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Distinct peripheral blood monocyte and neutrophil transcriptional programs following intracerebral hemorrhage and different etiologies of ischemic stroke.

ABSTRACT: Understanding cell-specific transcriptome responses following intracerebral hemorrhage (ICH) and ischemic stroke (IS) will improve knowledge of the immune response to brain injury. Transcriptomic profiles of 141 samples from 48 subjects with ICH, different IS etiologies, and vascular risk factor controls were characterized using RNA-seq in isolated neutrophils, monocytes and whole blood. In both IS and ICH, monocyte genes were down-regulated, whereas neutrophil gene expression changes were generally up-regulated. The monocyte down-regulated response to ICH included innate, adaptive immune, dendritic, NK cell and atherosclerosis signaling. Neutrophil responses to ICH included tRNA charging, mitochondrial dysfunction, and ER stress pathways. Common monocyte and neutrophil responses to ICH included interferon signaling, neuroinflammation, death receptor signaling, and NFAT pathways. Suppressed monocyte responses to IS included interferon and dendritic cell maturation signaling, phagosome formation, and IL-15 signaling. Activated neutrophil responses to IS included oxidative phosphorylation, mTOR, BMP, growth factor signaling, and calpain proteases-mediated blood-brain barrier (BBB) dysfunction. Common monocyte and neutrophil responses to IS included JAK1, JAK3, STAT3, and thrombopoietin signaling. Cell-type and cause-specific approaches will assist the search for future IS and ICH biomarkers and treatments.

SUBMITTER: Carmona-Mora P

PROVIDER: S-EPMC8142129 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Distinct peripheral blood monocyte and neutrophil transcriptional programs following intracerebral hemorrhage and different etiologies of ischemic stroke.

Carmona-Mora Paulina P Ander Bradley P BP Jickling Glen C GC Dykstra-Aiello Cheryl C Zhan Xinhua X Ferino Eva E Hamade Farah F Amini Hajar H Hull Heather H Sharp Frank R FR Stamova Boryana B

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20200922 6

Understanding cell-specific transcriptome responses following intracerebral hemorrhage (ICH) and ischemic stroke (IS) will improve knowledge of the immune response to brain injury. Transcriptomic profiles of 141 samples from 48 subjects with ICH, different IS etiologies, and vascular risk factor controls were characterized using RNA-seq in isolated neutrophils, monocytes and whole blood. In both IS and ICH, monocyte genes were down-regulated, whereas neutrophil gene expression changes were gener ...[more]

PMID: 32960689

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Project description:Background Data on the relative contribution of clinical and neuroimaging risk factors to acute ischemic stroke (AIS) versus intracerebral hemorrhage (ICH) occurring on oral anticoagulant treatment are scarce. Methods and Results Cross-sectional study was done on consecutive oral anticoagulant-treated patients presenting with AIS, transient ischemic attack (TIA), or ICH from the prospective observational NOACISP (Novel-Oral-Anticoagulants-In-Stroke-Patients)-Acute registry. We compared clinical and neuroimaging characteristics (small vessel disease markers and atherosclerosis) in ICH versus AIS/TIA (reference) using logistic regression. Among 734 patients presenting with stroke on oral anticoagulant treatment (404 [55%] direct oral anticoagulants, 330 [45%] vitamin K antagonists), 605 patients (82%) had AIS/TIA and 129 (18%) had ICH. Prior AIS/TIA, coronary artery disease, dyslipidemia, and worse renal function were associated with AIS/TIA (adjusted odds ratio [aOR] [95% CI] 0.51 [0.32-0.82], 0.48 [0.26-0.86], 0.55 [0.34-0.89], and 0.82 [0.75-0.90] per 10 mL/min). Prior ICH, older age, higher admission blood pressure, and statin treatment were associated with ICH (aOR [95% CI] 6.33 [2.87-14.04], 1.37 [1.04-1.81] per 10 years, 1.19 [1.10-1.29] per 10 mm Hg, and 1.81 [1.09-3.03]). Cerebral microbleeds and moderate-to-severe white matter hyperintensities contributed more to ICH (aOR [95% CI] 2.77 [1.34-6.18], and 2.62 [1.28-5.63]). Aortic arch, common and internal carotid artery atherosclerosis, and internal carotid artery stenosis ≥50% contributed more to AIS/TIA (aOR [95% CI] 0.54 [0.31-0.90], 0.29 [0.05-0.97], 0.48 [0.30-0.76], and 0.32 [0.13-0.67]). Conclusions In patients presenting with stroke on oral anticoagulant, AIS/TIA was 5 times more common than ICH. A high atherosclerotic burden (indicated by cardiovascular comorbidities and extracranial atherosclerosis) and prior AIS/TIA contributed more to AIS/TIA, while small vessel disease markers and prior ICH were stronger determinants for ICH. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02353585.

