2026 年 33 巻 2 号 p. 153-163
Aim: Intracranial artery calcification (IAC) in patients with acute ischemic stroke may cause cerebral hemodynamic injury and aggravate ischemia-reperfusion injury. However, its relationship with brain damage and clinical outcomes has not yet been fully explored.
Methods: Patients with acute anterior circulation ischemic stroke who underwent intravenous thrombolysis (IVT) were enrolled. Intracranial artery calcification (IAC) was assessed using the IAC volume and number of calcified vessels (NCV) on pre-IVT computed tomography. Outcomes included the degree of brain injury at 24 h post-IVT, measured by serum glial fibrillary acidic protein (GFAP) levels, final infarct volumes, intracranial hemorrhaging within 24 h of IVT, and a poor prognosis at 90 days (modified Rankin Scale ＞2). A multivariate regression analysis was conducted to evaluate the associations between IAC parameters and clinical outcomes.
Results: A total of 348 patients were enrolled in the study, of whom 273 (78.4%) had IAC. Patients were divided into four quartile groups (Q1, Q2, Q3, and Q4) based on the total IAC volume. The fourth quartile (Q4), which included patients with the highest IAC volume, was independently associated with elevated GFAP levels (odds ratio [OR] = 2.449, 95% confidence interval [CI], 1.057–5.673; P = 0.037). The second quartile (Q2) was independently associated with final infarct volume (β:0.483, 95% CI:0.014–0.952, P = 0.044). In addition, NCV was independently correlated with increased GFAP levels (OR = 1.265, 95% CI:1.010–1.584, P = 0.040) and a poor prognosis (OR = 1.270, 95% CI: 1.008-1.600, P = 0.043).
Conclusion: IAC was independently associated with the degree of brain injury, final infarct volume, and prognosis in patients after IVT.
Acute ischemic stroke (AIS) is characterized by high fatality and disability rates1, 2). Intravenous thrombolysis (IVT) is an effective method for early reperfusion that can significantly reduce the rates of disability and mortality in patients with AIS. However, IVT is still associated with a 2%-7% risk of symptomatic hemorrhagic transformation (HT) as a complication, with approximately half of the patients continuing to experience a poor functional prognosis3, 4). Therefore, early identification of prognostic markers is of great clinical importance to optimize treatment strategies and improve patient outcomes in a timely manner5).
Arterial calcification refers to the abnormal deposition of minerals in the form of calcium phosphate complexes along the vessel walls6). Intracranial arterial calcification (IAC) refers to calcification that occurs within intracranial arteries and is regarded as a proxy for intracranial atherosclerosis. IAC can be easily detected using routine computed tomography (CT). In patients with IAC, the calcification load increases and leads to hardening of the arterial wall, reducing vascular elasticity and compliance, which may destabilize cerebral hemodynamics7-9). Furthermore, some studies have suggested that chronic vascular calcification may impair the endothelial function and elevate oxidative stress, thereby exacerbating ischemia-reperfusion injury10-13). Collectively, these findings suggest that IAC can negatively influence the prognosis of patients who have undergone IVT, although the underlying mechanisms remain unclear.
Glial fibrillary acidic protein (GFAP) is a structural protein specific to astrocytes14). GFAP is released into the peripheral circulation following brain injury and blood-brain barrier disruption in patients with stroke. Thus, serum GFAP levels can serve as specific biomarkers of brain injury severity. Because GFAP can be detected at the bedside and yields results within a short period of time, it has great potential to assess the degree of brain damage in a timely manner15, 16).
We hypothesized that the presence of IAC exacerbates brain injury and contributes to poor clinical outcomes. Consequently, this study was designed to investigate the impact of IAC on patient clinical outcomes following IVT as well as to quantify the degree of brain injury based on serum GFAP levels measured 24 h post-IVT.
This study was a retrospective analysis of a prospective cohort that included consecutive patients with AIS who received IVT therapy in the Department of Neurology, First Hospital of Jilin University, from December 1, 2015, to September 30, 2020. All patients or their immediate family members provided written informed consent for inclusion, and the Ethics Committee of the First Hospital of Jilin University approved the study protocol (2015-156). All clinical investigations were conducted in accordance with the principles of the Declaration of Helsinki.
