Risk Of First Ischemic Stroke Research Articles

Secondhand smoke exposure can increase the risk of first ischemic stroke: A 10.7-year prospective cohort study in China

IntroductionPassive smoking is considered a major public health issue in China. Prospective evidence regarding the link between secondhand smoke (SHS) and ischemic stroke in China is scarce. MethodsThe China Kadoorie Biobank (CKB) study in Liuzhou City recruited 50,174 participants during 2004–2008. Of these 30,456 never-smokers were included in our study. The median follow-up period was 10.7 years. The incidence of ischemic stroke was obtained through the China Disease Surveillance Points (DSP) system and the Health Insurance (HI) database. Cox proportional risk models were used to evaluate the association between SHS exposure and ischemic stroke. ResultsDuring 320,678 person-years of follow-up, there were 2059 patients with ischemic stroke observed and the incidence of ischemic stroke was 6.42 per thousand person-years. Participants exposed to SHS daily faced a 21 % higher risk of ischemic stroke (HR = 1.21, 95 %CI: 1.09–1.34) compared to those exposed to SHS less than once a week. Subgroup analyses revealed that daily SHS exposure was linked to heightened risk of ischemic stroke among women, non-employed, and non-weekly tea drinkers. ConclusionsDaily SHS exposure was associated with higher risks of ischemic stroke. Proactive tobacco control strategies are necessary to decrease the risk of ischemic stroke in never smokers.

Association between plasma selenium and risk of ischemic stroke: A community-based, nested, and case-control study.

The prospective association between plasma Se and stroke risk remains inconclusive. The relationship between Se and ischemic stroke among a low circulating Se status population deserves more attention, especially for Chinese people who were a high-risk group for Se deficiency. The relationship between plasma Se concentration and ischemic stroke risk in a large-scale Chinese community-based population and any potential effect modifiers were investigated. A nested, case-control study, using data from the "China H-type Hypertension Registry Study" were conducted. A total of 1,904 first ischemic stroke cases and 1,904 controls matched for age, sex, and village were included in this study. The association between plasma Se and first ischemic stroke was evaluated by conditional logistic regression analyses. The median value of plasma Se was 65.8 μg/L among total participants. Overall, a significant inverse relationship between plasma Se and first ischemic stroke risk was found (per SD increment; adjusted OR: 0.87; 95% CI: 0.80 and 0.95). Accordingly, a significantly lower risk of first ischemic stroke was found in participants in quartile 3 (65.8-<77.8 μg/L) (adjusted OR: 0.78; 95% CI: 0.63 and 0.96) and quartile 4 (≥77.8 μg/L) (adjusted OR: 0.76; 95% CI: 0.59 and 0.96), compared with those in quartile 1 (<56.0 μg/L). Furthermore, a significantly lower ischemic stroke risk was found in those with lower low-density lipoprotein cholesterol (LDL-C) levels (<3.4 vs. ≥3.4 mmol/L; P for interaction = 0.015) or those with lower homocysteine levels (<12.1 (median) vs. ≥12.1 μmol/L; P for interaction = 0.027) at baseline. Plasma Se was significantly inversely associated with the risk of first ischemic stroke among a large-scale Chinese community-based population (most adults with hypertension and elevated total homocysteine), especially among those with lower LDL-C and lower homocysteine levels.

Inverse Association between Plasma Phylloquinone and Risk of Ischemic Stroke in Chinese Adults with Hypertension and High BMI: A Nested Case-Control Study

