Risk of acute cerebral infarction in patients with hypertension based on high-resolution MRI

Introduction

Hypertension is a major cause of premature death and cardiovascular and cerebrovascular diseases worldwide (1). Although hypertension is a nontransmissible and preventable disease, the aging of the population exacerbates its impact leading to multisystemic damage, including damage to the brain, heart, blood vessels, kidneys, and eyes (2-5). Hypertension is also a risk factor for atherosclerotic plaque formation (6), and the related mechanisms include shear and stretch stress, metabolic disorders, and immune and inflammatory responses (7,8). Acute cerebral infarction (ACI) is a serious clinical accident due to decreased blood flow, which is characterized by limited diffusion on magnetic resonance imaging (MRI). Approximately 8–50% of ACI are caused by atherosclerotic disease (9), and among them, about 20% are attributed to the carotid artery (10,11)._. Multiple studies have confirmed that vulnerable carotid atherosclerotic plaques can increase the risk of cerebrovascular events (12-14). Worldwide, around 816 million people aged 30–79 years are affected by carotid plaque (15). There is increasing evidence suggesting that specific components of plaque composition are risk factors for the occurrence of ACI, independent of the severity of carotid artery stenosis (16). High-resolution MRI (HR-MRI) vessel wall imaging can accurately differentiate plaque components such as intraplaque hemorrhage (IPH), surface irregularity, plaque enhancement, lipid core, calcification, and fibrous cap, with some components matching histological examinations up to 86.7% (17,18). However, the relationship between hypertension with ACI and characteristics of vulnerable carotid plaque on HR-MRI is currently unclear. Therefore, the aim of this study is to explore the risk factors for ACI and to determine the relationship between HR-MRI characteristics of vulnerable carotid plaques and ACI in patients with hypertension. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-24-2106/rc).

Methods

Study population

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and was approved by institutional board of Huashan Hospital Fudan University (No. KY-2021-965). The individual consent for this retrospective analysis was obtained. Data of the patients suspected as cerebrovascular disease due to clinical symptoms who had undergone carotid artery HR-MRI at the Department of Radiology of Huashan Hospital Fudan University between December 2018 and May 2024 were retrospectively collected. The inclusion criteria were as follows: (I) presence of hypertension defined in accordance with the criteria of the European Society of Hypertension [≥140 mmHg systolic blood pressure (SBP) and (or) ≥90 mmHg diastolic blood pressure (DBP)] or a history of hypertension such as taking antihypertensive medication; (II) ultrasound demonstrating intima-media thickness ≥1.5 mm at the bifurcation of the carotid artery and the initial segment of the internal carotid artery (19); (III) complete carotid artery HR-MRI and brain MRI; (IV) available routine blood tests and blood biochemistry results. The exclusion criteria were as follows: (I) presence of ACI caused by hemodynamic changes in the posterior circulation or cardiogenic ACI (n=19); (II) severe liver, kidney (renal/adrenal hypertension or creatinine abnormalities due to kidney tumors), or hematological disorders, or severe neurological conditions such as brain tumors and cerebral hemorrhage (n=65); (III) cerebral vasculitis, occlusion, or dissection (n=216); (IV) operation history of carotid stenting or carotid endarterectomy surgery (n=12); (V) poor image quality (n=21).

Basic clinical information was collected from the hospital admission system and included age, gender, body mass index (BMI), duration and grade of hypertension, history of diabetes, hyperlipidemia, cardiovascular disease, smoking, and National Institutes of Health Stroke Scale (NIHSS) scores (20). The history of diabetes and hyperlipidemia was diagnosed according to clinical standards (21). Routine blood tests and blood biochemistry parameters were evaluated using automated biochemical analyzers (colorimetric, scattering turbidimetry and immunoturbidimetric assays). Blood pressure measurement: After the subjects rested quietly for at least 5 min, sitting upper arm blood pressure was measured. The measurement was repeated after an interval of 1–2 min, and the average data were recorded. If the two readings of SBP or DBP differed by more than 5 mmHg, a third measurement was taken, and then the average of the three measurements was recorded. According to European Society of Hypertension, the grade of hypertension was defined as follows: grade 1, SBP 140–159 and (or) DBP 90–99 mmHg; grade 2, SBP 160–179 and (or) DBP 100–109 mmHg; grade 3, SBP ≥180 and (or) DBP ≥110 mmHg. The duration of hypertension was defined as the number of years since the patient’s self-reported diagnosis of the condition. Clinically, mild ACI was defined as NIHSS ≤5, while NIHSS >5 was considered moderate-to-severe ACI.

