Pub Date : 2024-08-01Epub Date: 2024-06-26DOI: 10.1161/STROKEAHA.124.046956
James F Meschia
Asymptomatic high-grade carotid stenosis is an important therapeutic target for stroke prevention. For decades, the ACAS (Asymptomatic Carotid Atherosclerosis Study) and ACST (Asymptomatic Carotid Surgery Trial) trials provided most of the evidence supporting endarterectomy for patients with asymptomatic high-grade stenosis who were otherwise good candidates for surgery. Since then, transfemoral/transradial carotid stenting and transcarotid artery revascularization have emerged as alternatives to endarterectomy for revascularization. Advances in treatments against atherosclerosis have driven down the rates of stroke in patients managed without revascularization. SPACE-2 (Stent-Protected Angioplasty Versus Carotid Endarterectomy-2), a trial that included endarterectomy, stenting, and medical arms, failed to detect significant differences in stroke rates among treatment groups, but the study was stopped well short of its recruitment goal. CREST-2 (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial) will be able to clarify whether revascularization by stenting or endarterectomy remains efficacious under conditions of intensive medical management. Transcarotid artery revascularization has a favorable periprocedural risk profile, but randomized trials comparing it to intensive medical management are lacking. Features like intraplaque hemorrhage on MRI and echolucency on B-mode ultrasonography can identify patients at higher risk of stroke with asymptomatic stenosis. High-grade stenosis with poor collaterals can cause hemispheric hypoperfusion, and unstable plaque can cause microemboli, both of which may be treatable risk factors for cognitive impairment. Evidence that there are patients with carotid stenosis who benefit cognitively from revascularization is presently lacking. New risk factors are emerging, like exposure to microplastics and nanoplastics. Strategies to limit exposure will be important without specific medical therapies.
无症状高位颈动脉狭窄是预防中风的重要治疗目标。几十年来,ACAS(无症状颈动脉粥样硬化研究)和 ACST(无症状颈动脉手术试验)试验提供了大部分证据,支持对无症状高级别颈动脉狭窄患者进行内膜剥脱术,这些患者在其他方面都是手术的理想人选。从那时起,经口/经桡动脉颈动脉支架植入术和经颈动脉血运重建术开始成为血管内膜切除术的替代方案。动脉粥样硬化治疗方法的进步降低了未接受血管再通治疗患者的中风发生率。SPACE-2(支架保护血管成形术与颈动脉内膜剥脱术-2)是一项包括内膜剥脱术、支架植入术和药物治疗的试验,未能检测出治疗组之间中风发生率的显著差异,但该研究在未达到招募目标的情况下就停止了。CREST-2(针对无症状颈动脉狭窄的颈动脉血运重建和医疗管理试验)将能明确在强化医疗管理的条件下,通过支架或内膜剥脱术进行血运重建是否仍然有效。经颈动脉血运重建术具有良好的围手术期风险特征,但目前尚缺乏将其与强化医疗管理进行比较的随机试验。核磁共振成像上的斑块内出血和 B 型超声波检查上的回声等特征可识别无症状狭窄的卒中高危患者。狭窄程度高且栓塞不畅可导致半球灌注不足,不稳定斑块可导致微栓子,这两种情况都可能是认知障碍的可治疗风险因素。目前尚缺乏证据表明颈动脉狭窄患者可从血管再通治疗中获得认知益处。新的风险因素正在出现,如接触微塑料和纳米塑料。如果没有特定的医学疗法,限制接触的策略将非常重要。
{"title":"William M. Feinberg Lecture: Asymptomatic Carotid Stenosis: Current and Future Considerations.","authors":"James F Meschia","doi":"10.1161/STROKEAHA.124.046956","DOIUrl":"10.1161/STROKEAHA.124.046956","url":null,"abstract":"<p><p>Asymptomatic high-grade carotid stenosis is an important therapeutic target for stroke prevention. For decades, the ACAS (Asymptomatic Carotid Atherosclerosis Study) and ACST (Asymptomatic Carotid Surgery Trial) trials provided most of the evidence supporting endarterectomy for patients with asymptomatic high-grade stenosis who were otherwise good candidates for surgery. Since then, transfemoral/transradial carotid stenting and transcarotid artery revascularization have emerged as alternatives to endarterectomy for revascularization. Advances in treatments against atherosclerosis have driven down the rates of stroke in patients managed without revascularization. SPACE-2 (Stent-Protected Angioplasty Versus Carotid Endarterectomy-2), a trial that included endarterectomy, stenting, and medical arms, failed to detect significant differences in stroke rates among treatment groups, but the study was stopped well short of its recruitment goal. CREST-2 (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial) will be able to clarify whether revascularization by stenting or endarterectomy remains efficacious under conditions of intensive medical management. Transcarotid artery revascularization has a favorable periprocedural risk profile, but randomized trials comparing it to intensive medical management are lacking. Features like intraplaque hemorrhage on MRI and echolucency on B-mode ultrasonography can identify patients at higher risk of stroke with asymptomatic stenosis. High-grade stenosis with poor collaterals can cause hemispheric hypoperfusion, and unstable plaque can cause microemboli, both of which may be treatable risk factors for cognitive impairment. Evidence that there are patients with carotid stenosis who benefit cognitively from revascularization is presently lacking. New risk factors are emerging, like exposure to microplastics and nanoplastics. Strategies to limit exposure will be important without specific medical therapies.</p>","PeriodicalId":21989,"journal":{"name":"Stroke","volume":null,"pages":null},"PeriodicalIF":7.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11331494/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141451496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-07-22DOI: 10.1161/STROKEAHA.124.046877
Brian Stamm, Regina Royan, Jinhong Cui, D Leann Long, Christina M Lineback, Oluwasegun P Akinyelure, Timothy B Plante, Deborah A Levine, Virginia J Howard, George Howard, Philip B Gorelick
Background: Recent hypertension guidelines for the general population have included race-specific recommendations for antihypertensives, whereas current stroke-specific recommendations for antihypertensives do not vary by race. The impact of these guidelines on antihypertensive regimen changes over time, and if this has varied by prevalent stroke status, is unclear.
