Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 2.1 (5-Year IF – 2.0)
Journal Citation Indicator (JCI) (2023) – 0.4
Scopus CiteScore – 3.7 (CiteScore Tracker 3.8)
Index Copernicus  – 171.00; MNiSW – 70 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

Download original text (EN)

Advances in Clinical and Experimental Medicine

Ahead of print

doi: 10.17219/acem/172700

Publication type: original article

Language: English

License: Creative Commons Attribution 3.0 Unported (CC BY 3.0)

Download citation:

  • BIBTEX (JabRef, Mendeley)
  • RIS (Papers, Reference Manager, RefWorks, Zotero)

Cite as:


Song B, Chen X, Pan K, Chen X. Unraveling the role of collateral circulation and serum ELAVL1 in carotid atherosclerosis and ischemic stroke: Insights from clinical observations [published online as ahead of print on December 6, 2023]. Adv Clin Exp Med. 2024. doi:10.17219/acem/172700

Unraveling the role of collateral circulation and serum ELAVL1 in carotid atherosclerosis and ischemic stroke: Insights from clinical observations

Bing Song1,C,D, Xiangyue Chen1,A,E,F, Kun Pan2,B,C, Xiaowei Chen1,B

1 Department of Ultrasound, Brain Hospital of Hunan Province, the Second People’s Hospital of Hunan Province, Changsha, China

2 Medical Basic Teaching Experimental Center, Medical College of Hunan University of Chinese Medicine, Changsha, China

Graphical abstract


Graphical abstracts

Abstract

Background. The (embryonic lethal, abnormal vision, drosophila)-like protein 1 (ELAVL1) is a newly discovered protein associated with cerebral ischemic/reperfusion (I/R) injury. However, little is known of ELAVL1 in ischemic stroke patients.

Objectives. To investigate the clinical significance of collateral circulation and serum ELAVL1 in patients with carotid atherosclerosis (CAS) and ischemic stroke.

Materials and methods. The present prospective cohort investigation included 317 ischemic stroke patients and 300 CAS patients admitted between March 2020 and March 2022. Collateral circulation was measured using digital subtraction angiography (DSA) and graded using the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) grading system. Enzyme-linked immunosorbent assays (ELISAs) were used to measure serum ELAVL1, C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α). The serum levels of total cholesterol (TC), triglyceride (TG), high-density leptin cholesterol (HDL-C), and low-density leptin cholesterol (LDL-C) were also measured.

Results. The serum levels of ELAVL1, CRP, IL-6, TNF-α, and LDL-C were all markedly higher, while HDL-C was significantly lower in ischemic stroke patients compared to the CAS patients. Serum ELAVL1 was markedly higher in ASITN/SIR grade 0–1 patients compared to grade 2–4 patients. Also, ELAVL1 correlated positively with serum CRP, IL-6, TNF-α, TC, and LDL-C, and negatively with HDL-C. Receiver operating characteristic (ROC) curves showed that ELAVL1 and collateral circulation have the potential to be used as biomarkers for the diagnosis of ischemic stroke. Meanwhile, CRP, IL-6, TNF-α, HDL-C, ASITN/SIR grading, and ELAVL1 were independent risk factors for ischemic stroke.

Conclusions. We found that serum ELAVL1 was associated with clinical outcomes of ischemic stroke patients, while the combination of ELAVL1 and collateral circulation could be used as a potential biomarker for ischemic stroke diagnosis.

Key words: ischemic stroke, collateral circulation, carotid atherosclerosis, biomarker, observational study

Background

Stroke is the second leading cause of disability and mortality worldwide, with over 13 million new cases annually.1, 2, 3 In the past 50 years, the overall incidence rate of stroke has shown a downward trend in high-income countries and an upward trend in low- and middle-income countries.4, 5 According to the 2022 global stroke statistics report, the proportion of people over 65 years old is proportional to the incidence rate of stroke, indicating that age is one of the critical risk factors for stroke.6, 7 Among stroke patients, over 85% have an ischemic stroke, for which carotid atherosclerosis (CAS) is one of the most common causes.8, 9 Generally, ischemic stroke is caused by occlusion of the middle cerebral artery, which leads to neuronal death due to insufficient blood and oxygen supply to the brain, resulting in brain tissue damage.10, 11

Ischemia/reperfusion (I/R) injury is an unavoidable pathological injury in stroke patients and a major cause of neurological damage.12, 13 Stroke-induced I/R injury can lead to permanent brain tissue damage and may cause cognitive impairment.14, 15 Despite the development of treatment strategies, the underlying molecular mechanisms of ischemic stroke are still unclear.16, 17 In recent years, many molecular biomarkers for ischemic stroke have been identified.18, 19 However, new potential biomarkers for ischemic stroke diagnosis and prediction of prognosis are still needed.

