Serum Soluble Corin and Long-Term Clinical Outcomes After Acute Ischemic Stroke.

BACKGROUND: Corin plays important roles in the regulation of blood volume and pressure and cardiac function by activating natriuretic peptide pathway, exerting multiple cardioprotective effects. But the impacts of soluble corin on clinical outcomes after ischemic stroke are unclear. We aimed to investigate the associations between serum soluble corin and long-term clinical outcomes after acute ischemic stroke. METHODS AND RESULTS: We measured the concentrations of serum soluble corin in 3162 participants (2010 men and 1152 women) from the China Antihypertensive Trial in Acute Ischemic Stroke. The clinical outcomes were recurrent stroke, cardiovascular events, all-cause mortality, and unfavorable functional outcome within 24 months after stroke. Risk reclassification for study clinical outcomes of models with soluble corin were evaluated. Serum soluble corin was inversely associated with recurrent stroke, cardiovascular events, and unfavorable functional outcome after ischemic stroke. After adjusting for multiple covariates, each additional SD of log-corin was associated with a 21% (95% CI, 11-30), 16% (95% CI, 6-26), and 12% (95% CI, 3-21) decreased risk for recurrent stroke, cardiovascular events, and unfavorable functional outcome, respectively. Furthermore, the addition of soluble corin to the basic model with conventional risk factors significantly improved risk discrimination for recurrent stroke, cardiovascular events, and the composite outcome of all-cause mortality and cardiovascular events, as shown by C-statistics (all P<0.05). CONCLUSIONS: Serum soluble corin was associated with decreased risks of long-term clinical outcomes, and may be a promising prognostic biomarker for risk stratification in patients with acute ischemic stroke.

Early vs Delayed Antihypertensive Treatment in Acute Single Subcortical Infarction: A Secondary Analysis of the CATIS-2 Randomized Clinical Trial.

Importance: The China Antihypertensive Trial in Acute Ischemic Stroke II (CATIS-2) suggests that early antihypertensive treatment did not reduce the risk of dependency or death in acute ischemic stroke (AIS), compared with delayed treatment. Single subcortical infarction (SSI) is an important stroke subtype, and the association of antihypertensive timing with clinical outcomes is unclear. Objective: To investigate the association of early vs delayed antihypertensive treatment with clinical outcomes in patients with SSI, stratified by the presence of parent artery disease (PAD) stenosis. Design, Setting, and Participants: This secondary analysis of the CATIS-2 randomized clinical trial included 106 hospitals in China between June 2018 and July 2022. In CATIS-2, patients with AIS within 24 to 48 hours of symptoms onset and elevated systolic blood pressure were eligible. Patients with SSI detected in diffusion-weighted imaging were included in the current post hoc subgroup analysis. Patients were grouped into (1) SSI with PAD stenosis and (2) SSI without PAD stenosis. Statistical analysis was performed from July 2023 to May 2024. Exposures: Early (immediate) vs delayed (starting on day 8) antihypertensive therapy. Main Outcome and Measure: Primary outcome was the combination of functional dependency or death (modified Rankin Scale score ≥3) at 90 days. Results: Among 997 patients with SSI in CATIS-2 (mean [SD] age, 62.4 [9.8] years; 612 [61.4%] men), 116 (11.6%) had SSI with PAD and 881 (88.4%) had SSI without PAD. There was no significant difference in the primary outcome between early and delayed antihypertensive treatment groups among all patients with SSI (8.8% vs 7.1%; OR, 1.25 [95% CI, 0.79-1.99]; P = .34). Among patients with SSI with PAD, early antihypertensive treatment was associated with increased risk of the primary outcome compared with delayed treatment (23.4% vs 7.7%; OR, 3.67 [95% CI, 1.14-11.86]; P = .03); this finding was not observed in patients with SSI without PAD (6.6% vs 7.1%; OR, 0.93 [95% CI, 0.55-1.57]; P = .77). Significant interaction with treatment and presence of PAD stenosis was detected for the primary outcome (P for interaction = .04). Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, early antihypertensive treatment was associated with an increased risk of functional dependency or death at 90 days among patients with SSI and coexisting PAD stenosis, compared with delayed antihypertensive treatment. Further studies are warranted for individualized BP management in patients with SSI by the presence of PAD. Trial Registration: ClinicalTrials.gov Identifier: NCT03479554.