Methods: The use of antihypertensive medications was studied cross-sectionally among self-identified Black and White participants, aged ≥45 years, with and without history of stroke, from the REGARDS study (Reasons for Geographic and Racial Differences in Stroke). Participants completed an in-home examination in 2003-2007 (visit 1) with/without an examination in 2013-2016 (visit 2). Stratified by prevalent stroke status, logistic regression mixed models examined associations between antihypertensive class use for visit 2 versus visit 1 and Black versus White individuals with an interaction adjusted for demographics, socioeconomic status, and vascular risk factors/vital signs.
Results: Of 17 244 stroke-free participants at visit 1, Black participants had greater adjusted odds of angiotensin-converting enzyme inhibitor usage than White participants (odds ratio [OR], 1.51 [95% CI, 1.30-1.77]). This difference was smaller in the 7476 stroke-free participants at visit 2 (OR, 1.16 [95% CI, 1.08-1.25]). In stroke-free participants at visit 1, Black participants had lower odds of calcium channel blocker (CCB) usage than White participants (OR, 0.47 [95% CI, 0.41-0.55]), but CCB usage did not differ significantly between Black and White stroke-free participants at visit 2 (OR, 1.02 [95% CI, 0.95-1.09]). Among 1437 stroke survivor participants at visit 1, Black participants had lower odds of CCB use than White participants (OR, 0.34 [95% CI, 0.26-0.45]). In 689 stroke survivor participants at visit 2, CCB use did not differ between Black and White participants (OR, 0.80 [95% CI, 0.61-1.06]).
Conclusions: Racial differences in the use of guideline-recommended antihypertensives decreased between 2003-2007 and 2013-2016 in stroke-free individuals. In stroke survivors, racial differences in CCB usage narrowed over the time periods. These findings suggest there is still a mismatch between race-specific hypertension guidelines and recent clinical practice.
{"title":"Trends in Black-White Differences of Antihypertensive Treatment in Individuals With and Without History of Stroke.","authors":"Brian Stamm, Regina Royan, Jinhong Cui, D Leann Long, Christina M Lineback, Oluwasegun P Akinyelure, Timothy B Plante, Deborah A Levine, Virginia J Howard, George Howard, Philip B Gorelick","doi":"10.1161/STROKEAHA.124.046877","DOIUrl":"10.1161/STROKEAHA.124.046877","url":null,"abstract":"<p><strong>Background: </strong>Recent hypertension guidelines for the general population have included race-specific recommendations for antihypertensives, whereas current stroke-specific recommendations for antihypertensives do not vary by race. The impact of these guidelines on antihypertensive regimen changes over time, and if this has varied by prevalent stroke status, is unclear.</p><p><strong>Methods: </strong>The use of antihypertensive medications was studied cross-sectionally among self-identified Black and White participants, aged ≥45 years, with and without history of stroke, from the REGARDS study (Reasons for Geographic and Racial Differences in Stroke). Participants completed an in-home examination in 2003-2007 (visit 1) with/without an examination in 2013-2016 (visit 2). Stratified by prevalent stroke status, logistic regression mixed models examined associations between antihypertensive class use for visit 2 versus visit 1 and Black versus White individuals with an interaction adjusted for demographics, socioeconomic status, and vascular risk factors/vital signs.</p><p><strong>Results: </strong>Of 17 244 stroke-free participants at visit 1, Black participants had greater adjusted odds of angiotensin-converting enzyme inhibitor usage than White participants (odds ratio [OR], 1.51 [95% CI, 1.30-1.77]). This difference was smaller in the 7476 stroke-free participants at visit 2 (OR, 1.16 [95% CI, 1.08-1.25]). In stroke-free participants at visit 1, Black participants had lower odds of calcium channel blocker (CCB) usage than White participants (OR, 0.47 [95% CI, 0.41-0.55]), but CCB usage did not differ significantly between Black and White stroke-free participants at visit 2 (OR, 1.02 [95% CI, 0.95-1.09]). Among 1437 stroke survivor participants at visit 1, Black participants had lower odds of CCB use than White participants (OR, 0.34 [95% CI, 0.26-0.45]). In 689 stroke survivor participants at visit 2, CCB use did not differ between Black and White participants (OR, 0.80 [95% CI, 0.61-1.06]).</p><p><strong>Conclusions: </strong>Racial differences in the use of guideline-recommended antihypertensives decreased between 2003-2007 and 2013-2016 in stroke-free individuals. In stroke survivors, racial differences in CCB usage narrowed over the time periods. These findings suggest there is still a mismatch between race-specific hypertension guidelines and recent clinical practice.</p>","PeriodicalId":21989,"journal":{"name":"Stroke","volume":null,"pages":null},"PeriodicalIF":7.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141749104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Surgical risk assessment is intriguing for clinical decision-making of brainstem cavernous malformation (BSCM) treatment. While the BSCM grading scale, encompassing size, developmental venous anomaly, crossing axial midpoint, age, and timing of intervention, is increasingly utilized, the clinical relevance of neurological fluctuation and recurrent hemorrhage has not been incorporated. This study aimed to propose a supplementary grading scale with enhanced predictive efficacy.
Methods: Using a retrospective nationwide registry of consecutive patients with BSCMs undergoing surgery in China from March 2011 to May 2023, a new supplementary BSCM grading scale was developed from a derivative cohort of 260 patients and validated in an independent concurrent cohort of 67 patients. The primary outcome was unfavorable neurological function (modified Rankin Scale score >2) at the latest follow-up. The performance of the supplementary grading system was evaluated for discrimination, calibration, and clinical utility and further compared with its original counterpart.
