Associations of Plasma Metabolites With Risks of Incident Stroke and Its Subtypes in Chinese Adults.

BACKGROUND: Metabolomics studies have identified various metabolic markers associated with stroke risk, yet much uncertainty persists regarding heterogeneity in these associations between different stroke subtypes. We aimed to examine metabolic profiles associated with incident stroke and its subtypes in Chinese adults. METHODS AND RESULTS: We performed a nested case-control study within the Dongfeng-Tongji cohort, including 1029 and 266 incident cases of ischemic stroke (IS) and hemorrhagic stroke (HS), respectively, with a mean follow-up period of 6.1±2.3 years. Fifty-five metabolites in fasting plasma were measured by ultra-high-performance liquid chromatography-mass spectrometry. We examined the associations of metabolites with the risks of total stroke, IS, and HS, with a focus on the comparison of associations of plasma metabolite with IS and HS, using conditional logistic regression. We found that increased levels of asymmetrical/symmetrical dimethylarginine and glutamate were significantly associated with elevated risk of total stroke (odds ratios and 95%, 1.20 [1.08-1.34] and 1.22 [1.09-1.36], respectively; both Benjamini-Hochberg-adjusted P <0.05). When examining stroke subtypes, asymmetrical/symmetrical dimethylarginine was nominally associated with both IS and HS (odds ratios [95% CIs]: 1.16 [1.03-1.31] and 1.39 [1.07-1.81], respectively), while glutamate was associated with only IS (odds ratios [95% CI]: 1.26 [1.11-1.43]). The associations of glutamate with IS risk were significantly stronger among participants with hypertension and diabetes than among those without these diseases (both P for interaction <0.05). CONCLUSIONS: This study validated the positive associations of asymmetrical/symmetrical dimethylarginine and glutamate with stroke risk, mainly that of IS, in a Chinese population, and revealed a novel unanimous association of with both IS and HS. Our findings provided potential intervention targets for stroke prevention.

Association of Initial Potassium Levels with the Type of Stroke in the Emergency Department.

Serum potassium levels are considered as a marker of cerebrovascular emergencies but there is less clarity on the association between initial serum potassium levels recorded on patient's arrival at the emergency department with the type of stroke. This is a case-control study using data of a tertiary care hospital in Japan from April 2018 to September 2019. We identified adult patients with hemorrhagic stroke including subarachnoid hemorrhage (cases) and those with ischemic stroke (controls). Data on age, sex, chief complaints, vital signs, and initial blood tests were collected. We analyzed the association between serum potassium levels and the type of stroke by drawing a LOWESS curve. Additionally, we fitted a logistic regression model to examine the association of interest. There were 416 stroke patients (158 hemorrhagic and 258 ischemic). The median age was 77 years (IQR: 68, 84), and 54% were male. The mean potassium level was 3.69 ± 0.55 mEq/L for hemorrhagic stroke and 4.08 ± 0.65 mEq/L for ischemic stroke. The LOWESS curve showed that the lower initial potassium level was linearly associated with a greater likelihood of hemorrhagic stroke. In the logistic regression model, the odds ratio for the risk of hemorrhagic stroke per 1 mEq/L lower potassium level was 3.31 (95% confidence interval [CI]: 2.24-5.04). This association remained significant in a multivariable model adjusting for other covariates (OR: 2.62 [95% CI: 1.70-4.16]). Initial potassium level was lower in patients with hemorrhagic stroke compared to those with ischemic stroke.

Body Mass Index in 1.9 Million Adolescents and Stroke in Young Adulthood.

Background and Purpose: There is a continuous rise in the prevalence of adolescent obesity and incidence of stroke among young adults in many Western countries, but the association between them is unclear. Methods: A nationwide population-based study of 1 900 384 Israeli adolescents (58% men; mean age, 17.3 years) who were evaluated before mandatory military service during 1985 and 2013. Body mass index was classified according to the US Center for Disease Control and Prevention percentiles. Primary outcome was a first stroke event as recorded by the Israeli National Stroke Registry between 2014 and 2018. Cox proportional hazard models were applied. Results: There were 1088 first stroke events (921 ischemic and 167 hemorrhagic; mean diagnosis age, 41.0 years). Adolescent body mass index was significantly associated with a graded increase in the risk for any stroke, ischemic stroke, but less so with hemorrhagic stroke. The hazard ratios for the first ischemic stroke event were 1.4 (95% CI, 1.2­1.6), 2.0 (95% CI, 1.6­2.4), and 3.4 (95% CI, 2.7­4.3) for the 50th to 84th percentile, overweight and obese groups, respectively, after adjustment for sex, age, and sociodemographic confounders with the 5th to 49th body mass index percentile group as the reference. The respective hazard ratios after further adjustment for diabetes status were 1.3 (1.1­1.5), 1.6 (1.3­2.0), and 2.4 (1.9­3.1). Results persisted when the cohort was divided by diabetes status and when ischemic stroke before age 30 was the outcome. Conclusions: High adolescent body mass index was associated with ischemic stroke in young adults with or without diabetes. The rising prevalence of adolescent obesity may increase the future burden of stroke in young adults.

