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Background: Osteoprotegerin was implicated in vascular injury and inflammatory responses, but its prognostic value in ischemic stroke remained unclear. We aimed to prospectively investigate the association between plasma osteoprotegerin and ischemic stroke prognosis combined with a Mendelian randomization analysis., Methods: Our prospective study follows the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) reporting guideline. We measured baseline plasma osteoprotegerin levels for 3490 ischemic stroke patients recruited between August 2009 and May 2013 in 26 hospitals across China. The primary outcome was a composite outcome of death and major disability at 3 months after ischemic stroke., Results: After adjustment for age, sex, admission National Institutes of Health Stroke Scale score, and other important covariates, elevated osteoprotegerin levels were associated with increased risks of primary outcome (odds ratio, 1.40 [95% CI, 1.05-1.88]), death (hazard ratio, 2.05 [95% CI, 1.04-4.08]), and composite outcome of death and vascular events (hazard ratio, 2.00 [95% CI, 1.15-3.48]) when 2 extreme quartiles were compared. Each 1-SD higher log-osteoprotegerin was associated with a 18% (95% CI, 6%-32%) increased risk of primary outcome, 69% (95% CI, 31%-118%) increased risk of death, and 53% (95% CI, 24%-89%) increased risk of composite outcome of death and vascular events, respectively. Multiple-adjusted spline regression model showed a linear association of osteoprotegerin with primary outcome ( P for linearity <0.001). Adding osteoprotegerin to conventional risk factors did not significantly improve discriminatory power (C statistics, 0.817 versus 0.818; P =0.232) but did slightly improve the risk reclassification of primary outcome (net reclassification improvement: 13.68%, P <0.001; integrated discrimination improvement: 0.23%, P =0.039). In Mendelian randomization analysis, genetically determined high plasma osteoprotegerin was associated with increased risk of primary outcome (odds ratio, 5.74 [95% CI, 1.12-29.44]; P =0.036)., Conclusions: Elevated plasma osteoprotegerin was associated with poor prognosis of ischemic stroke, and genetically determined high plasma osteoprotegerin was associated with an increased risk of primary outcome in Mendelian randomization analysis., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT01840072.

Aims: Sleep disorders are associated with an increased risk of cardiometabolic diseases in observational studies, but the causality remains unclear. In this study, we leveraged two-sample Mendelian randomization (MR) analyses to assess the causal associations of self-reported daytime napping, daytime sleepiness, and other sleep phenotypes with cardiometabolic diseases including ischaemic stroke (IS), coronary artery disease (CAD), heart failure (HF), and Type 2 diabetes mellitus (T2DM)., Methods and Results: We selected genetic variants as instrumental variables for self-reported daytime napping, daytime sleepiness, morning person, insomnia, short sleep duration, and long sleep duration from European-descent genome-wide association studies (GWASs). Summary statistics for cardiometabolic diseases originated from four different GWASs with a total of 2 500 086 participants. We used the inverse-variance weighted method to explore the role of self-reported sleep phenotypes on the aetiology of cardiometabolic diseases in the main analyses, followed by several sensitivity analyses for robustness validation. Genetically predicted self-reported daytime napping [T2DM: OR, 1.56 (95% confidence interval, 1.21-2.02)], insomnia [IS: OR, 1.07 (1.04-1.11)]; CAD: OR, 1.13 (1.08-1.17); HF: OR, 1.10 (1.07-1.14); T2DM: OR, 1.16 (1.11-1.22); and short sleep duration [CAD: OR, 1.37 (1.21-1.55)] were causally associated with an elevated risk of cardiometabolic diseases. Moreover, genetically determined self-reported daytime sleepiness [CAD: OR, 2.05 (1.18-3.57); HF: OR, 1.82 (1.15-2.87)] and morning person [HF: 1.06 OR, (1.01-1.11)] had potential detrimental effect on cardiometabolic risks., Conclusion: Self-reported daytime napping, insomnia, and short sleep duration had causal roles in the development of cardiometabolic diseases, while self-reported daytime sleepiness and morning person was the potential risk factor for cardiometabolic diseases., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The aim of this study is to investigate the capability using the China-PAR stroke equations for predicting 10-year risk of stroke among the Inner Mongolian population in China., Methods: A prospective cohort study was conducted among 2535 rural Inner Mongolian residents from June 2002 to July 2012. Participants were categorized into four subgroups according to their 10-year predicted stroke risks calculated using the China-PAR stroke equations: <5%, 5-9.9%, 10-19.9%, and ≥20%., Results: The C-statistic of the