The (embryonic lethal, abnormal vision, drosophila)-like protein 1 (ELAVL1) is a newly discovered protein associated with the development of many diseases, including brain I/R injury, the main pathological alteration in ischemic stroke.20, 21, 22 However, no clinical studies have focused on ELAVL1 in stroke patients. It is widely accepted that collateral circulation is changed and is associated with the clinical outcomes of ischemic stroke patients.23, 24, 25 Nonetheless, measuring collateral circulation alone might not be accurate enough to predict patients’ clinical outcomes.26

Objectives

In the present study, we aimed to investigate the clinical significance of collateral circulation and serum ELAVL1 in patients with CAS and ischemic stroke, focusing on their association with patients’ severity and prognosis. The study findings might provide a novel biomarker for CAS and ischemic stroke.

Materials and methods

Patients and study design

The present study was designed as a prospective cohort investigation and included 317 ischemic stroke patients admitted to our Department between March 2020 and March 2022. Ischemic stroke diagnosis was based on the guidelines of The Chinese Medical Association (2019 update).27, 28 The inclusion criteria were: 1. all patients were diagnosed with ischemic stroke using imaging methods, including computed tomography angiography (CTA), digital subtraction angiography (DSA) and magnetic resonance imaging (MRI); 2. patients received no anticoagulant therapy within 3 months before the study. The following patients were excluded: those receiving anticoagulant therapy within 3 months of study commencement, patients with hemorrhagic stroke, and patients with other systematic diseases. Additionally, 300 patients with CAS were enrolled as controls within the same study period. Among CAS patients, the following were excluded: patients with severe systematic infections, patients with cancer, and patients with severe cardiovascular, liver or renal diseases. All patients were consecutively enrolled. We recruited all cases who met the inclusion criteria during the study period. The ethical committee of the Brain Hospital of Hunan Province (Changsha, China) approved the study (Ethics Review Board No. 44; 2021).

Measurement of collateral circulation

The collateral circulation was measured with DSA and graded using the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) grading system, where 0–1 means poor compensatory collateral circulation, grade 2 is moderate compensatory circulation, and grade 3–4 is good compensatory circulation.29

Enzyme-linked immunosorbent assay

Blood samples were collected from all patients within 24 h of admission. Enzyme-linked immunosorbent assay (ELISA) was used to measure serum ELAVL1 (kit purchased from MyBioSource Inc., San Diego, USA), C-reactive protein (CRP), interleukin (IL)-6 and tumor necrosis factor alpha (TNF-α). Kits for CRP, IL-6, and TNF-α were purchased from Nanjing Jiancheng Bioengineering Institute, Nanjing, China, according to the manufacturer’s instructions.

Data collection

Demographic data, including age, sex, medical history, and complications, were recorded. The serum levels of total cholesterol (TC), triglyceride (TG), high-density leptin cholesterol (HDL-C), and low-density leptin cholesterol (LDL-C) were measured using an automatic Hitachi 7600 biochemical analyzer (Hitachi Corporation, Tokyo, Japan).

Statistical analyses

The data distribution was analyzed using the Kolmogorov–Smirnov method. All measurement data were non-normally distributed and expressed as median (range). Comparison between the 2 groups employed a Mann–Whitney U test, while χ2 tests compared rates (without half adjust). Spearman’s analysis was used for correlation analysis. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic value. Logistic regression was performed to analyze the risk factor of ischemic stroke. All calculations were made using IBM SPSS v. 22.0 (IBM Corporation, Armonk, USA) and GraphPad v. 6.0 (GraphPad Software, San Diego, USA), and p < 0.05 was defined as statistically different.

Results

Basic clinical characteristics

The present study included 317 ischemic stroke patients and 300 CAS patients. As shown in Table 1, no significant differences were found between the 2 groups of patients for age, sex, body mass index (BMI), or complications. However, serum CRP, IL-6, and TNF-α levels were markedly higher in ischemic stroke patients compared to the CAS patients (all p < 0.05). For lipid metabolism, TC and TG showed no significant difference, while LDL-C was remarkably higher and HDL-C was significantly lower in ischemic stroke patients (p < 0.05). For ASITN/SIR grading, the frequency of grade 0–1 was significantly higher in ischemic stroke patients compared to the CAS patients (p < 0.05).

