|Year : 2015 | Volume
| Issue : 1 | Page : 47-52
Intracranial atherosclerosis and inflammation: Lessons from the East and the West
Juan F Arenillas
Department of Neurology, Hospital ClínicoUniversitario, University of Valladolid, Valladolid, Spain
|Date of Submission||08-May-2015|
|Date of Acceptance||15-Jun-2015|
|Date of Web Publication||30-Sep-2015|
Juan F Arenillas
Department of Neurology, Hospital Clínico Universitario, University of Valladolid, Ramón y Cajal 3, Valladolid - 47003
Source of Support: None, Conflict of Interest: None
Intracranial atherosclerosis (ICAS) is a major cause of ischemic stroke worldwide. Patients affected by this disease have a high risk of suffering further ischemic strokes and other major vascular events despite the best medical therapy available. However, identification of factors that characterize a high-risk ICAS patient is a clinical problem that is yet to be solved. Inflammation is known to play a crucial role in all the stages of atherosclerosis affecting extracranial arterial beds but its role in ICAS is not firmly established. Circulating inflammatory biomarkers may represent a valuable tool to assess the importance of systemic and local (intraplaque) inflammation in ICAS pathogenesis. In this article, we have reviewed studies with inflammatory biomarkers performed in symptomatic and asymptomatic ICAS patients published in the recent literature. Their findings strongly support the hypothesis that inflammation determines the risk of progression and complication of symptomatic ICAS.
Keywords: Atherosclerosis, biomarkers, inflammation, intracranial, intracranial stenosis
|How to cite this article:|
Arenillas JF. Intracranial atherosclerosis and inflammation: Lessons from the East and the West. Brain Circ 2015;1:47-52
| Intracranial Atherosclerosis and Translational Research|| |
The ultimate aim of translational research is to provide applicable solutions to relevant clinical problems by means of a continuous crosstalk between clinical studies and basic research, as shown in [Figure 1].  Intracranial atherosclerosis (ICAS) is characterized by the development, progression, and complication of atherosclerotic plaques affecting the intracranial large arteries. ICAS represents the most common cause of ischemic stroke among patients of Asian ancestry. , Moreover, ICAS is more prevalent among Hispanics and Africans whereas in Caucasians, ICAS may account for 8-10% of all ischemic strokes.  Thus, taking the distribution of the world's population into account, ICAS may represent the most common cause of stroke globally. 
|Figure 1: Translational research in ICAS Stages of translational research in ICAS: 1) Identification of the most relevant clinical problems that remain to be solved through clinical observation 2) Development of clinical and basic research models oriented to solve the clinical problem (patient-oriented) 3) Cyclic crosstalk between clinical and basic research by which the findings obtained at each level influence methodology and result in interpretation at the other level 4) Clinical trial design and development based on the results of basic research and clinical pilot studies|
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According to these observations, ICAS represents a major health problem worldwide. However, there are important clinical problems affecting ICAS patients that are yet to be solved and these present as potential targets for translational research. First, symptomatic ICAS is still burdened with a high risk of recurrent stroke despite the best medical therapy although the aggressive medical treatment with or without stenting in high-risk patients with intracranial artery stenosis (SAMMPRIS) medical treatment paradigm was able to reduce the annual recurrence rate by almost 50% as compared to the rate reported in the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) study less than one decade earlier. , Second, symptomatic ICAS patients are burdened with a high global vascular risk and frequently have concomitant coronary heart and peripheral arterial diseases. , Therefore, the identification of factors that characterize high-risk ICAS patients is highly necessary. Third, the real importance of ICAS may be underestimated, especially in Caucasians. Traditionally, ICAS diagnosis has been done based on the detection of intracranial stenosis, but as high-resolution magnetic resonance imaging (HRMRI) artery-wall studies have shown, arterial remodeling is present in the intracranial arteries and accordingly, nonstenotic ICAS may become a common yet underrecognized problem.  Fourth, the relationship between ICAS, vascular cognitive impairment, and Alzheimer's disease is unclear and intriguing.  In this article, we have focused on the characterization of high-risk ICAS and more concretely, we attempted to review the evidence regarding the role of inflammation in determining the risks of progression and complication of ICAS.
| Inflammation in Atherosclerosis: Local and Systemic Views|| |
Atherosclerosis is a chronic inflammatory process of lipid-rich lesion growth in the vascular wall that can cause myocardial infarction and stroke among other clinical consequences.  An increased mechanistic understanding of the pathogenesis of atherosclerosis in other vascular beds has shown that inflammation plays a crucial role in all stages of atherothrombosis, from early atherosclerotic lesion formation to its progression and destabilization leading to clinical events. The dynamics of atherosclerosis over time can be seen as a struggle between the processes of vascular injury and repair where persistent inflammation leads to a predominance of aggressive mechanisms and a derangement of vascular reparative capacity. From a clinician's perspective, inflammation requires to be assessed in vivo and in real-time in order to be incorporated in the diagnosis and treatment of atherosclerotic patients. Extensive research is being carried out to develop imaging and molecular methods that will be able to detect and measure vascular inflammation such as positron emission tomography-magnetic resonance imaging (PET-MRI), HRMRI with inflammation-targeted contrasts, molecular imaging, and biomarkers.