Association of serum vaspin, apelin, and visfatin levels and stroke risk in a Chinese case-control study.

ABSTRACT: Adipose tissue acts as an active endocrine organ secreting a number of adipokines and may be involved in biological mechanism of stroke. Vaspin, apelin, and visfatin play important roles in the regulation of vascular disorders.Our aim was to evaluate whether the concentrations of vaspin, apelin, and visfatin were associated with stroke risk.A total of 235 patients with stroke (156 patients with ischemic stroke and 79 patients with hemorrhagic stroke) and 235 age- and gender-matched healthy controls were included in this study. A sandwich ELISA was developed to measure the serum vaspin, apelin, and visfatin levels.There was a statistically significant difference in the median levels of serum vaspin, apelin, and visfatin levels between stroke cases and controls (vaspin: 1.50 vs 1.07 ng/ml; apelin: 1.56 vs 1.32 pg/ml; visfatin: 23.40 vs 19.65 ng/ml; all P values <.001). Multiple logistic regression analysis showed that, serum vaspin and visfatin levels were significantly inversely associated with increased risk of stroke, and the odds ratios (ORs) in the highest tertile were 2.25 [95% confidence interval (CI) 1.38-3.67; P for trend <.001] for vaspin and 2.56 (95% CI 1.46-4.47; P for trend <.001) for visfatin, respectively, compared with the lowest tertile. Higher apelin levels were marginally associated with lower stroke risk (P for trend =.060).Our study indicated that higher vaspin, apelin, and visfatin levels might be associated with increased stroke risk. Necessary prospective cohort studies should be conducted to confirm this association in the future.

Blood Biomarkers to Differentiate Ischemic and Hemorrhagic Strokes.

OBJECTIVE: To validate a panel of blood biomarkers to differentiate between ischemic stroke (IS) and intracerebral hemorrhage (ICH) in patients with suspected stroke. METHODS: Patients with suspected stroke admitted within 4.5 hours after onset were enrolled. Blood samples were collected at hospital admission. Glial fibrillary acid protein (GFAP), retinol binding protein 4 (RBP-4), N-terminal proB-type natriuretic peptide (NT-proBNP), and endostatin were measured by immunoassays. Cutoff points were obtained for 100% specificity for IS. A high-sensitivity assay to measure GFAP and rapid point-of-care tests (POCTs) to measure RBP-4 and NT-proBNP were used in subsets of patients. Biomarker panels were evaluated in another cohort of 62 stroke mimics. RESULTS: A total of 189 patients (154 IS and 35 ICH) were enrolled. Patients with IS had higher RBP-4, NT-proBNP, and endostatin and lower GFAP levels than patients with ICH. The best biomarker combination for the identification of IS was RBP-4+NT-proBNP, which was able to identify 29.7% of patients with IS with 100% specificity. In the subset of patients for whom GFAP was measured with the high-sensitivity assay, RBP-4, NT-proBNP, and GFAP identified 51.5% of patients with IS with 100% specificity. When stroke mimics were included, specificities were reduced to 98.4 and 96.8%, respectively. POCTs of RBP-4 and NT-proBNP showed results similar results to those of conventional ELISAs. CONCLUSIONS: A biomarker panel including RBP-4, NT-proBNP, and GFAP provided moderate but potentially useful sensitivity rates at 100% specificity for IS diagnosis. If confirmed in future studies, this strategy might allow prehospital treatment in selected patients. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that a biomarker panel including RBP-4, NT-proBNP, and GFAP distinguishes IS from ICH with moderate accuracy.

Risk factors for acute stroke-associated pneumonia and prediction of neutrophil-to-lymphocyte ratios.