Results: Over a follow-up of at least 6 months after surgery, the unfavorable outcomes were 31% in the overall cohort (101/327 patients). A preoperative motor deficit (odds ratio, 3.13; P=0.001), recurrent hemorrhage (odds ratio, 3.05; P<0.001), timing of intervention (odds ratio, 7.08; P<0.001), and crossing the axial midpoint (odds ratio, 2.57; P=0.006) were associated with the unfavorable outcomes and composed the initial Huashan grading variables. A supplementary BSCM grading system was subsequently developed by incorporating the Huashan grading variables into the original BSCM grading scale. The predictive capability of the supplementary scale was consistently superior to the original counterpart in either the derivative cohort (area under the receiver operating characteristic curve, 0.74 [95% CI, 0.68-0.80] for the supplementary versus 0.68 [95% CI, 0.61-0.74] for the original) or the validation cohort (0.75 [95% CI, 0.62-0.87] versus 0.64 [95% CI, 0.48-0.81]).
Conclusions: This study highlights the neurological relevance of BSCM hemorrhage in surgical risk assessment. Via compositing preoperative motor function and recurrent hemorrhages, a supplementary grading scale may improve a dynamic risk assessment for clinical decisions in the management of BSCMs.
{"title":"Development and Validation of a Supplementary Grading Scale for Outcomes of Brainstem Cavernous Malformations.","authors":"Zongze Li, Junlin Lu, Mingjian Liu, Li Ma, Kai Quan, Hongfei Zhang, Peixi Liu, Yuan Shi, Xuchen Dong, Chao You, Rui Tian, Wei Zhu","doi":"10.1161/STROKEAHA.123.045943","DOIUrl":"10.1161/STROKEAHA.123.045943","url":null,"abstract":"<p><strong>Background: </strong>Surgical risk assessment is intriguing for clinical decision-making of brainstem cavernous malformation (BSCM) treatment. While the BSCM grading scale, encompassing size, developmental venous anomaly, crossing axial midpoint, age, and timing of intervention, is increasingly utilized, the clinical relevance of neurological fluctuation and recurrent hemorrhage has not been incorporated. This study aimed to propose a supplementary grading scale with enhanced predictive efficacy.</p><p><strong>Methods: </strong>Using a retrospective nationwide registry of consecutive patients with BSCMs undergoing surgery in China from March 2011 to May 2023, a new supplementary BSCM grading scale was developed from a derivative cohort of 260 patients and validated in an independent concurrent cohort of 67 patients. The primary outcome was unfavorable neurological function (modified Rankin Scale score >2) at the latest follow-up. The performance of the supplementary grading system was evaluated for discrimination, calibration, and clinical utility and further compared with its original counterpart.</p><p><strong>Results: </strong>Over a follow-up of at least 6 months after surgery, the unfavorable outcomes were 31% in the overall cohort (101/327 patients). A preoperative motor deficit (odds ratio, 3.13; <i>P</i>=0.001), recurrent hemorrhage (odds ratio, 3.05; <i>P</i><0.001), timing of intervention (odds ratio, 7.08; <i>P</i><0.001), and crossing the axial midpoint (odds ratio, 2.57; <i>P</i>=0.006) were associated with the unfavorable outcomes and composed the initial Huashan grading variables. A supplementary BSCM grading system was subsequently developed by incorporating the Huashan grading variables into the original BSCM grading scale. The predictive capability of the supplementary scale was consistently superior to the original counterpart in either the derivative cohort (area under the receiver operating characteristic curve, 0.74 [95% CI, 0.68-0.80] for the supplementary versus 0.68 [95% CI, 0.61-0.74] for the original) or the validation cohort (0.75 [95% CI, 0.62-0.87] versus 0.64 [95% CI, 0.48-0.81]).</p><p><strong>Conclusions: </strong>This study highlights the neurological relevance of BSCM hemorrhage in surgical risk assessment. Via compositing preoperative motor function and recurrent hemorrhages, a supplementary grading scale may improve a dynamic risk assessment for clinical decisions in the management of BSCMs.</p>","PeriodicalId":21989,"journal":{"name":"Stroke","volume":null,"pages":null},"PeriodicalIF":7.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141331671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Dendritic cells (DCs) regulate the immune response associated with T lymphocytes, but their role in stroke remains unclear. In this study, we investigated the causal relationship between DCs and T-cell response in intracerebral hemorrhage (ICH) by focusing on TLRs (toll-like receptors) that may modulate the function of DCs.
Methods: We studied the effects of TLR4, TLR2, and TLR9 on DC-mediated T-cell response and the outcomes of ICH using male C57BL/6 and CD11c-DTx (diphtheria toxin) receptor mice. We administered specific agents intraperitoneally or orally and evaluated the results using flow cytometry, real-time polymerase chain reaction, Western blotting, immunofluorescence staining, histopathology, and behavioral tests.
Results: TLR4 and TLR2 activation induces DC maturation and reduces the ratio of regulatory T to T-helper 17 cells in the brain and periphery after ICH. When either of these receptors is activated, it can worsen neuroinflammation and exacerbate ICH outcomes. TLR9 also promotes DC maturation, stabilizing the number of DCs, particularly conventional DCs. TLR9 has the opposite effects on regulatory T/T-helper 17 balance, neuroinflammation, and ICH outcomes compared with TLR4 and TLR2. Upon stimulation, TLR4 and TLR9 may achieve these effects through the p38-MAPK (p38-mitogen-activated protein kinase)/MyD88 (myeloid differentiation primary response gene 88) and indoleamine 2,3-dioxygenase 1 (IDO1)/GCN2 (general control nonderepressible 2) signaling pathways, respectively. DCs act as intermediaries for TLR-mediated T-cell response.
Conclusions: TLR-mediated opposing effects of DCs on T-cell response may provide novel strategies to treat ICH.
