Skip to main content

Association of peripheral neutrophil count with intracranial atherosclerotic stenosis

Abstract

Background

Inflammation plays an important role in atherosclerosis but the contribution of neutrophils to this process is unclear. We sought to assess whether neutrophil count is associated with intracranial atherosclerotic stenosis (ICAS).

Methods

A total of 2847 individuals were included in our study, including 1363 with acute ischemic stroke and 1484 normal controls without stroke. The presence of ICAS was confirmed by magnetic resonance angiography. The association between neutrophil count and ICAS was evaluated by multivariable logistic regression analysis.

Results

Among 2847 individuals included in this study, individuals with ICAS had higher neutrophil counts than those without ICAS in groups with and without stroke (P <  0.0001 for stroke group, P = 0.0097 for group without stroke). The multivariable logistic regression analysis showed that the third and fourth quartiles were independent predictors of ICAS in all the subjects (Q3: OR 1.81, 95% CI 1.39–2.37, Q4: OR 2.29, 95% CI 1.70–3.10) and patients in the fourth quartile had a higher risk for the occurrence of ICAS in stroke group (Q4: OR 2.82, 95% CI 1.79–4.48). However, there was no significant association between neutrophil count and ICAS in the group without stroke.

Conclusions

The levels of circulating neutrophils were associated with the presence of ICAS. Our findings suggest that neutrophils may play a role in the pathogenesis of stroke related to ICAS and emphasize the need to develop proper strategies to control neutrophil response for the treatment of ICAS.

Peer Review reports

Background

Stroke has attracted clinical and public health attention from all over the world. The number of patients with stroke, stroke-related deaths, physical disability, hospitalizations and the global burden are great and increasing [1, 2]. Accumulating evidence have shown that intracranial atherosclerotic stenosis (ICAS) is a major risk factor for ischemic stroke in Asia, especially in China, and is also known as an important pathogenetic mechanism of ischemic stroke [3,4,5]. At present, many researchers are paying more and more attention to the etiology of intracranial atherosclerosis. There is evidence suggesting that inflammatory processes contribute to both the initiation and progression of atherosclerosis [6, 7]. And even more importantly, an elevated number of activated of inflammatory markers have extremely important effect on the formation, evolution and destruction of atherosclerotic plaques [8, 9]. Atherosclerotic plaques were markedly infiltrated by various inflammatory cells, including activated macrophages, T cells, and mast cells [10,11,12,13]. These cells may provoke atherosclerotic plaque destabilization and the occurrence of acute thrombotic events by releasing matrix-degrading enzymes and thrombogenic substances [14,15,16]. Several studies have shown the correlation of increased peripheral inflammatory marker levels with various vascular diseases as well as the potential development and severity of atherosclerosis [6, 17], providing an indication that atherosclerosis is an inflammatory disease [18, 19]. Although intracranial atherosclerosis is viewed as a part of atherosclerotic disease, it is still unclear whether ICAS is also related to the inflammatory response.

Experimental studies on stroke have indicated that increased leukocytes enter into ischemic territory through chemotaxis of activated microglial cells within minutes of acute infarction onset [20]. Neutrophils are the first leukocyte subtype to infiltrate the areas of brain ischemia after cerebral infarctions and are considered to be markers of inflammation [21]. The elevated level of neutrophils accelerates inflammatory process by releasing various destructive materials (such as cytotoxins, reactive oxygen radicals, arachidonic acid, and proteolytic enzymes), which can cause damage to vascular endothelial cells and further promote the occurrence and progression of atherosclerosis [18, 22, 23]. Thus, endothelial dysfunction would might be an important pathophysiological link between neutrophils and ICAS. Several studies have suggested that elevation in neutrophil count is correlated with greater risk of ischemic brain injuries, vascular events as well as worsening functional outcomes [24,25,26,27]. However, the scientific information regarding the correlation of circulating neutrophils and ICAS is still lacking. Further studies to clarify the association are warranted.

Accordingly, the purpose of this study was to assess the relationship between peripheral neutrophil count and the presence of ICAS. The effect of neutrophil count on different locations of ICAS and ICAS burdens were also evaluated to help us develop a deeper understanding of ICAS.