BackgroundEvidence on the association between phylloquinone status and cardiovascular diseases is scarce and conflicting. These inconsistencies may be due to differences in individual characteristics of the study populations, which may modify the association. ObjectiveThis study aimed to evaluate the association between plasma phylloquinone and the risk of first total stroke and its subtypes, and to examine potential effect modifications by BMI in patients with hypertension. MethodsWe performed a nested case-control study including 604 first stroke cases and 604 matched controls. The mean age was 62.2 y (range, 45 to 75). Lower BMI was defined as <25 kg/m2 and higher BMI was defined as ≥25 kg/m2. The risks of the first stroke were estimated by ORs and 95% CIs using conditional logistic regression. The primary outcome was total stroke or ischemic stroke. ResultsThe relation between log-transformed phylloquinone concentration and stroke or ischemic stroke was modified by BMI. Higher phylloquinone concentrations were associated with lower stroke risk in those with a higher BMI. When plasma phylloquinone was assessed as tertiles, the adjusted ORs of first stroke and ischemic stroke for participants with a high BMI in tertile 2–3 were 0.70 (95% CI: 0.46, 1.08) and 0.57 (95% CI: 0.35, 0.92) compared with those in tertile 1, respectively. However, there was no significant association between plasma phylloquinone and risk of first total stroke or ischemic stroke for those with a lower BMI. Patients with a higher BMI and lower phylloquinone concentrations had the highest risk of ischemic stroke and showed a statistically significant difference compared with the reference group with a lower BMI and higher phylloquinone (OR = 1.80, 95% CI: 1.06, 3.10; P-interaction: 0.017). ConclusionsIn Chinese patients with hypertension, there was an inverse association between baseline plasma phylloquinone and risk of first ischemic stroke among those with a higher BMI. This trial was registered at clinicaltrials.gov as NCT00794885.

High-Density Lipoprotein Cholesterol and the Risk of First Ischemic Stroke in a Chinese Hypertensive Population.

Background and PurposeElevated high-density lipoprotein cholesterol (HDL-C) levels have displayed protection against cardiovascular disease. However, the association between specific lipoprotein classes and first ischemic stroke (IS) has not been well defined, particularly in higher-risk hypertensive populations. Our study evaluated the associations of HDL-C with first IS in a Chinese hypertensive population.MethodsThe study population was obtained from a community-based cohort study of hypertension in Lianyungang and Rongcheng, China. A nested case-control design was used that included 2463 identified first IS cases and 2463 controls matched by age ± 1 year, sex, and region.ResultsAfter adjusting for potential confounders, HDL-C was inversely associated with first IS (adjusted odds ratio [aOR]: 0.91; 95% confidence interval [CI]: 0.85–0.98). HDL-C levels of at least 65.4 mg/dL displayed a significant protective effect for first IS (aOR: 0.82; 95% CI: 0.69–0.98). Conversely, adverse effects of first IS were observed for low-density lipoprotein cholesterol (LDL-C) levels ≥138.1 mg/dL (aOR: 1.20; 95% CI: 1.02–1.42) and triglyceride (TG) levels ≥140.8 mg/dL (aOR: 1.27; 95% CI: 1.09–1.49). The risk associations of LDL-C and TG with first IS were attenuated in the presence of high HDL-C (≥53.0 mg/dL); an increased risk of first IS was only found in the presence of low HDL-C (<53.0 mg/dL) when LDL-C (aOR: 1.66; 95% CI: 1.19–2.31) and TG (aOR: 1.47; 95% CI: 1.17–1.84) were combined with HDL-C for analysis.ConclusionIn this community-based Chinese hypertensive population, higher HDL-C was a significant protective factor of first IS. These data add to the evidence describing the relationship between lipids and IS and suggest that HDL-C maybe is a marker of IS risk in Chinses hypertensive population.

Neutrophil counts and the risk of first stroke in general hypertensive adults.