Plasma Polyamines and Short-Term Adverse Outcomes Among Patients With Ischemic Stroke: A Prospective Cohort Study.

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.

Alcohol drinking modified the effect of plasma YKL-40 levels on stroke-specific mortality of acute ischemic stroke.

OBJECTIVES: Our study aimed to evaluate the association between plasma human cartilage glycoprotein-39 (YKL-40) and stroke-specific mortality at two years in acute ischemic stroke patients according to the drinking status and amount of alcohol consumption. We further investigated the effect of the interaction between these conditions and YKL-40 levels on the outcome. METHODS: We measured plasma YKL-40 levels in 3267 participants from the China Antihypertensive Trial in Acute Ischemic Stroke. Outcome data on stroke-specific mortality were collected at two years after stroke onset. RESULTS: During the two years of follow-up, 208 (6.4 %) patients, including 44 drinkers and 164 nondrinkers, died of stroke-specific causes. The patients in the highest quartile of YKL-40 had a 3.52-fold (95 % CI: 1.15-10.76, P for trend = 0.006) risk of stroke-specific mortality compared with those in the lowest quartile among drinkers. However, no significant association between YKL-40 and the outcome was observed among nondrinkers (HR: 1.18, 95 % CI: 0.75-1.86, P for trend = 0.08). Alcohol drinking modified the effect of YKL-40 on the outcome (P for interaction = 0.04). Subgroup analyses revealed that each 1-unit increase in log-transformed YKL-40 was associated with a 72 % greater risk of stroke-specific mortality for light drinkers. This association was amplified with a 226 % increased risk of the outcome among heavy drinkers. CONCLUSIONS: Elevated YKL-40 levels were associated with an increased risk of stroke-specific mortality at two years among drinkers with ischemic stroke. Drinking status substantially modified the effect of plasma YKL-40 levels on the outcome. This effect was amplified with the increased amount of alcohol consumption. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01840072.

Association of Cardiac Biomarkers in Combination With Cognitive Impairment After Acute Ischemic Stroke.

BACKGROUND: Poststroke cognitive impairment is a severe and common clinical complication that constitutes a substantial global health burden. We aimed to evaluate the association of 3 cardiac biomarkers in combination with poststroke cognitive impairment and their prognostic significance. METHODS AND RESULTS: This prospective study included 566 patients with ischemic stroke. Cardiac biomarkers, including sST2 (soluble suppression of tumorigenicity-2 receptor), GDF-15 (growth differentiation factor-15), and NT-proBNP (N-terminal pro-B-type natriuretic peptide), were measured. Cognitive impairment was defined as a Mini-Mental State Examination score of <27 or a Montreal Cognitive Assessment score of <25 at 3 months after ischemic stroke. Odds of cognitive impairment 3 months after ischemic stroke increased with the number of elevated cardiac biomarkers (sST2, GDF-15, and NT-proBNP; Ptrend<0.001). The multivariable adjusted odds ratios (95% CIs) of cognitive impairment defined by the Mini-Mental State Examination and Montreal Cognitive Assessment were 2.45 (1.48-4.07) and 1.86 (1.10-3.14) for the participants with ≥2 elevated cardiac biomarkers, respectively, compared with those without any elevated cardiac biomarker. Additionally, higher cardiac biomarker scores were associated with an increased risk of cognitive impairment (Ptrend<0.05). Simultaneously adding all 3 cardiac biomarkers to the basic model with traditional risk factors significantly improved the risk prediction of Mini-Mental State Examination-defined cognitive impairment (net reclassification improvement=34.99%, P<0.001; integrated discrimination index=2.67%, P<0.001). Similar findings were observed using the Montreal Cognitive Assessment scores. CONCLUSIONS: An increased number of elevated novel cardiac biomarkers were associated with an increased odds of poststroke cognitive impairment, suggesting that a combination of these cardiac biomarkers may improve the risk prediction of cognitive impairment. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01840072.