Methods

Study population

Study participants were prospectively recruited from January 2014 to June 2018 among individuals in the Department of Neurology of Qingdao Municipal Hospital for suspected stroke and individuals underwent comprehensive physical examination at Medical Examination Center of Qingdao Municipal Hospital. Most of the subjects from medical examination center had no serious health problems. And the costs of physical exam were to be paid by their company or by each participants. We used the Trial of Org 10,172 in acute stroke treatment (TOAST) typing to classify stroke mechanism and NIHSS scoring system to assess the severity of acute stroke [28]. We excluded subjects who: (1) under 40 years old; (2) underwent incomplete angiography and laboratory examination; (3) had atrial fibrillation, cardiac embolism, vascular disease and had underwent replacement; (4) had intracranial and external artery dissection, arteritis, moyamoya disease, muscular fiber dysplasia; (5) had infection, nausea, tumor, chronic liver disease and renal insufficiency. Ethics approval for this study was obtained from the Institutional Ethics Committees of Qingdao Municipal Hospital.

Finally, 1484 subjects without stroke controls and 1363 stroke patients (without ICAS n = 2090, with ICAS n = 757) were included in this study. We have strict age and gender matching between the case and control subjects.

Clinical and laboratory data

The baseline information were collected, including demographics, clinical characteristics, hypertension (defined as systolic ≥140 mmHg or diastolic ≥90 mmHg by repeating blood pressure measurement or having been treated with antihypertensive medication), diabetes mellitus (defined as fasting plasma glucose value ≥126 mg/dL, or 2-h postprandial plasma glucose ≥200 mg/dL, or glycosylated hemoglobin levels ≥6.5% for diabetes in multiple measurements, or having been treated with hypoglycemic medication), hyperlipidemia (defined as fasting total cholesterol level (TC) > 200 mg/dL or low-density lipoprotein cholesterol (LDL-C) ≥ 130 mg/dL or having received cholesterol-lowering drug), history of coronary heart disease, history of atrial fibrillation, history of stroke, smoking (current smoker or a patient who had quit smoking < 6 months previously) and alcohol use (defined as alcohol use > 2 units per day on average for men or > 1 unit per day on average for women).

All subjects underwent standardized laboratory examination. The fasting venous blood samples were obtained for biochemical analysis after 12 h of overnight fasting. Samples obtained through venipuncture were collected into test tubes containing anticoagulated blood. The neutrophil counts were tested using automated blood cell counter at the hematology laboratory on admission.

Imaging collection and analysis

All subjects were imaged with 1.5-Tesla or 3.0-Tesla MR scanners, including the sequence of diffusion weighted image (DWI), magnetic resonance imaging(MRI) and three-dimensional time-of-flight magnetic resonance angiography(MRA). ICAS was defined as the presence of 50–99% stenosis or the occlusion of the intracranial vessels according to Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial criteria [29, 30]. To assess the correlation between neutrophil count and the number of ICAS, we counted the number of vascular lesions as single, two or multiple (more than three). To analyse the effect of neutrophil count on different vasular stenosis sites,we dichotomized the locations of ICAS into anterior circulation, posterior circulation and both anterior circulation and posterior circulation. Two experienced neurologists, who were blinded to the participants’ clinical characteristics and biochemical results, visually reviewed all magnetic angiographic images to assess the presence and degree of ICAS lesions.

Statistical analysis

Results were expressed as mean ± standard deviation (SD) for continuous variables with normal distributions, and as median with interquartile range for the continuous skewed distributed data. Categorical data were presented as frequencies and proportions. The Shapiro-Wilk test was performed to evaluate the normality for the distribution of continuous variables. The baseline variables were compared between groups using Mann-Whitney U-test. Kruskal-Wallis test is used if the comparison is conducted among more than two groups. Differences in categorical variables were compared using a χ2 test. Neutrophil count was divided into quartiles. Logistic regression analysis was performed across neutrophil quartiles to examine the association of neutrophil count with ICAS. Differences in associations of neutrophil count with ICAS presence or absence were tested for statistical significance in a multivariable analysis. Multivariable regression was used to correct for possible confounding variables, which included those potential determinants of outcome that had significant clinical correlation or showed P values < 0.05 in univariate analysis.