背景:树突状细胞(DC)调节与T淋巴细胞相关的免疫反应,但它们在中风中的作用仍不清楚。在本研究中,我们通过关注可能调节 DC 功能的 TLR(类收费受体),研究了 DC 与脑内出血(ICH)中 T 细胞反应之间的因果关系:我们使用雄性 C57BL/6 和 CD11c-DTx(白喉毒素)受体小鼠研究了 TLR4、TLR2 和 TLR9 对 DC 介导的 T 细胞反应和 ICH 后果的影响。我们腹腔注射或口服了特定的药物,并使用流式细胞术、实时聚合酶链反应、Western 印迹、免疫荧光染色、组织病理学和行为测试对结果进行了评估:结果:TLR4 和 TLR2 激活可诱导 DC 成熟,并降低 ICH 后大脑和外周调节性 T 细胞与 T 辅助 17 细胞的比例。当这两种受体中的任何一种被激活时,都会加重神经炎症并加剧 ICH 的后果。TLR9 还能促进 DC 成熟,稳定 DC(尤其是传统 DC)的数量。与 TLR4 和 TLR2 相比,TLR9 对调节性 T/T-helper 17 平衡、神经炎症和 ICH 结果的影响正好相反。受刺激后,TLR4 和 TLR9 可分别通过 p38-MAPK(p38-mitogen-activated protein kinase)/MyD88(myeloid differentiation primary response gene 88)和吲哚胺 2,3-二氧化酶 1(IDO1)/GCN2(general control nonderepressible 2)信号通路达到上述效果。DC是TLR介导的T细胞反应的中介:结论:TLR介导的DC对T细胞反应的相反作用可能为治疗ICH提供新的策略。
{"title":"Toll-Like Receptors Mediate Opposing Dendritic Cell Effects on Treg/Th17 Balance in Mice With Intracerebral Hemorrhage.","authors":"Li Zhu, Junkui Shang, Yinuo Li, Zhiying Zhang, Peiji Fu, Yan Zong, Shuai Chen, Junmin Wang, Jiewen Zhang, Jian Wang, Chao Jiang","doi":"10.1161/STROKEAHA.124.046394","DOIUrl":"10.1161/STROKEAHA.124.046394","url":null,"abstract":"<p><strong>Background: </strong>Dendritic cells (DCs) regulate the immune response associated with T lymphocytes, but their role in stroke remains unclear. In this study, we investigated the causal relationship between DCs and T-cell response in intracerebral hemorrhage (ICH) by focusing on TLRs (toll-like receptors) that may modulate the function of DCs.</p><p><strong>Methods: </strong>We studied the effects of TLR4, TLR2, and TLR9 on DC-mediated T-cell response and the outcomes of ICH using male C57BL/6 and CD11c-DTx (diphtheria toxin) receptor mice. We administered specific agents intraperitoneally or orally and evaluated the results using flow cytometry, real-time polymerase chain reaction, Western blotting, immunofluorescence staining, histopathology, and behavioral tests.</p><p><strong>Results: </strong>TLR4 and TLR2 activation induces DC maturation and reduces the ratio of regulatory T to T-helper 17 cells in the brain and periphery after ICH. When either of these receptors is activated, it can worsen neuroinflammation and exacerbate ICH outcomes. TLR9 also promotes DC maturation, stabilizing the number of DCs, particularly conventional DCs. TLR9 has the opposite effects on regulatory T/T-helper 17 balance, neuroinflammation, and ICH outcomes compared with TLR4 and TLR2. Upon stimulation, TLR4 and TLR9 may achieve these effects through the p38-MAPK (p38-mitogen-activated protein kinase)/MyD88 (myeloid differentiation primary response gene 88) and indoleamine 2,3-dioxygenase 1 (IDO1)/GCN2 (general control nonderepressible 2) signaling pathways, respectively. DCs act as intermediaries for TLR-mediated T-cell response.</p><p><strong>Conclusions: </strong>TLR-mediated opposing effects of DCs on T-cell response may provide novel strategies to treat ICH.</p>","PeriodicalId":21989,"journal":{"name":"Stroke","volume":null,"pages":null},"PeriodicalIF":7.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141451495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-06-26DOI: 10.1161/STR.0000000000000472
{"title":"Correction to: Head Injury and Risk of Incident Ischemic Stroke in Community-Dwelling Adults.","authors":"","doi":"10.1161/STR.0000000000000472","DOIUrl":"10.1161/STR.0000000000000472","url":null,"abstract":"","PeriodicalId":21989,"journal":{"name":"Stroke","volume":null,"pages":null},"PeriodicalIF":7.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141459455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-07-09DOI: 10.1161/STROKEAHA.124.047643
Steven C Cramer, Livia Parodi, Zahra Moslemi, Robynne G Braun, Chad M Aldridge, Babak Shahbaba, Jonathan Rosand, E Alison Holman
Background: Genetic association studies can reveal biology and treatment targets but have received limited attention for stroke recovery. STRONG (Stroke, Stress, Rehabilitation, and Genetics) was a prospective, longitudinal (1-year), genetic study in adults with stroke at 28 US stroke centers. The primary aim was to examine the association that candidate genetic variants have with (1) motor/functional outcomes and (2) stress-related outcomes.
Methods: For motor/functional end points, 3 candidate gene variants (ApoE ε4, BDNF [brain-derived neurotrophic factor], and a dopamine polygenic score) were analyzed for associations with change in grip strength (3 months-baseline), function (3-month Stroke Impact Scale-Activities of Daily Living), mood (3-month Patient Health Questionnaire-8), and cognition (12-month telephone-Montreal Cognitive Assessment). For stress-related outcomes, 7 variants (serotonin transporter gene-linked promoter region, ACE [angiotensin-converting enzyme], oxytocin receptor, FKBP5 [FKBP prolyl isomerase 5], FAAH [fatty acid amide hydrolase], BDNF, and COMT [catechol-O-methyltransferase]) were assessed for associations with posttraumatic stress disorder ([PTSD]; PTSD Primary Care Scale) and depression (Patient Health Questionnaire-8) at 6 and 12 months; stress-related genes were examined as a function of poststroke stress level. Statistical models (linear, negative binomial, or Poisson regression) were based on response variable distribution; all included stroke severity, age, sex, and ancestry as covariates. Stroke subtype was explored secondarily. Data were Holm-Bonferroni corrected. A secondary replication analysis tested whether the rs1842681 polymorphism (identified in the GISCOME study [Genetics of Ischaemic Stroke Functional Outcome]) was related to 3-month modified Rankin Scale score in STRONG.