The inclusion criteria for patients were as follows: (1) age ≥ 18 years old, (2) AIS patients who received IVT with alteplase (0.9 mg/kg) within 4.5 h of onset, (3) a diagnosis of acute ischemic stroke in the anterior circulation confirmed by diffusion-weighted imaging (DWI) or follow-up CT, (4) completed baseline CT and 24-h follow-up CT, and (5) completed DWI 3–7 days after the stroke onset on magnetic resonance imaging (MRI). The exclusion criteria for patients were as follows: (1) mRS score ≥ 2 before the onset, (2) metallic or motion artifacts present on CT or MRI scans that might interfere with the measurement of infarct volume and calcification volume, and (3) underwent endovascular thrombectomy treatment.
Clinical Data Collection and Follow-UpDemographic information, vascular risk factors, and clinical data were collected for each participant. The demographic information included the name, sex, and age; vascular risk factors included smoking habit, drinking consumption, hypertension, diabetes mellitus, dyslipidemia, hyperhomocysteinemia, ischemic stroke, and coronary heart disease; and clinical information included blood pressure, heart rate, blood glucose level, onset-to-needle time (ONT), and infarct location. Stroke severity was assessed using the NIHSS score determined before IVT administration. Stroke was classified according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification criteria17). Infarct volume was calculated based on DWI of the brain using the 3D Slicer software. A good prognosis was defined as a 90-day follow-up mRS score ≤ 2, and a poor prognosis was defined as a 90-day follow-up mRS score ＞2.
CT Scanning Protocol and HT IdentificationBrain CT was performed at baseline and 24-h post-IVT using a 64-slice Philips CT scanner (Philips Healthcare, Best, Netherlands), with a slice thickness of 1.5 mm and a slice gap of 0.75 mm. All images were interpreted by two experienced neuroimaging physicians who were blinded to the patients’ clinical information and final diagnosis. HT was defined as any visible hemorrhaging on brain CT images collected 24 h after IVT and classified according to the European Collaborative Acute Stroke Study (ECASS) classification criteria18).
IAC QuantificationThe IAC was evaluated and quantified in seven primary vessels (including the C2-C7 segments of the bilateral internal carotid arteries, bilateral middle cerebral arteries, V4 segments of the bilateral vertebral arteries, and basilar artery) using baseline CT scans obtained before IVT. The ITK-SNAP medical image segmentation tool was used with an open-source software program developed by the National Institutes of Health and the National Center for Biomedical Imaging and Bioengineering for semi-quantitative image segmentation19). Calcification within the vessel regions was defined as a CT value ＞130 HU. By employing ITK-SNAP, the calcification regions were segmented and manually delineated on each consecutive slice to accurately determine the pixel count and volume of interest, allowing for the calculation of the calcification volume for each vessel (representative case illustrated in Fig.1). The ITK-SNAP tool allows reconstruction of CT images in the sagittal, coronal, and axial planes, enhancing the distinction between calcification and bone structures. The calcification parameters in our analysis included the number of calcified vessels (NCVs) and the total IAC volume. The total IAC volume was divided into four groups (Q1, Q2, Q3, and Q4) according to the interquartile range (IQR), as no internationally standardized reference values or grading system exists for calcification volumes. The fourth quartile (Q4) of the total calcification volume represented a severe vascular calcification burden. Measurements were conducted by two experienced radiologists, both of whom were blinded to the patients’ clinical details.
The areas with CT values ≥ 130 HU were semi-automatically screened (the blue areas were the areas with CT values ＜130 HU), and the calcification volume of each blood vessel was sketched with different colors. (a) Right and left vertebral artery calcification is labeled in pink, (b) the basilar artery in blue, (c) the right internal carotid artery in green, and the left internal carotid artery in red. (d) Quantitative calculation of the calcification volume.
Blood samples were collected 24 h post-IVT. In brief, venous blood was drawn from the median cubital vein of each patient and serum was obtained by centrifugation at 3000 rpm for 10 min within 2 h of collection. Subsequently, the serum samples were transferred to frozen storage tubes for storage in the biological sample library room of the Clinical Research Department of the First Hospital of Jilin University at −80℃ until analyses. Serum GFAP levels were quantified at the Stroke Center of the First Hospital of Jilin University using an automated chemiluminescent enzyme immunoassay system based on magnetic particles (MS Fast/Aceso 80A; Sophonix, Beijing, China).
