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Background and Aim: Observational studies have suggested a relationship between frailty and cardiovascular disease (CVD), but the causality is still uncertain. We used bidirectional Mendelian randomization (MR) design to investigate the potential causal associations between frailty and four main CVDs, including hypertension, myocardial infarction (MI), heart failure (HF), and atrial fibrillation (AF)., Methods and Results: Independent single-nucleotide polymorphisms for frailty index (FI) and CVDs (hypertension, MI, HF, and AF) were selected as genetic instruments based on European-descent genome-wide association studies (GWASs). Summary-level data for outcomes on FI (n = 175,226), hypertension (n = 463,010), MI (n = 171,875), HF (n = 977323), and AF (n = 1,030,836) was derived from five large-scale GWASs of European ancestry. We used the inverse-variance weighted (IVW) method to examine the bidirectional associations between FI and CVDs in the main analyses. In the IVW MR analyses, genetically determined high FI was significantly associated with increased risks of hypertension (odds ratio [OR] per 1-SD increase: 1.07 [95 % confidence interval, 1.05-1.08]), MI (OR per 1-SD increase: 1.74 [1.21-2.51]), HF (OR per 1-SD increase: 1.28 [1.10-1.48]), and AF (OR per 1-SD increase: 1.20 [1.08-1.33]). In addition, genetically determined hypertension (beta: 1.406 [1.225-1.587]), MI (beta: 0.045 [0.023-0.067]), HF (beta: 0.105 [0.066-0.143]) and AF (beta: 0.021 [0.012-0.031]) were significantly associated with high FI. These findings were robustly supported by a series of sensitivity analyses with different MR models., Conclusions: We found potential bidirectional causal associations between elevated FI and increased risks of CVD, suggesting mutual risk factors between frailty and CVD., (Copyright © 2023 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Plasma amino acid neurotransmitter dysregulation is suggested to be implicated in the development of ischemic stroke, but its prognostic value for ischemic stroke remains controversial., Objective: We aimed to prospectively investigate the associations between plasma amino acid neurotransmitters levels and adverse outcomes after ischemic stroke in a large-scale multicenter cohort study., Methods: We measured 4 plasma amino acid neurotransmitters (glutamic acid, aspartic acid, gamma-aminobutyric acid, and glycine) among 3486 patients with ischemic stroke from 26 hospitals across China. The primary outcome is the composite outcome of death or major disability (modified Rankin Scale score ≥3) at 3 mo after ischemic stroke., Results: After multivariate adjustment, the odds ratios of death or major disability for the highest versus the lowest quartile were 2.04 (95% confidence interval [CI]: 1.60,2.59; P-trend < 0.001) for glutamic acid, 2.03 (95% CI: 1.59, 2.59; P-trend < 0.001) for aspartic acid, 1.35 (95% CI: 1.06, 1.71; P-trend = 0.016) for gamma-aminobutyric acid, and 0.54 (95% CI: 0.42, 0.69; P-trend < 0.001) for glycine. Each standard deviation increment of log-transformed glutamic acid, aspartic acid, gamma-aminobutyric acid, and glycine was associated with a 34%, 34%, and 9% increased risk, and a 23% decreased risk of death or major disability, respectively (all P < 0.05), in a linear fashion as indicated by spline regression analyses (all P for linearity < 0.05). Addition of the 4 plasma amino acid neurotransmitters to conventional risk factors significantly improved the risk reclassification, as evidenced by integrated discrimination improvement and net reclassification improvement (all P < 0.05)., Conclusions: Increased glutamic acid, aspartic acid, and gamma-aminobutyric acid and decreased glycine in plasma are associated with adverse outcomes after ischemic stroke, suggesting that plasma amino acid neurotransmitters may be potential intervention targets for improving prognosis of ischemic stroke. The CATIS trial was registered at clinicaltrials.gov (registration number: NCT01840072; URL: ===https://clinicaltrials.gov/ct2/show/NCT01840072?cond=NCT01840072&draw=2&rank=1)., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Background and Aims: The causality between myeloperoxidase (MPO) and cardiovascular disease still remains unclear. We performed a two-sample Mendelian randomization (MR) study to estimate the potential causal effect of MPO on the risks of ischemic stroke, ischemic stroke subtypes, heart failure (HF), and atrial fibrillation (AF)., Methods