Results: The 763 enrollees were 63.1±14.9 (mean±SD) years of age, with a median initial National Institutes of Health Stroke Scale score of 4 (interquartile range, 2-9); outcome data were available in n=515 at 3 months, n=500 at 6 months, and n=489 at 12 months. At 1 year poststroke, the rs6265 (BDNF) variant was associated with poorer cognition (0.9-point lower telephone-Montreal Cognitive Assessment score, P=1×10-5). For stress-related outcomes, rs4291 (ACE) and rs324420 (FAAH) were risk factors linking increased poststroke stress with higher 1-year depression and PTSD symptoms (P<0.05), while rs4680 (COMT) linked poststroke stress with lower 1-year depression and PTSD. Findings were unchanged when considering stroke subtype. STRONG replicated GISCOME: rs1842681 was associated with lower 3-month modified Rankin Scale score (P=3.2×10-5).
Conclusions: This study identified genetic associations with cognitive function, depression, and PTSD 1 year poststroke. Genetic susceptibility to PTSD and depressive
{"title":"Genetic Variation and Stroke Recovery: The STRONG Study.","authors":"Steven C Cramer, Livia Parodi, Zahra Moslemi, Robynne G Braun, Chad M Aldridge, Babak Shahbaba, Jonathan Rosand, E Alison Holman","doi":"10.1161/STROKEAHA.124.047643","DOIUrl":"10.1161/STROKEAHA.124.047643","url":null,"abstract":"<p><strong>Background: </strong>Genetic association studies can reveal biology and treatment targets but have received limited attention for stroke recovery. STRONG (Stroke, Stress, Rehabilitation, and Genetics) was a prospective, longitudinal (1-year), genetic study in adults with stroke at 28 US stroke centers. The primary aim was to examine the association that candidate genetic variants have with (1) motor/functional outcomes and (2) stress-related outcomes.</p><p><strong>Methods: </strong>For motor/functional end points, 3 candidate gene variants (ApoE ε4, BDNF [brain-derived neurotrophic factor], and a dopamine polygenic score) were analyzed for associations with change in grip strength (3 months-baseline), function (3-month Stroke Impact Scale-Activities of Daily Living), mood (3-month Patient Health Questionnaire-8), and cognition (12-month telephone-Montreal Cognitive Assessment). For stress-related outcomes, 7 variants (serotonin transporter gene-linked promoter region, ACE [angiotensin-converting enzyme], oxytocin receptor, FKBP5 [FKBP prolyl isomerase 5], FAAH [fatty acid amide hydrolase], BDNF, and COMT [catechol-O-methyltransferase]) were assessed for associations with posttraumatic stress disorder ([PTSD]; PTSD Primary Care Scale) and depression (Patient Health Questionnaire-8) at 6 and 12 months; stress-related genes were examined as a function of poststroke stress level. Statistical models (linear, negative binomial, or Poisson regression) were based on response variable distribution; all included stroke severity, age, sex, and ancestry as covariates. Stroke subtype was explored secondarily. Data were Holm-Bonferroni corrected. A secondary replication analysis tested whether the rs1842681 polymorphism (identified in the GISCOME study [Genetics of Ischaemic Stroke Functional Outcome]) was related to 3-month modified Rankin Scale score in STRONG.</p><p><strong>Results: </strong>The 763 enrollees were 63.1±14.9 (mean±SD) years of age, with a median initial National Institutes of Health Stroke Scale score of 4 (interquartile range, 2-9); outcome data were available in n=515 at 3 months, n=500 at 6 months, and n=489 at 12 months. At 1 year poststroke, the rs6265 (BDNF) variant was associated with poorer cognition (0.9-point lower telephone-Montreal Cognitive Assessment score, <i>P</i>=1×10<sup>-5</sup>). For stress-related outcomes, rs4291 (ACE) and rs324420 (FAAH) were risk factors linking increased poststroke stress with higher 1-year depression and PTSD symptoms (<i>P</i><0.05), while rs4680 (COMT) linked poststroke stress with lower 1-year depression and PTSD. Findings were unchanged when considering stroke subtype. STRONG replicated GISCOME: rs1842681 was associated with lower 3-month modified Rankin Scale score (<i>P</i>=3.2×10<sup>-5</sup>).</p><p><strong>Conclusions: </strong>This study identified genetic associations with cognitive function, depression, and PTSD 1 year poststroke. Genetic susceptibility to PTSD and depressive","PeriodicalId":21989,"journal":{"name":"Stroke","volume":null,"pages":null},"PeriodicalIF":7.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11262965/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141559799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-07-22DOI: 10.1161/STROKEAHA.124.047568
Guangxiong Yuan, Thanh N Nguyen, Lei Liu, Rui Li, Hong Xia, Chen Long, Junxiong Wu, Jun Xu, Feng Huang, Bo He, Derong Wu, Hailing Wang, Can Feng, Yong Liang, Xianghong Zhou, Zhenhua Xiao, Li Luo, Yanjuan Hu, Bin Liu, Weibo Peng, Chao Zhang, Tao Cui, Gaoshan Zhao, Lihua Xu, Gaoting Ma, Wei Hu
Background: Stroke etiology could influence the outcomes in patients with basilar-artery occlusion (BAO). This study aimed to evaluate the differences in efficacy and safety of best medical treatment (BMT) plus endovascular treatment (EVT) versus BMT alone in acute BAO across different stroke etiologies.
