Investigation on the relationship between hemoglobin concentration and stroke risk: a bidirectional Mendelian randomization study.

Background: The relationship between hemoglobin concentration and stroke has garnered significant interest in the research community. However, findings from published observational epidemiological studies on this relationship have been inconclusive. By using publicly available genome-wide association study (GWAS) aggregated statistics, a two-sample Mendelian randomization analysis is conducted to explore the causal relationship between hemoglobin concentration and stroke. Methods: Summary statistics data from UK Biobank for hemoglobin concentration and from the FinnGen R9 and MEGASTROKE consortium for stroke are used. A series of quality control steps are taken to select eligible instrumental SNPs closely related to exposure. In order to make the conclusion more robust and reliable, several robust analysis methods are employed including inverse variance weighted, weighted median, MR-Egger regression, which are based on different assumptions of two-sample MR Analysis. Meanwhile, sensitivity analyses such as pleiotropy test and MR-Egg regression, are performed to mitigate horizontal pleiotropy and heterogeneity. Results: The two-sample Mendelian randomized study indicates a negative association between hemoglobin concentration and stroke, suggesting that hemoglobin concentration acts as a protective factor against stroke. From the FinnGen database, there is a negative association between hemoglobin concentration and stroke, with an odds ratio (OR) of 0.82 and a 95% confidence interval (CI) of 0.73-0.92, p = 0.0006. Similarly, the MEGASTROKE database findings reinforce this observation. The negative association between hemoglobin concentration and stroke (OR: 0.91, 95%CI: 0.83-1.00, p = 0.040), ischemic stroke (OR: 0.87, 95%CI: 0.79-0.96, p = 0.004), and cardiogenic stroke (OR: 0.82, 95% CI: 0.69-0.99, p = 0.039) further suggests that higher hemoglobin levels might confer a protective effect against these conditions. Conclusion: Hemoglobin concentration serves as a protective factor against stroke, and managing abnormal hemoglobin levels can effectively reduce the incidence of stroke.

Inflammation and endothelial function-related gene polymorphisms are associated with carotid atherosclerosis-A study of community population in Southwest China.

OBJECTIVES: To investigate the relationships between 18 single nucleotide polymorphisms with carotid atherosclerosis and whether interactions among these genes were associated with an increased risk of carotid atherosclerosis. METHODS: Face-to-face surveys were conducted with individuals aged 40 or older in eight communities. A total of 2377 individuals were included in the study. Ultrasound was used to detect carotid atherosclerosis in the included population. 18 loci of 10 genes associated with inflammation and endothelial function were detected. Gene-gene interactions were analyzed using generalized multifactor dimensionality reduction (GMDR). RESULTS: Among the 2377 subjects, 445 (18.7%) subjects had increased intima-media thickness in the common carotid artery (CCA-IMT), and 398 (16.7%) subjects were detected with vulnerable plaque. In addition, NOS2A rs2297518 polymorphism was associated with increased CCA-IMT, IL1A rs1609682, and HABP2 rs7923349 polymorphisms were associated with vulnerable plaque. Besides, GMDR analysis showed significant gene-gene interactions among TNFSF4 rs1234313, IL1A rs1609682, TLR4 rs1927911, ITGA2 rs1991013, NOS2A rs2297518, IL6R rs4845625, ITGA2 rs4865756, HABP2 rs7923349, NOS2A rs8081248, HABP2 rs932650. CONCLUSION: The prevalences of increased CCA-IMT and vulnerable plaque were high in Southwestern China's high-risk stroke population. Furthermore, inflammation and endothelial function-related gene polymorphisms were associated with carotid atherosclerosis.

Optic nerve sheath diameter and optic nerve sheath diameter/eyeball transverse diameter ratio in prediction of malignant progression in ischemic stroke.