One-Year Disability Trajectories and Long-Term Cardiovascular Events, Recurrent Stroke, and Mortality After Ischemic Stroke.

BACKGROUND: Patients with stroke are often affected by varying degrees of functional disability and have different evolution patterns in functional disability. However, little is known about the predictive usefulness of disability changes after stroke. We aimed to describe 1-year disability trajectories and to assess the associations of longitudinal disability trajectories with 24-month clinical outcomes after ischemic stroke. METHODS AND RESULTS: A total of 3533 patients with ischemic stroke from CATIS (China Antihypertensive Trial in Acute Ischemic Stroke) were studied. Distinct trajectories of disability were identified by the group-based trajectory model, as measured by modified Rankin Scale score within 12 months. Cox proportional hazards regression models were used to examine the associations of disability trajectories with 24-month cardiovascular events and all-cause mortality. We identified 4 distinct disability trajectories: no significant disability (562 participants [15.9%]), slight disability to recovery (1575 participants [44.6%]), severe to moderate disability (1087 participants [30.8%]), and persistent severe disability (309 participants [8.7%]). Compared with no significant disability trajectory, the multivariable adjusted hazard ratios (95% CIs) of patients within the persistent heavy-severe trajectory were 2.63 (1.20-5.76) for cardiovascular events, 2.55 (1.12-5.79) for recurrent stroke, and 6.10 (2.22-16.72) for all-cause mortality; notably, the hazard ratios (95% CIs) for patients within the severe to moderate disability trajectory were 1.99 (1.01-3.94) for cardiovascular events and 1.85 (1.03-3.33) for the composite outcome of cardiovascular events and all-cause mortality. CONCLUSIONS: Functional disability trajectories within 12 months after stroke onset were associated with the risk of 24-month adverse outcomes. Patients with persistent severe disability or severe to moderate disability had higher risk of cardiovascular events and all-cause mortality. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01840072.

Efficacy of Immediate Antihypertensive Treatment in Patients With Acute Ischemic Stroke With Different Blood Pressure Genetic Variants.

BACKGROUND: It remains unclear whether blood pressure (BP) genetic variants could modify the efficacy of immediate antihypertensive treatment after acute ischemic stroke. We conducted a secondary analysis of the CATIS (China Antihypertensive Trial in Acute Ischemic Stroke) to investigate the effect of early antihypertensive treatment on clinical outcomes among patients with acute ischemic stroke according to 5 BP-associated genetic variants. METHODS: The CATIS randomized 4071 patients with acute ischemic stroke with elevated systolic BP to receive antihypertensive treatment or discontinue all antihypertensive agents during hospitalization. Randomization was conducted centrally and was stratified by participating hospitals and use of antihypertensive medications. Five BP-associated single nucleotide polymorphisms (rs16849225, rs17030613, rs1173766, rs6825911, and rs35444 in FIGN-GRB14, ST7L-CAPZA1, NPR3, ENPEP, and near TBX3, respectively) were genotyped among 2590 patients. The primary outcome was a combination of death and major disability at 14 days or hospital discharge. A weighted BP genetic risk score was constructed by the 5 single nucleotide polymorphisms. RESULTS: At 14 days or hospital discharge, the primary outcome was not significantly different between antihypertensive treatment and control groups based on genotype subgroups for all 5 single nucleotide polymorphisms (all P>0.05 for interaction). In addition, the BP genetic risk score did not modify the effect of antihypertensive treatment. The odds ratios (95% CIs) for the primary outcome were 0.95 (0.71-1.26), 1.08 (0.80-1.44), and 0.91 (0.69-1.22) in patients with low, intermediate, and high BP genetic risk score, respectively (P=0.88 for interaction). CONCLUSIONS: Early antihypertensive treatment had a neutral effect on clinical outcomes among patients with acute ischemic stroke according to 5 BP-associated genetic variants. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01840072.

Association of sarcopenia with rapid kidney function decline and chronic kidney disease in adults with normal kidney function.