We compared neutrophil count among single, two and multiple ICAS groups using the Kruskal-Wallis test. To analyse the effect of neutrophil count on different vasular stenosis sites, we compared neutrophils among subgroups according to the vascular circulations. We classified the location of anterior and posterior circulation according to the classification method mentioned in the current literature [31]. P <  0.05 was considered to indicate a significant difference. Statistical analyses were performed using the R statistical software (version 3.4.3).

Results

Baseline characteristics

A total of 2847 individuals were included in this study, including 1363 with acute ischemic stroke (AIS) and 1484 without stroke controls. All the participants were further categorized into four groups: in stroke group, there are 474 (34.78%) patients with ICAS and 889 (65.22%) without ICAS; in the group without stroke, there are 283 (19.07%) subjects with ICAS and 1201 (80.93%) without ICAS.

The baseline characteristics of the study population are summarized in Table 1. The mean age of these subjects was 68.43 ± 11.17 (range, 40–97) years, and 1739 (61.08%) individuals were male. The levels of circulating neutrophils in stroke group were higher than those in the group without stroke (P <  0.0001). Compared to subjects without stroke, these patients with acute cerebral infarction had a higher level of neutrophils, a higher neutrophil-to-lymphocyte ratio and a lower level of lymphocytes. We further tried to look into the difference in neutrophil levels between males and females. We found that men had higher levels of neutrophils than women (P <  0.0001).

Table 1 Baseline Characteristics of the study population in the present study

Association between neutrophil count and ICAS

The levels of circulating neutrophils in subjects with ICAS were higher than those in subjects without ICAS (P <  0.0001).

The multivariable logistic regression analysis showed that the third and fourth quartiles were independent predictors of ICAS in all the subjects (Q3: OR 1.81, 95% CI 1.39–2.37, Q4: OR 2.29, 95% CI 1.70–3.10) and patients in the fourth quartile had a higher risk for the occurrence of ICAS in stroke group (Q4: OR 2.82, 95% CI 1.79–4.48) (Table 3). To evaluate the correlation between peripheral neutrophil count and ICAS lesions, we further carried out a subgroup analysis. Baseline characteristics of these subjects with and without ICAS are shown in Table 2. In subgroup analysis, the neutrophil counts were significantly higher in subjects with ICAS than those of subjects without ICAS in groups with and without stroke (P <  0.0001 for stroke group, P = 0.0097 for group without stroke) (Fig. 1). The multivariable logistic regression analysis showed that each quartile was associated with the occurrence of ICAS in stroke group (Q2: OR 1.44, 95% CI 1.00–2.08, Q3: OR 1.89, 95% CI 1.26–2.86, Q4: OR 2.82, 95% CI 1.79–4.48), whereas the association in the group without stroke was not significant (Table 3).

Table 2 Characteristics of the study population in the present study according to stroke and ICAS status
Fig. 1
figure 1

The levels of neutrophil count among four groups of participants. *The neutrophil counts were significantly higher in subjects with ICAS than those of subjects without ICAS in groups with and without stroke (P <  0.0001 for stroke group, P = 0.0097 for group without stroke)

Table 3 Logistic regression analysis of the association between neutrophil count and intracranial atherosclerotic stenosis according to quartiles of neutrophil count

Association between neutrophil count and the number and locations of ICAS

Among these participants, 757 (26.59%) of them were found to have ICAS, including 445 patients with single ICAS, 159 patients with two ICAS, and 153 patients with multiple ICAS (more than three). We further evaluated the correlation between neutrophil count and the number of ICAS. We found that patients in multiple ICAS group had higher levels of neutrophils than those in the other two groups (P <  0.0001) (Fig. 2). In addition, the effect of neutrophil count on different locations of ICAS was also analysed, and the highest count of neutrophils was found in the group with both anterior and posterior circulation ICAS (P <  0.0001) (Fig. 3).

