Most cases of sudden cardiac death and myocardial infarction arise from thrombotic coronary occlusion following coronary plaque rupture. Diabetic patients had more plaque ruptures and thrombus than non-diabetic patients in ACS, which may be associated with the greater rates of cardiovascular events in diabetes . However, available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The search for noninvasive approach to detect the plaque rupture was encouraged to perform. In our present study, the principal result shows that serum 1,5-AG, as a biomarker of short-term postprandial hyperglycemia and GV, might be an important surrogate marker of coronary plaque rupture in diabetic patients with NSTE-ACS.
1,5-AG is a naturally occurring 1-deoxy form of glucose. As glucose levels surpass the renal threshold for glucosuria (generally around 10 mmol/L), 1,5-AG is excreted in the urine leading to a rapid reduction in serum levels . Therefore, poor glycemic control is associated with low, rather than high, serum 1,5-AG levels. In the present study, we used IVUS to identify plaque rupture in culprit lesion of diabetic patients with NSTE-ACS and found that the 1,5-AG levels were significantly lower in patients with ruptured plaque than in patients without ruptured plaque. Meanwhile, patients with ruptured plaque had higher non-HDL-c levels and tendencies of higher HbA1c levels compared to patients with non-ruptured plaque. Univariate and multivariate logistic regression analyses showed that low 1,5-AG and high non-HDL-c levels were independent predictors of plaque rupture of culprit lesion in diabetic patients with NSTE-ACS. These results indicated that poor glycemic control and dyslipidemia may be associated with the coronary plaque rupture in diabetes. Preliminary data have shown that 1,5-AG could be expected to best reflect postprandial hyperglycemia in moderately controlled patients, and was more sensitive and specific than HbA1c . Furthermore, as PPG increments are the major contributors to GV in T2DM, 1,5-AG may be particularly suited for monitoring postprandial hyperglycemic excursions . Unlike HbA1c, 1,5-AG is not affected by hypoglycemia. As a result, 1,5-AG appears to differentiate patients with extensive PPG excursions despite having similar HbA1c levels. Selvin et al. reported that patients with low 1,5-AG levels had an increased risk of coronary artery disease, stroke, heart failure, and death compared to patients with high 1,5-AG levels . Takahashi et al. reported that low and exacerbated levels of 1,5-AG are associated with cardiac mortality in ACS patients . The study of Fujiwara et al. showed that 1,5-AG was associated with the presence of de novo coronary artery disease in both well-controlled diabetic and non-diabetic patients . Wada et al. found that low 1,5-AG level was associated with the severity of coronary artery calcification . The current study is the first to report that 1,5-AG levels are significantly associated with coronary plaque rupture in diabetic patients with NSTE-ACS. Moreover, the ROC curve analysis showed 1,5-AG displayed more significant value in predicting plaque rupture than HbA1c. These findings may partly explain the results of previous studies that 1,5-AG levels were associated with cardiovascular outcomes and support the hypothesis that PPG excursions is strongly associated with the atherosclerotic vulnerable plaque process.
Although the identified role of PPG excursions in the pathogenesis of plaque rupture has not been clarified, oxidative stress, inflammation and endothelial dysfunction may be involved in the process. It was demonstrated that glucose excursions increased oxidative stress than chronic hyperglycemia in T2DM . Ceriello et al. showed that targeting postprandial hyperglycemia has the potential to reduce oxidative stress . We have recently reported that glycemic variability, a component of which is PPG excursions, was significantly correlated with oxidative stress measured as urinary 8-iso-PGF2α in patients with ACS . The present study showed that serum 1,5-AG level, but not HbA1c, was strongly correlated with urinary 8-iso-PGF2α level in diabetic patients with NSTE-ACS. This is in accordance with the previous report of Kohata et al. that 1,5-AG is the strong correlate of oxidative stress in patients with T2DM , and it suggests that PPG excursions can be more important than mean glucose to induce oxidative stress in diabetes. It has been demonstrated that oxidative stress plays a key role in atherosclerotic plaque progression . Our previous study showed that increased urinary 8-iso-PGF2α levels were closely associated with greater absolute and percent necrotic core volumes of coronary lesions in diabetic patients . In a pathological study by Nishibe et al., 8-iso-PGF2α was found enriched in coronary plaque specimens especially from vulnerable patients, suggesting a crucial role of free radicals in the formation of vulnerable plaques . Yura et al. reported that 8-iso-PGF2α per se could stimulate endothelin-1 mRNA and protein expression in bovine aortic endothelial cells . Endothelin-1 may cause the stimulation of vascular smooth muscle proliferation and formation of macrophage-rich atherosclerotic plaques . In the study of Esposito et al., the results suggested that acute hyperglycemia, and not sustained elevation of blood glucose levels, could exaggerate inflammation by an oxidative mechanism . Teraguchi et al. reported that dynamic glucose fluctuation was positively and significantly associated with CD14bright CD16 + monocytes levels and might be related to coronary plaque rupture in patients with acute myocardial infarction . All these findings suggest that postprandial hyperglycemic excursions may be involved in progression and destabilization of coronary plaques through the preferential increase in oxidative stress, proinflammatory cytokines, and endothelial dysfunction. Optimizing PPG excursions management may be helpful to prevent the rupture of coronary plaque in diabetic patients.
Several study limitations should be considered in the interpretation of the results. First, the sample size was relatively small, so that it may have influenced the results and the statistical analyses. Second, because we evaluated only limited patients who underwent IVUS and didn’t meet any exclusion criteria, our results could have been affected by selection bias and cannot be generalized to all patients. Third, the assessment of plaque rupture was made by IVUS in this study. Although it has been demonstrated that IVUS can provide detailed, high-quality tomographic images to detect plaque rupture, it might be likely that some plaque ruptures were undetected. More detailed plaque morphology could be obtained by combining IVUS with optical coherence tomography (OCT), virtually increasing accuracy for plaque rupture detection. Finally, this is an observational study. The observational nature of analysis means that we cannot infer causality in the associations we have demonstrated. Future longitudinal and prospective studies are needed to address these issues.