The results of this study show that a large VAT area is associated with various characteristics of vulnerable coronary artery plaques on CTA in patients without DM, but not in patients with DM. The prevalence of vulnerable plaques was similar in all VAT area tertiles of patients with DM (about 20%) and in the highest VAT area tertile in patients without DM. These findings support the hypothesis that a large VAT area is a cardiometabolic risk factor that is significantly associated with vulnerable plaque before the development of DM, and that measurement of the VAT area is useful for assessing cardiovascular risk in patients without DM.
The results of this study show a positive association between a large VAT area and the NCP burden on CTA in patients without DM, but not in patients with DM. Several previous studies reported that the VAT area was an independent marker of CAD [13, 22]. Excess VAT triggers insulin resistance, which may be accompanied by release of inflammatory mediators and cytokines from dysfunctional adipose tissue and may be strongly associated with the formation and progression of coronary artery plaques. The different associations of the VAT area with characteristics of coronary plaques in different groups in this study may be explained by variations in HDL-cholesterol and HbA1c levels, which are known to be associated with cardiovascular risk [23, 24]. In patients without DM, the HDL- cholesterol and HbA1c levels changed unfavorably with increasing VAT area tertiles, whereas in patients with DM, these factors were not significantly different among the VAT area tertiles. The hsCRP level was significantly higher in the VAT area T3 group than in the T1 and T2 groups in patients without DM, but was not significantly different among tertiles in patients with DM. Another explanation is that hyperglycemia may be the main factor determining cardiovascular risk in patients with DM, and may override the effects of excess VAT-dependent inflammatory mediators and cytokines. Oxidative stress caused by hyperglycemia  and advanced glycation end products  may have greater effects on plaque characteristics in patients with DM than in patients without DM, and may attenuate the impact of the VAT area. However, our findings are not consistent with those of a cross-sectional study which reported that the amount of VAT was strongly associated with cardiometabolic risk factors regardless of type 2 diabetes status . This difference may be partly owed to differences in ethnicity of the study populations. The previous study was conducted in a population that included only 8.2% East Asian individuals, and did not include patients with suspected CAD, both of which were characteristics of our study subjects. Another study reported that the amount of VAT was not an independent coronary risk factor after adjustment for multiple covariates, although VAT was one of the variables influencing the development of atherosclerosis . This is consistent with our hypothesis that visceral obesity is an important coronary risk factor, but precedes the development of DM. In patients without DM in this study, hypertension, dyslipidemia, and high triglyceride level tended to be associated with vulnerable plaque, but these associations were not statistically significant. A large amount of VAT increased the risks of cardiovascular risk factors such as hypertension and dyslipidemia, but these factors may not have sufficient individual impact to lead to the development of vulnerable coronary plaques. In other words, the amount of VAT is considered to be a representative marker of cardiometabolic risk, and may therefore be associated with plaque characteristics.
In this study, the highest tertile of the VAT area included a higher proportion of men than the other tertiles in patients with and without DM. Although there were no significant differences between males and females in the majority of cardiovascular risk factors, HDL and triglyceride levels have been reported to have a greater impact on coronary artery disease in women than in men . In addition, smoking and inflammation (detected by a high CRP level) have been reported to have a more negative influence on coronary artery disease in women than in men. These sex differences may affect the prevalence of vulnerable plaque in different tertiles in patients without DM. However, our finding that there was a similar proportion of men in the highest tertile of the VAT area in patients with and without DM suggests that sex differences did not have a great impact on the associations between VAT and plaque characteristics.
The results of this study show associations between vulnerable coronary artery plaques and adiposity measurements on CT. VAT area T3, BMI T2, and WC T2 were significantly associated with vulnerable plaque in patients without DM. A previous study reported that a large VAT area was significantly associated with both the presence and extent of NCPs, whereas BMI and WC were not . One possible reason for this difference is that they did not analyze these factors separately in patients with and without DM.
It is easier to evaluate adipose tissue attenuation and volume on CT than on ultrasonography . Recently, the quality of abdominal fat attenuation has been reported to be associated with cardiometabolic risk, suggesting that evaluation of adipose tissue quality as well as quantity may be useful . Other studies reported that epicardial adipose tissue was independently associated with coronary artery disease and coronary plaque characteristics [32–35]. Further studies are needed to clarify the associations between deposition of various adipose tissues and coronary plaque characteristics.
Several limitations of this study should be considered. First, this study was a single-center, retrospective study that included only 456 Japanese patients with suspected CAD. These subjects had a higher prevalence of risk factors than the general population, and the results may not be applicable to the general population or to other ethnicities. Further investigation in a larger population is needed to definitively determine the associations among VAT, vulnerable plaque, and DM. Second, adipocytokine levels were not measured, and this study was unable to determine a causal relationship between the amount of VAT and plaque vulnerability. However, these biomarkers are under investigation, and the lack of adipocytokine data does not affect the relationship between VAT and vulnerable plaque shown by this study. Third, we excluded all patients with a history of coronary artery stenting or coronary artery bypass graft surgery because of the unreliability of coronary plaque assessment by CTA in such patients. Although this resulted in exclusion of 9% of the patients from our original study population, this probably had minimal effects on the analyses. As the accuracy of detection of obstructive CAD is decreased in patients with a high coronary artery calcium score [36, 37], there is concern that the prevalence of vulnerable plaque is underestimated in the higher VAT tertiles of patients with DM. However, our finding that there were no significant differences in coronary artery calcium scores among the different tertiles in patients with DM may alleviate concerns over this issue. Finally, the latest consensus document on coronary CTA  states that plaque characteristics in coronary CTA are not well established. Even though this study assessed plaque characteristics as previously reported , substantial additional technical developments will be required to define the usefulness of these characteristics in terms of patient management.
In conclusion, the results of this study show that a large VAT area is associated with characteristics of vulnerable coronary plaques on CTA in patients without DM, but not in patients with DM. Our findings support the hypothesis that VAT is a significant cardiometabolic risk factor that is associated with vulnerable plaque before the development of DM. CTA findings may help to improve risk stratification in such patients.