Methods: The study was a post hoc analysis of the ATTENTION trial (Trial of Endovascular Treatment of Acute Basilar-Artery Occlusion), which was a multicenter, randomized trial at 36 centers in China from February 2021 to September 2022. Patients with acute BAO were classified into 3 groups according to stroke etiology (large-artery atherosclerosis [LAA], cardioembolism, and undetermined cause/other determined cause [UC/ODC]). The primary outcome was a favorable outcome (modified Rankin Scale score of 0-3) at 90 days. Safety outcomes included symptomatic intracranial hemorrhage and 90-day mortality.
Results: A total of 340 patients with BAO were included, 150 (44.1%) had LAA, 72 (21.2%) had cardioembolism, and 118 (34.7%) had UC/ODC. For patients treated with BMT plus EVT and BMT alone, respectively, the rate of favorable outcome at 90 days was 49.1% and 23.8% in the LAA group (odds ratio, 3.08 [95% CI, 1.38-6.89]); 52.2% and 30.8% in the cardioembolism group (odds ratio, 2.45 [95% CI, 0.89-6.77]); and 37.5% and 17.4% in the UC/ODC group (odds ratio, 2.85 [95% CI, 1.16-7.01]), with P=0.89 for the stroke etiology×treatment interaction. The rate of symptomatic intracranial hemorrhage in EVT-treated patients with LAA, cardioembolism, and UC/ODC was 8.3%, 2.2%, and 3.2%, respectively, and none of the BMT-treated patients. Lower 90-day mortality was observed in patients with EVT compared with BMT alone across 3 etiology groups.
Conclusions: Among patients with acute BAO, EVT compared with BMT alone might be associated with favorable outcomes and lower 90-day mortality, regardless of cardioembolism, LAA, or UC/ODC etiologies. The influence of stroke etiology on the benefit of EVT should be explored by further trials.
背景:卒中病因可能影响基底动脉闭塞(BAO)患者的预后。本研究旨在评估在不同卒中病因的急性基底动脉闭塞症患者中,最佳药物治疗(BMT)加血管内治疗(EVT)与单纯BMT在疗效和安全性方面的差异:本研究是对ATTENTION试验(急性基底动脉闭塞的血管内治疗试验)的事后分析,该试验是一项多中心随机试验,于2021年2月至2022年9月在中国的36个中心进行。根据卒中病因将急性基底动脉闭塞症患者分为三组(大动脉粥样硬化[LAA]、心源性栓塞和病因未定/其他确定病因[UC/ODC])。主要结果是90天后的良好结果(修改后的Rankin量表评分为0-3分)。安全性结果包括无症状性颅内出血和 90 天死亡率:共纳入了 340 名 BAO 患者,其中 150 人(44.1%)患有 LAA,72 人(21.2%)患有心肌栓塞,118 人(34.7%)患有 UC/ODC。在接受 BMT 加 EVT 和单纯 BMT 治疗的患者中,LAA 组 90 天后的良好预后率分别为 49.1%和 23.8%(几率比 3.08 [95% CI, 1.38-6.89]);心肌栓塞组分别为 52.2%和 30.8%(几率比 3.08 [95% CI, 1.38-6.89])。心肌栓塞组分别为52.2%和30.8%(几率比,2.45 [95% CI,0.89-6.77]);UC/ODC组分别为37.5%和17.4%(几率比,2.85 [95% CI,1.16-7.01]),卒中病因×治疗交互作用的P=0.89。在接受EVT治疗的LAA、心源性栓塞和UC/ODC患者中,无症状性颅内出血的发生率分别为8.3%、2.2%和3.2%,而在接受BMT治疗的患者中,无症状性颅内出血的发生率。在3个病因组中,接受EVT治疗的患者90天死亡率低于单纯BMT治疗的患者:结论:在急性 BAO 患者中,无论心肌栓塞、LAA 或 UC/ODC 的病因如何,EVT 与单纯 BMT 相比可能会带来良好的预后和较低的 90 天死亡率。卒中病因对EVT获益的影响应通过进一步的试验来探讨:URL:https://www.clinicaltrials.gov;唯一标识符:NCT04751708。
{"title":"Effect of Stroke Etiology on Endovascular Treatment for Acute Basilar-Artery Occlusion: A Post Hoc Analysis of the ATTENTION Randomized Trial.","authors":"Guangxiong Yuan, Thanh N Nguyen, Lei Liu, Rui Li, Hong Xia, Chen Long, Junxiong Wu, Jun Xu, Feng Huang, Bo He, Derong Wu, Hailing Wang, Can Feng, Yong Liang, Xianghong Zhou, Zhenhua Xiao, Li Luo, Yanjuan Hu, Bin Liu, Weibo Peng, Chao Zhang, Tao Cui, Gaoshan Zhao, Lihua Xu, Gaoting Ma, Wei Hu","doi":"10.1161/STROKEAHA.124.047568","DOIUrl":"https://doi.org/10.1161/STROKEAHA.124.047568","url":null,"abstract":"<p><strong>Background: </strong>Stroke etiology could influence the outcomes in patients with basilar-artery occlusion (BAO). This study aimed to evaluate the differences in efficacy and safety of best medical treatment (BMT) plus endovascular treatment (EVT) versus BMT alone in acute BAO across different stroke etiologies.</p><p><strong>Methods: </strong>The study was a post hoc analysis of the ATTENTION trial (Trial of Endovascular Treatment of Acute Basilar-Artery Occlusion), which was a multicenter, randomized trial at 36 centers in China from February 2021 to September 2022. Patients with acute BAO were classified into 3 groups according to stroke etiology (large-artery atherosclerosis [LAA], cardioembolism, and undetermined cause/other determined cause [UC/ODC]). The primary outcome was a favorable outcome (modified Rankin Scale score of 0-3) at 90 days. Safety outcomes included symptomatic intracranial hemorrhage and 90-day mortality.