and Results: Seventeen independent single-nucleotide polymorphisms associated with MPO levels were identified as instrumental variables from a European-descent genome-wide association study. Summary-level data on ischemic stroke originated from the Multiancestry Genome-wide Association Study of Stroke Consortium with 440 328 European individuals. We used the inverse-variance weighted method to assess the potential causality of plasma MPO with ischemic stroke and its subtypes in the main analysis. Genetically determined higher plasma MPO concentration was significantly associated with increased risks of ischemic stroke (odds ratio [OR] per standard deviation [SD] increase, 1.05; 95% confidence interval [CI], 1.02-1.09; P = 0.002) and cardioembolic stroke (CES) (OR per SD increase, 1.10; 95% CI, 1.03-1.18; P = 0.005), but was not associated with risks of large artery stroke or small vessel stroke. In the secondary analysis, MPO was associated with a high risk of HF (OR per SD increase, 1.05; 95% CI, 1.02-1.07; P = 0.001) and AF (OR per SD increase, 1.04; 95% CI, 1.01-1.07; P = 0.004). MR-Egger regression showed no directional pleiotropy for all associations, and the sensitivity analyses further confirmed these findings., Conclusion: High plasma MPO levels were potentially associated with increased risks of ischemic stroke, CES, HF, and AF, suggesting that MPO plays an important role in the development of cardiovascular disease., Competing Interests: Declaration of competing interest Nothing to report., (Copyright © 2022 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Etiologic associations between some modifiable factors (metabolic risk factors and lifestyle behaviors) and cardiovascular disease (CVD) remain unclear. To identify targets for CVD prevention, we evaluated the causal associations of these factors with coronary artery disease (CAD) and ischemic stroke using a two-sample Mendelian randomization (MR) method., Methods and Results: Previously published genome-wide association studies (GWASs) for blood pressure (BP), glucose, lipids, overweight, smoking, alcohol intake, sedentariness, and education were used to identify instruments for 15 modifiable factors. We extracted effects of the genetic variants used as instruments for the exposures on coronary artery disease (CAD) and ischemic stroke from large GWASs (N = 60 801 cases/123 504 controls for CAD and N = 40 585 cases/406 111 controls for ischemic stroke). Genetically predicted hypertension (CAD: OR, 5.19 [95% CI, 4.21-6.41]; ischemic stroke: OR, 4.92 [4.12-5.86]), systolic BP (CAD: OR, 1.03 [1.03-1.04]; ischemic stroke: OR, 1.03 [1.03-1.03]), diastolic BP (CAD: OR, 1.05 [1.05-1.06]; ischemic stroke: OR, 1.05 [1.04-1.05]), type 2 diabetes (CAD: OR, 1.11 [1.08-1.15]; ischemic stroke: OR, 1.07 [1.04-1.10]), smoking initiation (CAD: OR, 1.26 [1.18-1.35]; ischemic stroke: OR, 1.24 [1.16-1.33]), educational attainment (CAD: OR, 0.62 [0.58-0.66]; ischemic stroke: OR, 0.68 [0.63-0.72]), low-density lipoprotein cholesterol (CAD: OR, 1.55 [1.41-1.71]), high-density lipoprotein cholesterol (CAD: OR, 0.82 [0.74-0.91]), triglycerides (CAD: OR, 1.29 [1.14-1.45]), body mass index (CAD: OR, 1.25 [1.19-1.32]), and alcohol dependence (OR, 1.04 [1.03-1.06]) were causally related to CVD., Conclusion: This systematic MR study identified 11 modifiable factors as causal risk factors for CVD, indicating that these factors are important targets for preventing CVD., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2022 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Ischemic stroke is a major contributor to global mortality and disability. Metabolomics represents a powerful tool for discovering biomarkers of ischemic stroke due to its ability to detect metabolites small enough to cross the blood-brain barrier. The aim of this study is to identify potential metabolic biomarkers for predicting 1-year vascular events and death after acute ischemic stroke (AIS)., Methods: We adopted a nested case-control design from a multicenter prospective cohort study. A total of 143 AIS patients with 1-year vascular events/death and 143 sex-, age- and center-matched patients without 1-year vascular events/death were selected, and further divided into the discovery set (n = 140) and validation set (n = 146). We then performed untargeted metabolomics analysis by liquid chromatography coupled to mass spectrometry., Results: Metabolomics analyses could predict 1-year vascular events and death after AIS using pattern recognition