The association between sarcopenia and kidney function remains poorly investigated. We aimed to evaluate the associations between sarcopenia status and kidney function (rapid kidney function decline and chronic kidney disease (CKD)) in middle-aged and older Chinese population. A total of 9375 participants from the China Health and Retirement Longitudinal Study 2011 were included in the cross-sectional analyses. A total of 5864 participants with eGFRcr-cys ≥ 60 ml/min per 1·73 m2 at baseline were included in the longitudinal analyses and were followed up in 2015. Sarcopenia status was defined according to the Asian Working Group for Sarcopenia 2019 criteria. In the cross-sectional analyses, possible sarcopenia and sarcopenia were significantly associated with an increased risk of CKD. During the 4 years of follow-up, 359 (6·12 %) participants experienced rapid decline in kidney function and 126 (2·15 %) participants developed CKD. After multivariable adjustment of baseline eGFRcr-cys level and other risk factors, possible sarcopenia (OR, 1·33; 95 % CI 1·01, 2·12) and sarcopenia (OR, 1·49; 95 % CI 1·05, 2·12) were associated with an increased risk of primary outcome (composite of rapid decline in kidney function (annualised decline in eGFRcr-cys ≥ 5 ml/min per 1·73 m2) and progression to CKD (eGFRcr-cys < 60 ml/min per 1·73 m2). Individuals with low muscle mass or low muscle strength alone also had an increased risk of rapid decline in kidney function and progression to CKD.

Albumin-Globulin Ratio and Common Carotid Artery Intima-Media Thickness in Patients with Ischemic Stroke.

BACKGROUND: The relationships between serum albumin, albumin-globulin (A/G) ratio, globulin and atherosclerosis in acute ischemic stroke (AIS) remain uncertain. We investigated the associations between serum albumin, A/G ratio, globulin levels and carotid atherosclerosis in patients with AIS. METHODS: A total of 1,339 AIS patients were enrolled. Admission A/G ratio was divided into quartiles, and serum albumin and globulin levels were also categorized. Carotid atherosclerosis was detected through the assessment of common carotid artery intima-media thickness (cIMT), and abnormal cIMT was characterized by mean and maximum cIMT values of ≥1 mm. We evaluated the relationships between A/G ratio, albumin, globulin and abnormal cIMT, using multivariable logistic regression models. RESULTS: In the multivariable-adjusted analysis, the highest A/G ratio quartile (Q4) was linked to a 59% decreased risk of abnormal mean cIMT (OR 0.41; 95% CI 0.29-0.60) and a 58% decreased risk of abnormal maximum cIMT (OR 0.42; 95% CI 0.30-0.60) when compared to the lowest quartile (Q1), respectively. Moreover, decreased albumin and elevated globulin levels were also associated with abnormal mean cIMT and maximum cIMT. In addition, the A/G ratio provided supplementary predictive capability beyond the already established risk factors, and the C-statistic of the A/G ratio for abnormal cIMT is larger than globulin (P <0.01). CONCLUSION: Decreased serum A/G ratio, albumin and elevated serum globulin were independently associated with abnormal cIMT in AIS patients. Moreover, the A/G ratio appeared to be a better predictor of abnormal cIMT.

Prognostic significance of plasma SDF-1 in acute ischemic stroke patients with diabetes mellitus: the CATIS trial.