Statistical AnalysesStatistical analyses were performed using the SPSS software program, version 27.0 (International Business Machines, West Grove, PA, USA). Statistical significance was set at P＜0.05. Measurement data are expressed as either the mean±standard deviation (SD) or the median and interquartile range (IQR) according to the results of the normality test. Categorical variables are presented as frequencies (percentages). The kappa statistic was used to evaluate the inter- and intra-rater reliability for detecting IAC and HT. Measurement data were compared between groups using either t-tests or Mann-Whitney U tests according to the results of the normality tests. Comparisons of categorical variables between the two groups were performed using the chi-squared test, corrected chi-squared test, or Fisher’s exact probability method. The Kruskal-Wallis H test was used to compare GFAP levels in the total volume of IAC among the four groups (Q1, Q2, Q3, and Q4), and the Bonferroni method was used to compare the groups. Correlations among GFAP levels, HT occurrence, the prognosis, and IAC were determined using a binary logistic regression analysis, and the two groups were divided based on the median GFAP levels post-IVT. Since the infarct volume distribution was skewed and based on previous studies, the linear regression between IAC and final infarct volume was determined using the natural logarithm of infarct volume. Sensitivity analyses were conducted to test the stability of the correlation results across the four regression models. Model 1 was unadjusted; Model 2 was adjusted for age and sex; Model 3 was adjusted for age, sex, smoking status, drinking status, hypertension, diabetes mellitus, and stroke history; and Model 4 was adjusted for age, sex, smoking status, drinking status, hypertension, diabetes mellitus, stroke history, previous treatment with antithrombotic agents, classification based on the TOAST, ONT, baseline NIHSS, fingertip blood glucose levels, and systolic pressure.
A total of 699 patients were initially recruited for this study. One hundred and one patients who were diagnosed with mimics or posterior circulation strokes, 42 who underwent endovascular treatment, and 208 who had unqualified CT/MRI were excluded. The flowchart of the study is shown in Fig.2. Ultimately, 348 patients with AIS receiving IVT were enrolled in the study, of whom 273 (78.4%) had IAC. Patient characteristics are listed in Table 1. Patients with IAC were more likely to have higher serum GFAP levels (28.27 vs. 18.69 pg/mL, P = 0.001), larger infarct volumes (5.16 vs. 2.70 mL, P = 0.002) and a poor prognosis (39.2% vs. 22.7%, P = 0.009) than those without IAC.
Flow chart of the study
| Variable | Total (n = 348) | IAC (n = 273) | Without IAC (n = 75) | P |
|---|---|---|---|---|
| Age (years) | 63 (55-71) | 64 (57-72) | 53 (45.5-60.5) | ＜0.001＊ |
| Sex (male, n (%)) | 249 (71.6%) | 194 (71.1%) | 55 (73.3%) | 0.773 |
| Smoking (n, %) | 196 (56.3%) | 155 (56.8%) | 41 (54.7%) | 0.793 |
| Drinking (n, %) | 167 (48.0%) | 133 (48.7%) | 34 (45.3%) | 0.696 |
| Hypertension (n, %) | 185 (53.2%) | 152 (55.7%) | 33 (44.0%) | 0.089 |
| Diabetes mellitus (n, %) | 60 (17.2%) | 54 (19.8) | 6 (8.0%) | 0.024＊ |