Carotid HR-MRI analysis

All of the participants who is suspected as cerebrovascular disease due to clinical symptoms underwent routine brain MRI scan and 3.0-T HR-MRI of the carotid artery, using an 8-channel phased array carotid artery coil and 20-channel phased array head and neck joint coil. The brain MRI was acquired by T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), T2-Flair, and diffusion-weighted imaging (DWI). HR-MRI included 3D T1WI (Philips Healthcare, Best, Netherlands), contrast-enhanced 3D T1WI (3D T1WI+C), and simultaneous non-contrast angiography and intraplaque hemorrhage (SNAP). For the patients with ACI, the ipsilateral carotid artery plaque was selected as the lesion subject. For the non-ACI patients, when plaques were present in both carotid arteries, the side with more severe stenosis was selected. ITK-SNAP software v.4.0.0 (www.itksnap.org/) was used to delineate the region of interest and calculate the plaque area, lumen area, vessel area, and plaque burden (plaque area/vessel area). IPH was defined as a hyperintense signal on SNAP (18). The presence of plaque enhancement was decided by higher signal intensity on post-contrast 3D T1WI images than on pre-contrast T1WI images (22). Plaque surface irregularity was defined as discontinuity of the fibrous cap on the plaque surface (23).

Statistical analysis

Continuous numerical data with a normal distribution were expressed as mean ± standard deviation (SD), while non-normally distributed data were expressed as median (interquartile range). Categorical data were expressed as counts and percentages. To analyze differences between the two groups, normally distributed data were analyzed using the independent-samples t test, non-normally distributed data were compared using the Mann-Whitney U test, and categorical data were analyzed using the Chi-squared test. Logistic regression was used to analyze the relationship among carotid plaque characteristics, clinical information, and the occurrence and severity of ACI in patients with hypertension, calculating the odds ratios (ORs) with a 95% confidence interval (CI). P values lower than 0.05 were considered statistically significant.

Results

Clinical and demographic characteristics and laboratory tests

A total of 162 patients with hypertension were included, namely 68 (42%) with ACI (hyperintense on DWI) and 94 (58%) without ACI. The representative MRI images of patients were shown in Figure 1 with ACI and Figure 2 without ACI. As shown in Table 1, the patients with ACI had longer duration of hypertension (14.54±8.86 vs. 11.01±7.84, P=0.008) and higher grade of hypertension (15/32/21 vs. 47/27/20, P=0.001) than those without ACI. In addition, the patients in the ACI group had higher levels of HbA1c [6.45 (5.90–7.53) vs. 6.10 (5.70–6.70), P=0.025] and serum creatinine (87.40±18.64 vs. 77.07±15.56, P<0.001). Furthermore, the patients with ACI had higher proportions of IPH [42 (61.76%) vs. 31 (32.98%), P<0.001] and plaque enhancement [52 (76.47%) vs. 54 (57.45%), P=0.012]. There were no significant intergroup differences in plaque surface irregularity, total plaque volume, plaque area, lumen area, vessel area, volume of IPH, and proportion of IPH volume. In addition, there were no significant intergroup differences in blood routine biochemistry parameters.

Figure 1 A 67-year-old hypertensive male with ACI of right temporal lobe caused by right carotid plaque. The top row showed brain MRI images. Right temporal lobe exhibited hypointensity on T1WI (A) but hyperintensity on T2WI (B), Flair (C) and DWI (D). The carotid plaque was marked in the below row (red arrows). Axis images (E,F) were reconstructed from the pre- and post-enhancement HR-MRI. Hyperintensity of carotid plaque on SNAP (G). ACI, acute cerebral infarction; DWI, diffusion-weighted imaging; HR-MRI, high-resolution magnetic resonance imaging; SNAP, simultaneous non-contrast angiography and intraplaque hemorrhage; T1WI, T1-weighted imaging; T2WI, T2-weighted imaging.