methods. Eight metabolites (e.g., LysoPC(18:1)) were identified as potential biomarkers of AIS prognosis. Four of them (e.g., PS(O-18:0/0:0)) were found to be significantly decreased in patients with early vascular events/death. Adding these metabolic biomarkers to traditional factors resulted in a great improvement of the predictive utility for 1-year vascular events/death, with net reclassification index and integrated discrimination improvement being 0.9143 (p < 0.0001) and 0.1906 (p < 0.0001) in the discovery cohort, and 0.9041 (p < 0.0001) and 0.1896 (p < 0.0001) in the validation cohort., Conclusions: This study found several metabolic biomarkers for 1-year vascular events and death after AIS, providing opportunities for the construction of prognostic models and the discovery of novel therapeutic targets., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background and Aims: Researchers have not determined whether the association between growth differentiation factor-15 (GDF-15) levels and stroke outcomes is modified by the diabetes status. We aimed to evaluate the prognostic value of GDF-15 among patients with ischemic stroke stratified by diabetes., Methods and Results: A total of 3001 patients with ischemic stroke were selected from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) and included in this study. The primary outcome was a composite outcome of death and vascular events at 3 months after acute ischemic stroke. An elevated GDF-15 level was significantly associated with the primary outcome in patients with diabetes but not in those without diabetes (p interaction  = 0.038). The multivariate-adjusted hazard ratio (95% confidence intervals) for the primary outcome was 3.33 (1.07-10.35) when 2 extreme tertiles were compared, and a linear association between GDF-15 levels and the primary outcome was observed in patients with diabetes (p for linearity = 0.046). The addition of serum GDF-15 to conventional risk factors improved the risk prediction for the primary outcome in patients with diabetes (net reclassification improvement: 31.98%, p = 0.043; integrated discrimination index: 0.85%, p = 0.034) but not in those without diabetes., Conclusions: A modifying effect of the diabetes status on the association between serum GDF-15 levels and ischemic stroke prognosis was observed. Elevated serum GDF-15 levels were associated with the primary outcome within 3 months after ischemic stroke in patients with diabetes, suggesting that GDF-15 may be an important prognostic factor for ischemic stroke in patients with diabetes., Competing Interests: Declaration of competing interest The authors report no disclosures., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

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 Aims: High serum netrin-1 levels decrease the risk of ischemic stroke and are negatively associated with outcomes after ischemic stroke. However, it remains unclear whether the association between netrin-1 and ischemic stroke prognosis is modified by lipid component levels., Methods and Results: We measured baseline serum netrin-1 levels in 3065 ischemic stroke patients from China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). The primary outcome was a combination of death and major disability (modified Rankin Scale score≥3) at 3 months after ischemic stroke. Total cholesterol (TC) levels could modify the association between netrin-1 and prognosis of ischemic stroke (P interaction  = 0.040). After multivariate adjustment, the odds ratios of the primary outcome associated with the highest quartile of netrin-1 were 0.39 (95%CI, 0.17-0.90; P trend  = 0.004) for the patients with high TC levels and 0.82 (95%CI, 0.61-1.11; P trend  = 0.149) for those with normal TC levels. Adding netrin-1 to conventional risk factors improved risk prediction for the primary outcome in the patients with high TC levels (net reclassification improvement: 26.8%, P = 0.015; integrated discrimination index: 1.6%, P = 0.028) but not in those with normal TC levels., Conclusions: Elevated netrin-1 is associated with improved prognosis at 3 months after ischemic stroke in the patients with high TC levels but not in those with normal TC levels. Further prospective studies from other populations and randomized clinical trials are needed to verify our findings and clarify the potential mechanisms., Competing Interests: Declaration of competing interest All authors report no disclosures relevant to the manuscript., (Copyright © 2020. Published by Elsevier B.V.)