| Previous stroke (n, %) | 48 (13.8%) | 43 (15.8%) | 5 (6.7%) | 0.057 |
| Coronary heart disease (n, %) | 70 (20.1%) | 61 (22.3%) | 9 (12.0%) | 0.051 |
| Dyslipidemia (n, %) | 204 (58.6%) | 164 (60.1%) | 40 (53.3%) | 0.354 |
| Hyperhomocysteinemia (n, %) | 107 (30.7%) | 84 (30.8%) | 23 (30.7%) | 1.000 |
| Previous antithrombotic agents (n, %) | 35 (10.1%) | 35 (12.8%) | 0 (0.0%) | ＜0.001＊ |
| ONT (min) | 179 (140.5-230.0) | 180 (144.0 -229.5) | 165 (130.0-232.5) | 0.539 |
| Baseline NIHSS | 8 (5-12) | 9 (5-12) | 6 (4-9.5) | 0.002＊ |
| Baseline fingertip blood glucose (mmol/l) | 7.20 (6.30-8.90) | 7.70 (6.70-9.57) | 6.80 (6.20-8.15) | ＜0.001＊ |
| Baseline systolic pressure (mmHg) | 159 (141-180) | 154 (140-168) | 145 (130.5-161.5) | 0.010＊ |
| Baseline diastolic pressure (mmHg) | 91 (81-101) | 88 (80 -98) | 89 (81-98) | 0.989 |
| TOAST criteria (n, %) | 0.397 | |||
| LAA | 118 (33.9%) | 98 (35.9%) | 20 (26.7%) | |
| SAO | 144 (41.4%) | 106 (38.8%) | 38 (50.7%) | |
| CE | 39 (11.2%) | 34 (12.5%) | 5 (6.7%) | |
| ODC | 2 (0.6%) | 0 (0.0%) | 2 (2.7%) | |
| UE | 45 (12.9%) | 35 (12.8%) | 10 (13.3%) | |
| IAC (n, %) | 273 (78.4%) | - | - | - |
| IAC volume (mm3) | 92.09 (7.55-317.70) | 197.40 (52.67-377.86) | - | - |
| Infarct volume (mL)c | 4.48 (1.24-16.34) | 5.16 (1.46-21.86) | 2.70 (0.85-7.87) | 0.001＊ |
| GFAP (ng/mL) | 26.28 (11.40-90.60) | 28.27 (13.31-110.10) | 18.69 (8.04-54.97) | 0.002＊ |
| HT (n, %) | 28 (8.0%) | 23 (8.4%) | 5 (6.7%) | 0.649 |
| mRS＞2 at 90 days | 124 (35.6%) | 107 (39.2%) | 17 (22.7%) | 0.009＊ |
Abbreviations: IAC: Intracranial Arterial Calcification; ONT: onset-to-needle time; NIHSS: National Institute of Health Stroke Scale; LAA: large artery atherosclerosis; CE: Cardio-aortic embolism, SAO: small artery occlusion; ODC: other determined cause; UE: undetermined etiology; GFAP: glial fibrillary acidic protein; HT: hemorrhagic transformation; mRS: modified Rankin Scale; Notes: ＊: p＜0.05.
Initially, the study population was divided into four groups (Q1, Q2, Q3, and Q4) according to the IQR of the overall IAC volume. A statistically significant difference in GFAP levels was observed among the four groups (P = 0.002), as shown in Table 2. As the total IAC volume increased, GFAP levels were correspondingly evaluated. In the regression analysis, the NCV and total IAC volume were significantly associated with higher levels of GFAP. This correlation remained consistent across models adjusted for various factors, indicating stability in the sensitivity analysis and that the NCV and total IAC volume had the potential to predict brain injury (Table 3). The distribution of NCV and IAC volume according to dichotomous GFAP levels is shown in Figs.3a and b.
| Overall IAC Volume, (mm3) | |||||||
|---|---|---|---|---|---|---|---|
|
Total (n = 348) |
Q1 (≤ 7.555, n = 87) |
Q2 (＞7.555, ≤ 92.089, n = 87) |
Q3 (＞92.089, ≤ 317.707, n = 87) |
Q4 (＞317.707, n = 87) |
H | P | |
| GFAP (pg/mL) |
26.280 (11.404-90.596) |
17.450 (7.589-46.569) |
23.660 (11.040-91.122) |
25.921 (13.260-117.140) a |
50.665 (23.036-132.206) ab |
25.597 | 0.002＊ |
Abbreviations: IAC: Intracranial Arterial Calcification; GFAP: glial fibrillary acidic protein. Notes: ＊: p＜0.05;a: Compared with Q1, P＜0.05 after adjustment; b: compared with Q2 P＜0.05 after adjustment.