Figure 2 A 56-year-old hypertensive male without ACI. There was not abnormal signal on brain MRI images (top row): T1WI (A), T2WI (B), Flair (C), and DWI (D). The carotid plaque was located in the below row (red arrows). Axis images (E,F) were reconstructed from the pre- and post-enhancement HR-MRI. No hyperintensity of carotid plaque on SNAP (G). ACI, acute cerebral infarction; DWI, diffusion-weighted imaging; HR-MRI, high-resolution magnetic resonance imaging; SNAP, simultaneous non-contrast angiography and intraplaque hemorrhage; T1WI, T1-weighted imaging; T2WI, T2-weighted imaging.

As shown in Table 2, the ACI group was further divided into two groups, namely 34 (50%) patients had mild ACI (NIHSS≤5) and 34 patients (50%) had moderate-to-severe ACI (NIHSS>5). The grade of hypertension was significantly different (13/16/5 vs. 4/15/15, P=0.007) between the two groups. The moderate-to-severe ACI group had higher proportions of IPH [23 (67.65%) vs. 12 (35.29%), P=0.008], surface irregularity [28 (82.35%) vs. 18 (52.94%), P=0.01], and plaque enhancement [31 (91.18%) vs. 24 (70.59%), P=0.031].

Regression analysis of risk factors in patients with ACI

Further analysis of various clinical information and HR-MRI characteristics of carotid plaques was conducted to explore their relationship with ACI in patients with hypertension. Univariate logistic regression analysis showed that duration of hypertension (OR, 1.05; 95% CI: 1.01–1.10; P=0.013), grade 2 [(OR, 2.89; 95% CI: 1.34–6.24; P=0.007) vs. grade 1] and grade 3 hypertension [(OR, 2.80; 95% CI: 1.20–6.52; P=0.017) vs. grade 1], serum creatinine levels (OR, 1.03; 95% CI: 1.01–1.05; P=0.001), IPH (OR, 3.28; 95% CI: 1.71–6.30; P<0.001), and plaque enhancement (OR, 2.41; 95% CI: 1.20–4.82; P=0.013) were the risk factors for the occurrence of ACI. Multivariate logistic regression analysis showed that duration of hypertension (OR, 1.06; 95% CI: 1.01–1.11; P=0.02), grade 2 [(OR, 3.05; 95% CI: 1.29–7.21; P=0.011) vs. grade 1] and grade 3 hypertension [(OR, 2.71; 95% CI: 1.01–6.98; P=0.039) vs. grade 1], serum creatinine levels (OR, 1.03; 95% CI: 1.01–1.05; P=0.023), IPH (OR, 2.89; 95% CI: 1.41–5.95; P=0.004), and plaque enhancement (OR, 2.37; 95% CI: 1.09–5.16; P=0.029) remained significant risk factors (Figure 3A).

Figure 3 Forest maps for the relationships between carotid plaque and ACI in patients with hypertension. (A) The duration of hypertension, higher hypertension grades, serum creatinine levels, IPH and plaque enhancement were identified as the risk factors for the occurrence of ACI. (B) Grade 3 hypertension and surface irregularity were related to the more severe form of ACI (NIHSS >5). ACI, acute cerebral infarction; CI, confidence interval; IPH, intraplaque hemorrhage; NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio.

In univariate regression analysis, grade 3 hypertension (OR, 9.75; 95% CI: 2.15–44.14; P=0.003), IPH (OR, 3.83; 95% CI: 1.40–10.48; P=0.009), surface irregularity (OR, 4.15; 95% CI: 1.37–12.58; P=0.012), and plaque enhancement (OR, 4.31; 95% CI: 1.07–17.39; P=0.04) were identified as the risk factors for moderate-to-severe ACI. In further multivariate regression analysis, only grade 3 hypertension (OR, 4.67; 95% CI: 1.24–17.56; P=0.023) and surface irregularity (OR, 4.09; 95% CI: 1.13–14.86; P=0.032) remained significant risk factors for moderate-to-severe ACI (Figure 3B).

Discussion

This study explored the risk factors associated with ACI in patients with hypertension and its relationship with HR-MRI characteristics of vulnerable carotid artery plaques. A recent study on the relationship between carotid artery vulnerable plaque and ACI has pointed out that the presence of lipid-rich necrotic core, IPH, and irregular plaque surface in the ACI group (60.87%) was significantly higher than that in the non-ACI group (22.73%), and ACI was more likely to occur in patients with hypertension (24). Our larger-sample-size study revealed that the hypertension group with ACI had a longer duration of hypertension, different hypertension grades, and higher levels of HbA1c and serum creatinine compared with the non-ACI group. Furthermore, regression analysis revealed that duration of hypertension, hypertension grade, serum creatinine levels, IPH, and plaque enhancement were the independent risk factors for ACI in patients with hypertension. In this study, for all ACI patients, surface irregularity and grade 3 hypertension were identified as the risk factors leading to moderate-to-severe ACI.

