To our knowledge, this is the first study to demonstrate that compared to NWL subjects, NWO subjects have a higher degree of vascular inflammation using 18 F-FDG-PET/CT. Furthermore, the findings also reveal the significant contribution of body fat to subclinical vascular inflammation, even in the normal BMI population. Thus, the main finding of the present study is that more active and earlier surveillance of subclinical vascular inflammation may be required to prevent clinical vascular events, even in patients who were not defined as obese by the classical definition.
BMI is calculated as the weight divided by the square of height. Body weight is mainly composed of muscle mass and fat mass. It is well known that muscle is a type of endocrine organ, exercise has an anti-inflammatory effect on vessels, and excess fat mass exerts harmful effects on vascular inflammation [30, 31]. Obesity is principally defined as the presence of excess fat mass with elevated cardiometabolic risk. Therefore, although BMI is the most easily used and widely accepted criteria for defining obesity , BMI can miscategorize a significant proportion of subjects who have lower muscle mass content and higher body fat levels as those having a same cardiovascular risk as healthy, non-obese subjects [7–10]. Previous studies have indicated the elevation of carotid artery TBR in obese subjects with BMI values of ≥25 kg/m2 or BMI values of ≥30 kg/m2. In addition, several studies identified a persistent positive correlation between TBR and BMI even after adjusting for confounding factors [32, 34]. However, none of these studies assessed the possibility of NWO, previously classified as not obese, as a potential risk for vascular inflammation. The importance of our study lies in identifying NWO as a novel risk factor for increased vascular inflammation and in determining that body fat itself, rather than BMI, is more important as a driving force for this subclinical inflammation.
Several reports have indicated that visceral fat may have a greater harmful effect on vascular inflammation than subcutaneous fat . When we analyzed the degree of vascular inflammation in subjects with excess visceral fat or in subjects with excess subcutaneous fat by generating new parameters such as “the ratio of visceral-to-subcutaneous fat amount” or “the ratio of subcutaneous-to-visceral fat amount,” the value of TBRmean and TBRmax were found to be higher in the subjects with higher visceral-to-subcutaneous fat ratio and lower in the subjects with higher subcutaneous-to-visceral fat ratio. This suggests that varying ratios of depot-specific fat amount may have different effects on vascular inflammation (Data not shown). Moreover, we suggest that the ratio of visceral-to-subcutaneous adipose tissue may be essential for vascular inflammation, even in normal weight subjects. However, it should be considered that an increment in the absolute amount of total fat, regardless of whether it involves visceral or subcutaneous fat, may definitely exert a harmful effect on vascular inflammation, even in normal weight subjects, as shown in the present data. Although we could not extensively analyze the depot-specific effect of body fat on vascular inflammation in normal weight subjects in the present study, the findings obtained in the present study indicate that this topic warrants further investigation.
De Lorenzo et al. reported that the levels of inflammatory cytokines interleukin-6 and tumor necrosis factor-α, which are secreted by adipose tissue, are elevated in NWO subjects compared to their NWL counterparts . These fat-derived inflammatory factors can affect the development of atherosclerosis [36, 37]. In addition, Yoo et al. suggested that circulating adipocyte fatty acid binding protein, primarily expressed in adipocytes, is an independent determinant of vascular inflammation measured by 18 F-FDG-PET/CT . Moreover, the NWO population in the present study also exhibited higher levels of the inflammation marker CRP, although the difference was not significant. Thus, these findings demonstrate that subclinical vascular inflammation may be caused by direct or indirect inflammatory signals from adipose tissue in NWO subjects. NWO subjects may be genetically predisposed to obesity and elevated cardiovascular risk , whereas the regulation of caloric excess may prohibit the development of obesity and elevation of cardiovascular risk . As subclinical atherosclerosis can finally be presented as a clinically significant cardiovascular event , future strategies to identify susceptible subjects (such as NWO individuals in the present study) and to develop interventions to prohibit the development of a cardiovascular event in the population with subclinical atherosclerosis are warranted. These findings also emphasize that it is critical to identify a useful biomarker for selecting the population at risk for adipose tissue-associated vascular inflammation, including subjects with a normal BMI. The usefulness of the biomarkers may be validated with the non-invasive 18 F-FDG-PET/CT imaging technique as conducted in our study.
Before the introduction of 18 F-FDG-PET/CT as a non-invasive imaging tool for visualizing the early inflammation of atherosclerosis in the vessel, there was no definite method to detect subclinical atherosclerosis [42, 43]. The current methods such as intima-media thickness, coronary computed tomography angiography, and coronary angiography mainly evaluate the structural change of the vessels, which is a manifestation of progressed atherosclerosis . In the present analysis, importantly, some patients in the NWO group had a very high degree of vascular inflammation (TBRmax > 2.0), a finding that has not been observed in NWL subjects thus far. Severe inflammatory lesions may result in a clinically meaningful CVD event [45, 46]. In addition, studies involving non-invasive functional imaging of vascular inflammation using 18 F-FDG-PET/CT indicated that these highly inflammatory lesions can serve as targets of earlier intervention in NWO subjects, the results of which were promising in a small population [34, 47–50]. However, further studies would need to investigate whether the use of this technique results in a clinically significant reduction of future vascular events.
This study has several limitations. Our study used an arbitrary cutoff value of BF% based on the tertiles of BF% to define NWO. However, there is no established cutoff value for delineating the harmful effect of body fat on a cardiometabolic event. Therefore, although arbitrary, we followed the method used in a previously published paper . Determination of the optimal cutoff value of BF% for discriminating the subjects at high risk for future CVD events will be necessary. Second, we used a relatively simple BI method to evaluate the body fat. However, there are concerns that the BI method might underestimate upper body obesity , and dual energy X-ray absorptiometry might be more accurate for evaluating BF%. In contrast, the BI method has several advantages such as the avoidance of radiation exposure, simplicity, and low cost, suggesting the utility of BF estimation in large-scale studies . Third, this study is a cross-sectional study that cannot confirm a direct causal relationship between BF and vascular inflammation. Nevertheless, to our knowledge, this is the first study to target the NWO population specifically in a community-oriented cohort. Furthermore, this study has a relatively large sample size among studies on vascular inflammation using 18 F-FDG-PET/CT. Nevertheless, a prospective study with a longer study period is warranted in the future to confirm whether vascular inflammation assessed by 18 F-FDG-PET/CT is actually associated with CVD events.