Serum ELAVL1 was associated with collateral circulation

To further investigate the role of ELAVL1 in CAS and ischemic stroke patients, the levels of ELAVL1 in different patients were determined. Serum ELAVL1 was significantly upregulated in ischemic stroke patients compared to the CAS patients (p < 0.05, Figure 1A). Furthermore, serum ELAVL1 was markedly higher in ASITN/SIR grade 0–1 patients than in grade 2–4 patients (p < 0.05, Figure 1B). These results indicated that serum ELAVL1 might be associated with collateral circulation in CAS and ischemic stroke patients.

Serum ELAVL1 was associated with inflammatory cytokines and lipid metabolism

We conducted additional correlation analysis for serum ELAVL1, inflammatory cytokines, and lipid metabolism. As shown in Table 2, serum ELAVL1 was positively correlated with serum CRP, IL-6, TNF-α, TC, and LDL-C, and negatively correlated with HDL-C (all p < 0.05), suggesting that serum ELAVL1 was associated with the clinical outcomes of CAS in ischemic stroke patients.

Diagnostic value of ELAVL1 and collateral circulation for ischemic stroke

The ROC curves were used to determine the diagnostic value of ELAVL1 and collateral circulation for ischemic stroke. The ELAVL1 showed good diagnostic value for ischemic stroke, with an area under the curve (AUC) = 0.904, sensitivity = 79.18%, specificity = 78.67%, and a cutoff value >10.56 ng/mL (Figure 2A). Collateral circulation (ASITN/SIR grading) also demonstrated diagnostic value for ischemic stroke, with an AUC = 0.625, sensitivity = 61.88%, specificity = 54.20%, and a cutoff value <2.5 (Figure 2B).

When practicing the diagnostic mode in the patients using the cutoff value, both ELAVL1 and ASITN/SIR grading could be used as diabetic markers. The combination of ELAVL1 and ASITN/SIR grading showed better sensitivity and accuracy (Table 3). All of these results imply that ELAVL1 and collateral circulation have the potential to be used as biomarkers for the diagnosis of ischemic stroke. Figure 3 shows a typical DSA image of the collateral circulation.

Risk factors for ischemic stroke by logistic regression

Finally, we used univariate and multivariate logistic regression to analyze the risk factors for ischemic stroke. In univariate logistic regression, CRP, IL-6, TNF-α, LDL-C, HDL-C, ASITN/SIR grading, and ELAVL1 were risk factors for ischemic stroke. While in multivariate logistic regression, CRP, IL-6, TNF-α, HDL-C, ASITN/SIR grading, and ELAVL1 were independent risk factors for ischemic stroke (Table 4).

Discussion

Stroke is the primary cause of death in China. According to data from China’s National Stroke Epidemiology Survey, the age-standardized incidence rate of stroke in adults is approx. 1115 cases per 100,000 individuals, with a mortality rate of 115 per 100,000.30 Over the past decade, while the incidence rates have been decreasing in high-income countries, China has seen a gradual increase in stroke incidence, though the mortality rate has remained relatively stable.31, 32 Ischemic strokes primarily result from occlusion of the cerebral arteries, leading to insufficient blood and oxygen supply to the brain, causing neuronal death and subsequent brain tissue damage.

Currently, ischemic stroke treatment mainly involves thrombolysis, anticoagulation therapy, and surgical interventions.33 However, the occurrence of I/R injury after treatment often proves difficult to avoid and constitutes a major contributor to neuronal damage. Nonetheless, there are currently no specific drugs or therapies available to effectively address I/R injury and the resulting cognitive impairments following stroke. Thus, timely diagnosis of ischemic stroke is of great significance for patients’ treatment and prognosis. In the present study, we demonstrated that serum ELAVL1 was elevated in ischemic stroke patients and correlated with collateral circulation and clinical outcomes. As such, combining collateral circulation and ELAVL1 could be used as a potential biomarker for ischemic stroke diagnosis.