We found that the ACI group suffered hypertension for a longer period of time and in a more severe form than the non-ACI group. Importantly, longer duration and higher grade of hypertension were the independent factors for developing ACI, which is consistent with previous research (25). In patients with hypertension, adding duration of hypertension to the modified CHA₂DS₂-VASc score [congestive heart failure, hypertension, age ≥75 years (doubled), diabetes mellitus, prior stroke or TIA (doubled), vascular disease, age 65–74 years, female] significantly improved its predictive value for ACI (25). A 2024 study showed that both hypertension grade and hypertension duration were associated with general pre-stroke features in univariate analysis (26). Tanvir Chowdhury Turin’s study indicated that hypertension grade significantly affected the lifetime risk of stroke. Although the difference was not large, patients with grade 2 hypertension had a higher lifetime risk of stroke compared with those with grade 1 hypertension (27). The mechanisms linking hypertension and ACI are complex and diverse. On the one hand, elevated blood pressure damages endothelial cells and smooth muscle cells in the blood vessels (28), and their interaction can lead to local thrombosis and plaque formation, thereby increasing the likelihood of ischemic lesions and cerebrovascular lesions associated with vascular stenosis (29). On the other hand, chronic hypertension impairs cerebral autoregulation, leading to cerebral hypoperfusion and potentially triggering ACI (30,31). Experiments on hypertensive mice demonstrated that cerebrovascular spasms and ischemic stroke were induced through key components of store-operated calcium entry, involving polycystin-2 (32), stromal interaction molecule 1, and Orai3 (33).

Our data indicated that the patients with hypertension and ACI had higher proportions of IPH and plaque enhancement compared with those without ACI. Furthermore, these two plaque features were independent risk factors for ACI [OR, 2.89 (95% CI: 1.41–5.95); OR, 2.37 (95% CI: 1.09–5.16)]. Hosseini et al. conducted a meta-analysis and found an OR of 10.02 (95% CI: 5.46–18.38) for the association between IPH and future occurrence of ACI (34). Gupta et al. conducted a larger meta-analysis and reported an OR of 4.59 (95% CI: 2.92–7.23) for the association between IPH and future occurrence of ACI (13). In our study, the 95% CI was likely smaller because this was a retrospective study focusing on individuals with hypertension, unlike the previous two studies. The presence of IPH indicates an increase in the number of new vessels and the area of macrophage infiltration (4). However, in patients with hypertension, these neovessels are more fragile and immature, and macrophages prevent cholesterol efflux, leading to lipid accumulation (35). This promotes both the immediate and long-term progression of the plaque, increasing the likelihood of plaque instability and embolism in distal cerebral vessels.

Plaque enhancement increases the risk of ACI in patients with hypertension. Numerous previous studies have demonstrated that plaque enhancement is an imaging marker for cerebral infarction (36-38). Huang et al. attempted to qualitatively and quantitatively assess the relationship between plaque enhancement and intracranial atherosclerotic stenosis (ICAS). They found that plaque enhancement was significantly associated with symptomatic ICAS and that it was an independent risk factor for symptomatic ICAS (37). Furthermore, plaque enhancement was significantly associated with the progression of ICAS and recurrent stroke during the follow-up period (38). Plaque enhancement is an important marker of plaque vulnerability in both extracranial and intracranial arteries, which is primarily associated with active inflammation, neovascularization, and increased endothelial permeability (39).

Furthermore, an important finding of this study was that serum creatinine was an independent risk factor for ACI in patients with hypertension. From the perspective of molecular biology, certain microRNAs can explain the relationship between serum creatinine and ACI. miR-122-5p (OR, 1.0001; 95% CI: 1.0000–1.0002) and serum creatinine levels (OR, 1.02; 95% CI: 1.01–1.04) can predict secondary ischemic stroke in patients with primary cardiovascular disease (40). Creatinine is a marker of kidney function, and we speculate that elevated creatinine in patients with hypertension indicates kidney damage, which is closely related to cerebrovascular disease.

