Even though the ISR is widely discussed in cerebral large artery stenting for a long period, the exact risk factors are still in debated. ISR involves many aspects, including age, sex, cerebrovascular risk factors, family history or hereditary factor, stenosis site, plaque features, length or diameter of stent, stent type, vessel tortuosity.As we all know, ISR signifies the increased odds of stroke recurrence, so it is necessary to take an in depth investigation to identify the related risk factors and take effective measures in advance.
It is believed that the pathophysiological mechanisms of ISR are referred to many factors. First, the elastic retraction of the vessel wall at the stent is the early factor for ISR after stenting19. Second, the inflammation respond was a pivotal pathophysiological mechanism in ISR. The vessel wall's inflammation promotes the proliferation and migration of vascular smooth muscle cells into the vessel intima, further leading to neointimal hyperplasia. Leukocytes and neutrophils could also be used as important biomarkers of the inflammatory response, and characterized by many influencing factors and lack of specificity. However, some blood cells ratios, like neutrophil/lymphocyte, could reflect the inflammation degree in vascular walls20. Our article demonstrates that platelet and C-reactive protein are higher in ISR group, which shows a trend of activated inflammatory status. However, the numbers of related blood cells did not reflect the difference between the two groups, which may be related to the relatively small sample size, especially in the ISR group. Third, during the stenting, stents would destroy the vascular endothelial cells, leading to release and aggregation of inflammatory mediators, such as platelets, macrophages and cytokines, which further remodel the vascular wall form ISR21. After stenting, chronic mechanical stimulation of vessel wall promotes vascular smooth muscle cells proliferation, contributes to extracellular matrix formation22,and ultimately leads to ISR7. As time goes on, the vascular wall at the stent site under an inflammatory status for a long time, the vascular endothelial cells would be dysplastic and the stents cannot be completely covered, which further intake lipid excessively and accelerate the formation of neoatherosclerosis23,24. Therefore, many studies had paid attention to the effect stent type, stent length, residual stenosis rate and stenosis sites on ISR. There was no consistent conclusion about the effect of stent type on IRS17,25,26, therefore, we did not include it as a variable. Also the diameters and hemodynamics states between intracranial and extracranial vessels might affect IRS. Kang et.al1noted that ISR was more common after stenting in intracranial stenosis than extracranial stenosis. But there was no statistically significant difference in our study, because the sample size was small. After stenting, the higher residual stenosis rate would promote local thrombosis formation and result in lower vascular wall shear stress, which further activates the inflammatory response in the blood vessel wall. Oteros R et.al27suggested that the risk of ISR was lowest when residual stenosis rate was no more than 30%. In our study, there was a significant difference in residual stenosis rate among the two groups, and it was an independent risk factor for ISR, which is agreed with previous studies. Our result implied that residual stenosis rate should be minimized after cerebral large artery stenting.
In recent years, collateral circulation is an important predictor of clinical outcome for acute ischemic stroke. Abundant collateral circulation could lessen disease severity, minimize infarct volume and improve clinical prognosis. Several studies suggested that the proximal anterior circulation stroke patients with poor collateral circulation would not benefit from stenting 28. According to our knowledge, the correlation between collateral circulation and ISR had been reported more frequently in coronary artery PCI. Some researches revealed that poor collateral circulation was an important predictor of ISR after PCI, while others showed the opposite conclusion12,29,30. We speculate that this phenomenon is due to the different evaluation methods of collateral circulation,because the vascular perfusion pressure is usually used to evaluate the collateral circulation of the coronary artery in prior researches. However, it is indirect and imprecise13,14. Sometimes, the elevated perfusion pressure in ischemic cerebral tissue may be related to the recanalization of occluded vessels, but it does not refer to the abundant collateral circulation. Until now, few researches are found about the relationship between collateral circulation and ISR after cerebral large artery stenting. In our research, we first reported that collateral circulation was an independent factor for ISR after cerebral anterior circulation large artery stenting. The mechanisms, we consider, may be due to the following reasons: first, after stenting the vascular wall shear stress dramatic decline in poor collateral circulation patients, which increases the expression of proinflammatory genes and leads to intimal hyperplasia22. Second, the patients with poor collateral circulation after stenting have a greater change in blood flow in-stent sites, which leads to the activation of vascular endothelial cells, the releases of inflammatory cytokines, and remodelling of the blood vessels31. Third, the patients with poor collateral circulation have higher vasoconstrictor peptide, which may increase vasoconstrictor force and promote restenosis14. In brief, we hypothesize that hemodynamics changes, expression of inflammatory gene, and released of inflammatory cytokines in patients with poor collateral circulation would contribute to ISR. Therefore, we assume that the evaluation of collateral circulation before cerebral large artery stenting may help to predict the risk of ISR. Currently, there are lots of methods to evaluate the cerebral collateral circulation, including DSA, computed tomographic angiography, computed tomographic perfusion and some other magnetic resonance based methods. All of these methods have their own characteristics, but DSA is the gold standard for diagnosis18. Because all the included patients in our study underwent DSA during stenting, so we used this method to evaluated cerebral collateral circulation. We found that many studies utilize the ASITN/SIR score to evaluate the collateral circulation that distal to severe carotid artery stenosis32,33, basically the same way we did.