BACKGROUND AND OBJECTIVES: Evidence on the associations between baseline stromal cell-derived factor (SDF)-1 and clinical outcomes in acute ischemic stroke patients is lacking. The present study aimed to examine the relationship between plasma SDF-1 levels and clinical outcomes based on a large multicenter study of the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). METHODS: Secondary analysis was conducted among 3,255 participants from the CATIS trial with a baseline measurement of plasma SDF-1 levels. We evaluated the associations between plasma SDF-1 levels and one-year recurrent stroke, cardiovascular events, and all-cause mortality using Cox regression models. We further investigated the prognostic effect of SDF-1 on clinical outcomes in patients with different characteristics. RESULTS: Higher plasma SDF-1 levels were not associated with recurrent stroke, cardiovascular events, and all-cause mortality at one-year after ischemic stroke (all P trend ≥ 0.05). There were significant interactions between plasma SDF-1 levels and history of diabetes mellitus on recurrent stroke (P = 0.005), cardiovascular events (P = 0.007) and all-cause mortality (P = 0.04) at one year. In patients with diabetes mellitus, plasma SDF-1 was significantly associated with an increased risk of recurrent stroke and cardiovascular events after adjustment for confounders. For example, 1-SD higher log-SDF-1 was associated with a hazard ratio (95% confidence interval) of 1.65 (1.18-2.32) for recurrent stroke and 1.47 (1.08-1.99) for the cardiovascular events, but not all-cause mortality 1.36 (0.96-1.93) at one year. However, there were no associations between plasma SDF-1 and clinical outcomes in patients without diabetes mellitus (all P > 0.05). The addition of plasma SDF-1 to the conventional risk factors model significantly improved the risk prediction of all outcomes. Similarly, findings between elevated SDF-1 levels and two-year outcomes were found only in patients with diabetes mellitus. CONCLUSIONS: Elevated plasma SDF-1 was significantly associated with an increased risk of recurrent stroke and cardiovascular events only in ischemic patients with diabetes mellitus.

Plasma Amino Acid Neurotransmitters and Ischemic Stroke Prognosis: A Multicenter Prospective Study.

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).

Early versus delayed antihypertensive treatment in patients with acute ischaemic stroke: multicentre, open label, randomised, controlled trial.

OBJECTIVES: To compared the effect of early antihypertensive treatment started within 24-48 h of stroke onset versus delaying treatment until day eight on reducing dependency or death. DESIGN: Multicentre, randomised, open label trial. SETTING: 106 hospitals in China between 13 June 2018 and 10 July 2022. PARTICIPANTS: 4810 patients (≥40 years) were enrolled with acute ischaemic stroke within 24-48 h of symptom onset and elevated systolic blood pressure between 140 mm Hg and <220 mm Hg. INTERVENTIONS: Patients were randomly assigned to receive antihypertensive treatment immediately after randomisation (aimed at reducing systolic blood pressure by 10%-20% within the first 24 h and a mean blood pressure <140/90 mm Hg within seven days) or to discontinue antihypertensive medications for seven days if they were taking them, and then receive treatment on day 8 (aimed at achieving mean blood pressure <140/90 mm Hg). MAIN OUTCOME MEASURES: The primary outcome was the combination of functional dependency or death (modified Rankin scale score ≥3) at 90 days. Intention to treat analyses were conducted. RESULTS: 2413 patients were assigned to the early treatment group and 2397 were assigned to the delayed treatment group. Mean systolic blood pressure was reduced by 9.7% (from 162.9 mm Hg to 146.4 mm Hg) in the early treatment group and by 4.9% (from 162.8 mm Hg to 154.3 mm Hg) in the delayed treatment group within 24 h after randomisation (P for group difference <0.001). Mean systolic blood pressure was 139.1 mm Hg in the early treatment group and 150.9 mm Hg in the delayed treatment group on day seven (P for group difference <0.001). Additionally, 54.6% of patients in the early treatment group and 22.4% in the delayed treatment group had blood pressure of less than 140/90 mm Hg (P<0.001 for group difference) on day seven. At day 90, 289 trial participants (12.0%) in the early treatment group, compared with 250 (10.5%) in the delayed treatment group, had died or experienced a dependency (odds ratio 1.18 (95% confidence interval 0.98 to 1.41), P=0.08). No significant differences in recurrent stroke or adverse events were reported between the two groups. CONCLUSIONS: Among patients with mild-to-moderate acute ischaemic stroke and systolic blood pressure between 140 mm Hg and <220 mm Hg who did not receive intravenous thrombolytic treatment, early antihypertensive treatment did not reduce the odds of dependency or death at 90 days. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03479554.

Magnitude of Systolic Blood Pressure Reduction and Early Achieved Blood Pressure and Clinical Outcomes After Acute Ischemic Stroke.