Further research revealed that grade 3 hypertension was a risk factor for developing moderate-to-severe ACI. A longitudinal study on Caucasian individuals examining the relationship between hypertension grade and clinical cardiovascular events indicated that in the absence of dynamic blood pressure information, grade 3 hypertension (1.93 per 100 patient-years; P<0.01 vs. grade 1 and grade 2) was independently associated with cardiovascular events (41). We hypothesize that higher blood pressure level leads to intense turbulent flow of blood at the bifurcation of vessels and then shear stress changes (42), resulting in severe local vascular endothelial damage; besides, the increase of trans-wall pressure causes the reactive thickening of the blood vessel wall, which promotes the formation of plaque further induces more severe ACI. Previous studies using multi-angle axial and oblique vascular wall imaging found that surface irregularity was an independent risk factor for developing ipsilateral ACI (OR, 6.08; 95% CI: 2.52–14.68) (43). The exact mechanism explaining the link between plaque surface irregularity and ACI is not well understood, but the data from ultrasound imaging suggest that surface irregularity may be a marker of systemic atherosclerosis rather than a potential source of embolism (44). Vascular imaging studies supported a strong correlation between irregular plaque surfaces in carotid arteries and microscopic plaque rupture, hemorrhage, or systemic infection states (45). In our study, the irregularity of plaque surface may represent ulceration or calcification histologically (46), which may lead to repeated rupture of plaques, causing stroke recurrence or more severe symptoms.

There are some limitations to our study. (I) The sample size was relatively small. Considering that hypertension is a common condition, future efforts will focus on collecting multicenter data to expand the sample size. (II) This study was a clinically retrospective study, which cannot elucidate the exact mechanism underlying the relationship between vulnerable carotid plaque characteristics and ACI in patients with hypertension. (III) Our study lacked the pathological gold standard for reference, and future studies should combine pathology, ultrasound, and other modalities to validate our findings. (IV) Blood pressure measurement was a single assessment outcome, and future work should pay more attention to the long-term follow-up on hypertension classification and consider the influence of antihypertensive medications. (V) These variables are self-reported and may have an impact on the results, and we will increase the sample size to reduce the bias in the future. (VI) The diversity of drug types in the late 60s may have an impact on the results, and a larger sample size will be required.

Conclusions

Patients with ACI tend to have longer duration and higher grade of hypertension, and elevated serum creatinine levels. These indicators collectively increase the risk of ACI. In addition, in patients with hypertension, HR-MRI characteristics of vulnerable carotid plaques (such as IPH and plaque enhancement) are risk factors for ACI, and surface irregularity is related to moderate-to-severe ACI.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-24-2106/rc

