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Background: Impaired cardiac function was suggested to be implicated in the functional recovery after ischemic stroke, but the prognostic value of cardiac biomarkers among ischemic stroke patients remains unclear. We aimed to prospectively explore the associations of serum lactate dehydrogenase (LDH), plasma N-terminal pro-brain natriuretic peptide (NT-proBNP), and plasma high-sensitivity cardiac troponin T (hs-cTnT) with adverse clinical outcomes after ischemic stroke in a large-scale cohort study., Methods: We measured serum LDH, plasma NT-proBNP, and plasma hs-cTnT levels at baseline among 5056 ischemic stroke patients from the Minhang Stroke Cohort study. All patients were followed up at 3 months after ischemic stroke onset. The primary outcome was composite outcome of death and major disability (modified Rankin Scale [mRS] score ≥ 3) at 3 months after stroke onset, and secondary outcomes included death and ordered 7-level categorical score of the mRS., Results: During 3 months of follow-up, 1584 patients developed the primary outcome. Baseline serum LDH, plasma NT-proBNP, and plasma hs-cTnT were positively associated with the risk of adverse outcomes after ischemic stroke. The multivariable-adjusted odds ratios of primary outcome for the highest versus lowest quartile of LDH, NT-proBNP, and hs-cTnT were 1.37 (95% CI 1.13-1.66; P trend  = 0.001), 2.51 (95% CI, 2.00-3.16; P trend  < 0.001), and 2.24 (95% CI 1.77-2.83; P trend  < 0.001), respectively. Each SD increase of log-transformed cardiac biomarker score was associated with a 49% (95% CI 37-62%; P < 0.001) increased risk of primary outcome. Multivariable-adjusted spline regression analyses showed linear relationships between cardiac biomarkers and the risk of primary outcome (all P for linearity < 0.001). Moreover, adding LDH, NT-proBNP, hs-cTnT, or cardiac biomarker score to conventional risk factors significantly improved the risk reclassification of primary outcome after ischemic stroke (all P < 0.05)., Conclusion: High LDH, NT-proBNP, hs-cTnT, and cardiac biomarker score were independently associated with increased risks of adverse clinical outcomes among ischemic stroke patients, suggesting that cardiac biomarkers might be potential prognostic biomarkers for ischemic stroke., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Polyamines have been reported to be associated with neurological function, but the associations between polyamines and the prognosis of ischemic stroke remain unclear. We aimed to prospectively investigate whether elevated plasma polyamine levels are associated with adverse outcomes in patients with ischemic stroke., Methods and Results: Plasma polyamine levels were measured at admission in 3570 patients with acute ischemic stroke, and clinical outcomes were assessed at 3 months after stroke onset. The primary outcome was a composite outcome of death and major disability (modified Rankin Scale score≥3), and secondary outcomes included the individual outcomes of death and major disability. During a 3-month follow-up period, 877 participants (25.1%) experienced the primary outcome. Increased putrescines were associated with a decreased risk of the primary outcome (the highest versus the lowest tertile: odds ratio, 0.72 [95% CI, 0.58-0.91]; P =0.005) and major disability (odds ratio, 0.59 [95% CI, 0.47-0.74]; P <0.001). Conversely, increased spermidines were associated with an increased risk of death (hazard ratio, 1.86 [95% CI, 1.10-3.14]; P =0.020), and increased spermines were associated with an increased risk of the primary outcome (odds ratio, 1.36 [95% CI, 1.08-1.71]; P =0.009) and major disability (odds ratio, 1.27 [95% CI, 1.01-1.59]; P =0.041)., Conclusions: Among patients with ischemic stroke, high plasma putrescine levels were associated with a decreased risk of adverse outcomes, whereas high plasma spermidine and spermine levels were associated with an increased risk of adverse outcomes. Further studies are needed to investigate whether targeting these polyamines can improve the prognosis of patients with ischemic stroke., Registration: https://clinicaltrials.gov. Identifier: NCT01840072.