Background: The optic nerve sheath diameter (ONSD)/eyeball transverse diameter (ETD) ratio has been suggested in the evaluation of intracranial pressure (ICP). The aim of this study was to evaluate the predictive value of ONSD and ONSD/ETD in relation to risk for secondary malignant middle cerebral artery infarction (MMI). Methods: A total of 91 patients with MCA occlusion were included in this study. Data were divided into two groups based on development of MMI or not. ONSD and ETD were measured by unenhanced computed tomography (CT). The differences in ONSD and the ONSD/ETD ratios between the MMI and non-MMI groups were compared. Receiver operating characteristic curve analyses were used to test the diagnostic value of ONSD and ONSD/ETD independently, to predict MMI. Results: The ONSD in the MMI group and non-MMI group were 5.744 ± 0.140 mm and 5.443 ± 0.315 mm, respectively (P = 0.001). In addition, the ONSD/ETD ratios in the MMI group and non-MMI group were 0.258 ± 0.008 and 0.245 ± 0.006, respectively (P = 0.001). The receiver operating characteristic (ROC) curve demonstrated an area under the curve (AUC) for ONSD of 0.812 [95% confidence interval (CI): 0.718-0.906, P = 0.001], with a sensitivity of 97.4% and a specificity of 66.0% at the cut-off value of 5.520 mm. The AUC for ONSD/ETD ratio in predicting occurrence of MMI was 0.895 (95% CI: 0.823-0.968, P = 0.001), with a sensitivity of 84.2% and a specificity of 92.5% at a cut-off value of 0.250. Conclusion: In acute stroke patients with massive cerebral infarction, an increased ONSD or ONSD/ETD ratio increases the odds of malignant progression and may be used as an indicator for emergent therapeutic interventions. In addition, the ONSD/ETD ratio may be more valuable than ONSD in predicting the malignant progression of acute stroke patients.

MMP9 SNP and MMP SNP-SNP interactions increase the risk for ischemic stroke in the Han Hakka population.

OBJECTIVES: To investigate the association of eight variants of four matrix metalloproteinase (MMP) genes with ischemic stroke (IS) and whether interactions among these single nucleotide polymorphisms (SNPs) increases the risk of IS. METHODS: Among 547 patients with ischemic stroke and 350 controls, matrix-assisted laser desorption/ionization time of flight mass spectrometry was used to examine eight variants arising from four different genes, including MMP-1 (rs1799750), MMP-2 (rs243865, rs2285053, rs2241145), MMP-9 (rs17576), and MMP-12 (rs660599, rs2276109, and rs652438). Gene-gene interactions were employed using generalized multifactor dimensionality reduction (GMDR) methods. RESULTS: The frequency of rs17576 was significantly higher in IS patients than in controls (p = .033). Logistic regression analysis revealed the AG and GG genotypes of rs17576 to be associated with a higher risk for IS, with the odds ratio and 95% confidence interval being 2.490 (1.251-4.959) and 2.494 (1.274-4.886), respectively. GMDR analysis showed a significant SNP-SNP interaction between rs17576 and rs660599 (the testing balanced accuracy was 53.70% and cross-validation consistency was 8/10, p = .0107). Logistic regression analysis showed the interaction between rs17576 and rs660599 to be an independent risk factor for IS with an odds ratio of 1.568 and a 95% confidence interval of 1.152-2.135. CONCLUSION: An MMP-9 rs17576 polymorphism is associated with increased IS risk in the Han Hakka population and interaction between MMP-9 rs17576 and MMP-12 rs660599 is associated with increased IS risk as well.

1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) Urea Exerts Neuro-Protective Effects Against Ischemic Injury via Suppressing JNK/p38 MAPK-Mediated Mitochondrial Apoptosis Pathway.

BACKGROUND: 1-trifluoromethoxyphenyl-3-(1- propionylpiperidin-4-yl) urea (TPPU) is a novel soluble epoxide hydrolase inhibitor which can protect against cerebral ischemic injury in middle cerebral artery occlusion rat model. However, the effects and potential mechanisms of TPPU on mitochondrial dysfunction are poorly understood. MATERIALS AND METHODS: In oxygen-glucose deprivation/reperfusion (OGD/R)-induced cortical neurons, the effect of TPPU on cell viability was measured by MTT assay and apoptosis was evaluated using TUNEL assay. Mitochondria were observed by transmission electron microscopy and Mitotracker green staining assay, mitochondrial membrane potential was determined by JC-1 staining assay, activities of mitochondrial respiratory chain complexes (MRCC) I-IV and ATPase were measured by MRCC Activity Assay Kits and spectrophotometer. Western blot was used to investigate the effects of TPPU on apoptosis-related proteins. RESULTS: TPPU treatment demonstrated significant protective effect on the OGD/R-induced cortical neurons by reducing cell death and number of apoptotic cells, stabilizing mitochondrial ultrastructure and morphology, increasing mitochondrial membrane potential and activities of MRCC I-IV and ATPase. Furthermore, TPPU treatment might effectively reverse the upregulation of caspase-3, Bax, p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal protein kinase (JNK), alleviate the inhibition of Bcl-2 in OGD/R-induced cortical neurons. CONCLUSIONS: TPPU exerts a marked neuroprotective effect against mitochondrial dysfunction after cerebral ischemia potentially via suppressing JNK/p38 MAPK-mediated mitochondrial apoptosis signal pathway, it may be a promising neuroprotective agent for cerebral ischemia.

Single nucleotide polymorphisms in the ANGPTL4 gene and the SNP-SNP interactions on the risk of atherosclerotic Ischaemic stroke.