Fig. 2
figure 2

Differences in neutrophil count among groups according to the number of intracranial stenosis. *In multiple ICAS group, individuals had higher levels of neutrophil than those in other two groups (P <  0.0001)

Fig. 3
figure 3

Differences in neutrophil count among groups according to ICAS lesion locations. *The highest count of neutrophils was found in the group with both anterior and posterior circulation ICAS (P <  0.0001)

Discussion

The major finding of this study was that peripheral neutrophil count was associated with ICAS. Higher neutrophil level was associated with greater risk of ICAS in patients with AIS, but there was no significant correlation in subjects without stroke. In addition, we also found that the number and locations of ICAS were associated with the neutrophil count. Neutrophils might play an important role in the presence of ICAS. Given the difference in neutrophil count between subjects with and without stroke, neutrophils may increase the occurrence of symptomatic intracranial atherosclerotic stenosis.

Many studies have indicated that vascular risk factors and metabolic syndrome have been considered to be crucial determinants of ICAS [5, 27, 32]. Atherosclerosis is increasingly considered to be a chronic inflammatory disease [18, 19], which plays a pivotal role in the development and destabilization of atherosclerosis [6, 7]. Neutrophils, as major determinants of inflammation, have become the focus in exploring the relationship between neutrophil levels and vascular stenosis. Previous studies confirmed that coronary artery stenoses are associated with high neutrophil count in patients with chronic stable angina [33]. Studies have also shown that carotid artery disease has a relationship with neutrophils in patients with peripheral arterial disease [34].

Stroke is closely related to intracranial atherosclerotic disease, which occurs through various mechanisms such as artery-to-artery embolism, hemodynamic insufficiency, situ thrombotic occlusion, and branch occlusion [5].In the Northern Manhattan Study, intracranial atherosclerosis caused ischemic stroke in 9% of white individuals, 17% of African-American, and 15% of Hispanic. Intracranial stenosis was reported in 33–37% of Chinese patients admitted to hospital with ischemic stroke [31]. Several studies indicated that AIS was associated with increased circulating markers of the inflammatory response, including peripheral neutrophil count, peripheral leukocyte count, C-reactive protein and so on [24, 35]. Similar to these studies, our study demonstrated that there existed high levels of neutrophils in patients with AIS. The increased number of activated peripheral neutrophils could result in atherosclerotic lesions by increased adhesion to and damage of the endothelial tissue as well as the secretion of destructive components [8]. Therefore, endothelium cell dysfunction would be an indispensable pathophysiological link between neutrophils and ICAS lesions.

The potential mechanism associating neutrophils with ICAS remains unclear, and the following mechanisms might explain their relationship. Firstly, neutrophils have been regarded as major components of the inflammatory response, which are able to generate detrimental materials when activated [22, 26]. These substances not only regulate acute inflammatory response, but also result in endothelial dysfunction [22, 36]. Research has suggested that endothelial impairment is deemed to be an early marker for atherosclerotic lesions and is beneficial to all stages of atherosclerosis [22, 36]. Given this relationship between endothelial dysfunction and atherosclerosis, there might be an important pathophysiological link between neutrophils and ICAS. Secondly, previous studies indicated that an elevated level of leukocytes was correlated with diabetes, obesity and hypertriglyceridemia, hence supporting the statement that inflammation is part of the metabolic syndrome [37, 38]. Studies have emphasized that metabolic syndrome was closely associated with the progress of atherosclerosis [32, 37]. These evidences imply that neutrophils may lead to atherosclerosis by affecting metabolic condition. Moreover, some studies have suggested that levels of inflammatory markers involved in the process of atherosclerosis are associated with vascular risk factors [39, 40]. Therefore, the mechanism underlying the association between neutrophils and ICAS may be that there are larger burdens of various vascular risk factors in subjects with increased neutrophil count. Further research is needed to identify possible mechanisms.

