Pre-existence of Diabetes Mellitus Improves Cerebral Perfusion During Middle Cerebral Artery Severe Stenosis or Chronic Occlusion

Abstract

Background and Purpose—Collateral flow compensation followed by cerebrovascular stenosis is closely correlated to acute ischemic stroke (AIS) and chronic cerebral hypoperfusion. Many evidences indicated that diabetes mellitus (DM) probably had impact on it, but the exact extent was unclear. Aim of this study is to investigate the impact of DM on collateral flow of patients with severe stenosis or occlusion of middle cerebral artery (MCA).

Methods—We retrospectively identified patients from our registry of patients who had severe stenosis or occlusion in the MCA diagnosed by digital substraction angiography (DSA), besides it, collateral flow compensation was also assessed by magnetic resonance perfusion (MRP). Relative parameters of perfusion (MTT, TTP, CBF, CBV) in the different areas including Am, Lm, Pm, Bm were compared between diabetic and non-diabetic patients. Based on this background, multivariable logistic regression was used to identify the independent correlation between DM and above MRP values with obvious difference, so did the correlation between they and HbA1c or fasting blood glucose (FBG) through Spearman correlation coefficient.

Results—105 patients were included in this study, with 73 patients belong to non-diabetes mellitus (NDM) group and 32 patients belong to DM group. Older age, higher fibrinogen (FIB) and fasting blood glucose (FBG), higher percent of hypertension were seen in the DM group compared to the NDM group. Higher ipsilateral/contralateral ratio of CBF and CBV in Lm area was observed in DM group in contrast with NDM group, and lower ipsilateral/contralateral ratio of MTT was observed in DM group in Am and Lm areas, so did TTP in Lm and Pm areas. Independent correlation was also maintained between DM and Lm-CBF, Lm-CBV, Lm-MTT, Lm-TTP, Am-MTT, Pm-TTP through multivariable logistic regression. Both FBG and HbA1c were correlated to part of above parameters of ipsilateral/contralateral ratio, while the impact of FBG was more prominent.

Conclusions—DM can partly improve cerebral hypoperfusion due to severe stenosis or occlusive in the MCA, which is probably originated from microvascular remodeling induced by pre-existence of DM.

1. Introduction

Atherosclerosis of middle cerebral artery (MCA) progressed to severe stenosis or occlusion, is a major cause of ischemic event in anterior circulation. Generally, annual stroke incidence in patients with symptomatic MCA stenosis and asymptomatic MCA stenosis were 12.5% and 2.8% respectively[1]. Collateral flow compensation, activated in response to chronic cerebral ischemia, is the decisive factor in the pathogenesis of ischemic cerebrovascular events. There were leptomeningeal arteries and new vessels formation (NVF) along the target MCA involved in this kind of collateral circulation compensation. Neovascularization is an innate physiologic response by which tissues respond to various stimuli including ischemia through collateral arteriogenesis and NVF from existing vessels or from endothelial progenitor cells[2].

The causes of cerebrovascular disease in diabetic patients are multifactorial, including intra/extracranial vascular diseases and microvascular pathology. Diabetes mellitus (DM) was independently related to a greater degree of intracranial atherosclerosis and a high number of involved vessels [3], also it had a major impact on the neovascularization process but responsed varies between different organ systems. Metabolic abnormalities caused by DM induce microvascular changes are most closely associated with ischemic stroke.

Associations between diabetes and the collateral status have been investigate, indicating that collateralization has a significant impact on the functional outcome [4–7]. That was the reason why patients with DM tend to develop more severe events in cerebrovascular and cardiovascular diseases[8, 9]. How about the impact of DM on collateral flow compensation in the condition of hypoperfusion? Previous studies demonstrated that reduced coronary collateralization in type 2 diabetic patients with severe coronary artery stenosis or chronic total occlusion [10], which was unknown in the patients with intracranial artery stenosis or occlusion.

Study of chronic hyperglycemia on cerebral microvascular remodeling revealed that MTT values in the nonischemic cerebral hemisphere were significantly longer in the patients with HbA1c > 6.5% compared to those with HbA1c ≤ 6.5% [11]. Also, impaired collateral flow compensation was confirmed in the Type 2 Diabetic Mice with common carotid artery occlusion (CCAO)[12]. All the evidences seemed to suggest that similar impact was played on cerebrovascular and cardiovascular, that is reduced collateralization in diabetic patients with steno-occlusive MCA.

Perfusion weighted imaging (PWI) is a well-established technique to evaluate collaterals in clinical practice, and relative parameters can be sensitive to identify the hypo-perfusion areas. In the current study, perfusion of magnetic resonance imaging (MRI) was done in all patients with severe stenosis or occlusion MCA, and final goal is to investigate the impact of diabetes on collateral flow compensation reflected by cerebral perfusion with intracranial artery stenosis or occlusion.

2. Methods

3. Results

4. Discussion

Aim of this study was to investigate the effect of DM on collateral circulation in patients with unilateral MCA severe stenosis or occlusion. Therefore, we compared MRP parameters between diabetic and non-diabetic patients. We found that diabetic patients had better collateral circulation compared with non-diabetic patients, and this kind of impact was independent correlation with DM.

Perfusion techniques provide functional and circulatory information on collateral flow[14]. Numerous studies have addressed the possibility of obtaining information on collateral circulation using MR perfusion. Some investigators have used perfusion measures like the time to maximum of the residue function (Tmax), relative cerebral blood flow (rCBF ) and relative cerebral blood volume (rCBV), assuming that the severity of hypoperfusion in large artery stenosis is directly related to the abundance of collateral vessels[15–18].