Project description:BackgroundIntracerebral hemorrhage (ICH) is associated with an increased risk of ischemic stroke. Whether there are racial and ethnic disparities in the risk of ischemic stroke after ICH is poorly understood. We therefore aimed to test the hypothesis that non-Hispanic Black and Hispanic ICH patients have a higher risk of ischemic stroke compared with non-Hispanic White ICH patients.MethodsWe performed a retrospective cohort study using the Healthcare Cost and Utilization Project (HCUP) on all hospitalizations at all nonfederal hospitals in Florida from 2005 to 2018 and New York from 2006 to 2016. Race and ethnicity were coded as a single variable in HCUP. We included patients with an ICH, and without a prior or concomitant diagnosis of ischemic stroke, ascertained using validated International Classification of Diseases-Clinical Modification-9 and 10 diagnosis codes. Using Cox proportional hazard models, we studied the relationship between race and risk of ischemic stroke starting from the time of discharge from ICH hospitalization, after adjustment of demographics and vascular comorbidities.ResultsWe included 91 342 patients with ICH-62% non-Hispanic White, 18% non-Hispanic Black, and 12% Hispanic patients. Non-Hispanic Black and Hispanic patients were younger and had a higher prevalence of cardiovascular comorbidities; however, atrial fibrillation was more prevalent among non-Hispanic White patients. During a median follow-up period of 4.4 years (interquartile range, 1.5-8.1), an incident ischemic stroke occurred in 3377 (6%) non-Hispanic White, 1323 (8%) non-Hispanic Black, and 844 (8%) Hispanic patients. In adjusted Cox models, the risk of an ischemic stroke was significantly higher among non-Hispanic Black patients (hazard ratio, 1.6 [95% CI, 1.5-1.8]) and Hispanic patients (hazard ratio, 1.4 [95% CI, 1.3-1.5]), compared with non-Hispanic White patients. Similar results were obtained in sensitivity analyses when using death as a competing risk and after excluding patients with atrial fibrillation and valvular heart disease.ConclusionsIn a large heterogeneous cohort of patients with ICH, we found that non-Hispanic Black and Hispanic patients had a significantly higher risk of ischemic stroke compared with non-Hispanic White patients.

Project description:Background and Purpose- Patients with intracerebral hemorrhage (ICH) and atrial fibrillation (AF) are at risk for ischemic events. While risk calculators (CHA2DS2-VASc and HAS-BLED) have been validated to assess risk for ischemic stroke and major bleeding in AF patients, decisions about anticoagulation must consider the net clinical benefit of anticoagulation. Furthermore, stroke and bleeding risk are highly correlated, making decisions more difficult. Methods- We examined patients in the GERFHS III study (Genetic and Environmental Risk Factors for Hemorrhagic Stroke)-a population-based retrospective study of spontaneous ICH patients without a structural or traumatic cause in the Greater Cincinnati/Northern Kentucky region between July 2008 and December 2012. CHA2DS2-VASc and HAS-B(L)ED (minus L because labile international normalized ratio was unavailable) scores were calculated for ICH patients with AF. Using a Markov state transition model, we estimated net clinical benefit of anticoagulation relative to no treatment in quality-adjusted life years (QALYs). We defined minimal clinically relevant benefit as 0.1 QALYs. Results- Among 1186 cases of spontaneous ICH, 95 cases had AF and met our survival criteria. Within 1 year, 8 of 95 (8%) would be expected to have a major bleeding event on anticoagulation, and 5 of 95 (5%) of patients would be expected to have an ischemic stroke off anticoagulation. Sixty-eight of 95 (71%) patients would have higher risk for major bleeding than for ischemic stroke. Anticoagulation with directly acting anticoagulants would result in no clinically significant gain or loss in 73%. Roughly 12% would gain >0.1 QALYs, and 15% would lose >0.1 QALYs. Among patients receiving aspirin, most have no significant net clinical benefit or loss. Overall, anticoagulation of the entire cohort would result in an aggregate loss of 0.92 QALYs. Conclusions- Our analysis suggests that universal anticoagulation after ICH would be associated with a net loss of QALY. Additional factors should be considered before anticoagulating patients with AF after ICH. Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT00930280.

Dataset Information

Distinct peripheral blood monocyte and neutrophil transcriptional programs following intracerebral hemorrhage and different etiologies of ischemic stroke.

Publications

Distinct peripheral blood monocyte and neutrophil transcriptional programs following intracerebral hemorrhage and different etiologies of ischemic stroke.

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