Interestingly, we found that the number of ICAS had correlation with circulating neutrophil count. Many studies have shown that the severity of coronary heart disease and carotid stenosis has association with inflammatory markers [6, 18, 27, 33, 34, 41]. We found that the neutrophil count was significantly higher in the multiple ICAS group, indicating that the greater number of ICAS may be associated with the higher levels of neutrophils. We also found that ICAS locations had correlation with elevated neutrophil count. However, a previous study demonstrated that there was no significant correlation between ICAS locations and inflammation [42], considering that atherosclerosis is a systemic disease. The result was inconsistent with our study. The inconsistency may be due to the heterogeneity of ethnicity, differences in arterial or genetic susceptibility, regional difference and study design of different studies. A prior study indicated that different locations of intracranial stenosis are associated with different vascular risk factors and demographic features [43], whereas the mechanisms associating neutrophil count with vascular stenosis locations are not well known. We need to explore the underlying mechanism between them in future research. We further assessed the difference in neutrophil levels between genders. Compared to women, men had higher levels of neutrophils. The result may indicate that men were more likely to have ICAS than women. This result is consistent with a published article [44].

This study had several limitations. First, since this is a cross-sectional study, definitive conclusions on the association between neutrophils and ICAS cannot be reached. Further prospective studies are warranted to confirm our findings. Second, this is a single center study. Although we had a relatively large sample size, selection biases and race difference should also be taken into account. Thus, the application of our results to different demographic groups should be approached cautiously. Third, our study found that there is no relationship between neutrophil count and ICAS in the group without stroke. This result may be due to that the sample size is not large enough to reflect the actual relationship between neutrophils and ICAS. Therefore, we need to expand the sample size to further explore the association between neutrophils and ICAS in the group without stroke. Fourth, we measured the neutrophil level at a single time point and the acute stage of stroke. The dynamic change of neutrophil counts at different stages could not be presented in this study.

Conclusion

To summarize, neutrophil count was correlated with the presence of ICAS. We also found that the number and locations of ICAS had relationship with neutrophils. Our findings suggest that neutrophils may play a role in the pathogenesis of stroke related to ICAS and emphasize the need to develop proper strategies to control neutrophil response for the treatment of ICAS. More studies will be needed to better evaluate the correlation between peripheral neutrophil count and ICAS.

Availability of data and materials

The datasets are available from the corresponding author on reasonable request.

Abbreviations

AIS:

Acute ischemic stroke

CI:

Confidence Interval

DWI:

Diffusion weighted image

FLAIR:

Fluid attenuated inversion recovery imaging

ICAS:

Intracranial atherosclerotic stenosis

LDL-C:

Low-density lipoprotein cholesterol

MRA:

Magnetic resonance angiography

MRI:

Magnetic resonance imaging

OR:

Odd Ratio

Q3:

Quartile 3

Q4:

Quartile 4

SD:

Standard deviation

TC:

Total cholesterol level

TIA:

Transient ischemic attacks

WASID:

Warfarin-Aspirin Symptomatic Intracranial Disease

References

  1. Wang Y, Lu Z, Sun S, Yang Y, Zhang B, Kang Z, et al. Risk factors, topographic patterns and mechanism analysis of intracranial atherosclerotic stenosis ischemic stroke. Int J Neurosci. 2017;127(3):267–75. https://doi.org/10.1080/00207454.2016.1188298.

    Article  CAS  PubMed  Google Scholar 

  2. Feigin VL, Forouzanfar MH, Krishnamurthi R, Mensah GA, Connor M, Bennett DA, et al. Global and regional burden of stroke during 1990–2010: findings from the Global Burden of Disease Study 2010. Lancet. 2014;383(9913):245–54.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Niu JW, Gao S, Cui LY, Peng B, Zhu YC, Ni J, et al. Intracranial atherosclerosis in Chinese young adult stroke patients. J Stroke Cerebrovasc Dis. 2014;23(6):1519–23. https://doi.org/10.1016/j.jstrokecerebrovasdis.2013.12.030.

    Article  PubMed  Google Scholar 

  4. Wong KS, Huang YN, Gao S, Lam WW, Chan YL, Kay R. Intracranial stenosis in Chinese patients with acute stroke. Neurology. 1998;50(3):812–3.