On the other hand, drug therapy after cerebral artery stenting involves a comprehensize management, including antiplatelet, lipid-lowering, and controlling other traditional vascular risk factors 34,35. The optimal treatment strategy after stenting remains controversial. The aggregation of platelets and the inflammatory response of vascular walls after stenting play a vital role in ISR. After stenting, platelet deposition in the injured vascular wall and promote the synthesis of extracellular matrix25. Antiplatelet drugs and statins are the primary therapeutic medicine. However, their role in lowering the risk of ISR is still unclear. Akbulut M et al.36observed that antiplatelet treatment would significantly lower the odds of intimal hyperplasia and ISR after PCI. Dual antiplatelet therapy might also play an important role in lowering the risk of ISR after cerebral artery stenting 37. Statins can lower the risk of ISR by inhibiting proliferation and migration of vascular smooth muscle cells34. Leone AM et al.38confirmed that statins should keep the low-density lipoprotein cholesterol﹤70mg/dl to reduce the formation of neoatherosclerosis. Our study found that the combination of antiplatelet drugs and statins for long-term could effectively reduce ISR risk after after anterior cerebral large artery stenting. Therefore, standard medicine treatment, the combination of antiplatelet and statins for more than 3 month, is recommonded for such patients to reduce the risk of ISR. However, this was a retrospective study, and we did not collect the information about the dose of antiplatelet and statins agents, so it is impossible to determine the optimal oral dose to reduce the risk of restenosis. We hope this problem will be clear in our future research.
Currently, DSA is the gold standard for evaluation of intracranial artery stenosis. However, this method has lots of limitations, such as radiation damage and contrast agent allergy. It is not convenient for follow-up, so we look forward to applying more accurate and less invasive methods. In our research, we used carotid artery ultrasound and Transcranial Doppler sonography to follow-up visit, and they are readily available and non-invasion diagnostic tools for evaluation of ISR. Compared with DSA, ultrasound was proved to have a high sensitivity (100%) and specificity (93.3%) in detecting of severe cerebral anterior circulation large artery stenosis16. Transcranial Doppler sonography is a real-time diagnostic tool for intracranial blood flow monitoring. Compared with DSA, it has higher consistency in evaluating of intracranial artery stenosis, and it could be used as a reliable tool for follow-up15.
There are some limitations to our study. First, it involved retrospectively observational research and the materials collection in a predetermined manner, so the information bias cannot be ruled out. Second, this research was a single centre study, and the selection bias may affect reliability. Third, a relatively limited proportion of the study population was involved, especially the ISR group. Although this situation was objective, it might affect the statistical results inevitably. A prospective systemic study would obtain more precise results based on our encouraging preliminary conclusion. Finally, carotid artery ultrasound and Transcranial Doppler were performed by different operators, and we collected clinical outcome via face to face or telephone interview, which may affect the homogeneity of examination and the accuracy of information.