Funding: This work was supported by National Nature Science Foundation of China (Nos. 82372048 and 82402393), Shanghai Municipal Commission of Science and Technology (Nos. 22TS1400900, 23S31904100, and 22YF1405000), and Science and Technology Commission of Shanghai Municipality (No. 24SF1904201).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-2106/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the institutional board of Huashan Hospital Fudan University (No. KY-2021-965). The individual consent for this retrospective analysis was obtained.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Al-Makki A, DiPette D, Whelton PK, Murad MH, Mustafa RA, Acharya S, et al. Hypertension Pharmacological Treatment in Adults: A World Health Organization Guideline Executive Summary. Hypertension 2022;79:293-301. [Crossref] [PubMed]
2. Hunt RD, Cipolla MJ. Chronic hypertension alters the relationship between collateral blood flow cortical cerebral blood flow, and brain tissue oxygenation. J Cereb Blood Flow Metab 2024;44:1227-37. [Crossref] [PubMed]
3. Solanki JD, Vohra AS, Hirani CN, Bhatt DN. Arterial stiffness is associated with prehypertension in both non-hypertensives and treated hypertensives-A matched case control study. Indian Heart J 2024;76:224-8. [Crossref] [PubMed]
4. Okawa Y, Mitsuhashi T. Association between blood pressure and new onset of chronic kidney disease in non-diabetic Japanese adults: A population-based longitudinal study from 1998 to 2023. Nutr Metab Cardiovasc Dis 2024;34:2395-404.
5. Daxer B, Radner W, Fischer F, Cocoșilă AL, Ettl A. Aetiology, Diagnosis and Treatment of Arterial Occlusions of the Retina-A Narrative Review. Medicina (Kaunas) 2024;60:526. [Crossref] [PubMed]
6. Benvidi A, Firoozabadi B. Simulation of plaque formation in a realistic geometry of a human aorta: effects of endothelial layer properties, heart rate, and hypertension. Biomech Model Mechanobiol 2024;23:1723-40. [Crossref] [PubMed]
7. Dinh QN, Drummond GR, Sobey CG, Chrissobolis S. Roles of inflammation, oxidative stress, and vascular dysfunction in hypertension. Biomed Res Int 2014;2014:406960. [Crossref] [PubMed]
8. Liu X, Yang M, Lip GYH, McDowell G. Plasma Biomarkers for Hypertension-Mediated Organ Damage Detection: A Narrative Review. Biomedicines 2024;12:1071. [Crossref] [PubMed]
9. Tian D, Yang Q, Dong Q, Li N, Yan B, Fan D. Trends in stroke subtypes and vascular risk factors in a stroke center in China over 10 years. Sci Rep 2018;8:5037. [Crossref] [PubMed]
10. Grau AJ, Weimar C, Buggle F, Heinrich A, Goertler M, Neumaier S, Glahn J, Brandt T, Hacke W, Diener HC. Risk factors, outcome, and treatment in subtypes of ischemic stroke: the German stroke data bank. Stroke 2001;32:2559-66. [Crossref] [PubMed]
11. Wang J, Wang L, Shen Y, Gong X, Ju Y. Relationship Between Carotid Artery Angle and Plaque Morphology in Acute Cerebral Infarction Patients. Neurologist 2022;27:240-4. [Crossref] [PubMed]
12. van Dam-Nolen DHK, Truijman MTB, van der Kolk AG, Liem MI, Schreuder FHBM, Boersma E, Daemen MJAP, Mess WH, van Oostenbrugge RJ, van der Steen AFW, Bos D, Koudstaal PJ, Nederkoorn PJ, Hendrikse J, van der Lugt A, Kooi MEPARISK Study Group. Carotid Plaque Characteristics Predict Recurrent Ischemic Stroke and TIA: The PARISK (Plaque At RISK) Study. JACC Cardiovasc Imaging 2022;15:1715-26. [Crossref] [PubMed]
13. Gupta A, Baradaran H, Schweitzer AD, Kamel H, Pandya A, Delgado D, Dunning A, Mushlin AI, Sanelli PC. Carotid plaque MRI and stroke risk: a systematic review and meta-analysis. Stroke 2013;44:3071-7. [Crossref] [PubMed]
14. Kopczak A, Schindler A, Sepp D, Bayer-Karpinska A, Malik R, Koch ML, Zeller J, Strecker C, Janowitz D, Wollenweber FA, Hempel JM, Boeckh-Behrens T, Cyran CC, Helck A, Harloff A, Ziemann U, Poli S, Poppert H, Saam T, Dichgans M. Complicated Carotid Artery Plaques and Risk of Recurrent Ischemic Stroke or TIA. J Am Coll Cardiol 2022;79:2189-99. [Crossref] [PubMed]