OBJECTIVES: The purpose of this study was to investigate the impact of single nucleotide polymorphisms (SNPs) in the ANGPTL4 gene and the SNP-SNP interactions on atherosclerotic ischemic stroke (IS) risk. PATIENTS AND METHODS: A case-control study was conducted. A total of 360 patients with atherosclerotic IS and 342 controls between December 2018 and December 2019 from Longyan First Hospital affiliated to Fujian Medical University were included. A logistic regression model was used to examine the association between SNPs and atherosclerotic IS risk. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Generalized multifactor dimensionality reduction was employed to analyze the SNP-SNP interaction. RESULTS: Logistic regression analysis showed that atherosclerotic IS risk was significantly lower in carriers with the rs11672433-T allele than those with the CC genotype (CT+ TT vs. CC); adjusted OR, 0.005; 95% CI, 0.02-0.11. We found a significant 2-locus model (P = 0.0010) involving rs11672433 and rs4076317; the cross-validation consistency of this model was 10 of 10, and the testing accuracy was 57.96%. Participants with the CT or TT of rs11672433 and CC of rs4076317 genotype have the lowest atherosclerotic IS risk, compared to subjects with CC of rs11672433 and the CC of rs4076317 genotype, OR (95%CI) was 0.06(0.02-0.22), after covariates adjustment for gender, age, smoking and alcohol status, hypertension, Diabetes mellitus, TG, TC, HDL-C, LDL-C, Uric acid. CONCLUSIONS: We found that rs11672433 was associated with decreased atherosclerotic IS risk; we also found that gene-gene interaction between rs11672433 and rs4076317 was associated with decreased atherosclerotic IS risk.

Association Between Carotid Artery Perivascular Fat Density and Embolic Stroke of Undetermined Source.

AIM: This study aims to retrospectively evaluate the association between pericarotid inflammation and the presence of embolic stroke of undetermined source (ESUS). METHODS: In total, 126 patients with ESUS and 118 patients with ischemic stroke from large artery atherosclerosis (LAA) were enrolled. All the patients underwent brain MRI and a neck CT angiography (CTA) examination. Reviewers were blinded to infarct location and stroke cause. Paired t-tests assessed within-subjects differences in mean Hounsfield units (HUs) in carotid perivascular fat between the cerebral infarction side and contralateral side for ESUS and LAA ischemic stroke cases. The unpaired Student's t-test was used to assess between-subjects differences in mean HUs between ESUS and LAA ischemic stroke cases. RESULTS: In both the ESUS cases and LAA ischemic stroke cases, the pericarotid fat density around the carotid artery ipsilateral to the stroke significantly increased compared with contralateral stroke position in both the groups (ESUS cases -56.31 ± 18.70 vs. -67.31 ± 20.01, p = 0.000; LAA ischemic stroke cases -51.62 ± 19.95 vs. -64.58 ± 22.68, p = 0.000). However, there was no significant difference in ipsilateral and contralateral positions to infarct between ESUS cases and LAA ischemic stroke cases (ipsilateral to infarct -56.31 ± 18.70 vs. -51.62 ± 19.95, p = 0.059; contralateral to infarct -67.31 ± 20.01 vs. -64.58 ± 22.68, p = 0.320). CONCLUSION: We found increased density in the fat surrounding carotid artery ipsilateral to stroke compared with contralateral in ESUS, suggesting the presence of an inflammatory reaction that extends beyond the vessel lumen in patients with ESUS with a risk factor profile similar to LAA strokes.

[Clinical effect of Liyan Tongqiao acupuncture in treatment of post-stroke dysphagia: an analysis based on diffusion tensor imaging].

OBJECTIVE: To investigate the clinical change of post-stroke dysphagia after the intervention of Liyan Tongqiao （relieving sore-throat and dredging orifices）acupuncture using cranial diffusion tensor imaging (DTI). METHODS: A total of 60 patients with post-stroke dysphagia were enrolled and randomly divided into Liyan Tongqiao acupuncture group and neurology treatment group, with 30 patients in each group. The patients in the neurology treatment group were given routine neurology treatment and swallowing rehabilitation training, and those in the Liyan Tongqiao acupuncture group received acupuncture at Sishencong (EX-HN1), Baihui (GV20), bilateral Tai-yang (EX-HN5), and bilateral Fengchi (GB20) and tongue triple acupuncture, with an electroacupuncture apparatus for EX-HN1, bilateral GB20, and tongue triple acupuncture, for a needle retaining time of 30 minutes each time, once a day and 5 times a week, in addition to the treatment in the neurology treatment group. Each course of treatment was 3 weeks, and both groups were treated for 2 courses. Swallowing function assessment and cranial DTI were performed after treatment. RESULTS: After 6 weeks of treatment, both groups had a marked improvement in swallowing function, a significantly greater change in video fluoroscopic swallowing study (VFSS) score and a higher mean FA value (P<0.05). Compared with the neurology treatment group, the Liyan Tongqiao acupuncture group had a marked improvement in swallowing function, a significantly greater change in VFSS score in the pharyngeal phase and a higher mean FA value (P<0.05). CONCLUSION: Liyan Tongqiao acupuncture can improve dysphagia and swallowing function in the pharyngeal phase in VFSS, possibly by promoting the remodeling of cerebral cortex and increasing the FA value of infarct zone through the stimulation of related acupoint signals.