Rationale: 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., Objective: The aim of this study was to investigate the combined effect of NT-proBNP and galectin-3 on clinical outcomes in ischemic stroke patients., Methods: 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., Results: 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)., Conclusion: 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., (Copyright © 2020. Published by Elsevier B.V.)

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; P trend  = 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 (P linearity  = 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., Competing Interests: Declaration of Competing Interest All authors report no disclosures relevant to the manuscript., (Copyright © 2020. Published by Elsevier B.V.)

Background and Aims: We aimed to examine the association between baseline platelet count (PLT) and prognosis of acute ischemic stroke according to lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) mass., Methods: A total of 3254 patients with acute ischemic stroke were included in this analysis. The primary outcome was a combination of major disability and all-cause mortality (modified Rankin Scale score ≥3) at 3 months after stroke. Secondary outcome was major disability and all-cause mortality, respectively., Results: The prognosis value of PLT for primary outcome was significantly modified by Lp-PLA 2 mass (p interaction  = 0.002). After multivariate adjustment, elevated PLT was associated with the increased risk of primary outcome in patients with high Lp-PLA 2 mass (odds ratio [OR], 1.64; 95% confidence interval [CI], 1.09-2.48; p trend  = 0.002), but not in those with low Lp-PLA 2 mass (OR, 0.94; 95%CI, 0.62-1.42; p trend  = 0.181), when comparing two extreme PLT quartiles. A similar association was found between elevated PLT and major disability (p interaction  = 0.001). Elevated PLT was associated with increased risk of major disability only in patients with high Lp-PLA 2 mass (OR, 1.54; 95%CI, 1.03-2.31; p trend  = 0.007), for the highest quartile vs the lowest quartile. Each 100 × 10 9 /L increment in PLT was associated with 42% (95%CI, 12%-79%) increased risk of primary outcome and 33% (95%CI, 6%-68%) increased risk of major disability in those with high Lp-PLA 2 mass., Conclusions: The elevated PLT was associated with poor prognosis of acute ischemic stroke only in patients with high Lp-PLA 2 mass. Lp-PLA 2 might be an important factor influencing the prognosis value of PLT for clinical outcomes in acute ischemic stroke patients., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Aims: High serum hepatocyte growth factor (HGF) levels increase the risk of ischemic stroke and are probably associated with outcomes after ischemic stroke. However, it remains unclear whether the association between HGF and ischemic stroke prognosis is modified by blood lipid status., Methods and Results: Data were derived from the CATIS (China Antihypertensive Trial in Acute Ischemic Stroke), and we measured baseline serum HGF levels in 3027 ischemic stroke patients. The primary outcome was a combination of death and major disability (modified Rankin Scale score≥3) at 2 years after ischemic stroke. Blood lipid status could modify association between HGF and ischemic stroke prognosis (P interaction  = 0.002). After multivariate adjustment, the odds ratios of primary outcome associated with the highest tertile of HGF were 2.13 (95% CI, 1.45-3.14; P trend <0.001) for patients with dyslipidemia and 0.81 (95% CI, 0.54-1.22; P trend  = 0.310) for those with normal lipids. Adding HGF to conventional risk factors improved risk prediction for primary outcome in patients with dyslipidemia (net reclassification improvement: 24.28%, P < 0.001; integrated discrimination index: 0.43%, P = 0.022) but not in those with normal lipids. Secondary analyses further revealed that HDL-C was the main lipid component to modify the prognostic significance of serum HGF among ischemic stroke patients., Conclusions: There was a modified effect of blood lipid status on the association between serum HGF and ischemic stroke prognosis. Elevated serum HGF was associated with outcomes in ischemic stroke patients with dyslipidemia, especially low HDL-C. Further studies are warranted to replicate our findings and clarify the potential biological mechanisms., (Copyright © 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Endostatin is implicated in the atherosclerosis process and serves as a