China-PAR stroke equations for 10-year stroke was 0.58, and the result from Hosmer-Lemeshow 'goodness-of-fit' test showed that the China-PAR stroke equations fitted the Inner Mongolian women well ( χ 2   = 11.18, P = 0.192). The adjusted hazard ratios of stroke were 3.86 (95% CI: 1.12-13.29) for 5-9.9% category, 10.37 (95% CI: 2.70-39.84) for 10-19.9% category, and 17.00 (95% CI: 3.54-81.63) for ≥20% category among Inner Mongolian women using the <5% category as reference ( P for trend <0.001). However, the China-PAR stroke equations underestimated the 10-year stroke risk in Inner Mongolian men, and the calibration was unsatisfactory ( χ 2  = 15.82, P = 0.045)., Conclusion: The China-PAR stroke equations have potential predictive ability for 10-year stroke risk in the rural Inner Mongolian women, while it might not suit the rural Inner Mongolian men well. The performance of China-PAR stroke equations in other ethnic groups in China will need to be further evaluated.

Background To evaluate the prognostic value of plasma YKL-40 (human cartilage glycoprotein-39) for acute ischemic stroke. Methods and Results We measured plasma YKL-40 levels in 3377 participants from CATIS (China Antihypertensive Trial in Acute Ischemic Stroke). Study outcome data on death, major disability (modified Rankin Scale score ≥3), and vascular diseases were collected at 3 months after stroke onset. The primary outcome was defined as a combination of death and major disability. During the 3-month follow-up, 828 participants (24.5%) experienced major disability or died. After multivariate adjustment, the highest YKL-40 quartile was associated with an increased risk of the primary outcome (odds ratio, 1.426 [95% CI, 1.105-1.839]; P trend =0.01) compared with the lowest quartile. Each SD increase in log-transformed YKL-40 level was associated with a 15.5% (95% CI, 5.6-26.3%) increased risk of the primary outcome. The multivariable-adjusted spline regression models showed a linear dose-response relationship between YKL-40 and clinical outcomes. Adding YKL-40 to a model containing conventional risk factors significantly improved the reclassification power for the primary outcome (net reclassification improvement: 15.61%, P <0.001; integrated discrimination index: 0.37%, P =0.099). Conclusions A higher YKL-40 level in the acute phase of ischemic stroke was associated with an increased risk of mortality and major disability at 3 months after stroke, indicating that YKL-40 may play an important role as a prognostic marker of ischemic stroke. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01840072.P =0.099). Conclusions A higher YKL-40 level in the acute phase of ischemic stroke was associated with an increased risk of mortality and major disability at 3 months after stroke, indicating that YKL-40 may play an important role as a prognostic marker of ischemic stroke. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01840072.

Background and Objectives: Thrombomodulin has been suggested to be implicated in ischemic stroke because of its anticoagulant, anti-inflammatory, and cytoprotective properties. We aimed to investigate the associations of plasma thrombomodulin levels with clinical outcomes after ischemic stroke in a multicenter prognostic cohort study., Methods: Our multicenter prognostic cohort study included 3,532 Chinese ischemic stroke patients from the China Antihypertensive Trial in Acute Ischemic Stroke. All patients were followed up at 3 months after ischemic stroke onset. The primary outcome was the composite outcome of death and major disability (modified Rankin Scale [mRS] score ≥3) at 3 months after ischemic stroke. Secondary outcomes included major disability (mRS score 3-5), vascular events, and the ordered 7-level categorical score of the mRS., Results: During 3 months of follow-up, 867 participants experienced the primary outcome. After multivariate adjustment, the adjusted odds ratios or hazard ratios associated with the highest quartile of plasma thrombomodulin were 0.75 (95% CI 0.59-0.97; p trend = 0.029) for the primary outcome, 0.73 (95% CI 0.56-0.94; p trend = 0.028) for major disability, and 0.80 (95% CI 0.42-1.51; p trend = 0.232) for vascular events. In addition, a significantly better shift in the distribution of the mRS score was observed with higher thrombomodulin quartiles ( p trend = 0.005). A multivariable-adjusted spline regression model showed a linear relationship between plasma thrombomodulin and the risk of primary outcome ( p for linearity = 0.027). Subgroup analyses further confirmed these associations., Discussion: Increased plasma thrombomodulin levels at baseline were associated with decreased risks of adverse clinical outcomes at 3 months after ischemic stroke, suggesting a protective role of thrombomodulin in the development of ischemic stroke. Further studies from various populations are needed to replicate our findings., (© 2022 American Academy of Neurology.)