15. Song P, Fang Z, Wang H, Cai Y, Rahimi K, Zhu Y, Fowkes FGR, Fowkes FJI, Rudan I. Global and regional prevalence, burden, and risk factors for carotid atherosclerosis: a systematic review, meta-analysis, and modelling study. Lancet Glob Health 2020;8:e721-9. [Crossref] [PubMed]
16. Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W Jr, Rosenfeld ME, Schwartz CJ, Wagner WD, Wissler RW. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 1995;92:1355-74. [Crossref] [PubMed]
17. Cai JM, Hatsukami TS, Ferguson MS, Small R, Polissar NL, Yuan C. Classification of human carotid atherosclerotic lesions with in vivo multicontrast magnetic resonance imaging. Circulation 2002;106:1368-73. [Crossref] [PubMed]
18. Li D, Qiao H, Han Y, Han H, Yang D, Cao J, Xu H, Wang T, Wang Y, Shen J, Zhao X. Histological validation of simultaneous non-contrast angiography and intraplaque hemorrhage imaging (SNAP) for characterizing carotid intraplaque hemorrhage. Eur Radiol 2021;31:3106-15. [Crossref] [PubMed]
19. Touboul PJ, Hennerici MG, Meairs S, Adams H, Amarenco P, Bornstein N, et al. Mannheim carotid intima-media thickness consensus (2004-2006). An update on behalf of the Advisory Board of the 3rd and 4th Watching the Risk Symposium, 13th and 15th European Stroke Conferences, Mannheim, Germany, 2004, and Brussels, Belgium, 2006. Cerebrovasc Dis 2007;23:75-80. [Crossref] [PubMed]
20. Niizuma K, Nishimura N, Hasegawa K, Moritoyo T, Kudo K, Bell J, Wald M, Umeda Y, Kuribayashi K, Toda Y, Tominaga T, Hasumi K. Anti-Inflammatory Thrombolytic JX10 (TMS-007) in Late Presentation of Acute Ischemic Stroke. Stroke 2024;55:2786-94. [Crossref] [PubMed]
21. Standards of Medical Care in Diabetes-2019 Abridged for Primary Care Providers. Clin Diabetes 2019;37:11-34. [Crossref] [PubMed]
22. Lu M, Zhang H, Liu D, Liu X, Zhang L, Peng P, Yuan F, Liu S, Sheng F, Liu Y, He Y, Zhao X, Zhang Q, Fu H, Han C, Cai J. Association of intracranial vessel wall enhancement and cerebral hemorrhage in moyamoya disease: a high-resolution magnetic resonance imaging study. J Neurol 2021;268:4768-77. [Crossref] [PubMed]
23. Wu F, Song H, Ma Q, Xiao J, Jiang T, Huang X, Bi X, Guo X, Li D, Yang Q, Ji X, Fan Z. WISP Investigators. Hyperintense Plaque on Intracranial Vessel Wall Magnetic Resonance Imaging as a Predictor of Artery-to-Artery Embolic Infarction. Stroke 2018;49:905-11. [Crossref] [PubMed]
24. Tang Y, Zhang J, Liu W, Jin W, Li S, Qian Z, Kong X, Zhang R, Hu J, Li B, Yuan W, Zhang Y. Analysis of carotid vulnerable plaque MRI high-risk features and clinical risk factors associated with concomitant acute cerebral infarction. BMC Cardiovasc Disord 2023;23:173. [Crossref] [PubMed]
25. Kim TH, Yang PS, Yu HT, Jang E, Shin H, Kim HY, Uhm JS, Kim JY, Sung JH, Pak HN, Lee MH, Joung B, Lip GYH. Effect of hypertension duration and blood pressure level on ischaemic stroke risk in atrial fibrillation: nationwide data covering the entire Korean population. Eur Heart J 2019;40:809-19. [Crossref] [PubMed]
26. Tian J, Zhang K, Cui J, Qin J, Wang B, Zhou L, Li T, Bu K, Li Z, Liu L, Wang Q, Yuan S, Ma L, Wang Y, Wang R, Meng C, Zhou B, Guo L, Liu X. Brain frailty associated with stroke events in anterior circulation large artery occlusion. BMC Neurol 2024;24:97. [Crossref] [PubMed]
27. Turin TC, Okamura T, Afzal AR, Rumana N, Watanabe M, Higashiyama A, Nakao Y, Nakai M, Takegami M, Nishimura K, Kokubo Y, Okayama A, Miyamoto Y. Hypertension and lifetime risk of stroke. J Hypertens 2016;34:116-22. [Crossref] [PubMed]
28. Li J, Tian Y, Shi Y, Cui Y, Lian J, Liu P. Association of vulnerable plaques with white matter hyperintensities on high-resolution magnetic resonance imaging. Quant Imaging Med Surg 2024;14:3606-18. [Crossref] [PubMed]
29. Genkel V, Kuznetsova A, Lebedev E, Salashenko A, Savochkina A, Nikushkina K, Pykhova L, Sumerkina V, Shaposhnik I. Carotid total plaque area as an independent predictor of short-term subclinical polyvascular atherosclerosis progression and major adverse cardiac and cerebrovascular events. Ther Adv Cardiovasc Dis 2023;17:17539447231194861. [Crossref] [PubMed]