| Model1 | Model2 | Model3 | Model4 | |||||
|---|---|---|---|---|---|---|---|---|
| OR (95%CI) | P | OR (95%CI) | P | OR (95%CI) | P | OR (95%CI) | P | |
| NCV (per 1 count) | 1.421 | ＜0.001＊ | 1.224 | 0.049＊ | 1.284 | 0.019＊ | 1.265 | 0.040＊ |
| (1.185-1.704) | (1.001-1.498) | (1.041-1.583) | (1.010-1.584) | |||||
| Overall IAC volume | ||||||||
| Q1 | Ref. | Ref. | Ref. | Ref. | ||||
| Q2 | 1.544 | 0.164 | 1.259 | 0.477 | 1.413 | 0.302 | 0.982 | 0.962 |
| (0.838-2.846) | (0.667-2.376) | (0.733-2.726) | (0.469-2.057) | |||||
| Q3 | 1.857 | 0.047＊ | 1.386 | 0.328 | 1.441 | 0.291 | 1.353 | 0.443 |
| (1.009-3.471) | (0.721-2.663) | (0.731-2.838) | (0.625-2.929) | |||||
| Q4 | 4.712 | ＜0.001＊ | 2.913 | 0.004＊ | 3.367 | 0.002＊ | 2.449 | 0.037＊ |
| (2.482-8.946) | (1.403-6.049) | (1.578-7.185) | (1.057-5.673) | |||||
Abbreviations: IAC: Intracranial Arterial Calcification; NCV: Number of Calcified Vessels; OR: odds ratio; CI: confidence interval. Notes: ＊: p＜0.05; Model 1: unadjusted; Model 2: adjusted for age and gender; Model 3: adjusted for age, gender, smoking, drinking, hypertension, diabetes ellitus, and previous stroke; Model 4: adjusted for age, gender, smoking, drinking, hypertension, diabetes mellitus, previous stroke, previous antithrombotic agents, TOAST criteria, ONT, baseline NIHSS, fingertip blood glucose, systolic pressure.
Stacked percentage diagram
The correlations between the NCV, overall IAC volume, and final infarct volume are shown in Table 4. For the overall IAC volume, we found that a higher IAC volume (Q2) was independently associated with a larger final infarct volume than the patients with lowest IAC volume (Q1) after adjusting for confounders (β: 0.483, 95% confidence interval [CI]: 0.014-0.952, P = 0.044). Although a significant association between Q3 and Q4 levels of IAC volume and infarct volume was only found in unadjusted models, a tendency toward a positive correlation was indicated in multivariate regression.
| Model1 | Model2 | Model3 | Model4 | |||||
|---|---|---|---|---|---|---|---|---|
|
Unstandardized β (95%CI) |
P |
Unstandardized β (95%CI) |
P |
Unstandardized β (95%CI) |
P |
Unstandardized β (95%CI) |
P | |
| NCV (per 1 count) | 0.139 | 0.037＊ | 0.124 | 0.098 | 0.132 | 0.087 | 0.082 | 0.262 |
| (0.008-0.269) | (-0.023-0.271) | (-0.019-0.284) | (-0.062-0.227) | |||||
| Overall IAC volume | ||||||||
| Q1 | Ref. | Ref. | Ref. | Ref. | ||||
| Q2 | 0.632 | 0.007＊ | 0.610 | 0.011＊ | 0.622 | 0.011＊ | 0.483 | 0.044＊ |
| (0.177-1.087) | (0.142-1.078) | (0.145-1.098) | (0.014-0.952) | |||||
| Q3 | 0.491 | 0.031＊ | 0.451 | 0.064 | 0.458 | 0.065 | 0.316 | 0.191 |
| (0.046-0.936) | (-0.026-0.927) | (-0.028-0.944) | (-0.159-0.791) | |||||
| Q4 | 0.471 | 0.041＊ | 0.419 | 0.119 | 0.429 | 0.118 | 0.181 | 0.495 |
| (0.020-0.921) | (-0.109-0.947) | (-0.110-0.967) | (-0.341-0.703) | |||||
Abbreviations: IAC: Intracranial Arterial Calcification; NCV: Number of Calcified Vessels; CI: confidence interval. Notes: ＊: p＜0.05; Model 1: unadjusted; Model 2: adjusted for age and gender; Model 3: adjusted for age, gender, smoking, drinking, hypertension, diabetes mellitus, and previous stroke; Model 4: adjusted for age, gender, smoking, drinking, hypertension, diabetes mellitus, previous stroke, previous antithrombotic agents, TOAST criteria, ONT, baseline NIHSS, fingertip blood glucose, systolic pressure.