Background: Serum Dickkopf-1 (Dkk-1) levels are associated with poor ischemic stroke prognosis, although their impact on poststroke depression (PSD) remains unclear. This study aimed to examine the association between serum Dkk-1 levels and PSD., Methods: Serum Dkk-1 levels were measured in 564 patients with ischemic stroke who participated in the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). The patients' depression status at 3 months after stroke was assessed using the Hamilton Rating Scale for Depression (HRSD-24). The HRSD score cutoff point for the diagnosis of depression was ≥8., Results: A total of 224 (39.72%) patients were categorized as having PSD 3 months after ischemic stroke. After adjusting for potential confounders, including age, sex, and other important covariates, elevated Dkk-1 levels were associated with an increased risk of PSD (odds ratio [OR], 1.92; 95% confidence interval [CI], 1.14-3.22; P trend  = 0.037). Similarly, each standard deviation (SD) increase in log-transformed Dkk-1 levels was associated with a 24% increased risk of PSD (OR, 1.24; 95% CI, 1.03-1.49; P = 0.025). Subgroup analyses further confirmed the significant associations between Dkk-1 levels and PSD., Conclusion: Higher serum Dkk-1 levels at baseline are independently associated with an increased risk of PSD at 3 months after stroke, suggesting that Dkk-1 levels may be a promising prognostic biomarker for PSD., Limitations: This study measured serum Dkk-1 levels only in the acute phase of stroke not in different phases; therefore, the relationship between dynamic changes in Dkk-1 levels and PSD could not be evaluated., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background The effect of serum growth differentiation factor 15 (GDF-15) on poststroke depression (PSD) remains unknown. This study aimed to investigate the association between serum GDF-15 and PSD among patients with ischemic stroke. Methods and Results This study was based on a random sample from CATIS (China Antihypertensive Trial in Acute Ischemic Stroke). A total of 572 patients from 7 participating hospitals with GDF-15 levels were included in this analysis. The study outcome was depression (Hamilton Depression Rating Scale score ≥8) at 3 months after ischemic stroke. A total of 231 (40.4%) patients with stroke experienced PSD within 3 months. The multivariate-adjusted odds ratio of PSD associated with the highest tertile of serum GDF-15 was 2.92 (95% CI, 1.36-6.27) compared with the lowest tertile. Each SD increase in log-transformed GDF-15 was associated with a 42% (95% CI, 2%-97%) increased risk of PSD, and a linear association between serum GDF-15 and the risk of PSD was observed ( P for linearity=0.006). Conclusions Elevated serum GDF-15 levels in the acute phase of ischemic stroke were independently associated with PSD, suggesting that GDF-15 may be a valuable prognostic biomarker for PSD.