</p><p><strong>Results: </strong>A total of 340 patients with BAO were included, 150 (44.1%) had LAA, 72 (21.2%) had cardioembolism, and 118 (34.7%) had UC/ODC. For patients treated with BMT plus EVT and BMT alone, respectively, the rate of favorable outcome at 90 days was 49.1% and 23.8% in the LAA group (odds ratio, 3.08 [95% CI, 1.38-6.89]); 52.2% and 30.8% in the cardioembolism group (odds ratio, 2.45 [95% CI, 0.89-6.77]); and 37.5% and 17.4% in the UC/ODC group (odds ratio, 2.85 [95% CI, 1.16-7.01]), with <i>P</i>=0.89 for the stroke etiology×treatment interaction. The rate of symptomatic intracranial hemorrhage in EVT-treated patients with LAA, cardioembolism, and UC/ODC was 8.3%, 2.2%, and 3.2%, respectively, and none of the BMT-treated patients. Lower 90-day mortality was observed in patients with EVT compared with BMT alone across 3 etiology groups.</p><p><strong>Conclusions: </strong>Among patients with acute BAO, EVT compared with BMT alone might be associated with favorable outcomes and lower 90-day mortality, regardless of cardioembolism, LAA, or UC/ODC etiologies. The influence of stroke etiology on the benefit of EVT should be explored by further trials.</p><p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov; Unique identifier: NCT04751708.</p>","PeriodicalId":21989,"journal":{"name":"Stroke","volume":null,"pages":null},"PeriodicalIF":7.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141749100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-06-27DOI: 10.1161/STROKEAHA.123.045766
Eva A Mistry, Jane C Khoury, Dawn O Kleindorfer, Brett M Kissela, Kathleen S Alwell, Adam S Jasne, Simona Ferioli, Felipe De Los Rios La Rosa, Elisheva Coleman, Stacie L Demel, Kyle B Walsh, Sabreena J Slavin, Michael Star, Mary Haverbusch, Jason Mackey, Daniel Woo, Yasmin N Aziz, Mirjam R Heldner, Urs Fischer, Ashutosh P Jadhav, Tudor G Jovin, Gregory W Albers, Raul G Nogueira, Pooja Khatri
Background: As stroke endovascular thrombectomy (EVT) treatment indications expand, understanding population-based EVT eligibility becomes critical for resource planning. We aimed to project current and future population-based EVT eligibility in the United States.
Methods: We conducted a post hoc analysis of the physician-adjudicated GCNKSS (Greater Cincinnati Northern Kentucky Stroke Study; 2015 epoch), a population-based, cross sectional, observational study of stroke incidence, treatment, and outcomes across a 5-county region. All hospitalized patients ≥18 years of age with acute ischemic stroke were ascertained using the International Classification of Diseases, Ninth Revision codes 430-436 and Tenth Revision codes I60-I67 and G45-G46 and extrapolated to the US adult census 2020. We determined the rate of EVT eligibility within the GCNKSS population using time from last known well to presentation (0-5 versus 5-23 hours), presenting National Institutes of Health Stroke Scale, and prestroke modified Rankin Scale. Both conservative and liberal estimates of prevalence of large vessel occlusion and large core were then applied based on literature review (unavailable within the 2015 GCNKSS). This eligibility was then extrapolated to the 2020 US population.
Results: Of the 1 057 183 adults within GCNKSS in 2015, 2741 had an ischemic stroke and 2176 had data available for analysis. We calculated that 8659 to 17 219 patients (conservative to liberal) meet the current guideline-recommended EVT criteria (nonlarge core, no prestroke disability, and National Institutes of Health Stroke Scale score ≥6) in the United States. Estimates (conservative to liberal) for expanded EVT eligibility subpopulations include (1) 5316 to 10 635 by large core; (2) 10 635 to 21 270 by mild presenting deficits with low National Institutes of Health Stroke Scale score; (3) 13 572 to 27 089 by higher prestroke disability; and (4) 7039 to 14 180 by >1 criteria. These expanded eligibility subpopulations amount to 36 562 to 73 174 patients.
Conclusions: An estimated 8659 to 17 219 adult patients in the United States met strict EVT eligibility criteria in 2020. A 4-fold increase in population-based EVT eligibility can be anticipated with incremental adoption of recent or future positive trials. US stroke systems need to be rapidly optimized to handle all EVT-eligible patients with stroke.