OBJECTIVES: This study aimed to analyze the risk factors for stroke-associated pneumonia (SAP) and assess the predictive effect of neutrophil-to-lymphocyte ratio (NLR) on acute SAP. METHODS: The study included acute stroke patients from April 2018 to June 2019. These patients were divided into the SAP and Non-SAP groups. The patients' history of chronic diseases was assessed, including history of hypertension, diabetes, hyperlipidemia, chronic lung disease, and current smoking status. The clinical characteristics of all studied cases were recorded, including the initial stroke type (cerebral infarction or cerebral hemorrhage), National Institute of Health Stroke Scale (NIHSS) score, indwelling nasogastric tubes, stroke-associated pneumonia within 7 days of hospitalization, and length of hospitalization. The study also recorded the laboratory testing data, including fasting blood glucose, triglyceride, total cholesterol, low-density lipoprotein cholesterol, glycosylated hemoglobin, and high-sensitivity C-reactive protein (hsCRP) as well as white blood cell (WBC), neutrophil, and lymphocyte counts. SPSS 19.0 was used for statistical analysis. RESULTS: A total of 328 eligible acute stroke patients were included. Among all participants, SAP occurred in 64 (19.5%) patients. In the SAP group, the patients were older, the proportion of cerebral hemorrhage was higher, the NIHSS score was higher, and more patients had nasogastric tubes (P < 0.05). Concomitantly, the blood glucose, hsCRP, WBC count, neutrophil count, and NLR of the SAP group were significantly higher than those of the Non-SAP group, whereas the lymphocyte count was significantly lower than that of the Non-SAP group (P < 0.05). Multivariable analysis of Binary Logistic regression revealed that stroke type (cerebral hemorrhage), indwelling gastric tube, and NLR were independent risk factors for SAP. Receiver operating characteristic curve analysis demonstrated that the area under the curve for the NLR's ability to predict SAP was 0.861. The optimal cutoff threshold, sensitivity, and specificity were 3.745, 0.891, and 0.727, respectively. CONCLUSIONS: The risk factors for SAP were multifaceted. Cerebral hemorrhage, indwelling nasogastric tube, and high NLR were independent risk factors. An early NLR had a predictive effect on the occurrence of SAP in patients with acute stroke.

Lipid levels and the risk of hemorrhagic stroke: A dose-response meta-analysis.

BACKGROUND AND AIMS: Hemorrhagic stroke (HS) could damage human health and impose heavy social and economic burden around the world. An accumulating number of studies revealed the effect of lipid levels on HS, whereas the results were inconsistent. Therefore, we conducted a dose-response meta-analysis to evaluate the relationship between lipid levels and HS. METHODS AND RESULTS: We searched the databases for relative cohort studies, which were published before April 2020. We pooled adjusted effect size and performed the dose-response analysis by random-effect model. 31 eligible studies with 2,291,643 participants and 12,147 hemorrhagic stroke cases were included. An inverse association was observed between the risk of hemorrhagic stroke and total cholesterol (TC) (RR: 0.72; 95% CI: 0.64-0.82) or low-density lipoprotein cholesterol (LDL-C) (RR: 0.69; 95% CI: 0.53-0.89). Additionally, in dose-response analysis, the non-linear trend was also found between TC, high-density lipoprotein cholesterol (HDL-C), and risk of HS. When the level of TC and HDL-C was about 6 and 1.3 mmol/L separately, the risk of HS was decreased to the lowest. And we found a linear trend that for every 1 mmol/L triglyceride (TG) increase, the risk of HS decreased by 7%. CONCLUSION: TC and LDL-C were both inversely related to the risk of HS. In dose-response analysis of TG, we also found the inverse linear trend. Furthermore, the non-linear trend suggested the level of TC and HDL-C was about 6 and 1.3 mmol/L separately could lead to the lowest risk of HS.

Early predictive blood markers of hemorrhagic stroke - influence of cytoflavin therapy.

Examination of the patterns of free-radical processes (FRP) and changes of the early screening markers to predict the course of hemorrhagic stroke (HS) and applied pathophysiologically based therapy can be of great practical importance. This study aimed to determine early changes in the parameters of oxidative stress and routine biochemistry blood tests in patients with HS and to assess their relationship with clinical outcome. The effects of early applied cytoflavin were also investigated. The prospective study included 151 patients with HS. Forty-eight percent of patients in the standard conservative therapy were given cytoflavin antioxidant energy therapy from the first day of hospitalization. The neurological status, neuroimaging, biochemical blood tests and FRP were assessed on days 1, 5, 10, and 20 of hospitalization. In patients with HS, an imbalance of all stages of FRP was detected proportionately to the severity of HS. The malondialdehyde concentration above 5.3 µmol/L, the number of leukocytes above 15 800, glucose above 11.9 mmol/L, lactate dehydrogenase above 574 IU/L, and lactate above 2.5 mmol/L, detected on the first day, predetermined a high risk of death. Additional cytoflavin treatment allowed stabilizing the clinical laboratory picture of HS, improved the treatment results, and reduced hospital mortality rate.

Diagnostic Accuracy of Glial Fibrillary Acidic Protein and Ubiquitin Carboxy-Terminal Hydrolase-L1 Serum Concentrations for Differentiating Acute Intracerebral Hemorrhage from Ischemic Stroke.