Among 348 patients, 28 (8.0%) had HT. The results of the binary logistic regression and sensitivity analyses showed that there was no significant difference in the NCV (P = 0.202), overall IAC volume (P = 0.178), or HT. The results are presented in Supplemental Tables 1 and 2.
| Variable | HT (n = 28) | Non-HT (n = 320) | P Value |
|---|---|---|---|
| Age (years) | 64.5 (52.5-73.0) | 61 (54-69) | 0.457 |
| Sex (male (n, %)) | 21 (75%) | 228 (71.3%) | 0.673 |
| Smoking (n, %) | 14 (50%) | 182 (56.9%) | 0.482 |
| Drinking (n, %) | 14 (50%) | 171 (53.4%) | 0.824 |
| Hypertension (n, %) | 14 (50%) | 149 (46.6%) | 0.727 |
| Diabetes mellitus (n, %) | 7 (25%) | 53 (16.6%) | 0.257 |
| Previous stroke (n, %) | 4 (14.3%) | 44 (13.8%) | 0.937 |
| Coronary heart disease (n, %) | 4 (17.9%) | 65 (20.3%) | 0.756 |
| ONT (min) | 210 (162.0-245.5) | 178 (135.25-228.75) | 0.022＊ |
| Baseline NIHSS | 11.5 (6.5-14.0) | 8 (5-11) | 0.011＊ |
| Baseline fingertip blood glucose (mmol/l) | 8.45 (6.80-10.95) | 7.20 (6.23-8.78) | 0.041＊ |
| Baseline systolic pressure (mmHg) | 155 (141.5-178.5) | 160 (141-180) | 0.811 |
| TOAST Criteria (n, %) | ＜0.001＊ | ||
| LAA | 11 (39.3%) | 107 (33.4%) | |
| SAO | 4 (14. 3%) | 140 (43.8%) | |
| CE | 10 (35. 7%) | 29 (9.1%) | |
| ODC | 0 (0.0%) | 2 (0.6%) | |
| UE | 3 (10.7%) | 42 (13.1%) | |
| NCV | 2 (1-3) | 2 (1-2) | 0.202 |
| IAC (n, %) | 23 (82.1%) | 250 (78.1%) | 0.620 |
| IAC volume (mm3) | 165.46 (16.63-430.47) | 88.87 (4.47-302.33) | 0.178 |
Abbreviations: IAC: Intracranial Arterial Calcification; NCV: Number of Calcified Vessels; ONT: onset-to-needle time; NIHSS: National Institute of Health Stroke Scale; LAA: large artery atherosclerosis; CE: Cardio-aortic embolism, SAO: small artery occlusion; ODC: other determined cause; UE :undetermined etiology; HT: hemorrhagic transformation; Notes: ＊: p＜0.05.
| Model1 | Model2 | Model3 | Model4 | |||||
|---|---|---|---|---|---|---|---|---|
| OR (95%CI) | P | OR (95%CI) | P | OR (95%CI) | P | OR (95%CI) | P | |
| NCV (per 1 count) | 1.197 | 0.259 | 1.174 | 0.368 | 1.137 | 0.481 | 1.070 | 0.727 |
| (0.876-1.635) | (0.828-1.664) | (0.796-1.625) | (0.731-1.567) | |||||
| Overall IAC volume | ||||||||
| Q1 | 1 | 1 | 1 | 1 | ||||
| Q2 | 1.435 | 0.551 | 1.428 | 0.568 | 1.438 | 0.568 | 1.045 | 0.947 |
| (0.437-4.709) | (0.421-4.845) | (0.413-5.008) | (0.284-3.848) | |||||
| Q3 | 1.215 | 0.756 | 1.192 | 0.790 | 1.180 | 0.806 | 0.931 | 0.921 |
| (0.357-4.139) | (0.327-4.346) | (0.314-4.430) | (0.227-3.824) | |||||
| Q4 | 2.130 | 0.185 | 2.111 | 0.263 | 2.088 | 0.287 | 1.474 | 0.593 |
| (0.697-6.513) | (0.571-7.807) | (0.538-8.099) | (0.356-6.106) | |||||
Abbreviations: IAC: Intracranial Arterial Calcification; NCV: Number of Calcified Vessels; OR: odds ratio; CI: confidence interval. Notes: ＊: p＜0.05; Model 1: unadjusted; Model 2: adjusted for age and gender; Model 3: adjusted for age, gender, smoking, drinking, hypertension, diabetes mellitus, and previous stroke; Model 4: adjusted for age, gender, smoking, drinking, hypertension, diabetes mellitus, previous stroke, previous antithrombotic agents, TOAST criteria, ONT, baseline NIHSS, fingertip blood glucose, systolic pressure.