    Article  CAS  PubMed  Google Scholar 

  5. Bang OY. Intracranial atherosclerosis: current understanding and perspectives. J Stroke. 2014;16(1):27–35. https://doi.org/10.5853/jos.2014.16.1.27.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Jander S, Sitzer M, Schumann R, Schroeter M, Siebler M, Steinmetz H, et al. Inflammation in high-grade carotid stenosis: a possible role for macrophages and T cells in plaque destabilization. Stroke. 1998;29(8):1625–30.

    Article  CAS  PubMed  Google Scholar 

  7. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362(6423):801–9. https://doi.org/10.1038/362801a0.

    Article  CAS  PubMed  Google Scholar 

  8. Ernst E, Hammerschmidt DE, Bagge U, Matrai A, Dormandy JA. Leukocytes and the risk of ischemic diseases. JAMA. 1987;257(17):2318–24.

    Article  CAS  PubMed  Google Scholar 

  9. Shah PK. Plaque disruption and thrombosis. Potential role of inflammation and infection. Cardiol Clin. 1999;17(2):271–81.

    Article  CAS  PubMed  Google Scholar 

  10. Gown AM, Tsukada T, Ross R. Human atherosclerosis. II. Immunocytochemical analysis of the cellular composition of human atherosclerotic lesions. Am J Pathol. 1986;125(1):191–207.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Jonasson L, Holm J, Skalli O, Bondjers G, Hansson GK. Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis (Dallas, Tex). 1986;6(2):131–8.

    CAS  Google Scholar 

  12. van der Wal AC, Das PK, van de B, Berg D, van der Loos CM, Becker AE. Atherosclerotic lesions in humans. In situ immunophenotypic analysis suggesting an immune mediated response. Lab Invest. 1989;61(2):166–70.

    PubMed  Google Scholar 

  13. Kaartinen M, Penttila A, Kovanen PT. Mast cells in rupture-prone areas of human coronary atheromas produce and store TNF-alpha. Circulation. 1996;94(11):2787–92.

    Article  CAS  PubMed  Google Scholar 

  14. Wilcox JN, Smith KM, Schwartz SM, Gordon D. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci U S A. 1989;86(8):2839–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Galis ZS, Sukhova GK, Lark MW, Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest. 1994;94(6):2493–503. https://doi.org/10.1172/jci117619.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Moreno PR, Bernardi VH, Lopez-Cuellar J, Murcia AM, Palacios IF, Gold HK, et al. Macrophages, smooth muscle cells, and tissue factor in unstable angina. Implications for cell-mediated thrombogenicity in acute coronary syndromes. Circulation. 1996;94(12):3090–7.

    Article  CAS  PubMed  Google Scholar 

  17. Lombardini R, Vaudo G, Ciuffetti G. Leukocyte-endothelial cell interactions and vascular injury in the earliest preclinical stages of atherosclerosis. Haematologica. 1997;82(2):253.

    CAS  PubMed  Google Scholar 

  18. Mayer FJ, Gruenberger D, Schillinger M, Mannhalter C, Minar E, Koppensteiner R, et al. Prognostic value of neutrophils in patients with asymptomatic carotid artery disease. Atherosclerosis. 2013;231(2):274–80. https://doi.org/10.1016/j.atherosclerosis.2013.10.002.

    Article  CAS  PubMed  Google Scholar 

  19. Davis NE. Atherosclerosis--an inflammatory process. Journal of insurance medicine (New York, NY). 2005;37 1:72–5.

  20. Nilupul Perera M, Ma HK, Arakawa S, Howells DW, Markus R, Rowe CC, et al. Inflammation following stroke. J Clin Neurosci. 2006;13(1):1–8. https://doi.org/10.1016/j.jocn.2005.07.005.

    Article  CAS  PubMed  Google Scholar 

  21. Yamagami S, Tamura M, Hayashi M, Endo N, Tanabe H, Katsuura Y, et al. Differential production of MCP-1 and cytokine-induced neutrophil chemoattractant in the ischemic brain after transient focal ischemia in rats. J Leukoc Biol. 1999;65(6):744–9.

    Article  CAS  PubMed  Google Scholar 

  22. Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation. 2004;109 23(Suppl 1):Iii27–32. https://doi.org/10.1161/01.CIR.0000131515.03336.f8.

