The primary results of JAPAN–ACS indicated that diabetes mellitus attenuated the effect of statins in terms of plaque regression. The present sub-study of JAPAN-ACS investigates the association between plaque progression/regression and the serum levels of AGEs as well as sRAGE. The baseline AGEs level was significantly higher in patients with plaque progression (8.4 ± 2.2 vs. 9.4 ± 1.9U/ml), although this association was independent of diabetes mellitus. In addition, there was no correlation between the change in AGEs levels and percent change in PV, although the AGEs levels reduced significantly during 10 months of follow-up. The sRAGE levels did not demonstrate any correlation with plaque progression or regression. Further, in the present study, although the AGEs levels were not different between patients with diabetes and those without, they were significantly higher in smokers than in nonsmokers, and they tended to be higher in men than in women.
There is accumulating evidence that AGEs and RAGE are implicated in the pathogenesis of various devastating disorders such as diabetic vascular complications, cardiovascular disease, Alzheimer’s disease, cancer growth and metastasis, insulin resistance and non-alcoholic steatohepatitis [15, 16, 23–25]. Harmful effects of AGEs were predominantly observed in large vessels [26–28]. Indeed, it was reported that AGEs decreased large vessel elasticity and elicited inflammatory and pro-thrombotic responses in the vessel wall, thereby being involved in vascular complications [26–28]. Furthermore, the expression levels of AGEs and RAGE were increased in diabetic atherosclerotic lesions [29, 30] Because AGEs are generated not only from Amadori products under hyperglycemic conditions, but also from dicarbonyl compounds derived from the Maillard reaction, the auto-oxidation of reducing sugars and other metabolic pathways of glucose . They include heterogeneous molecules such as carboxymethyllysine, pentosidine, and glyceraldehyde-derived AGEs [23–25]. In the present study, we measured levels of glyceraldehyde-derived AGEs, which could reflect inflammatory oxidative stress conditions and/or hyperglycaemic states [23–25]. Thus the levels of AGEs measured here may be influenced by both the presence of diabetes mellitus and its long-term control of hyperglycemia, and by additional oxidative stress conditions such as smoking status.
In this study, the baseline levels of AGEs were significantly higher in patients with plaque progression than in those without progression, although the reduction in the levels of AGEs did not correlate with the change in PV. In the multivariate logistic regression analysis, the presence of diabetes mellitus and baseline level of AGEs were significant, independent variables associated with the plaque progression. This further supports the pathological role for AGEs in accelerated atherosclerosis in humans.
In the present study, although statin therapy reduced the levels of AGEs, this reduction did not correlate with the change in PV. AGEs are hardly degraded and remain for a long time in diabetic vessels even after glycemic control and oxidative stress conditions have been improved . Therefore, the phenomenon of so-called metabolic memory could be explained, in part, by AGEs . In other words, the harmful effects of AGEs on plaque progression may not be easily reversed by short-term statin therapy. Former smokers remain at an increased risk for developing lung cancer and cardiovascular disease even years after they stop smoking . Because this phenomenon has an interesting analogy to metabolic memory, and because tobacco smoking is a major environmental source of AGEs in humans , the deleterious effects of smoking on atherosclerosis could be mediated, in part, by AGEs. In this study, the levels of sRAGE did not show any relationship to plaque progression or regression. Although RAGE definitely plays an important role in atherosclerotic progression [33, 34], the value of measuring sRAGE levels remains uncertain. Further study is warranted.
Although the present study indicated the possible adverse effect of AGEs on plaque regression during the statin therapy, some limitations should be considered. First, AGEs and sRAGE levels were measured in 208 frozen samples from patients who participated in JAPAN–ACS that only accounted for two-thirds of all participants. However, the lack of sample did not occur systematically, and the effects were small if present. Second, the end point of the JAPAN–ACS trial was the change in total atheroma volume, whose index may not be affected by the AGE–RAGE axis. However, given the pivotal role of the AGE–RAGE axis in experimental atherosclerosis [15, 28–30], the present findings could provide some new insight into the pathophysiology of plaque progression and regression in patients with ACS. Finally, the number of patients with plaque progression was small. Thus, to avoid the overloading of multivariate model, we could not include all potential confounders. We thus used the factors associated with in the previous study to adjust the confounding as much as possible.