely to be males (p < 0.001), and have less smokers (p = 0.003), we next analyzed all subsequent clinical and biochemical characteristics after adjusting for age, sex, and smoking as covariates using ANCOVA.
Compared to the NWL group, the NWO group had a significantly higher mean PWV value even after adjusting with age, sex, and smoking as covariates (1474.0 ± 275.4 vs. 1380.7 ± 234.3 cm/s, p = 0.006). However, there were no significant differences in the prevalence of any coronary calcium (CACS >0; 27.2 % vs. 24.3 %, p = 0.509), severe coronary calcium (CACS >100; 9.2 % vs. 8.4 %, p = 0.286), nor mean difference of log (CACS + 1) (0.43 ± 0.78 vs. 0.39 ± 0.77, p = 0.264) between the NWL and NWO groups. There was no difference in the incidence of significant coronary artery stenosis (>50 % stenosis of any major vessel) between the two groups (2.1 % vs. 3.9 %, p = 0.075).
Next, we evaluated the prevalence of coronary artery plaque according to the plaque characteristics. The plaques were classified as calcified, mixed, or soft as previously defined. The prevalence of any plaque and the log value of the number of coronary segments with any plaque in the NWO subjects were not significantly different between the two groups (45.2 % vs. 35.6 %, p = 0.176 for the prevalence of any coronary plaque; 0.22 ± 0.26 vs. 0.17 ± 0.25, p = 0.295 for the log{(number of segments with plaque) + 1}). When the prevalence of plaque was analyzed according to the plaque characteristics, NWO subjects had a significantly higher prevalence of soft plaque (21.6 % vs. 14.5 %, p = 0.039) compared to the NWL subjects. However, there were no differences in the incidence of calcified or mixed plaques. Detailed comparisons of the parameters are summarized in Table 2 . We also analyzed the difference of the prevalence of soft plaque in the sex- and BMI-matched pairs (n = 230 for each group). The PWV value and the prevalence of soft plaque were consistently higher in the NWO subjects compared NWL subjects in the matched pairs (PWV, 1484.3 ± 282.4 vs. 1379.5 ± 251.0 cm/s, p < 0.001; soft plaque, 21.7 % vs. 13.5 %, p = 0.026)
To analyze the risk factors for elevated PWV and the number of coronary segments with plaque, we performed univariate and multivariate regression analyses ( Table 3 ). On univariate analysis, age, systolic and diastolic BP, body fat percentage, amount of visceral fat, amount of subcutaneous fat, and fasting glucose, triglyceride, HDL-cholesterol, and CRP levels were significantly associated with PWV and also with log{(number of segments with plaque) + 1}. To analyze the effect of fat on PWV and the number of coronary segments with plaque, we also performed a multivariate regression analysis with the above significant risk factors. After adjusting for other factors such as age, systolic BP, and fasting glucose, triglyceride, and CRP levels, the amount of visceral fat was an independent risk factor for the number of coronary segments with plaque. However, none of the factors related to fat (body fat percentage and amount of visceral fat or subcutaneous fat) were predictive of PWV after adjusting for other risk factors in a multivariate correlation analysis.
To determine the actuarial risk of subclinical atherosclerosis in NWO subjects compared to NWL subjects, we divided the whole population into tertiles according to PWV values. The population was also divided into those with or without coronary plaques and those with or without soft plaques. The risk of being in the highest tertile of PWV was 1.394-fold higher in the NWO group compared to the NWL group after adjusting for age and sex (adjusted OR 1.394, 95 % confidence interval [CI] 1.043–1.862, p = 0.025). This turned nonsignificant after further adjusting for systolic BP and fasting glucose, HDL, and CRP levels. Although the risk of having any plaque was higher in NWO compared NWL (adjusted OR 1.494, 95 % CI 1.160–1.924, p = 0.002), this also turned out to be nonsignificant after adjusting for age and sex. However, the risk of having a soft coronary plaque in the NWO group was significantly higher than that in the NWL group, even after adjusting for age and sex (adjusted OR 1.586, 95 % CI 1.146–2.194, p = 0.005). This importance of NWO subjects having soft coronary plaque was persistently significant, even with the addition of other factors known to influence the development of atherosclerosis, such as systolic BP, fasting glucose, HDL, CRP levels, hypertension medication, diabetes medication, lipid-lowering agents, antiplatelet agents, the smoking status, and physical activity (adjusted OR 1.460, 95 % CI 1.027–2.074, p = 0.035) ( Table 4 ).
Results
Clinical and Biochemical Characteristics of the Study Population
Clinical and biochemical characteristics of the study subjects are presented in Table 1 . In total, 52.5 % (n = 1795) and 8.3 % (n = 283) of the whole study population (n = 3546) were categorized as NWL and NWO, respectively, after excluding the subjects who did not meet the inclusion criteria. Because NWO subjects were older (p < 0.001) and NWO were less likely to be males (p < 0.001), and have less smokers (p = 0.003), we next analyzed all subsequent clinical and biochemical characteristics after adjusting for age, sex, and smoking as covariates using ANCOVA.