The ELAVL1 is a newly discovered protein associated with the development of many diseases, such as cardiovascular disease (CVD) and cerebral I/R injury. In myocardial I/R injury, ELAVL1 was significantly elevated, and knockdown of ELAVL1 could inhibit ferroptosis and improve I/R injury.34 Du et al. demonstrated that ELAVL1 was upregulated in cerebral I/R injury and facilitated neurobehavioral impairments and brain infractions after I/R treatment in animal models.22 In an early study, ELAVL1 expression was increased in human hearts and ventricular cardiomyocytes under hyperglycemic conditions and was accompanied by increased inflammation and pyroptosis.35 However, up until now, no study has reported on ELAVL1 in stroke and CAS patients.

In the present research, we demonstrated ELAVL1 upregulation in ischemic stroke patients for the first time, which was associated with inflammation and lipid metabolism, and correlated with collateral circulation. Furthermore, higher levels of ELAVL1 were associated with worse clinical outcomes, consistent with in vitro and animal studies using ischemia models. Besides myocardial injury, ELAVL1 also facilitates cellular injury in other diseases. A recent study reported that ELAVL1 knockdown led to the suppression of pyroptosis by inhibiting NLRP3 (NLR family pyrin domain containing 3) in the HK-2 renal tubular cell model of diabetic nephropathy.36 In kidney I/R injury, ELAVL1 promoted ferritinophagy in HK-2 cells and thus aggravated ferroptosis and oxidative stress.37 Similar results are also shown in Parkinson’s disease.

Researchers found that elevated ELAVL1 and NLRP3 induced pyroptosis, while downregulation of ELAVL1 inhibited pyroptosis, pyroptosis-induced inflammation and oxidative stress.38 These studies imply a correlation between ELAVL1 and inflammation/oxidative stress, which was also seen in our work, where we demonstrated ELAVL1 was positively correlated with serum CRP, IL-6 and TNF-α. Thus, we speculate that the upregulation of ELAVL1 in ischemic stroke patients is also related to increased inflammatory responses and oxidative stress. However, we did not measure oxidative stress in this study.

Collateral circulation has been widely investigated in stroke patients. It was reported that patients with good DSA collaterals had markedly smaller hypoperfusion volumes and perfusion mismatch volumes, which was also associated with the hypoperfusion intensity ratio.39 In another study, Sui et al. demonstrated that ASITN/SIR grading was associated with the National Institutes for Health Stroke Scale (NHISS) and prognosis of wake-up stroke patients.40 In a meta-analysis, the authors demonstrated that collateral circulation status and final infarct volume (FIV) are independent outcome predictors for ischemic stroke patients.41 A more recent study investigated the short-term prognosis of wake-up stroke patients and found that patients with ASITN/SIR grade 2–3 had lower NIHSS and modified Rankin scores (mRS) and higher Barthel index (BI) scores after treatment, indicating collateral circulation is associated with the prognosis of wake-up stroke patients.40 However, a recent study demonstrated that inter- and intraobserver agreement of collateral circulation grading using the ASITN/SIR score was poor,26 suggesting that ASITN/SIR grading alone might not be accurate enough for predicting clinical outcomes of ischemic stroke patients.

In addition to ischemic stroke, ASITN/SIR grading is also used to measure collateral circulation in intracranial arterial stenosis and subarachnoid hemorrhage.42, 43 In our study, we also found that the frequency of 0–1 ASITN/SIR grading was markedly higher in ischemic stroke patients. Besides, we observed that ELAVL1 was negatively associated with ASITN/SIR grades, and when combined, they have the potential for ischemic stroke diagnosis. These findings may provide a potential and novel method for the prediction/diagnosis of ischemic stroke.

Limitations

The study had some limitations. The sample size was small, and the patients were all from a single center. Furthermore, the molecular mechanisms of ELAVL1 in ischemic stroke need to be illustrated in future studies. To further understand the role of ELAVL1 in ischemic stroke, we will conduct studies using both myocardial I/R injury animal models and cellular models. Also, expanding the sample size in clinical investigations is needed in the future.

Conclusions

Serum ELAVL1 was associated with clinical outcomes of ischemic stroke patients. The combination of ELAVL1 and collateral circulation could be used as a potential strategy for the diagnosis of ischemic stroke. All of these results might provide a novel method for the diagnosis of ischemic stroke patients. Since timely treatment is critical, especially in acute ischemic stroke, we think that early diagnosis is of great significance. Thus, novel serum markers may help physicians gather more information on the patients’ condition and better understand the risk for patients susceptible to stroke. However, more clinical and basic studies are still needed to provide deeper insights into the role of ELAVL1 in ischemic stroke.

Data availability

All original data can be obtained from the corresponding author on proper request.

Consent for publication

Not applicable.