BACKGROUND: Biomarkers indicative of intracerebral hemorrhage (ICH) may help triage acute stroke patients in the pre-hospital phase. We hypothesized that serum concentration of glial fibrillary acidic protein (GFAP) in combination with ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1), measured by a rapid bio-assay, could be used to distinguish ICH from ischemic stroke. METHODS: This prospective two-center study recruited patients with a clinical diagnosis of acute stroke both in the pre-hospital phase and at hospital admission (within 4 and 6 h after symptom onset, respectively). Blood samples were analyzed for concentrations of GFAP and UCH-L1 using ELISA techniques. The reference standard was the diagnosis of ICH, ischemic stroke, or stroke mimicking condition achieved after clinical workup including brain imaging. RESULTS: A total of 251 patients were included (mean age [± SD] 72 ± 15 years; 5 ICH, 23 ischemic strokes and 14 stroke mimics in the pre-hospital part; and 59 ICH, 148 ischemic strokes and 2 stroke mimics in the in-hospital part). Mean delay (± SD) from symptom onset to blood withdrawal was 130 ± 79 min for the pre-hospital patients and 136 ± 86 min for the in-hospital patients. Both GFAP and UCH-L1 serum concentrations were higher in patients having ICH as compared to other diagnoses (GFAP: median 330 ng/L [interquartile range 64-7060, range 8-56,100] vs. 27.5 ng/L [14-57.25, 0-781], p < 0.001; UCH-L1: 401 ng/L [265-764, 133-1812] vs. 338 ng/L [213-549.5, 0-2950], p = 0.025). Area-under-the-curve values were 0.866 (95% CI 0.809-0.924, p < 0.001) for GFAP, and 0.590 (0.511-0.670, p = 0.033) for UCH-L1. Regarding overall diagnostic accuracy, UCH-L1 did not add significantly to the performance of GFAP. CONCLUSIONS: GFAP may differentiate ICH from ischemic stroke and stroke mimics. A point-of-care test to distinguish between ischemic and hemorrhagic strokes might facilitate triage to different treatment pathways or locations, or be used to select patients for trials of ultra-early interventions.

The association between monocyte to high-density lipoprotein ratio and hemorrhagic transformation in patients with acute ischemic stroke.

Hemorrhagic transformation (HT) is a common complication in patients with acute ischemic stroke. We investigated whether the monocyte to high-density lipoprotein ratio (MHR) is related to HT. Consecutive patients with ischemic stroke within 24 h of symptom onset were included in this study. HT was diagnosed by follow-up brain imaging after admission, and was classified as asymptomatic or symptomatic according to whether patients showed any neurologic worsening. Logistic regression was performed to estimate the association between MHR and HT. Of the 974 enrolled patients, 148 (15.2%) developed HT, and 24 (2.5%) patients experienced symptomatic HT. Compared to the highest MHR tertile (> 0.37), the lowest MHR tertile (< 0.22) was associated with 1.81-fold increase (95% CI 1.08-3.01, P = 0.024) in the odds of HT and 3.82-fold increase (95% CI 1.04-14.00, P = 0.043) in the odds of symptomatic HT after adjustment for possible confounders. Using a multivariate logistic regression model with restricted cubic spline, we found that elevated MHR was associated with a decreased risk of HT and symptomatic HT. In summary, lower MHR was independently associated with increased risk of HT and symptomatic HT in patients with ischemic stroke.

Serum uric acid and risk of stroke and its types: the Circulatory Risk in Communities Study (CIRCS).

The role of serum uric acid as a predictor of stroke among the general Japanese population remains controversial. We conducted a prospective cohort study of 5235 men and 8185 women aged 40-79 years at baseline between 1985 and 1994 in four Japanese communities, who were initially free from stroke, coronary heart disease, and medication for hyperuricemia or gout. Cox proportional hazards models were used to estimate sex-specific hazard ratios of stroke and its types in relation to serum uric acid level. During a median follow-up of 23.1 years, we recorded 1018 (488 men and 530 women) incident strokes, including 222 (99 and 123) intraparenchymal hemorrhages, 113 (33 and 80) subarachnoid hemorrhages and 667 (347 and 320) ischemic strokes. After adjustment for age, community and known cardiovascular risk factors, the multivariable hazard ratios (95% CIs) in the highest vs. lowest quintile of serum uric acid were 1.45 (1.07-1.96) for total stroke, 1.20 (0.65-2.20) for intraparenchymal hemorrhage, 1.46 (0.69-3.09) for subarachnoid hemorrhage and 1.61 (1.07-2.41) for ischemic stroke in women. The corresponding multivariable hazard ratios (95% CIs) in men were 1.02 (0.74-1.35), 0.83 (0.40-1.72), 1.19 (0.38-3.75) and 1.00 (0.70-1.41). Furthermore, those positive associations with risks of total and ischemic strokes in women were more evident in nonusers of antihypertensive medication than the users. In conclusion, elevated serum uric acid level is an independent predictor of total stroke in women but not in men. The positive association in women was mostly attributable to ischemic stroke and was more pronounced among nonusers of antihypertensive medication.