Differences in PWV, Coronary Calcium, and Incidence of Intracoronary Stenosis/Plaque Between the NWL and NWO Subjects
Compared to the NWL group, the NWO group had a significantly higher mean PWV value even after adjusting with age, sex, and smoking as covariates (1474.0 ± 275.4 vs. 1380.7 ± 234.3 cm/s, p = 0.006). However, there were no significant differences in the prevalence of any coronary calcium (CACS >0; 27.2 % vs. 24.3 %, p = 0.509), severe coronary calcium (CACS >100; 9.2 % vs. 8.4 %, p = 0.286), nor mean difference of log (CACS + 1) (0.43 ± 0.78 vs. 0.39 ± 0.77, p = 0.264) between the NWL and NWO groups. There was no difference in the incidence of significant coronary artery stenosis (>50 % stenosis of any major vessel) between the two groups (2.1 % vs. 3.9 %, p = 0.075).
Next, we evaluated the prevalence of coronary artery plaque according to the plaque characteristics. The plaques were classified as calcified, mixed, or soft as previously defined. The prevalence of any plaque and the log value of the number of coronary segments with any plaque in the NWO subjects were not significantly different between the two groups (45.2 % vs. 35.6 %, p = 0.176 for the prevalence of any coronary plaque; 0.22 ± 0.26 vs. 0.17 ± 0.25, p = 0.295 for the log{(number of segments with plaque) + 1}). When the prevalence of plaque was analyzed according to the plaque characteristics, NWO subjects had a significantly higher prevalence of soft plaque (21.6 % vs. 14.5 %, p = 0.039) compared to the NWL subjects. However, there were no differences in the incidence of calcified or mixed plaques. Detailed comparisons of the parameters are summarized in Table 2 . We also analyzed the difference of the prevalence of soft plaque in the sex- and BMI-matched pairs (n = 230 for each group). The PWV value and the prevalence of soft plaque were consistently higher in the NWO subjects compared NWL subjects in the matched pairs (PWV, 1484.3 ± 282.4 vs. 1379.5 ± 251.0 cm/s, p < 0.001; soft plaque, 21.7 % vs. 13.5 %, p = 0.026)
Correlation Between Cardiometabolic Factors and PWV or Number of Coronary Segments With Plaque
To analyze the risk factors for elevated PWV and the number of coronary segments with plaque, we performed univariate and multivariate regression analyses ( Table 3 ). On univariate analysis, age, systolic and diastolic BP, body fat percentage, amount of visceral fat, amount of subcutaneous fat, and fasting glucose, triglyceride, HDL-cholesterol, and CRP levels were significantly associated with PWV and also with log{(number of segments with plaque) + 1}. To analyze the effect of fat on PWV and the number of coronary segments with plaque, we also performed a multivariate regression analysis with the above significant risk factors. After adjusting for other factors such as age, systolic BP, and fasting glucose, triglyceride, and CRP levels, the amount of visceral fat was an independent risk factor for the number of coronary segments with plaque. However, none of the factors related to fat (body fat percentage and amount of visceral fat or subcutaneous fat) were predictive of PWV after adjusting for other risk factors in a multivariate correlation analysis.
Independent Risk Factors for Subclinical Atherosclerosis in NWO
To determine the actuarial risk of subclinical atherosclerosis in NWO subjects compared to NWL subjects, we divided the whole population into tertiles according to PWV values. The population was also divided into those with or without coronary plaques and those with or without soft plaques. The risk of being in the highest tertile of PWV was 1.394-fold higher in the NWO group compared to the NWL group after adjusting for age and sex (adjusted OR 1.394, 95 % confidence interval [CI] 1.043–1.862, p = 0.025). This turned nonsignificant after further adjusting for systolic BP and fasting glucose, HDL, and CRP levels. Although the risk of having any plaque was higher in NWO compared NWL (adjusted OR 1.494, 95 % CI 1.160–1.924, p = 0.002), this also turned out to be nonsignificant after adjusting for age and sex. However, the risk of having a soft coronary plaque in the NWO group was significantly higher than that in the NWL group, even after adjusting for age and sex (adjusted OR 1.586, 95 % CI 1.146–2.194, p = 0.005). This importance of NWO subjects having soft coronary plaque was persistently significant, even with the addition of other factors known to influence the development of atherosclerosis, such as systolic BP, fasting glucose, HDL, CRP levels, hypertension medication, diabetes medication, lipid-lowering agents, antiplatelet agents, the smoking status, and physical activity (adjusted OR 1.460, 95 % CI 1.027–2.074, p = 0.035) ( Table 4 ).
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