Tables


Table 1. Basic characteristics of all patients

Variables

Ischemic stroke (n = 317)

CAS (n = 300)

p-value

Age [years]

52 (35–70)

51 (35–70)

0.891

Sex (male : female, %)

179 (56.47) : 138 (43.53)

165 (55.00) : 135 (45.00)

0.834

BMI [kg/m2]

25.12 (18.01–31.99)

24.57 (18.03–31.74)

0.714

Complications, n (%)

diabetes

75 (23.66)

70 (23.33)

0.735

hypertension

69 (21.77)

57 (19.00)

current smoker

141 (44.48)

124 (41.33)

CRP [mg/L]

27.24 (5.32–49.73)

12.67 (3.02–24.95)

<0.001

IL-6 [pg/mL]

32.29 (5.05–59.90)

16.95 (5.04–29.98)

<0.001

TNF-α [pg/mL]

22.98 (5.01–39.85)

12.24 (5.02–19.85)

<0.001

TC [mmol/L]

4.36 (3.25–5.37)

4.22 (3.26–5.38)

0.189

TG [mmol/L]

1.49 (0.93–2.02)

1.44 (0.94–2.01)

0.659

LDL-C [mmol/L]

3.15 (2.21–4.00)

2.88 (2.17–3.79)

<0.001

HDL-C [mmol/L]

1.10 (0.95–1.23)

1.12 (0.97–1.25)

0.002

ASITN/SIR grading, n (%)

0–1

194 (61.20)

85 (28.33)

<0.001

2–4

123 (38.80)

215 (71.67)
The p-values were calculated between CAS and ischemic stroke patients using Student’s t-test of Mann–Whitney U test for normally or non-normally distributed data, respectively. χ2 test was used for comparing rates. CAS – carotid atherosclerosis; BMI – body mass index; CRP – C-reactive protein;
IL-6 – interleukin 6; TNF-α – tumor necrosis factor alpha; TC – total cholesterol; TG – triglyceride; LDL-C – low-density-lipoprotein cholesterol; HDL-C – high-density-lipoprotein cholesterol; ASITN/SIR – American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology.
Table 2. Spearman’s correlation among serum (embryonic lethal, abnormal vision, drosophila)-like protein 1 (ELAVL1), inflammatory cytokines and lipid metabolism in all patients

Variables

Spearman’s correlation

p-value

CRP

0.354

<0.001

IL-6

0.334

<0.001

TNF-α

0.335

<0.001

TC

0.098

0.015

TG

−0.019

0.632

LDL-C

0.146

<0.001

HDL-C

−0.076

0.049
BMI – body mass index; CRP – C-reactive protein; IL-6 – interleukin 6;
TNF-α – tumor necrosis factor alpha; TC – total cholesterol; TG – triglyceride; LDL-C – low-density-lipoprotein cholesterol;
HDL-C – high-density-lipoprotein cholesterol.
Table 3. Diagnostic value of (embryonic lethal, abnormal vision, drosophila)-like protein 1 (ELAVL1) and collateral circulation for ischemic stroke

Methods

True positive

False positive

True negative

False negative

Sensitivity

Specificity

Accuracy

ELAVL1

251

64

236

66

79.18%

78.67%

78.93%

ASITN/SIR grading

232

158

142

85

73.19%

47.33%

60.62%

ELAVL1 + ASITN/SIR grading

300

188

112

17

94.64%

37.33%

66.77%
* Sensitivity = true positive/(true positive + false negative) × 100%; specificity = true negative/(true negative + false positive) × 100%; accuracy = (true positive + true negative)/(true positive + false negative + false positive + true negative) × 100%; ASITN/SIR – American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology.
Table 4. Logistic regression for risk factors of unstable plaque