Among the 348 patients included, 124 (35.6%) had a poor prognosis. The NCV was significantly associated with a poor three-month prognosis in the univariate and multivariate regression analyses (Table 5). The distribution of NCV according to the three-month prognosis is shown in Fig.3c. However, a significant association between the IAC volume and prognosis was only found in univariate regression, suggesting that IAC volume may not be an independent risk factor for a poor prognosis (Table 5).
| Model1 | Model2 | Model3 | Model4 | |||||
|---|---|---|---|---|---|---|---|---|
| OR (95%CI) | P | OR (95%CI) | P | OR (95%CI) | P | OR (95%CI) | P | |
| NCV (per 1 count) | 1.350 | 0.002＊ | 1.315 | 0.009＊ | 1.300 | 0.015＊ | 1.270 | 0.043＊ |
| (1.121-1.624) | (1.070-1.616) | (1.053-1.605) | (1.008-1.600) | |||||
| Overall IAC volume | ||||||||
| Q1 | Ref. | Ref. | Ref. | Ref. | ||||
| Q2 | 1.895 | 0.053 | 1.785 | 0.089 | 1.794 | 0.091 | 1.532 | 0.251 |
| (0.992-3.621) | (0.916-3.476) | (0.911-3.535) | (0.739-3.175) | |||||
| Q3 | 1.477 | 0.245 | 1.336 | 0.415 | 1.332 | 0.430 | 1.136 | 0.745 |
| (0.765-2.851) | (0.665-2.684) | (0.654-2.713) | (0.528-2.443) | |||||
| Q4 | 2.401 | 0.008＊ | 2.078 | 0.055 | 2.085 | 0.058 | 1.612 | 0.249 |
| (1.263-4.562) | (0.986-4.382) | (0.975-4.460) | (0.716-3.627) | |||||
Abbreviations: IAC: Intracranial Arterial Calcification; NCV: Number of Calcified Vessels; OR: odds ratio; CI: confidence interval. Notes: ＊: p＜0.05; Model 1: unadjusted; Model 2: adjusted for age and gender; Model 3: adjusted for age, gender, smoking, drinking, hypertension, diabetes mellitus, and previous stroke; Model 4: adjusted for age, gender, smoking, drinking, hypertension, diabetes mellitus, previous stroke, previous antithrombotic agents, TOAST criteria, ONT, baseline NIHSS, fingertip blood glucose, systolic pressure.
The present study demonstrated that the IAC was independently associated with serum GFAP levels, final infarct volume, and the clinical prognosis in patients with AIS who underwent IVT. These findings suggest that early intervention is necessary in stroke patients with IAC, particularly in high-risk populations.
IAC results from the deposition of pathological minerals within the cerebral vascular system20). Beyond aging, conditions such as diabetes, chronic kidney disease, genetic diseases, and other pathological processes may also be related to the occurrence of IAC21, 22). Previous studies have reported an association between IAC and hemodynamic instability, which suggests that IAC reduces the ability of cerebral vessels to regulate blood flow23). Thus, it can be inferred that the IAC may play a crucial role in subsequent brain injury after acute ischemic stroke, as hemodynamic instability may reduce the rescue effect of IVT on the ischemic penumbra and could aggravate ischemia reperfusion injury. However, few studies have provided direct evidence regarding IAC and brain injury in patients with ischemic stroke.
In the present study, we found that the IAC was independently associated with the serum levels of GFAP and the final infarct volume. Furthermore, it is worth mentioning that among those with IAC, the comparisons of the lowest quartile and second quartile groups revealed that the total calcification volume was independently associated with a larger final infarction volume; this relationship was not observed in patients with total calcification volume in the third and fourth quartiles. However, as the total IAC volume increased, a corresponding gradual increase in GFAP expression was observed within each quartile of total calcification volume. These findings further indicate that IAC aggravates brain tissue injury in patients with acute ischemic stroke.