Background We aimed to evaluate the relationships between the magnitude of systolic blood pressure (SBP) reduction and achieved SBP in the acute phase of ischemic stroke onset and subsequent clinical outcomes. Methods and Results This study was a secondary analysis of CATIS (China Antihypertensive Trial in Acute Ischemic Stroke), a multicenter randomized controlled trial of 4071 patients with acute ischemic stroke. SBP reduction was defined as the proportional SBP changes from baseline to 24 hours after randomization, and achieved SBP was the mean of SBP measurements at day 7. The study outcomes included functional outcome of death or major disability (modified Rankin Scale score ≥3), death, and cardiovascular events at 3 months after recruitment. Compared with the reference group of increase or no change in SBP within the first 24 hours, the odds ratios (95% CIs) of functional outcome of death or major disability were 0.62 (0.47-0.83) and 0.61 (0.42-0.87) for the reduction of 11% to 20% and >20%, respectively. Compared with participants in highest achieved SBP group (≥160 mm Hg) at day 7, odds ratios or hazard ratios of lower achieved SBP (<130 mm Hg) were 0.54 (95% CI, 0.37-0.80) for functional outcome, and 0.36 (95% CI, 0.17-0.80) for death or cardiovascular events. Conclusions A moderate magnitude of SBP reduction and a lower early achieved SBP were associated with a decreased risk of poor functional outcome, death, and cardiovascular events after acute ischemic stroke. Further studies are warranted to confirm these findings. REGISTRATION: URL: ClinicalTrials.gov; Unique identifier: NCT01840072.

Effects of concurrent TP53 mutations on the efficacy and prognosis of targeted therapy for advanced EGFR mutant lung adenocarcinoma.

BACKGROUND: How concurrent TP53 mutations affect targeted therapy of advanced Epidermal Growth Factor Receptor (EGFR) mutant lung adenocarcinoma remains controversial, particularly the deep classification of TP53 mutations. METHODS: This study retrospectively analyzed the clinical data of advanced EGFR mutant lung adenocarcinoma patients treated with EGFR-tyrosine kinase inhibitors (TKIs) in the First Affiliated Hospital of Soochow University. The survival rates were compared using Log-rank tests. Potential prognostic factors were identified using multivariate Cox hazard regression models. RESULTS: Total 156 advanced lung adenocarcinoma patients treated with EGFR-TKIs were included in this study. Multivariate analysis showed that male [hazard rate (HR): 1.537, 95% confidence interval (CI): 1.055-2.240, P = 0.025], brain metastasis (HR: 1.707, 95%CI: 1.086-2.682, P = 0.020) and concurrent TP53 mutations (HR: 1.569, 95%CI: 1.051-2.341, P = 0.028) were independent negative predictors of progression-free survival (PFS). EGFR L858R mutations (HR: 2.475, 95%CI: 1.443-4.248, p = 0.001), smoking history (HR: 2.530, 95%CI: 1.352-4.733, P = 0.004) and concurrent TP53 mutations (HR: 2.326, 95%CI: 1.283-4.218, P = 0.005) were associated with worse survival. Further analysis revealed that mutations in TP53 exons 4, 5 and 8 (P<0.05), missense mutations (P = 0.006) and nondisruptive mutations (P<0.001) were associated with shorter PFS, whereas mutations in TP53 exons 5 and 7 (P<0.05), missense mutations and non-missense mutations (P = 0.006; P = 0.007), disruptive mutations and nondisruptive mutations (P = 0.013; P = 0.013) were all associated with poorer survival times. In addition, the PFS and overall survival (OS) of nondisruptive mutations in exon 7 were worse than those in other exons (P = 0.041; P<0.001). CONCLUSIONS: Concurrent TP53 mutations conferred worse EGFR-TKIs efficacy and prognosis in advanced EGFR mutant lung adenocarcinoma and the effects of different TP53 mutation types were heterogeneous.

Lipoprotein(a) and functional outcome of acute ischemic stroke when discordant with low-density lipoprotein cholesterol.