Variables

Univariate

Multivariate

OR

95% CI

p-value

OR

95% CI

p-value

Age

0.999

0.984–1.014

0.893

0.985

0.944–1.028

0.488

Sex

1.061

0.772–1.458

0.714

1.388

0.546–3.528

0.490

BMI

0.992

0.955–1.032

0.699

1.041

0.931–1.164

0.479

Diabetes

0.982

0.677–1.425

0.924

0.678

0.243–1.890

0.458

Hypertension

0.843

0.569–1.249

0.395

1.058

0.326–3.435

0.925

Current smoker

0.879

0.639–1.210

0.430

0.562

0.217–1.455

0.235

CRP

0.862

0.840–0.883

<0.001

0.818

0.766–0.873

<0.001

IL-6

0.896

0.879–0.914

<0.001

0.868

0.823–0.916

<0.001

TNF-α

0.843

0.818–0.868

<0.001

0.804

0.746–0.867

<0.001

TC

0.840

0.649–1.089

0.189

1.144

0.560–2.336

0.712

TG

0.896

0.547–1.466

0.661

0.910

0.234–3.536

0.892

LDL-C

0.445

0.322–0.616

<0.001

0.613

0.245–1.536

0.296

HDL-C

26.709

3.701–192.777

0.001

8452.881

24.213–2.95×106

0.002

ASITN/SIR grading

1.520

1.348–1.714

<0.001

0.433

0.331–0.566

<0.001

ELAVL1

0.561

0.512–0.615

<0.001

1.560

1.122–2.170

0.008
95% CI – 95% confidence interval; OR – odds ratio; BMI – body mass index; CRP – C-reactive protein; IL-6 – interleukin 6; TNF-α – tumor necrosis factor alpha; TC – total cholesterol; TG – triglyceride; LDL-C – low-density-lipoprotein cholesterol; HDL-C – high-density-lipoprotein cholesterol; ELAVL1 – (embryonic lethal, abnormal vision, drosophila)-like protein 1; ASITN/SIR – American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology.

Figures


Fig. 1. A. Serum ELAV (embryonic lethal, abnormal vision, drosophila)-like protein 1 (ELAVL1) was evaluated in ischemic stroke patients using an enzyme-linked immunosorbent assay (ELISA) and compared to carotid atherosclerosis (CAS) patients; B. Serum ELAVL1 was evaluated using ELISA in patients with different American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) grades. Lines indicate the median (range)
Fig. 2. A. Receiver operating characteristic (ROC) curve of ELAV (embryonic lethal, abnormal vision, drosophila)-like protein 1 (ELAVL1) for the diagnosis of ischemic stroke; B. ROC curve of American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) grading for diagnosis of ischemic stroke
Fig. 3. A typical digital subtraction angiography (DSA) image of collateral circulation from a 52-year-old male patient

References (43)