    Article  CAS  Google Scholar 

  23. Tamhane UU, Aneja S, Montgomery D, Rogers EK, Eagle KA, Gurm HS. Association between admission neutrophil to lymphocyte ratio and outcomes in patients with acute coronary syndrome. Am J Cardiol. 2008;102(6):653–7. https://doi.org/10.1016/j.amjcard.2008.05.006.

    Article  PubMed  Google Scholar 

  24. Buck BH, Liebeskind DS, Saver JL, Bang OY, Yun SW, Starkman S, et al. Early neutrophilia is associated with volume of ischemic tissue in acute stroke. Stroke. 2008;39(2):355–60. https://doi.org/10.1161/strokeaha.107.490128.

    Article  PubMed  Google Scholar 

  25. Becker KJ. Targeting the central nervous system inflammatory response in ischemic stroke. Curr Opin Neurol. 2001;14(3):349–53.

    Article  CAS  PubMed  Google Scholar 

  26. Zhu B, Liu H, Pan Y, Jing J, Li H, Zhao X, et al. Elevated neutrophil and presence of intracranial artery stenosis increase the risk of recurrent stroke. Stroke. 2018;49(10):2294–300. https://doi.org/10.1161/strokeaha.118.022126.

    Article  PubMed  Google Scholar 

  27. Ovbiagele B, Lynn MJ, Saver JL, Chimowitz MI. Leukocyte count and vascular risk in symptomatic intracranial atherosclerosis. Cerebrovascular diseases (Basel, Switzerland). 2007;24 (2–3):283–288; doi: https://doi.org/10.1159/000105681.

    Article  PubMed  Google Scholar 

  28. Chen PH, Gao S, Wang YJ, Xu AD, Li YS, Wang D. Classifying ischemic stroke, from TOAST to CISS. CNS Neurosci Ther. 2012;18(6):452–6. https://doi.org/10.1111/j.1755-5949.2011.00292.x.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Chimowitz MI, Kokkinos J, Strong J, Brown MB, Levine SR, Silliman S, et al. The warfarin-aspirin symptomatic intracranial disease study. Neurology. 1995;45(8):1488–93.

    Article  CAS  PubMed  Google Scholar 

  30. Samuels OB, Joseph GJ, Lynn MJ, Smith HA, Chimowitz MI. A standardized method for measuring intracranial arterial stenosis. AJNR Am J Neuroradiol. 2000;21(4):643–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Qureshi AI, Caplan LR. Intracranial atherosclerosis. Lancet. 2014;383(9921):984–98. https://doi.org/10.1016/s0140-6736(13)61088-0.

    Article  PubMed  Google Scholar 

  32. Bang OY. Intracranial atherosclerotic stroke: specific focus on the metabolic syndrome and inflammation. Curr Atheroscler Rep. 2006;8(4):330–6.

    Article  CAS  PubMed  Google Scholar 

  33. Avanzas P, Arroyo-Espliguero R, Cosin-Sales J, Quiles J, Zouridakis E, Kaski JC. Multiple complex stenoses, high neutrophil count and C-reactive protein levels in patients with chronic stable angina. Atherosclerosis. 2004;175(1):151–7. https://doi.org/10.1016/j.atherosclerosis.2004.03.013.

    Article  CAS  PubMed  Google Scholar 

  34. Sirico G, Spadera L, De Laurentis M, Brevetti G. Carotid artery disease and stroke in patients with peripheral arterial disease. The role of inflammation. Monaldi Arch Chest Dis. 2009;72(1):10–7. https://doi.org/10.4081/monaldi.2009.337.

    Article  PubMed  Google Scholar 

  35. Grau AJ, Boddy AW, Dukovic DA, Buggle F, Lichy C, Brandt T, et al. Leukocyte count as an independent predictor of recurrent ischemic events. Stroke. 2004;35(5):1147–52. https://doi.org/10.1161/01.str.0000124122.71702.64.

    Article  PubMed  Google Scholar 

  36. Chung JW, Oh MJ, Cho YH, Moon GJ, Kim GM, Chung CS, et al. Distinct roles of endothelial dysfunction and inflammation in intracranial atherosclerotic stroke. Eur Neurol. 2017;77(3–4):211–9. https://doi.org/10.1159/000460816.