{"title":"Projections of Endovascular Therapy-Eligible Patients With Stroke for the US Population.","authors":"Eva A Mistry, Jane C Khoury, Dawn O Kleindorfer, Brett M Kissela, Kathleen S Alwell, Adam S Jasne, Simona Ferioli, Felipe De Los Rios La Rosa, Elisheva Coleman, Stacie L Demel, Kyle B Walsh, Sabreena J Slavin, Michael Star, Mary Haverbusch, Jason Mackey, Daniel Woo, Yasmin N Aziz, Mirjam R Heldner, Urs Fischer, Ashutosh P Jadhav, Tudor G Jovin, Gregory W Albers, Raul G Nogueira, Pooja Khatri","doi":"10.1161/STROKEAHA.123.045766","DOIUrl":"10.1161/STROKEAHA.123.045766","url":null,"abstract":"<p><strong>Background: </strong>As stroke endovascular thrombectomy (EVT) treatment indications expand, understanding population-based EVT eligibility becomes critical for resource planning. We aimed to project current and future population-based EVT eligibility in the United States.</p><p><strong>Methods: </strong>We conducted a post hoc analysis of the physician-adjudicated GCNKSS (Greater Cincinnati Northern Kentucky Stroke Study; 2015 epoch), a population-based, cross sectional, observational study of stroke incidence, treatment, and outcomes across a 5-county region. All hospitalized patients ≥18 years of age with acute ischemic stroke were ascertained using the <i>International Classification of Diseases, Ninth Revision</i> codes 430-436 and <i>Tenth Revision</i> codes I60-I67 and G45-G46 and extrapolated to the US adult census 2020. We determined the rate of EVT eligibility within the GCNKSS population using time from last known well to presentation (0-5 versus 5-23 hours), presenting National Institutes of Health Stroke Scale, and prestroke modified Rankin Scale. Both conservative and liberal estimates of prevalence of large vessel occlusion and large core were then applied based on literature review (unavailable within the 2015 GCNKSS). This eligibility was then extrapolated to the 2020 US population.</p><p><strong>Results: </strong>Of the 1 057 183 adults within GCNKSS in 2015, 2741 had an ischemic stroke and 2176 had data available for analysis. We calculated that 8659 to 17 219 patients (conservative to liberal) meet the current guideline-recommended EVT criteria (nonlarge core, no prestroke disability, and National Institutes of Health Stroke Scale score ≥6) in the United States. Estimates (conservative to liberal) for expanded EVT eligibility subpopulations include (1) 5316 to 10 635 by large core; (2) 10 635 to 21 270 by mild presenting deficits with low National Institutes of Health Stroke Scale score; (3) 13 572 to 27 089 by higher prestroke disability; and (4) 7039 to 14 180 by >1 criteria. These expanded eligibility subpopulations amount to 36 562 to 73 174 patients.</p><p><strong>Conclusions: </strong>An estimated 8659 to 17 219 adult patients in the United States met strict EVT eligibility criteria in 2020. A 4-fold increase in population-based EVT eligibility can be anticipated with incremental adoption of recent or future positive trials. US stroke systems need to be rapidly optimized to handle all EVT-eligible patients with stroke.</p>","PeriodicalId":21989,"journal":{"name":"Stroke","volume":null,"pages":null},"PeriodicalIF":7.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141459458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Neuronal apoptosis plays an essential role in the pathogenesis of brain injury after subarachnoid hemorrhage (SAH). BAP1 (BRCA1-associated protein 1) is considered to exert pro-apoptotic effects in multiple diseases. However, evidence supporting the effect of BAP1 on the apoptotic response to SAH is lacking. Therefore, we aimed to confirm the role of BAP1 in SAH-induced apoptosis.
Methods: Enzyme-linked immunosorbent assay (ELISA) was used to detect BAP1 expression in the cerebrospinal fluid. Endovascular perforation was performed in mice to induce SAH. Lentiviral short hairpin RNA targeting BAP1 mRNA was transduced into the ipsilateral cortex of mice with SAH to investigate the role of BAP1 in neuronal damage. Luciferase and coimmunoprecipitation assays were performed to investigate the mechanism through which BAP1 participates in hemin-induced SAH.
Results: First, BAP1 expression was upregulated in the cerebrospinal fluid of patients with SAH and positively associated with unfavorable outcomes. ATF2 (activating transcription factor-2) then regulated BAP1 expression by binding to the BAP1 promoter. In addition, BAP1 overexpression enhanced P53 activity and stability by reducing P53 proteasome-mediated degradation. Subsequently, elevated P53 promoted neuronal apoptosis via the P53 pathway. Inhibition of the neuronal BAP1/P53 axis significantly reduced neurological deficits and neuronal apoptosis and improved neurological dysfunction in mice after SAH.
Conclusions: Our results suggest that the neuronal ATF2/BAP1 axis exerts a brain-damaging effect by modulating P53 activity and stability and may be a novel therapeutic target for SAH.
{"title":"ATF2/BAP1 Axis Mediates Neuronal Apoptosis After Subarachnoid Hemorrhage via P53 Pathway.","authors":"Qi Tian, Chengli Liu, Jianming Liao, Guijun Wang, Wenrui Han, Xiaoxing Xiong, Zhibiao Chen, Lijuan Gu, Mingchang Li","doi":"10.1161/STROKEAHA.123.045781","DOIUrl":"10.1161/STROKEAHA.123.045781","url":null,"abstract":"<p><strong>Background: </strong>Neuronal apoptosis plays an essential role in the pathogenesis of brain injury after subarachnoid hemorrhage (SAH). BAP1 (BRCA1-associated protein 1) is considered to exert pro-apoptotic effects in multiple diseases. However, evidence supporting the effect of BAP1 on the apoptotic response to SAH is lacking. Therefore, we aimed to confirm the role of BAP1 in SAH-induced apoptosis.</p><p><strong>Methods: </strong>Enzyme-linked immunosorbent assay (ELISA) was used to detect BAP1 expression in the cerebrospinal fluid. Endovascular perforation was performed in mice to induce SAH. Lentiviral short hairpin RNA targeting <i>BAP1</i> mRNA was transduced into the ipsilateral cortex of mice with SAH to investigate the role of BAP1 in neuronal damage. Luciferase and coimmunoprecipitation assays were performed to investigate the mechanism through which BAP1 participates in hemin-induced SAH.</p><p><strong>Results: </strong>First, BAP1 expression was upregulated in the cerebrospinal fluid of patients with SAH and positively associated with unfavorable outcomes. ATF2 (activating transcription factor-2) then regulated BAP1 expression by binding to the BAP1 promoter. In addition, BAP1 overexpression enhanced P53 activity and stability by reducing P53 proteasome-mediated degradation. Subsequently, elevated P53 promoted neuronal apoptosis via the P53 pathway. Inhibition of the neuronal BAP1/P53 axis significantly reduced neurological deficits and neuronal apoptosis and improved neurological dysfunction in mice after SAH.</p><p><strong>Conclusions: </strong>Our results suggest that the neuronal ATF2/BAP1 axis exerts a brain-damaging effect by modulating P53 activity and stability and may be a novel therapeutic target for SAH.</p>","PeriodicalId":21989,"journal":{"name":"Stroke","volume":null,"pages":null},"PeriodicalIF":7.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141535319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}