The present study showed that the increased NCV was independently associated with a poor functional outcome prognosis in patients receiving IVT. Specifically, each additional NCV increased the risk of a poor prognosis by 30%. The effects of IAC, such as extensive calcification distribution, may result in poorer responses to intravenous thrombolytic drugs due to an impaired endothelial function, among other possible factors, resulting in a reduced vascular patency rate, which can further affect tissue perfusion compensation and the functional prognosis of patients24, 25). Our findings confirm that a higher IAC burden, reflected by increased IAC volume or NCV, may exacerbate brain injury and lead to poor ischemic stroke outcomes. Quantitative IAC parameters, such as IAC volume and NCV, could serve as valuable predictors of brain injury severity and a poor prognosis after IVT in patients with ischemic stroke, potentially reporting risk stratification and guiding individualized treatment strategies. Furthermore, IAC may represent a novel intervention target for the management of ischemic stroke. Future studies should aim to develop and evaluate intervention strategies specifically tailored to patients with a high calcification burden to improve clinical outcomes in this high-risk population.
Theoretically, arterial calcification may increase the risk of HT following IVT26), although no correlation between the two factors was observed in the present study. There are several possible explanations for this discrepancy in the results. First, the patients who experienced HT had higher NIHSS scores than those who did not experience HT, indicating that patients who experienced complications were more likely to have more severe and long-standing vascular system damage. Therefore, the impact of arterial calcification on the vascular function and HT occurrence may have been overshadowed by the impact of higher NIHSS scores. In addition, the number of HT cases in this cohort was limited, and further research with a larger sample size is required to clarify the relationship between calcification and HT occurrence.
The IAC is an imaging marker that can be readily identified on CT and is independently associated with brain tissue injury in patients with AIS undergoing thrombolysis. Furthermore, IAC was significantly correlated with both the final infarction volume and clinical outcomes. Consequently, IAC serves as a critical foundation for risk stratification and treatment decision-making in the clinical management of patients with AIS. For patients exhibiting a high burden of IAC, it is essential to promptly implement personalized treatment strategies and initiate neuroprotective interventions at an early stage. Such measures are pivotal in minimizing brain tissue damage and enhancing patient prognosis. In the future, its application may extend to all stroke patients, enabling the systematic evaluation of IAC for the early detection and prevention of stroke.
In clinical practice, controlling blood pressure, blood sugar, and lipid levels is important in stroke prevention. Our findings suggest that it is essential to improve the management and monitoring of patients with a high calcification burden, as identified using non-contrast CT in clinical practice. Early prevention of adverse cerebrovascular events and implementation of timely interventions are crucial to avoid a poor prognosis.
Several limitations associated with the present study warrant mention. First, this was a single-center study with a relatively small sample size, and further analyses will be needed to validate our findings in larger multicenter cohorts. Second, quantitative measurement of the IAC volume based on non-contrast-enhanced CT is a sensitive and reliable imaging marker that has been shown to be representative of a patient’s calcification burden. However, no other calcification features were analyzed, such as calcification subtype or atherosclerotic plate ulceration, which are also known to have the potential to affect hemodynamic changes in patients. Finally, this study was based primarily on retrospective baseline CT scan data, and long-term follow-up data were not collected to assess longitudinal changes in calcification and their association with clinical outcomes. Therefore, further studies are warranted.
Ultimately, this study confirmed that the IAC was independently associated with serum GFAP levels, final infarct volume, and the clinical prognosis in patients receiving IVT. These findings suggest the importance of early intervention in high-risk stroke patients with IAC.
We thank the Department of Biobank, Division of Clinical Research, the First Hospital of Jilin University, for providing human tissues.
This work was supported by the Science and Technology Department of Jilin Province (grant number YDZJ202301ZYTS027), Radiology and Technology Innovation Center of Jilin Province (grant number YDZJ202402029CXJD), and the Jilin Province Imaging Big Data Medical Engineering Innovation Research and Development Engineering Laboratory (grant number LSWSRCZX2020-068).
This study was approved by the Ethics Committee of the First Hospital of Jilin University (2015–156). Written informed consent was obtained from all participants, who had the right to withdraw from the study at any point.
Data associated with the study have not been deposited into a publicly available repository and will be made available on request.
The authors declare that they have no conflicts of interest.