    Article  CAS  PubMed  Google Scholar 

  37. Festa A, D'Agostino R Jr, Howard G, Mykkanen L, Tracy RP, Haffner SM. Chronic subclinical inflammation as part of the insulin resistance syndrome: the insulin resistance atherosclerosis study (IRAS). Circulation. 2000;102(1):42–7.

    Article  CAS  PubMed  Google Scholar 

  38. Stewart RA, White HD, Kirby AC, Heritier SR, Simes RJ, Nestel PJ, et al. White blood cell count predicts reduction in coronary heart disease mortality with pravastatin. Circulation. 2005;111(14):1756–62. https://doi.org/10.1161/01.cir.0000160924.73417.26.

    Article  CAS  PubMed  Google Scholar 

  39. Kannel WB, Anderson K, Wilson PW. White blood cell count and cardiovascular disease. Insights from the Framingham Study. JAMA. 1992;267(9):1253–6.

    Article  CAS  PubMed  Google Scholar 

  40. Margolis KL, Manson JE, Greenland P, Rodabough RJ, Bray PF, Safford M, et al. Leukocyte count as a predictor of cardiovascular events and mortality in postmenopausal women: the Women's Health Initiative observational study. Arch Intern Med. 2005;165(5):500–8. https://doi.org/10.1001/archinte.165.5.500.

    Article  PubMed  Google Scholar 

  41. Marino F, Tozzi M, Schembri L, Ferraro S, Tarallo A, Scanzano A, et al. Production of IL-8, VEGF and Elastase by Circulating and Intraplaque Neutrophils in Patients with Carotid Atherosclerosis. PloS One. 2015;10(4):e0124565. https://doi.org/10.1371/journal.pone.0124565.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Nam KW, Kwon HM, Jeong HY, Park JH, Kim SH, Jeong SM. High neutrophil to lymphocyte ratios predict intracranial atherosclerosis in a healthy population. Atherosclerosis. 2018;269:117–21. https://doi.org/10.1016/j.atherosclerosis.2017.12.035.

    Article  CAS  PubMed  Google Scholar 

  43. Turan TN, Makki AA, Tsappidi S, Cotsonis G, Lynn MJ, Cloft HJ, et al. Risk factors associated with severity and location of intracranial arterial stenosis. Stroke. 2010;41(8):1636–40. https://doi.org/10.1161/strokeaha.110.584672.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Wityk RJ, Lehman D, Klag M, Coresh J, Ahn H, Litt B. Race and sex differences in the distribution of cerebral atherosclerosis. Stroke. 1996;27(11):1974–80. https://doi.org/10.1161/01.str.27.11.1974.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank all patients and controls for their participation in this study.

Competing of interests

The authors declare that they have no competing interests.

Funding

This study was supported by grants from the Taishan Scholars Program of Shandong Province (ts201511109 and tsqn20161079) and Qingdao Key Health Discipline Development Fund. The grants of Taishan Scholars Program of Shandong Province (ts201511109) provide financial aid to the data collection of the manuscript; grants of Qingdao Key Health Discipline Development Fund contribute to the analyzed data of the manuscript; grants of Taishan Scholars Program of Shandong Province (tsqn20161079) pay for the publication charges.

Author information

Authors and Affiliations

Authors

Contributions

JTY and LT designed the study and wrote the manuscript. XZ and XHH performed the analysis and interpretation of data as well as manuscript writing. YHM, XNS, XPC, and JHS were responsible for the acquisition and interpretation of data and the manuscript revision. The authors read and approved the final manuscript.

Corresponding authors

Correspondence to Jing-Hui Song, Lan Tan or Jin-Tai Yu.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the ethic committee of Qingdao Municipal Hospital. Written informed consent form was obtained from all participants or their legal representatives.

Consent for publication

Not applicable.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, X., Hou, XH., Ma, YH. et al. Association of peripheral neutrophil count with intracranial atherosclerotic stenosis. BMC Neurol 20, 65 (2020). https://doi.org/10.1186/s12883-020-01641-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12883-020-01641-3

Keywords