Background: Conventional prognostic risk factors can only partly explain the adverse clinical outcomes after ischemic stroke. We aimed to establish a set of prognostic metrics and evaluate its public health significance on the burden of adverse clinical outcomes of ischemic stroke., Methods: All patients were from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). We established prognostic metrics of ischemic stroke from 20 potential biomarkers in a propensity-score-matched extreme case sample (n = 146). Pathway analysis was conducted using Ingenuity Pathway Analysis. In the whole CATIS population (n = 3575), we evaluated effectiveness of these prognostic metrics and estimated their population-attributable fractions (PAFs) related to the risk of clinical outcomes. The primary outcome was a composite outcome of death or major disability (modified Rankin Scale score ≥3) at 3 months after stroke., Results: Matrix metalloproteinase-9 (MMP-9), S100A8/A9, high-sensitivity C-reactive protein (hsCRP), and growth differentiation factor-15 (GDF-15) were selected as prognostic metrics for ischemic stroke. Pathway analysis showed significant enrichment in inflammation and atherosclerosis signaling. All 4 prognostic metrics were independently associated with poor prognosis of ischemic stroke. Compared with patients having 1 or 0 high-level prognostic metrics, those with 4 had higher risk of primary outcome (OR: 3.84, 95%CI: 2.67-5.51; PAF: 37.4%, 95%CI: 19.5%-52.9%)., Conclusion: The set of prognostic metrics, enriching in inflammation and atherosclerosis signaling, could effectively predict the prognosis at 3 months after ischemic stroke and would provide additional information for the burden of adverse clinical outcomes among patients with ischemic stroke., (© American Association for Clinical Chemistry 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Dickkopf-3 (Dkk-3) is implicated in the progression of atherosclerosis. This study aimed to investigate the association between serum Dkk-3 and the prognosis of ischemic stroke., Methods: We measured serum Dkk-3 levels in 3344 ischemic stroke patients from CATIS (China Antihypertensive Trial in Acute Ischemic Stroke). The primary outcome was a combination of death and vascular events within 3 months after ischemic stroke., Results: During 3 months of follow-up, the cumulative incidence rates of primary outcome among ischemic stroke patients in five quintiles of serum Dkk-3 (from low to high) were 4.49%, 3.74%, 2.54%, 5.23%, and 6.73%, respectively (log-rank p = 0.004). Multivariable Cox proportional hazards regression analyses showed that compared with the third quintile of serum Dkk-3, the adjusted hazard ratios (95% confidence intervals) associated with the first and fifth quintile were 3.49 (1.46-8.34) and 4.23 (1.86-9.64) for primary outcome, 3.47 (1.06-11.36) and 5.30 (1.81-15.51) for death, and 2.66 (1.01-7.01) and 3.35 (1.33-8.40) for vascular events, respectively. Multivariable-adjusted Cox proportional hazards regression model with restricted cubic splines showed a U-shaped association between serum Dkk-3 and the risk of primary outcome (p for nonlinearity = 0.030). Moreover, adding serum Dkk-3 to conventional risk factors could improve the predictive power for primary outcome (net reclassification improvement 28.44%, p < 0.001; integrated discrimination improvement 0.48%, p = 0.001)., Conclusions: Both low and high serum Dkk-3 levels are associated with increased risks of death and vascular events within 3 months after ischemic stroke, indicating that serum Dkk-3 may have a special effect on the prognosis of ischemic stroke. We also found that serum Dkk-3 might be a prognostic biomarker for ischemic stroke. Further studies are needed to replicate our findings and to determine the optimal levels of serum Dkk-3.