BACKGROUND: Several studies have indicated that residual cardiovascular risk might be associated with elevated lipoprotein(a) [Lp(a)] even in the setting of controlled low-density lipoprotein cholesterol (LDL-C). We aimed to prospectively examine the association between Lp(a) and unfavorable functional outcome among patients with acute ischemic stroke when Lp(a) and LDL-C were discordant. METHODS: Based on samples from the Infectious Factors, Inflammatory Markers and Prognosis of Acute Ischemic Stroke study, 973 patients with baseline plasma Lp(a) levels were included. The primary outcome was the composite outcome of death or major disability (modified Rankin Scale score of 3-6) at 6 months. Logistic regression models were used to estimate the risk for the primary outcome. Discordance analyses were performed, using difference in percentile units (>10 units), to detect the relative risk when Lp(a) and LDL-C were discordant. RESULTS: In total, 201 (20.7%) participants experienced major disability or death at 6 months. The multivariable-adjusted odds ratio (OR) for the highest quartile was 1.88 [95% confidence interval (CI): 1.16-3.04] compared with the lowest quartile. Each 1-SD higher log-Lp(a) was associated with a 23% increased risk (95% CI: 2%-47%) for the primary outcome. Compared with the concordant group, the high Lp(a)/low LDL-C discordant group was associated with increased risk for the primary outcome (adjusted OR: 1.59, 95% CI: 1.01-2.52). CONCLUSIONS: Elevated plasma Lp(a) levels were associated with increased risk of major disability and death at 6 months. Discordantly high Lp(a)/low LDL-C was associated with an unfavorable functional outcome, supporting the predictive potential of plasma Lp(a) after ischemic stroke, especially when discordant with LDL-C. Key messages What is already known on this topic Previous studies have indicated that a positive association between increased lipoprotein(a) [Lp(a)] and cardiovascular disease risk remained even in patients who achieved controlled low-density lipoprotein cholesterol (LDL-C) levels. The findings of studies exploring the association between Lp(a) and unfavorable clinical outcomes of stroke were inconsistent, and whether Lp(a) can predict the risk of unfavorable functional outcome in stroke patients when Lp(a) and LDL-C levels are discordant remains unknown. What this study adds Elevated plasma Lp(a) levels were associated with increased risk of major disability and death at 6 months beyond LDL-C levels in acute ischemic stroke patients. How this study might affect research, practice, or policy The combination of LDL-C-lowering therapies and Lp(a)-lowering therapies may have better clinical efficacy for patients with ischemic stroke, and it is of great clinical interest to further explore this possibility in dedicated randomized trials.

Plasma homeostatic chemokines CCL19 and CCL21 and the prognosis of ischemic stroke in two Chinese prospective cohorts.

BACKGROUND: The homeostatic chemokines CCL19 and CCL21 are involved in carotid plaque vulnerability and post-ischemic neuroinflammatory responses. This study aimed to examine the prognostic values of CCL19 and CCL21 in ischemic stroke. METHODS: Plasma CCL19 and CCL21 were measured in 4483 ischemic stroke patients from two independent cohorts of CATIS (China Antihypertensive Trial in Acute Ischemic Stroke) and IIPAIS (Infectious Factors, Inflammatory Markers, and Prognosis of Acute Ischemic Stroke), and participants were followed up at 3 months after stroke. The primary outcome was the composite outcome of death or major disability. The associations of CCL19 and CCL21 levels with the primary outcome were examined. RESULTS: In CATIS, multivariable-adjusted odds ratios of the primary outcome in the highest quartiles of CCL19 and CCL21 compared with the lowest quartiles were 2.06 and 2.62, respectively. In IIPAIS, odds ratios of the primary outcome in the highest quartiles of CCL19 and CCL21 were 2.81 and 2.78 compared with the lowest quartiles, respectively. In the pooled analysis of the two cohorts, odds ratios of the primary outcome associated with the highest quartiles of CCL19 and CCL21 were 2.24 and 2.66, respectively. Similar findings were observed in the analysis with major disability, death, and the composite outcome of death or cardiovascular events as the secondary study outcomes. Adding CCL19 and CCL21 to conventional risk factors significantly improved risk reclassification and discrimination for adverse outcomes. CONCLUSIONS: Both CCL19 and CCL21 levels were independently associated with adverse outcomes within 3 months after ischemic stroke and should be further investigated for risk stratification and potential therapeutic targets of ischemic stroke.