The relationship between inflammation and atherosclerosis might have to be considered from both a local and a systemic perspective.  Locally, inflammatory infiltration within the atherosclerotic lesion renders the plaque more vulnerable, i.e., prone to rupture and suffer thrombotic complications. Systemically, persisting chronic inflammation is characterized by excessive circulating inflammatory cells and proinflammatory cytokines. Circulating monocytes can be recruited inside the evolving atherosclerotic lesion via adhesion molecules expressed on the dysfunctional endothelium and can then enter the plaque, thereby kindling inflammation inside it. Moreover, circulating inflammatory cytokines originating from different sources may exert their effects on the endothelium, rendering it more proinflammatory and prothrombotic. In this context, inflammatory blood biomarkers may represent a valuable tool to assess in vivo and in real-time the interplay between systemic and local inflammations. Vascular risk factors such as hypertension and hypercholesterolemia can induce the expression of circulating inflammatory mediators that lead to altered wall function and promotion of atherosclerosis progression. While the overexpression of some inflammatory mediators such as interleukin-6 (IL-6) and C-reactive protein (CRP) may inform us about the existence of an ongoing chronic systemic inflammation;  other inflammatory molecules such as lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) are released into the blood stream from the inflammatory cells that reside inside the atherosclerotic lesion, thus reflecting the plaques' intrinsic inflammatory activity. 
| Inflammation and Icas: Unresolved Questions|| |
While the deleterious role of persisting inflammation in atherosclerosis is clear in all extracranial arterial beds, the lack of access to pathological specimens from symptomatic ICAS patients makes it difficult to ascertain how inflammation is involved in ICAS pathogenesis. [Figure 2] illustrates the main groups of prognostic factors that may influence the outcome of symptomatic ICAS according to the recent literature. Regarding the factors associated with the intracranial atherosclerotic plaque itself, more attention is increasingly being paid to plaque activity. In this context, what we know from other arterial territories is that not only are plaque morphology and the degree of stenosis relevant but that plaque activity may also play a crucial role in determining the atherosclerotic lesion's risk. Moreover, due to the process of arterial remodeling, large atherosclerotic plaques may grow outwardly without causing overt stenosis. The main question that remains to be clarified here is whether the inflammatory state of the plaque is the main contributor to the risk of giving rise to acute clinical events in ICAS as it happens in other arterial beds.
|Figure 2: Symptomatic ICAS prognostic factor schema The main prognostic factors in symptomatic ICAS that we know, thanks to the research done during the last few decades, could be summarized following this schema. These groups of factors interact among themselves in each ICAS patient and determine the risk of disease progression and clinical recurrence. Inflammation may have a dual role in ICAS since the inflammatory response is controlled systemically and at the same time, local inflammatory infiltration inside the atheromatous plaque may determine plaque activity. In fact, inflammation typically exemplifies the intimate interplay between systemic and local factors that may be as crucial for ICAS as it is for atherosclerosis affecting other arterial beds|
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Why would atherosclerosis have a differential behavior in intracranial arteries? Why do some investigators believe that it is not possible to directly extrapolate what we have learnt from other arterial territories and just apply it to ICAS? First, some classic reports based on necropsy series stated that atheromatous plaques found in intracranial arteries were frequently stable and did not often show the morphological features traditionally associated with vulnerable plaques. , This vision has dominated the field until recent works demonstrated that symptomatic intracranial atherosclerotic plaques can exhibit the hallmarks of unstable plaques such as intraplaque vasculature, intraplaque hemorrhage, or plaque rupture. ,, And second, intracranial arteries have differential anatomic features and are exposed to particular hemodynamic factors. They are muscular-type arteries that contain only a few medial elastic fibers, a thick and dense internal elastic lamina, and a few adventitial vasa vasorum, and they lack an external elastic lamina.  Moreover, the compliance of the aorta and the carotid arteries maintains a low pulse pressure in the intracranial arteries, retarding the development of ICAS until the extracranial arteries' stiffness increases with age and exposure to vascular risk factors. In addition, intracranial arteries were reported with an enhanced antioxidant capacity.  These unique features are claimed to justify the special characteristics of intracranial atherosclerotic lesions found in the recent necropsy series such as fibrosis, small lipid pools, and a low grade of inflammatory infiltration by macrophages and T cells.  However, this necropsy study was performed in asymptomatic patients and this theoretical plaque stability is a contrast with to the aggressive clinical behavior of this disease once it becomes symptomatic as has been mentioned earlier in this manuscript. Other recent studies found increased inflammatory infiltration in the middle cerebral artery symptomatic versus asymptomatic atherosclerotic lesions.  Therefore, further research is needed to clarify this issue.