promising cardiovascular biomarker, while its clinical significance in ischemic stroke patients remains unclear. We aimed to examine the association between endostatin and mortality and disability after ischemic stroke., Methods: A total of 3463 acute ischemic stroke patients with measured plasma endostatin from the China Antihypertensive Trial in Acute Ischemic Stroke were included in this study. The primary outcome was death or severe disability (modified Rankin scale score of 4-6), and secondary outcomes included death and vascular events., Results: After 3-month follow-up, 402 (11.61%) participants experienced severe disability or died. Compared with the lowest quartile of endostatin, odds ratios or hazard ratios (95% confidence intervals) for the highest quartile were 1.47 (1.04-2.09) for the primary outcome, and 2.36 (1.23-4.54) for death after adjustment for multiple covariates, including age, sex, admission NIH Stroke Scale score and systolic blood pressure. Each 1-SD higher log-transformed endostatin was associated with a 20% (6%-36%) increased risk for primary outcome. Adding plasma endostatin to the basic model constructed with conventional factors significantly improved risk stratification of primary outcome, as observed by the category-free net reclassification index of 20.5% (95% CI 10.1%-30.8%; p < 0.001) and integrated discrimination improvement of 0.3% (95% CI 0.01%-0.6%; p = 0.04)., Conclusions: Increased baseline plasma endostatin levels in acute ischemic stroke were associated with increased risk of mortality and severe disability at 3 months. Plasma endostatin may serve as an important prognostic marker for risk stratification in patients with ischemic stroke., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background and Aims: We aimed to evaluate the ability of multiple novel biomarkers representing several pathophysiological pathways to improve risk prediction of post-stroke cognitive impairment., Methods: 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., Results: 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., Conclusions: 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., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background and Aims: The association between homocysteine and prognosis of ischemic stroke remains controversial, and the role of platelet count on the effects of homocysteine in the prognosis of ischemic stroke is still not elucidated., Methods: A total of 3229 acute ischemic stroke patients from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) with homocysteine and platelet measurements were included in this analysis. They were prospectively followed up for death, recurrent stroke and vascular events within 1 year after acute ischemic stroke., Results: There was a significant interaction effect between platelet count and homocysteine level on death (p for interaction < 0.05) within 1 year after ischemic stroke. After multivariate adjustment, high homocysteine level was associated with increased risk of 1-year mortality in patients with low platelet level (hazard ratio, 1.70; 95% confidence interval, 1.01-2.88) but not in those with high platelet level (hazard ratio, 1.08; 95% confidence interval, 0.65-1.75). The addition of homocysteine to a model containing conventional risk factors improved risk prediction of 1-year death (net reclassification index 0.53%, p < 0.001; integrated discrimination improvement 0.07%, p < 0.001)., Conclusions: High homocysteine may be merely an independent risk factor of death in ischemic stroke patients with low platelet levels. Further prospective studies from other populations and randomized clinical trials are needed to verify our findings and clarify the potential mechanisms., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Previous studies have reported that extreme low and high hemoglobin levels are positively associated with the risk of ischemic stroke. However, there are few reports on the relationship between hemoglobin at acute phase and clinical outcomes after ischemic stroke and the results of their association to date are inconsistent. We aimed to investigate the association between them in a large prospective cohort of ischemic stroke patients., Methods: Baseline hemoglobin levels were measured in 3881 patients with acute ischemic stroke. The primary outcome was defined as composite outcome of major disability and death (modified Rankin Scale score ≥ 3) at 3 months after stroke onset. Secondary outcomes were separately those of major disability