Combined Role of Inflammatory Biomarkers and Red Blood Cell Distribution Width in Predicting In-hospital Outcomes of Acute Ischemic Stroke Patients Undergoing Thrombolysis.

BACKGROUND: To investigate the combined effect of red blood cell distribution width (RDW) and inflammatory biomarkers on in-hospital outcomes of acute ischemic stroke(AIS) patients with thrombolysis. METHODS: 417 AIS patients with thrombolysis were included. The participants were divided into four groups according to the cut-off of white blood cell (WBC) or C reactive protein (CRP) and RDW: LWLR, LWHR, HWLR, and HWHR; or LCLR, LCHR, HCLR, and HCHR (L-low, Hhigh, W-WBC, C-CRP, R-RDW). Logistic regression models were used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) of in-hospital pneumonia and functional outcome across the four subgroups. RESULTS: Patients with higher RDW and inflammatory biomarkers levels have the highest risk of in-hospital outcomes. Compared with patients in the LWLR group, the ORs (95% CIs) of those in the HWHR group were 12.16 (4.21-35.14) and 9.31 (3.19-27.17) for in-hospital pneumonia and functional outcome. The ORs (95% CIs) of those in the HCHR group were 6.93 (2.70-17.78) and 3.38 (1.10-10.39) for in-hospital pneumonia and functional outcome, compared with patients in the LCLR group. Simultaneously adding RDW and WBC or CRP to the basic model with established risk factors significantly improved risk discrimination and reclassification for pneumonia and functional outcome (all p <0.05). CONCLUSIONS: Combined RDW and inflammatory biomarkers within 4.5 hours had a better predictive power for in-hospital outcomes of AIS patients with thrombolysis.

The relationship between neurological function trajectory, assessed by repeated NIHSS measurement, and long-term cardiovascular events, recurrent stroke, and mortality after ischemic stroke.

BACKGROUND: Clinically significant changes in neurological deficits frequently occur after stroke onset, reflecting further neurological injury or neurological improvement. However, the National Institutes of Health Stroke Scale (NIHSS) score is only evaluated once in most studies, usually at stroke onset. Utilizing repeated measures of NIHSS scores to identify different trajectories of neurological function may be more informative and provide more useful predictive information. We determined the association of neurological function trajectories with long-term clinical outcomes after ischemic stroke. METHODS: A total of 4025 participants with ischemic stroke from the China Antihypertensive Trial in Acute Ischemic Stroke were included. Patients were recruited from 26 hospitals across China between August 2009 and May 2013. A group-based trajectory model was used to identify distinct neurological function trajectories, as measured by NIHSS at admission, 14 days or hospital discharge, and 3 months. Study outcomes were cardiovascular events, recurrent stroke, and all-cause mortality during 3-24 months after ischemic stroke onset. Cox proportional hazards models were used to examine the associations of neurological function trajectories with outcomes. RESULTS: We identified three distinct subgroups of NIHSS trajectories: persistent severe (persistent high NIHSS scores during the 3-month follow-up), moderate (NIHSS scores started at around 5 and gradually reduced), and mild (NIHSS scores always below 2). The three trajectory groups had different clinical profiles and different risk of stroke outcomes at 24-month follow-up. Compared to the mild trajectory group, patients in the persistent severe trajectory group had a higher risk of cardiovascular events (multivariable-adjusted hazard ratios (95% confidence intervals) = 1.77 (1.10-2.86)), recurrent stroke (1.82 (1.10-3.00)), and all-cause mortality (5.64 (3.37-9.43)). Those with moderate trajectory had an intermediate risk: 1.45 (1.03-2.04) for cardiovascular events and 1.52 (1.06-2.19) for recurrent stroke. CONCLUSION: Longitudinal neurological function trajectories derived from repeated NIHSS measurements during the first 3 months after stroke provide additional predictive information and are associated with long-term clinical outcomes. The trajectories characterized by persistent severe and moderate neurological impairment were associated with increased risk of subsequent cardiovascular events.