Preceding Antithrombotic Treatment is Associated With Acute Ischemic Stroke Severity and Functional Outcome at 90 Days Among Patients With Atrial Fibrillation.

BACKGROUND: Antithrombotic therapies are known to prevent ischemic stroke (IS) for patients with atrial fibrillation (AF), but are often underused in clinical practice. The aim of present study was to investigate the prevalence of patients with acute IS with known history of AF who were not receiving antithrombotic treatment before stroke and to evaluate the association of preceding antithrombotic treatment with stroke severity and outcomes at 90 days after admission. MATERIALS AND METHODS: This was a retrospective, multi-center, observational study of 748 patients with acute IS and known history of AF admitted to 6 participating hospitals between March 2016 and October 2017. The primary outcome was stroke severity at admission as assessed using National Institutes of Health Stroke Scale (NIHSS) score. The secondary outcome was functional outcome at 90 days after admission as measured by modified Rankin Scale (mRS) score. RESULTS: A total of 748 patients, 54 (7.2%) were receiving therapeutic warfarin (international normalized ratio [INR] ≥ 2) and 100 (13.4%) had subtherapeutic warfarin anticoagulation (INR < 2), 340 (45.5%) were receiving antiplatelet treatment, and 254 (34.0%) were not receiving any antithrombotic treatment prior to stroke. Compared with no antithrombotic treatment, therapeutic warfarin (OR: 0.64; 95% CI: 0.52-0.82; P = .022), and antiplatelet therapy only (OR: 0.89; 95% CI: 0.76-0.96; P = .041) were associated with lower odds ratio of moderate or severe stroke (NIHSS ≥ 16). Patients receiving preceding therapeutic warfarin (OR: 1.32; 95% CI: 1.22-3.57; P = .025), antiplatelet therapy only (OR: 1.13; 95% CI: 1.07-2.59; P = .043), and subtherapeutic warfarin with INR 1.5 to 1.99 (OR: 1.15; 95% CI: 1.10-2.66; P = .042) had higher odds ratio of better functional outcome (mRS ≤ 2) at 90 days. CONCLUSIONS: Among patients with AF who had experienced an acute IS, inadequate therapeutic warfarin preceding the stroke was very prevalent in China. Therapeutic warfarin was associated with less severe stroke and better functional outcome at 90 days.

Matrix metalloproteinase-9 gene polymorphisms are associated with ischemic stroke severity and early neurologic deterioration in patients with atrial fibrillation.

OBJECTIVES: The mechanisms of ischemic stroke severity and early neurologic deterioration (END) are not fully understood. The aim of the present study was to investigate the association of six variants in MMP-9 gene with ischemic stroke severity and the risk for END in ischemic stroke (IS) patients with atrial fibrillation (AF). METHODS: This was a multi-center, prospective, observational study of 615 acute IS patients with AF admitted to six participating hospitals between June 2016 and October 2017. Ischemic stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) score on admission. END was defined as an increase of four or more points in NIHSS within 10 days of admission. Six variants of MMP-9 gene were examined using mass spectrometry. RESULTS: Among the 615 enrolled patients, 112 (18.2%) patients presented with moderate or severe stroke (NIHSS score ≥16), and 108 (17.6%) patients suffered from END within 10 days of admission. Multiple logistic analysis showed that prestroke antiplatelet therapy, prestroke anticoagulant therapy, rs3918242 CT/TT, and rs3787268 AG/GG were independent predictors for stroke severity. Cox proportional hazard regression revealed that diabetes mellitus, prestroke antiplatelet therapy, prestroke anticoagulant therapy, rs1056628 AC/CC, and rs3918242 CT/TT were independently associated with the risk of END. CONCLUSIONS: The incidence of moderate or severe stroke and END was very common in acute IS patients with AF. MMP-9 polymorphisms were independently associated with severe stroke and higher risk of END, and prestroke antithrombotic treatment was associated with less severe stroke and lower risk of END in patients with AF.