and death., Results: Compared with the lowest quartile of hemoglobin, the multivariate adjusted odds ratios (95% confidence intervals) associated with the highest quartile were 1.38 (1.03-1.86), 1.49 (1.11-1.99), 0.79 (0.41-1.52) for primary outcome, major disability and death, respectively. Multiple-adjusted spline regression model showed linear associations of hemoglobin levels with primary outcome (P for linearity =0.037) and major disability (P for linearity =0.004). Subgroup analyses further confirmed the positive association between high hemoglobin and poor prognosis of ischemic stroke., Conclusions: Elevated hemoglobin levels in the acute phase were associated with poor prognosis at 3 months after ischemic stroke. Further prospective studies from other samples of ischemic stroke patients are needed to validate our findings., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Serum soluble corin has been suggested to be associated with hyperglycemia by cross-sectional study. However, the prospective relationship between them remains unclear, and whether lipid component influences the relationship between them has not yet been studied., Methods: A total of 1961 participants who were free from hyperglycemia were enrolled at baseline in 2010. The serum soluble corin concentrations were measured at baseline and all participants were followed up for hyperglycemia in 2014., Results: The association between serum soluble corin and hyperglycemia incidence was appreciably modified by high density lipoprotein cholesterol (HDL-C) (P interaction  = 0.04). Elevated serum soluble corin was associated with the risk of hyperglycemia only in the HDL-C ≥1.04 mmol/l subgroup rather than all participants. In participants with HDL-C ≥1.04 mmol/l, the adjusted odds ratio (95% CU) of hyperglycemia associated with the fourth quartiles of corin was 1.78 (1.08-2.94) compared with the lowest quartile of serum soluble corin, and there was a positive linear dose-response relationship between them (P for linearity <0.01). The ordinal analysis showed an association between serum soluble corin and hyperglycemia severity (adjusted OR, 1.81; 95% CI, 1.10-2.99; P trend  = 0.02, when 2 extreme quartiles were compared). The addition of serum soluble corin to conventional risk factors improved risk prediction for hyperglycemia (net reclassification index: 0.16; integrated discrimination improvement: 0.01) in participants with HDL-C ≥1.04 mmol/l., Conclusion: Serum soluble corin might be a valuable biomarker in prediction of future hyperglycemia in population with HDL-C ≥1.04 mmol/l, suggesting that corin might play a potential role in glucose metabolism., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Recent studies have reported that NOS3 plays an important role in cardiovascular pathology, whereas the association of NOS3 and hypertension (HT) has been controversial between African Americans and European whites. Here, we aimed to further investigate the genetic effect of unexplored loci at NOS3 on the susceptibility of HT in the Han Chinese population., Methods and Results: The association of three polymorphisms; rs4496877, rs1808593 and rs3918186 to HT was tested in a case control study that included 2012 HT cases and 2210 controls. Association analysis showed that there was no significant association between rs4496877, rs1808593 and rs3918186 of NOS3 and HT in the whole study population. Stratification analysis indicated that rs3918186 was significantly associated with HT in the ≥55-year-old population (OR = 1.245, 95% CI = 1.010-1.534, P = 0.04). The rs4496877 and rs1808593 were significantly associated with HT in the male population (P = 0.015) and <55-year-old population (P = 0.025), respectively (OR = 3.254, 95% CI = 1.257-8.425 and OR = 1.683, 95% CI = 1.066-2.657, respectively). Quantitative trait analysis showed that there were significant differences in systolic blood pressure (SBP) among the genotypes (AA, AT and TT) of rs3918186 in the non-intervention populations (P = 0.016). GMDR analysis showed that drinking and rs3918186 had significant interaction effects for risk of HT., Conclusions: The findings of this study indicated that the rs4496877, rs1808593 and rs3918186 polymorphisms of NOS3 contribute to the genetic susceptibility of HT and that rs3918186 was associated with SBP in the Chinese population. Age and gender might modify the genetic effect of NOS3 on HT, and drinking significantly interacts with rs3918186., (Copyright © 2015 Elsevier Inc. All rights reserved.)