  1. Saini V, Guada L, Yavagal DR. Global epidemiology of stroke and access to acute ischemic stroke interventions. Neurology. 2021;97(20 Suppl 2):S6–S16. doi:10.1212/WNL.0000000000012781
  2. Guzik A, Bushnell C. Stroke epidemiology and risk factor management. Continuum (Minneap Minn). 2017;23(1):15–39. doi:10.1212/CON.0000000000000416
  3. Barthels D, Das H. Current advances in ischemic stroke research and therapies. Biochim Biophys Acta Mol Basis Dis. 2020;1866(4):165260. doi:10.1016/j.bbadis.2018.09.012
  4. Béjot Y. Forty years of descriptive epidemiology of stroke. Neuro­epidemiology. 2022;56(3):157–162. doi:10.1159/000525220
  5. Chen B, Wei S, Low SW, et al. TRPM4 blocking antibody protects cerebral vasculature in delayed stroke reperfusion. Biomedicines. 2023;11(5):1480. doi:10.3390/biomedicines11051480
  6. Thayabaranathan T, Kim J, Cadilhac DA, et al. Global stroke statistics 2022. Int J Stroke. 2022;17(9):946–956. doi:10.1177/17474930221123175
  7. Li J, Li C, Subedi P, et al. Light alcohol consumption promotes early neurogenesis following ischemic stroke in adult C57BL/6J mice. Biomedi-cines. 2023;11(4):1074. doi:10.3390/biomedicines11041074
  8. Logroscino G, Beghi E. Stroke epidemiology and COVID-19 pandemic. Curr Opin Neurol. 2021;34(1):3–10. doi:10.1097/WCO.0000000000000879
  9. Bos D, Arshi B, Van Den Bouwhuijsen QJA, et al. Atherosclerotic carotid plaque composition and incident stroke and coronary events. J Am Coll Cardiol. 2021;77(11):1426–1435. doi:10.1016/j.jacc.2021.01.038
  10. Feske SK. Ischemic stroke. Am J Med. 2021;134(12):1457–1464. doi:10.1016/j.amjmed.2021.07.027
  11. Tanaka M, Vécsei L. Editorial of Special Issue “Crosstalk between Depression, Anxiety, and Dementia: Comorbidity in Behavioral Neurology and Neuropsychiatry.” Biomedicines. 2021;9(5):517. doi:10.3390/biomedicines9050517
  12. Gomez F, El-Ghanem M, Feldstein E, et al. Cerebral ischemic reperfusion injury: Preventative and therapeutic strategies [published online as ahead of print on September 21, 2022]. Cardiol Rev. 2022. doi:10.1097/CRD.0000000000000467
  13. Tanaka M, Toldi J, Vécsei L. Exploring the etiological links behind neurodegenerative diseases: Inflammatory cytokines and bioactive kynurenines. Int J Mol Sci. 2020;21(7):2431. doi:10.3390/ijms21072431
  14. Amorim S, Felício AC, Aagaard P, Suetta C, Blauenfeldt RA, Andersen G. Effects of remote ischemic conditioning on cognitive performance: A systematic review. Physiol Behav. 2022;254:113893. doi:10.1016/j.physbeh.2022.113893
  15. Di Gregorio F, Battaglia S. Advances in EEG-based functional connectivity approaches to the study of the central nervous system in health and disease. Adv Clin Exp Med. 2023;32(6):607–612. doi:10.17219/acem/166476
  16. Campbell BCV, De Silva DA, Macleod MR, et al. Ischaemic stroke. Nat Rev Dis Primers. 2019;5(1):70. doi:10.1038/s41572-019-0118-8
  17. Iadecola C, Buckwalter MS, Anrather J. Immune responses to stroke: Mechanisms, modulation, and therapeutic potential. J Clin Invest. 2020;130(6):2777–2788. doi:10.1172/JCI135530
  18. Martinez E, Martorell J, Riambau V. Review of serum biomarkers in carotid atherosclerosis. J Vasc Surg. 2020;71(1):329–341. doi:10.1016/j.jvs.2019.04.488
  19. Kamtchum-Tatuene J, Jickling GC. Blood biomarkers for stroke diagnosis and management. Neuromol Med. 2019;21(4):344–368. doi:10.1007/s12017-019-08530-0
  20. Zhang Z, Yao Z, Wang L, et al. Activation of ferritinophagy is required for the RNA-binding protein ELAVL1/HuR to regulate ferroptosis in hepatic stellate cells. Autophagy. 2018;14(12):2083–2103. doi:10.1080/15548627.2018.1503146
  21. Zhang J, Wang H, Chen H, et al. ATF3-activated accelerating effect of LINC00941/lncIAPF on fibroblast-to-myofibroblast differentiation by blocking autophagy depending on ELAVL1/HuR in pulmonary fibrosis. Autophagy. 2022;18(11):2636–2655. doi:10.1080/15548627.2022.2046448
  22. Du Y, Zhang R, Zhang G, Wu H, Zhan S, Bu N. Downregulation of ELAVL1 attenuates ferroptosis-induced neuronal impairment in rats with cerebral ischemia/reperfusion via reducing DNMT3B-dependent PINK1 methylation. Metab Brain Dis. 2022;37(8):2763–2775. doi:10.1007/s11011-022-01080-8
  23. Ginsberg MD. The cerebral collateral circulation: Relevance to pathophysiology and treatment of stroke. Neuropharmacology. 2018;134:280–292. doi:10.1016/j.neuropharm.2017.08.003
  24. Desai SM, Jha RM, Linfante I. Collateral circulation augmentation and neuroprotection as adjuvant to mechanical thrombectomy in acute ischemic stroke. Neurology. 2021;97(20 Suppl 2):S178–S184. doi:10.1212/WNL.0000000000012809