Previous studies have explored the relationship between diabetes and collateral circulation with inconsistent conclusions. Some studies have suggests there is no association between diabetes and the extent of pial collaterals in ischemic stroke patients[19]. Menon et al. analyzed patients with AIS treated with intravenous thrombolysis (IVT), mechanical thrombectomy (MT), or basic care and found no association of the blood glucose level and the collateralization [5, 7]. A small study published by Gersing et al. did not find a difference of collateral status between DM patient and NDM patient receiving MT [6]. However, Jan et al. showed that the prevalent elevated glucose levels showed a significant association with the collateral status in the diabetic subgroup [20]. Rosso C et al. shows that collateralization and infarct core did not differ between DM patient and DM patient group, whereas the penumbra was significantly smaller in DM patient than in DM patient [21, 22]. Bin et al shown that greater extent of collateral (more than one-third of the MCA distribution) was detect in DM patents with moyamoya disease. It may means that DM could promote pial collateral vessel formation in patients with chronic cerebral ischemia[23], which is consistent with our findings. Our study shows that in patients with severe stenosis or occlusion of MCA, the ipsilateral collateral circulation of DM patients is more abundant than NDM.

Although presence of a chronic totally occluded lesion has been considered as a prerequisite for spontaneous collateral recruitment, the mechanism of collateral vessel growth is complex, and even becomes more complicated by the presence of DM in which multiple biochemical and cellular components are involved[10, 24–26]. Continuous exposure to hyperglycemia, oxidative stress and increased systemic inflammation factors might induce many changes in the vascular that might accelerate vascular stenosis [27]. The effect of diabetes on collateral supply varies among different organ systems leadings to either impaired or excessive neovascularization. For example, research has shown that DM is associated with reduced coronary collateralization[28]. Excessive angiogenesis occurs in the retina while impaired angiogenesis occurs in the peripheral vasculature[19, 29–31].

The mechanism of neovascularization affected by DM in various organs remains unclear. Through, some study showed angiogenesis was deficient in diabetes groups after ischemic [32, 33]. Li et al. have confirmed that angiogenesis and arteriogenesis showed remarkable increases in the number of collaterals, the diameters of the collaterals, the number of anastomoses, and microvessel density in DM Goto-Kakizaki rats[34]. Similar to this conclusion, Mostafa et al. provide evidence that even after a short duration of relatively mild hyperglycemia, there are structural changes in the cerebral vessels still exist[35]. Some experimental results also revealed a significant rise in the level of vascular endothelial growth factor (VEGF) and nitrotyrosine[36]. Diabetic rats had augmented neovascularization. Both angiogenesis and arteriogenesis were observe, suggesting the adaptive mechanisms are capillary sprouting and remodeling of native collaterals into functional arterioles[19]. The levels of growth factors and cytokines that were regarded as important in the collateral vessels, such as the expression of VEGF, basic fibroblast growth factor, transforming growth factor, granulocyte colony-stimulating factor, and hepatocyte growth factor. It also have been proven be elevated in many studies in intracranial and extracranial artery stenosis disease patients [2, 4, 37, 38]. Angiogenesis is a complex procedure involving many positive and negative regulators. The expression of growth factors and cytokines described above might be higher in MCA stenosis patients complicated with DM than in patients without DM. Thus, more formation regarding collateral angiogenesis can be detected in MCA severe stenosis or occlusion patients with DM.

In this study, we compared the collateral supply among diabetic and nondiabetic patients through MR perfusion parameters, which is confirming that there was more frequently collateral formation of patients with severe stenosis or occlusion of MCA in the DM group. We recognize that there are several limitations have founded in this study. First, a potential weakness of our study is the small sample (especially the number of patients with DM was low). All the potential confound factors could not be controlled, and some influential factors were not taken into account. However, this also provides us with a different point of view and larger sample studies are need to further supports our research results. Second, Markers of longstanding poorly controlled diabetes such as hemoglobin A1C levels, FBG were available of these patients. Duration of diabetes and diabetic control may have varied considerably among patients and contributed of differences in MR perfusion data. Third, we studied the relationship between MR perfusion parameters and collateral circulation, and did not further follow-up and evaluate the risk of late strokes, which will be our next research direction.

5. Conclusions

The present study revealed that patients with severe stenosis or occlusion of MCA with DM had more collateral circulation assessed by MR perfusion imaging. Findings from this study may help individualize blood sugar management in patients with macrovascular stenosis. Further clinical studies and basic research are need to explore the factors affecting formation of the collateral vessels in severe stenosis of large artery patients associated with DM.

Declarations

Acknowledgments

We are grateful to the patients who were willing to share their medical data. We thank the participants of this work for their contribution.

Authors’ contributions

Jia-hui Zhang and Zheng Li: Contributions to the data collection and writing original draft. Mei-juan Zhang and Chuan-shuai Tian: Prepared figure and tables. Yun Luo: Contributions to the design of the study and review the final manuscript. All authors have read and approved the manuscript.

Funding

This work was supported by National Natural Science Foundation of China (81671140) and the Nanjing Medical Science and technique Development Foundation(QRX17002).

Availability of data and materials

All data related to this study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

This study was performed in accordance with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Nanjing Drum Tower hospital (No.2016-169-01).Written informed consents were obtained from all participants.

Consent for publication

Not applicable.

Competing interests

The authors declare no conflicts of interest.

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