Background and Purpose: Complement C3 has been implicated in inflammation and ischemia/reperfusion injury, but its impact on the prognosis of ischemic stroke remains unclear. Aim of this study was to prospectively investigate the association between serum complement C3 and adverse clinical outcomes after ischemic stroke. Methods: We measured serum complement C3 levels for 3474 patients with ischemic stroke in 26 participating hospitals and collected data of clinical outcomes at 3 months after ischemic stroke. The primary outcome was composite outcome of death and major disability (modified Rankin Scale score ≥3) at 3 months after stroke onset and secondary outcomes included major disability, death, and vascular events. Results: During 3 months of follow-up, 866 participants (25.4%) developed primary outcome. After multivariate adjustment, elevated serum complement C3 levels were associated with increased risk of primary outcome (odds ratio, 1.30 [95% CI, 1.02–1.65]; P trend =0.038) when 2 extreme tertiles were compared. Each SD increase of log-transformed complement C3 was associated with 13% (95% CI, 2%–25%) increased risk of primary outcome. Multivariable-adjusted spline regression model showed a linear relationship between serum complement C3 and the risk of primary outcome ( P linearity =0.022). Addition of serum complement C3 to conventional risk factors significantly improved the risk prediction of primary outcome (net reclassification index: 8.87%, P =0.028; integrated discrimination index: 0.19%, P =0.029). Conclusions: High serum complement C3 levels at baseline were associated with increased risks of adverse clinical outcomes at 3 months after ischemic stroke, suggesting that serum complement C3 may be a valuable prognostic biomarker for ischemic stroke.

Aims Sleep disorders are associated with 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 ischemic stroke (IS), coronary artery disease (CAD), heart failure (HF), and type 2 diabetes mellitus (T2DM). Methods 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 etiology of cardiometabolic diseases in the main analyses, followed by several sensitivity analyses for robustness validation. Results Genetically predicted self-reported daytime napping (T2DM: OR, 1.56 [95% CI, 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 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. Conclusions 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.

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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 1unit 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.

Background and purposeThe association between annual household income and prognosis of ischaemic stroke remains debatable. We aimed to prospectively investigate the relationship between annual household income and prognosis at 3 months after ischaemic stroke.MethodsWe included 3975 participants from the China Antihypertensive Trial in Acute Ischemic Stroke. All participants were categorised into three groups according to annual household income per capita: <¥10 000 (Chinese Yuan Renminbi (RMB)), ¥10 000–19 999 and ≥¥20 000. The primary outcome was a composite outcome of death and major disability (modified Rankin Scale score ≥3) at 3 months after stroke onset, and secondary outcomes included major disability, death, and vascular events. A meta-analysis was conducted to incorporate the results of the current study and previous studies on the association of income level with outcomes after stroke.ResultsWithin 3 months after ischaemic stroke, 1002 participants (25.20%) experienced primary outcome (880 major disabilities and 122 deaths). After multivariate adjustment, low annual household income level was associated with increased risk of the primary outcome (OR 1.60; 95% CI: 1.12 to 2.31; Ptrend=0.034) when two extreme groups were compared. The meta-analysis confirmed the significant association between income level and death or major disability after stroke (pooled relative risk for lowest vs highest income level, 1.31 (95% CI: 1.18 to 1.45)).ConclusionsLow annual household income per capita was significantly associated with increased risks of adverse clinical outcomes at 3 months after ischaemic stroke, independently of established risk factors. Further studies from other samples are needed to replicate our findings due to a reason for excluding some patients who had a severe stroke in this study.Trial registration numberClinicalTrials.gov (http://wwwclinicaltrialsgov) Registry (NCT01840072).