  25. Liebeskind DS, Saber H, Xiang B, et al. Collateral circulation in thrombectomy for stroke after 6 to 24 hours in the DAWN trial. Stroke. 2022;53(3):742–748. doi:10.1161/STROKEAHA.121.034471
  26. Ben Hassen W, Malley C, Boulouis G, et al. Inter- and intraobserver reliability for angiographic leptomeningeal collateral flow assessment by the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) scale. J NeuroIntervent Surg. 2019;11(4):338–341. doi:10.1136/neurintsurg-2018-014185
  27. Liu L, Chen W, Zhou H, et al. Chinese Stroke Association guidelines for clinical management of cerebrovascular disorders: Executive summary and 2019 update of clinical management of ischaemic cerebrovascular diseases. Stroke Vasc Neurol. 2020;5(2):159–176. doi:10.1136/svn-2020-000378
  28. Gu HQ, Yang X, Wang CJ, et al. Clinical characteristics, management, and in-hospital outcomes in patients with stroke or transient ischemic attack in China. JAMA Netw Open. 2021;4(8):e2120745. doi:10.1001/jamanetworkopen.2021.20745
  29. Consoli A, Pizzuto S, Sgreccia A, et al. Angiographic collateral venous phase: A novel landmark for leptomeningeal collaterals evaluation in acute ischemic stroke [published online as ahead of print on December 20, 2022]. J NeuroIntervent Surg. 2022. doi:10.1136/jnis-2022-019653
  30. Wu S, Wu B, Liu M, et al. Stroke in China: Advances and challenges in epidemiology, prevention, and management. Lancet Neurol. 2019;18(4):394–405. doi:10.1016/S1474-4422(18)30500-3
  31. Wang W, Jiang B, Sun H, et al. Prevalence, incidence, and mortality of stroke in China: Results from a nationwide population-based survey of 480 687 adults. Circulation. 2017;135(8):759–771. doi:10.1161/CIRCULATIONAHA.116.025250
  32. Ma Q, Li R, Wang L, et al. Temporal trend and attributable risk factors of stroke burden in China, 1990–2019: An analysis for the Global Burden of Disease Study 2019. Lancet Public Health. 2021;6(12):e897–e906. doi:10.1016/S2468-2667(21)00228-0
  33. Rabinstein AA. Update on treatment of acute ischemic stroke. Continuum (Minneap Minn). 2020;26(2):268–286. doi:10.1212/CON.0000000000000840
  34. Chen HY, Xiao ZZ, Ling X, Xu RN, Zhu P, Zheng SY. ELAVL1 is transcriptionally activated by FOXC1 and promotes ferroptosis in myocardial ischemia/reperfusion injury by regulating autophagy. Mol Med. 2021;27(1):14. doi:10.1186/s10020-021-00271-w
  35. Jeyabal P, Thandavarayan RA, Joladarashi D, et al. MicroRNA-9 inhibits hyperglycemia-induced pyroptosis in human ventricular cardiomyocytes by targeting ELAVL1. Biochem Biophys Res Commun. 2016;471(4):423–429. doi:10.1016/j.bbrc.2016.02.065
  36. Li X, Zeng L, Cao C, et al. Long noncoding RNA MALAT1 regulates renal tubular epithelial pyroptosis by modulated miR-23c targeting of ELAVL1 in diabetic nephropathy. Exp Cell Res. 2017;350(2):327–335. doi:10.1016/j.yexcr.2016.12.006
  37. Sui M, Xu D, Zhao W, et al. CIRBP promotes ferroptosis by interacting with ELAVL1 and activating ferritinophagy during renal ischaemia–reperfusion injury. J Cell Mol Med. 2021;25(13):6203–6216. doi:10.1111/jcmm.16567
  38. Zhang Q, Huang XM, Liao JX, et al. LncRNA HOTAIR promotes neuronal damage through facilitating NLRP3 mediated-pyroptosis activation in Parkinson’s disease via regulation of miR-326/ELAVL1 axis. Cell Mol Neurobiol. 2021;41(8):1773–1786. doi:10.1007/s10571-020-00946-8
  39. Guenego A, Fahed R, Albers GW, et al. Hypoperfusion intensity ratio correlates with angiographic collaterals in acute ischaemic stroke with M1 occlusion. Eur J Neurol. 2020;27(5):864–870. doi:10.1111/ene.14181
  40. Sui H, Yan C, Yang J, Zhao X. Clinical significance of evaluation of collateral circulation in short-term prognosis of wake-up stroke patients. Adv Clin Exp Med. 2021;30(2):183–188. doi:10.17219/acem/121927
  41. Malhotra K, Safouris A, Goyal N, et al. Association of statin pretreatment with collateral circulation and final infarct volume in acute ischemic stroke patients: A meta-analysis. Atherosclerosis. 2019;282:75–79. doi:10.1016/j.atherosclerosis.2019.01.006
  42. Hao X, Wang S, Jiang C, et al. The relation between plasma miR-126 levels and cerebral collateral circulation in patients with intracranial arterial stenosis. Neurol Neurochir Pol. 2021;55(3):281–288. doi:10.5603/PJNNS.a2021.0019
  43. Al-Mufti F, Witsch J, Manning N, et al. Severity of cerebral vasospasm associated with development of collaterals following aneurysmal sub-arachnoid hemorrhage. J Neurointervent Surg. 2018;10(7):638–643. doi:10.1136/neurintsurg-2017-013410
© Wroclaw Medical University