## 4 Discussion
In the present study, although patients with low levels of cystatin C showed a lower median value of CAC score, we did not find any statistically significant association after univariable and multivariable analysis. These findings contrast with those observed by [PERSON] et al. [32] who found a positive correlation between Agatston score and cystatin C levels in 410 stable patients. These discrepancies may be related to both different clinical setting and different sample size. Thirdly, unlike the previous imagine techniques that provide just morphological information, \({}^{18}\)F-FDG-PET is a molecular noninvasive imaging technique that reports on the metabolic activity of atherosclerosis since glucose is the major substrate for macrophages resident in plaque [33]. \({}^{18}\)F-FDG uptake in macrophages is positively correlated with the level of pro-inflammatory activation [34]. Accordingly, the relationship between arterial \({}^{18}\)F-FDG signal and plaque macrophage infiltration has been reported both in animal models [35] and humans, especially at the level of carotid plaques, aorta, and iliac-femoral arteries [36; 37; 38]. In the present study, we found that \({}^{18}\)F-FDG uptake in the thoracic DA was associated with low levels of serum cystatin C after adjustment for CRP and eGRF. This association was not observed for the \({}^{18}\)F-FDG uptake in the AA wall suggesting that the presence of atherosclerotic plaques increases substantially from the ascending aorta to the descending aorta [39]. Therefore, findings of the present study support in vivo data obtained from experimental studies showing that macrophage activation in atherosclerotic lesions is associated with an increased level of elastolytic cathepsins and decreased level of their inhibitors, such as cystatin C [40; 41]. Notably, our study had several exclusion criteria aimed at excluding cardiac and non-cardiac conditions that may be associated with either secondary forms of acute coronary syndrome or release of pro-inflammatory mediators. In particular, patients with heart failure [42], corticoid treatment [43], and thyroid dysfunction [44] that may have influenced circulating cystatin C levels were excluded. Taken together, the findings of our study do not support the theory that high levels of cystatin C are independently associated with the extent of coronary disease. On the contrary, we showed that metabolic plaque activity in the DA wall was associated with low levels of serum cystatin C. Given these observations and the available literature, we suggest that high levels of cystatin C represent mainly a marker of renal function abnormalities that promote impaired outcome, rather than a marker of atherosclerosis. The results of the present study should be interpreted with caution in light of some limitations. Since no data were available regarding the relationship between FDG uptake in the aortic wall and serum cystatin C levels we were prevented from calculating the sample size a priori. Nonetheless, we found a statistically significant association between FDG uptake in the DA and cystatin C levels. However, this finding showed a certain degree of imprecision with wide confidence intervals. As mentioned above, owing to our small sample size we could have missed some significant relationship as well. Although the 2 study groups were well balanced in terms of baseline characteristics, the effect of unknown confounders on cystatin C values cannot be ruled out. In particular, we do not know the distribution of genetic polymorphisms in the study population. Because of several technical issues such as \({}^{18}\)F-FDG -PET low spatial resolution, small size of coronary plaques, cardiac motion, and myocardium avidity for glucose as energetic substrate, using \({}^{18}\)F-FDG-PET to measure inflammation in coronary artery plaques is suboptimal [45]. Conversely, \({}^{18}\)F-sodium fluoride [45] has been shown to better identify coronary plaques with high-risk features, but this was beyond the scope of our study.