This community-based study investigated the association between HbA1c and carotid IPH detected by HR-MRI. We found that high HbA1c was significantly associated with carotid plaque IPH, which suggested that HbA1c may be an independent indicator for IPH in carotid plaques.
In this study, the prevalence of intraplaque hemorrhage was 4.2% (25/598), broadly in line with the prevalence of IPH in Atherosclerosis Risk in Communities (ARIC) study (5.4%)-an asymptomatic community-based cohort (12). In the population-based Rotterdam study, the prevalence of IPH detected by high-resolution MRI was almost 25% (13) (14), which was much higher than the prevalence in our study. However, a comparison of IPH prevalence between our study and the Rotterdam study was not reasonable because the difference of enrollment criteria. The Rotterdam study was conducted in participants with carotid wall thickening≥2.5 mm on ultrasound, and these selected subjects underwent MRI scanning. Furthermore, subjects from the Rotterdam study were elder compared with our study (70.3±10.2 vs.59.7±13.8), which could also contribute to the prevalence discrepancy. Generally, the prevalence of carotid IPH increases with age (15).
In this study, we found that the level of HbA1c was associated with carotid IPH, which was a primary characteristic of vulnerable plaques. Previous studies have identified the association between HbA1c and subclinical atherosclerosis, suggesting that HbA1c may be involved in the early stage of atherosclerosis (4, 5, 16, 17). As the development of atherosclerosis, the rupture of vulnerable carotid plaques could result in ischemic stroke (1). Association between glycation and ischemic stroke has also been observed (6, 18-22). Chronic exposure to raised glycemia could play an essential role in developing stroke (23, 24). This is consistent with the hypothesis that advanced glycation end products may be involved in every stage of atherosclerosis. Recently, in the population-based Rotterdam study, Mujaj and colleagues found that serum insulin levels were associated with the presence of IPH (OR, 1.42; 95% CI, 1.12-1.7) (25). They speculated that insulin medicated abnormal neovascularization through an increased level of vascular endothelial growth factor. The association between HbA1c and IPH in carotid plaque may be explained by the inflammatory response in adventitia induced by hyperglycemia. IPH is primarily caused by leakage and rupture of immature neovessels, which were a result of invasion from the adventitia vasa vasorum towards the intima (26). About 80% of the vasa vasorum within the plaque had poor integrity and was vulnerable to leakage (27). Adventitial inflammation has been associated with vasa vasorum neovascularization, which plays a role in red blood cell extraction, macrophage activation, and lipid core expansion, further promoting the destabilization of atherosclerotic plaques (2, 26, 28-30). Besides, oxidative stress induced by hyperglycemia increased micro-vessels in plaques according to the extent of inflammatory cells, such as the increased activity of macrophage matrix metalloproteinase. Micro-vessel density in plaques is further increased in patients with diabetes, leading high risk of intraplaque hemorrhage (31).
Another plausible explanation would be that hyperglycemic injury may also be a major cause of microvascular damage. The production of reactive oxygen species (ROS), which contributed to the formation of advanced glycation end products (AGE), could lead to endothelial damages (32) and, finally, microvascular injuries. The cascades triggered by AGE played a dominant role in the onset and progression of microvascular complications of diabetes (33, 34). Moreover, tissue hypoxia, due to decreased oxygen-carrying capacity of hemoglobin in a hyperglycemic environment, could promote neovascularization, leading to leakage and hemorrhage.
In terms of clinical practice, our findings may have clinical implications given that the HbA1c level conveys information on IPH, which is regarded as the most vulnerable plaque component. As a trigger of plaque vulnerability (35), the presence of IPH may predict cerebrovascular events (36) (37). Early identification of IPH in carotid plaques is of great significance in stroke prevention (38). he association found in this study between IPH and HbA1c may explain to some extent the association between HbA1c and ischemic stroke. These findings provide further clues for the risk stratification of patients in clinical practice.
Limitations and Future Directions
This study has some limitations that should be acknowledged. First, this study was designed as a cross-sectional study, and follow-up information on stroke events was not collected. Consequently, only the association HbA1c and carotid plaque IPH was investigated, and the causal relationship could not be determined. Second, given that all the participants in this study were recruited from the Tsinghua community in Beijing, potential selection bias should be considered when considering the generalization of the findings. Third, the sample size was not large enough. Large-scale, more representative samples and prospective studies are needed to investigate the association between HbA1c and carotid plaque IPH in the future.