Background and Hypothesis To identify promising drug targets for psychiatric disorders, we applied Mendelian randomization (MR) design to systematically screen blood metabolome for potential mediators of psychiatric disorders and further predict target-mediated side effects. Study Design We selected 92 unique blood metabolites from 3 metabolome genome-wide association studies (GWASs) with totally 147 827 participants. Summary statistics for bipolar disorder (BIP), attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), major depressive disorder (MDD), schizophrenia (SCZ), panic disorder (PD), autistic spectrum disorder (ASD), and anorexia nervosa (AN) originated from the Psychiatric Genomics Consortium, involving 1 143 340 participants. Mendelian randomization (MR) analyses were conducted to estimate associations of blood metabolites with psychiatric disorders. Phenome-wide MR analysis was further performed to predict side effects mediated by metabolite-targeted interventions. Results Eight metabolites were identified associated with psychiatric disorders, including five established mediators: N -acetylornithine (BIP: OR, 0.72 [95% CI, 0.66–0.79]; SCZ: OR, 0.74 [0.64–0.84]), glycine (BIP: OR, 0.62 [0.50–0.77]), docosahexaenoic acid (MDD: OR, 0.96 [0.94–0.97]), 3-Hydroxybutyrate (MDD: OR, 1.14 [1.08–1.21]), butyrylcarnitine (SCZ: OR, 1.22 [1.12–1.32]); and three novel mediators: 1-arachidonoylglycerophosphocholine (1-arachidonoyl-GPC)(BIP: OR, 0.31 [0.23–0.41]), glycoproteins (BIP: OR, 0.94 [0.92–0.97]), sphingomyelins (AN: OR, 1.12 [1.06–1.19]). Phenome-wide MR analysis showed that all identified metabolites except for N -acetylornithine and 3-Hydroxybutyrate had additional effects on nonpsychiatric diseases, while glycine, 3-Hydroxybutyrate, N -acetylornithine, and butyrylcarnitine had no adverse side effects. Conclusions This MR study identified five established and three novel mediators for psychiatric disorders. N -acetylornithine, glycine, 3-Hydroxybutyrate, and butyrylcarnitine might be promising targets against psychiatric disorders with no predicted adverse side effects. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

• First study of the combined effect of NT-proBNP and galectin-3 on the stroke prognosis. • Simultaneously increased NT-proBNP and galectin-3 increased the risk of prognosis. • Using NT-proBNP and galectin-3 together can accurately predict stroke prognosis. N-terminal pro-brain natriuretic peptide (NT-proBNP) and galectin-3 are important biomarkers related to ischemic stroke. However, the predictive value of the combination of them has not been examined in previous studies. The aim of this study was to investigate the combined effect of NT-proBNP and galectin-3 on clinical outcomes in ischemic stroke patients. A total of 2694 patients (63.62% males; mean age = 62.4 in admission) with serum NT-proBNP and galectin-3 measured simultaneously were included in this study. The primary outcome was composite outcome of death or major disability 1 year after stroke onset. Secondary outcomes were separately death, major disability, vascular events and the composite outcome of vascular events or death. The participants were divided into 4 groups according to NT-proBNP and galectin-3. Odd ratios (ORs; for nonevent outcome without time variables: primary outcome, major disability) or hazard ratios (HRs; for event outcome with time variables: death, vascular events, and the composite outcome of vascular events or death) were calculated to assess the association of NT-proBNP and galectin-3 status with adverse outcomes. At the 1-year follow-up, 589 patients experienced a primary outcome after stroke onset. After adjustment for potential confounders, high NT-proBNP/high galectin-3 group were associated with increased risks of primary outcome (OR: 1.43; 95% confidence interval [CI], 1.02–2.00; P value = 0.039), death (HR: 2.74; 95% CI, 1.42–5.29; P value = 0.003), and the composite outcome of vascular events or death (HR: 1.66; 95% CI, 1.06–2.58; P value = 0.026). Statistical tests for interactions between the 4 groups and primary outcome or death were not significant (all P interaction > 0.05). Simultaneously increased NT-proBNP and galectin-3 significantly increased the risk of poor clinical outcomes 1 year after ischemic stroke. Using NT-proBNP and galectin-3 together can result in an accurate prediction of ischemic stroke prognosis. [ABSTRACT FROM AUTHOR]