Background and Aims: Osteopontin is implicated in atherosclerosis, and its expression is upregulated in response to brain injury. The aim of this study was to prospectively investigate the associations between plasma osteopontin levels and adverse clinical outcomes in ischemic stroke patients., Methods: We measured baseline plasma osteopontin levels in 3545 ischemic stroke patients from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). The primary outcome was the composite outcome of death and major disability (modified Rankin scale score ≥3) at 1 year after ischemic stroke, and secondary outcomes included major disability, death, and the composite outcome of death and vascular events., Results: During 1 year of follow-up, patients in the fourth quartile of plasma osteopontin had the highest risks of primary outcome, major disability, death, and the composite outcome of death and vascular events. After multivariate adjustment, the odds ratios or hazard ratios (95 % confidence intervals) associated with each standard deviation increase in log-transformed osteopontin were 1.20 (1.09-1.33) for primary outcome, 1.11 (1.00-1.23) for major disability, 1.29 (1.10-1.52) for death, and 1.15 (1.01-1.30) for the composite outcome of death and vascular events. The addition of plasma osteopontin to conventional risk factors significantly improved the risk reclassification for the primary outcome (net reclassification improvement: 16.91%, p < 0.001; integrated discrimination improvement: 0.43%, p = 0.002)., Conclusions: Elevated plasma osteopontin levels at baseline were associated with increased risks of adverse clinical outcomes at 1 year after ischemic stroke, suggesting that osteopontin is a promising prognostic biomarker for ischemic stroke., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Purpose: Elevated serum matrix metalloproteinase-8 (MMP-8) concentrations are associated with high risk of vascular disease, but the causality remains unclear. A two-sample Mendelian randomization (MR) study was performed to examine the causal effect of serum MMP-8 concentrations on the risk of ischaemic stroke, ischaemic stroke subtypes and coronary artery disease., Methods: Ten independent single-nucleotide polymorphisms related to serum MMP-8 concentrations were identified as instrumental variables from a genome-wide association study of 6049 European subjects. Genetic association estimates for ischaemic stroke were obtained from the Multiancestry Genome-wide Association Study of Stroke consortium with 446,696 European individuals. The inverse-variance weighted method was applied to assess the causal associations of serum MMP-8 with ischaemic stroke and its subtypes in the main analysis., Results: No significant causal association was observed for MMP-8 levels with total ischaemic stroke, large artery stroke or cardioembolic stroke. Genetically determined 1 - unit higher log-transformed serum MMP-8 concentration was associated with an increased risk of small vessel stroke (odds ratio 1.25; 95% confidence interval 1.12-1.39; p < 0.001). In secondary analysis, a similar adverse impact was reported for MMP-8 on coronary artery disease (odds ratio 1.05; 95% confidence interval 1.01-1.10; p = 0.017). Sensitivity analyses further confirmed the relationship between serum MMP-8 level and small vessel stroke and coronary artery disease. Mendelian randomization Egger regression showed no evidence of pleiotropic bias., Conclusions: High serum MMP-8 concentrations were causally associated with increased risks of small vessel stroke and coronary artery disease. The mechanism underlying the effect of serum MMP-8 on the vascular system requires further investigation., (© 2021 European Academy of Neurology.)

: Various tools are currently available to quantify the risks of adverse clinical outcomes after an ischemic stroke. This study aimed to validate and compare prognostic scales among Chinese patients with ischemic stroke. : We compared three stroke prognostic scales (Stroke Prognostication using Age and the National Institutes of Health Stroke Scale-100 [SPAN-100], Totaled Health Risks in Vascular Events [THRIVE], and Acute Stroke Registry and Analysis of Lausanne [ASTRAL]) in 3870 Chinese patients with ischemic stroke from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). The 2-year primary outcome was a combination of death and major disability (modified Rankin Scale score ≥3). : Among all the scales, the ASTRAL score had the best accuracy for predicting 2-year prognosis in Chinese patients with ischemic stroke. The C-statistic of the ASTRAL score for the 2-year primary outcome was 0.79 (95% confidence interval [CI]: 0.78–0.80), and the Hosmer–Lemeshow goodness-of-fit test showed that the ASTRAL score fitted Chinese patients with ischemic stroke well (χ2 = 9.83, P = 0.277). The incidences of the primary outcome in the <5%, 5%–9.9%, 10%–19.9%, and ≥20% risk groups based on the ASTRAL scores were 3.93%, 7.55%, 14.29%, and 41.81%, respectively (odds ratio: 1.23; 95% CI: 1.21–1.26; P < 0.001). : The ASTRAL score had higher efficacy than the SPAN-100 and THRIVE scores in predicting 2-year adverse outcomes among Chinese patients with ischemic stroke, suggesting that it could be a valuable risk assessment tool for the 2-year prognosis of such patients. [ABSTRACT FROM AUTHOR]