New imaging methods such as HRMRI may help us understand the real importance of inflammation in ICAS and whether it varies between individuals and also across the different intracranial arteries. The first study aiming to correlate HRMRI findings with plaque histology showed little inflammation inside the basilar artery plaque, although the plaque was not deemed to be symptomatic.  Interestingly, HRMRI postcontrast enhancement of intracranial atherosclerotic plaques is more frequent in symptomatic plaques than in asymptomatic plaques but whether this phenomenon reflects the degree of inflammatory infiltration inside the plaque is yet to be elucidated. 
| Inflammatory Biomarkers in ICAS|| |
Together with wall-imaging techniques, biomarker studies represent another valuable method to assess the participation of inflammation in ICAS in vivo. [Table 1] summarizes some of the most relevant studies with inflammatory blood biomarkers in ICAS, which have been published during the past 15 years. ,,,,,,,,,,,,, These studies can be categorized in three groups. The first group comprises cross-sectional studies conducted on stroke patients where biomarker concentration is compared across different stroke subtypes, including ICAS. ,,, Among them, the study conducted in Caucasian patients showed that the ICAS group had the highest level of adhesion molecules, which first suggested the existence of an endothelial inflammatory activation in this condition.  However, the other three studies conducted on Asian patients found significantly lower concentrations of CRP and matrix metalloproteinase 2 (MMP-2) in the ICAS group as compared to the extracranial atherosclerosis group.
The strongest evidence in favor of the involvement of inflammation in ICAS pathogenesis comes from the second group of longitudinal studies, which evaluated the capacity of several inflammatory biomarkers to predict ICAS progression ,, and the risk of recurrent stroke and other vascular events in symptomatic ICAS patients. ,,, Baseline CRP  and IL-6  level in Caucasian and Asian symptomatic ICAS patients, respectively, predicted ICAS progression in long-term follow-up studies. Regarding the risk of clinical recurrence, biomarkers of systemic inflammation, such as CRP and leukocyte count, were also found to be predictors of further ischemic strokes and other major vascular events in symptomatic ICAS patients. ,, Taken together, these findings suggest that persisting systemic inflammation may promote the progression and complication of atherosclerosis in the intracranial arteries also, as it does extracranially. Besides these markers of systemic inflammation, other molecules that are more informative about the local inflammatory activity within the atherosclerotic plaque, such as adhesion molecules and Lp-PLA 2 , have also been evaluated in these longitudinal studies. , In this context, the most relevant findings were derived from the Biomarkers of Ischemic Outcomes in Symptomatic Intracranial Stenosis (BIOSIS) study, a biomarker study affiliated with the SAMMPRIS clinical trial the results of which were presented partially at the 2014 International Stroke Conference.  Interestingly, Lp-PLA 2 level at the study entry predicted specifically further ischemic strokes within the symptomatic intracranial stenosis territory as well as any major ischemic event during follow-up. This observation strongly supports the hypothesis that local inflammation inside the intracranial atherosclerotic plaque may determine its risk of complication, giving rise to further clinical events.
Finally, the third group of investigations comprises population-based studies aiming to identify factors associated with asymptomatic ICAS in apparently healthy individuals. ,, According to those investigating, the relevance of systemic inflammation in the development of asymptomatic ICAS remains controversial. In two of the investigations, the CRP level was found to be lower in asymptomatic ICAS than in extracranial atherosclerosis; , the largest study identified CRP as an independent predictor of asymptomatic ICAS and intracranial atheromatous burden.
Regarding their potential clinical applicability, inflammatory biomarkers in ICAS could be very useful for:
- Risk stratification in ICAS patients by helping to identify those patients at a higher risk of future ischemic stroke or major vascular events, thus aiding in preventive strategies design;
- The evaluation and monitoring of the intensity of plaque's inflammatory activity over time and its response to different therapies; and
- The identification of new therapeutic targets and drugs against ICAS progression and complication.
In order to develop this promising potential and be able to incorporate inflammatory biomarkers into the clinical routine, some of the highest priorities for future research would be:
- New biomarker discovery using molecular pathway's arrays and "omics" technology,
- Advanced statistics to identify biomarkers whose predictive capacity has an added value over the prediction provided by well-established risk factors in ICAS,
- Multimodal studies combining modern imaging methods and biomarker technology, and
- Basic research with biomarkers in animal models of ICAS.
| Conclusion|| |
A growing body of evidence provided by biomarker studies strongly supports the hypothesis that inflammation is involved in the progression and complication of symptomatic ICAS. Thus, inflammatory biomarkers may have an increasing clinical applicability in the identification of high-risk ICAS patients and in monitoring the response to preventive therapies. Moreover, some of the biomarkers themselves could become therapeutic targets for new anti-inflammatory strategies. Finally, multimodal studies combining modern imaging methods and novel biomarker technology might be needed to clarify the role of inflammation in ICAS and its therapeutic potential.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
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