Background and Aims: Netrin-1 was a laminin-related protein involved in neurovascular protection, and we previously discovered that decreased serum netrin-1 was associated with poor prognosis of ischemic stroke. However, the relationship between serum netrin-1 level and the risk of ischemic stroke remains unclear. The aim of this study was to investigate the association between netrin-1 level and risk of ischemic stroke.Methods and Results: A case-control study including 591 ischemic stroke patients and 591 age- and sex-matched healthy individuals was conducted, and serum netrin-1 concentrations were quantitatively determined via enzyme-linked immunosorbent assay for all participants. The serum netrin-1 levels were significantly lower in the ischemic stroke patients than those in matched controls (median, 496.4 vs 652.1 pg/mL; P < 0.001). After adjustment for potential confounders, the odds ratio of ischemic stroke associated with the highest quartile of netrin-1 was 0.07 (95% CI: 0.01-0.65; Ptrend = 0.018) compared with the lowest quartile of netrin-1. Each 1-standard deviation increase of log-transformed netrin-1 was associated with a lower odds of ischemic stroke (odds ratio: 0.45, 95% CI: 0.22-0.94; P = 0.032), and a dose-response relationship between serum netrin-1 and ischemic stroke was observed (Plinearity = 0.003). Incorporating netrin-1 to conventional risk factors improved the discriminatory power for ischemic stroke (net reclassification index = 98.0%, P < 0.001; integrated discrimination improvement = 0.28%, P = 0.027).Conclusions: Serum netrin-1 was decreased in patients with ischemic stroke compared with healthy controls, suggesting that there was a potential role of netrin-1 in the pathogenesis of ischemic stroke. [ABSTRACT FROM AUTHOR]

We aimed to evaluate the ability of multiple novel biomarkers representing several pathophysiological pathways to improve risk prediction of post-stroke cognitive impairment. We conducted a prospective multicenter study in 638 ischemic stroke patients with elevated blood pressure based on a random subsample from China Antihypertensive Trial in Acute Ischemic Stroke and measured 12 circulating biomarkers in these participants. Cognitive impairment was assessed at 3 months after stroke with definitions of Mini-Mental State Examination (MMSE) score <27 or Montreal Cognitive Assessment (MoCA) score <25. According to MMSE score, 1 SD increase of rheumatoid factor (odds ratio [OR] 1.22, 95% confidence interval [CI] 1.02–1.46), matrix metalloproteinase-9 (OR 1.47, 95% CI 1.22–1.77) and total homocysteine (OR 1.22, 95% CI 1.01–1.49) after log transformation was significantly associated with the risk of post-stroke cognitive impairment. The ORs associated with their simultaneously high levels were 4.89 (95% CI, 2.31–10.35; p trend <0.001) and 3.09 (95% CI, 1.60–5.98; p trend <0.001) for cognitive impairment and the severity of cognitive impairment, respectively. Adding these 3 biomarkers to conventional model significantly improved the risk prediction of cognitive impairment (C statistic 0.729 vs. 0.688, p = 0.004; net reclassification improvement = 33.67%, p < 0.001; integrated discrimination index = 4.61%; p < 0.001). Similar significant findings were observed when cognitive impairment was defined by MoCA score. Combination of rheumatoid factor, matrix metalloproteinase-9 and total homocysteine can improve the risk prediction of cognitive impairment among ischemic stroke patients with elevated blood pressure. Further studies are warranted to validate our findings and explore their roles as potential therapeutic targets. Image 1 • The first study using multiple biomarkers to examine improvement in risk prediction for post-stroke cognitive impairment. • This prospective study is by far the largest biomarker study of post-stroke cognitive impairment. • Combination of RF, MMP-9 and tHcy might improve the risk prediction of post-stroke cognitive impairment. • RF, MMP-9 and tHcy should be measured simultaneously among ischemic stroke patients in future clinical practice. • Further studies are warranted to explore their roles as potential therapeutic targets. [ABSTRACT FROM AUTHOR]