30. Leonardi-Bee J, Bath PM, Phillips SJ, Sandercock PAIST Collaborative Group. Blood pressure and clinical outcomes in the International Stroke Trial. Stroke 2002;33:1315-20. [Crossref] [PubMed]
31. Yang K, Zhu X, Feng Y, Shen F, Chen J, Fu N, Sun J, Fu Y. Abnormal blood pressure circadian rhythms are relevant to cerebral infarction and Leukoaraiosis in hypertensive patients. BMC Neurol 2020;20:36. [Crossref] [PubMed]
32. Zhao R, Zhou M, Li J, Wang X, Su K, Hu J, Ye Y, Zhu J, Zhang G, Wang K, Du J, Wang L, Shen B. Increased TRPP2 expression in vascular smooth muscle cells from high-salt intake hypertensive rats: The crucial role in vascular dysfunction. Mol Nutr Food Res 2015;59:365-72. [Crossref] [PubMed]
33. Jiang W, Ye L, Yang Y, Wang P, Pan W, Du J, Shen B, Wang K. TRPP2 associates with STIM1 to regulate cerebral vasoconstriction and enhance high salt intake-induced hypertensive cerebrovascular spasm. Hypertens Res 2019;42:1894-904. [Crossref] [PubMed]
34. Hosseini AA, Kandiyil N, Macsweeney ST, Altaf N, Auer DP. Carotid plaque hemorrhage on magnetic resonance imaging strongly predicts recurrent ischemia and stroke. Ann Neurol 2013;73:774-84. [Crossref] [PubMed]
35. Tan Y, Nie F, Wu G, Guo F, Wang Y, Wang L. Impact of H-Type Hypertension on Intraplaque Neovascularization Assessed by Contrast-Enhanced Ultrasound. J Atheroscler Thromb 2022;29:492-501. [Crossref] [PubMed]
36. Wang T, Li C, Li S, Tang P, Guo Q, Fang L. High-resolution magnetic resonance imaging features of time-of-flight magnetic resonance angiography signal loss and its relevance to ischemic stroke. Quant Imaging Med Surg 2024;14:6820-9. [Crossref] [PubMed]
37. Huang LX, Wu XB, Liu YA, Guo X, Ye JS, Cai WQ, Wang SW, Luo B. Qualitative and quantitative plaque enhancement on high-resolution vessel wall imaging predicts symptomatic intracranial atherosclerotic stenosis. Brain Behav 2023;13:e3032. [Crossref] [PubMed]
38. Zhai SJ, Jia L, Kukun HJ, Wang YL, Wang H, Ding S, Jia WX. Predictive power of high-resolution vessel wall magnetic resonance imaging in ischemic stroke. Am J Transl Res 2022;14:664-71.
39. Chung GH, Kwak HS, Hwang SB, Jin GY. High resolution MR imaging in patients with symptomatic middle cerebral artery stenosis. Eur J Radiol 2012;81:4069-74. [Crossref] [PubMed]
40. Badacz R, Kleczyński P, Legutko J, Żmudka K, Gacoń J, Przewłocki T, Kabłak-Ziembicka A. Expression of miR-1-3p, miR-16-5p and miR-122-5p as Possible Risk Factors of Secondary Cardiovascular Events. Biomedicines 2021;9:1055. [Crossref] [PubMed]
41. Angeli F, Verdecchia P, Reboldi G. Prognostic impact of hypertension grading. Eur J Intern Med 2024;126:83-8. [Crossref] [PubMed]
42. Hayashi K, Naiki T. Adaptation and remodeling of vascular wall; biomechanical response to hypertension. J Mech Behav Biomed Mater 2009;2:3-19. [Crossref] [PubMed]
43. Zhou D, Li J, Liu D, Ji LY, Wang NQ, Deng J, Wang JC, Ye M, Zhao XH. Irregular surface of carotid atherosclerotic plaque is associated with ischemic stroke: a magnetic resonance imaging study. J Geriatr Cardiol 2019;16:872-9. [Crossref] [PubMed]
44. Prabhakaran S, Rundek T, Ramas R, Elkind MS, Paik MC, Boden-Albala B, Sacco RL. Carotid plaque surface irregularity predicts ischemic stroke: the northern Manhattan study. Stroke 2006;37:2696-701. [Crossref] [PubMed]
45. Lovett JK, Gallagher PJ, Hands LJ, Walton J, Rothwell PM. Histological correlates of carotid plaque surface morphology on lumen contrast imaging. Circulation 2004;110:2190-7. [Crossref] [PubMed]
46. Takaya N, Yuan C, Chu B, Saam T, Polissar NL, Jarvik GP, Isaac C, McDonough J, Natiello C, Small R, Ferguson MS, Hatsukami TS. Presence of intraplaque hemorrhage stimulates progression of carotid atherosclerotic plaques: a high-resolution magnetic resonance imaging study. Circulation 2005;111:2768-75. [Crossref] [PubMed]