We aimed to investigate the association between neutrophil counts and first stroke and examine possible effect modifiers among treated hypertensive adults. This is a post hoc analysis of the China Stroke Primary Prevention Trial (CSPPT). A total of 11,878 hypertensive adults with data on neutrophil counts at baseline were included in the current study. The primary outcome was first stroke. During a median follow-up of 4.5 years, 414 (3.5%) participants experienced a first stroke, including 358 with ischemic stroke, 55 with hemorrhagic stroke and one with uncertain type of stroke. Compared with participants in quartile 1 (<2.9 × 109/L) of neutrophil counts, those in the upper quartiles (quartile 2-4 [≥2.9 × 109/L]) had a significantly higher risk of first stroke (HR, 1.35; 95% CI: 1.02, 1.78) or first ischemic stroke (HR, 1.38; 95% CI: 1.02, 1.86). Moreover, a strong positive association between neutrophil counts and first ischemic stroke was found in participants with total homocysteine (tHcy) levels <15 μmol/L (HR, 1.74; 95% CI: 1.17, 2.58; vs. ≥15 μmol/L; HR, 0.91; 95% CI: 0.57, 1.46, P interaction = 0.042) at baseline or time-averaged mean arterial pressure (MAP) ≥102 mmHg (median) (HR, 1.92; 95% CI: 1.27, 2.89; vs. <102 mmHg; HR, 0.89; 95% CI: 0.57, 1.41, P interaction = 0.015) during the treatment period. However, no such association between neutrophil counts and first hemorrhagic stroke was found. In summary, high baseline neutrophil counts were associated with an increased risk of first ischemic stroke among hypertensive patients, especially in those with low tHcy at baseline or high time-averaged MAP during the treatment period.

Association between plasma copper levels and first stroke: a community-based nested case–control study

ABSTRACT Background and aims Uncertainty remains regarding the association between the risk of stroke and plasma copper levels in population with copper mostly in normal range due to limited data. We examined the association between baseline plasma copper and risk of first stroke in Chinese community-dwelling population. Methods We conducted a nested case control study from ‘H-type Hypertension and Stroke Prevention and Control Project’. A total of 1255 first stroke cases and 1255 controls matched for age, sex and study site were included in the analysis. Conditional logistic regression analyses were performed to evaluate the association between plasma copper and first stroke. Results The overall mean of copper was 15.90 (2.66) μmol/L. In total, 94.26% participants’ copper concentration was in the normal range by Mayo Clinic laboratory reference values. Smoothing curve showed that the associations of plasma copper with first stroke and its subtypes were linear. Each standard deviation (SD) increment of plasma copper was independently and positively associated with risk of first stroke [odds ratio (OR): 1.17, 95% confidence interval (CI): 1.07–1.28]. The multivariable ORs with 95% CIs for total stroke, ischemic stroke and hemorrhagic stroke in the highest versus the lowest quartile of plasma copper were 1.49 (1.16–1.90; P-trend = 0.001), 1.46 (1.12–1.92; P-trend = 0.004) and 2.05 (0.95–4.38; P-trend = 0.050), respectively. Conclusions Baseline plasma copper was positively associated with risk of first ischemic stroke in an approximately linear fashion among Chinese community population (80.32% hypertensives), although their copper levels were mostly within the normal range according to current reference values. Our findings warrant additional investigation.

Nonlinear relationship between serum total bilirubin levels and initial ischemic stroke in patients with non-valvular atrial fibrillation.

ObjectiveThis study aimed to examine the relationship between total bilirubin levels and initial ischemic stroke in patients with non-valvular atrial fibrillation.MethodsThis was a retrospective study. Atrial fibrillation was diagnosed by 24-hour Holter electrocardiography and serum total bilirubin levels were divided into quintiles. Ischemic stroke was diagnosed by symptoms, signs, and a medical image examination. The multivariate Cox proportional hazards model and survival analysis were used to estimate the association of total bilirubin with initial ischemic stroke.ResultsWe studied 316 patients with non-valvular atrial fibrillation. During follow-up, there were 42 (13.29%) first ischemic strokes. After multivariate adjustment, for each 1 µmol/L increase in total bilirubin, the risk of first ischemic stroke increased by 4% (95% confidence interval [CI]: 1.01, 1.07). When using the first quintile as the reference, from the second to fifth quintiles, the risks of first ischemic stroke were 0.52 (95% CI: 0.17, 1.65), 0.23 (95% CI: 0.06, 0.87), 0.92 (95% CI: 0.32, 2.67), and 1.33 (95% CI: 1.09, 4.41), respectively. The optimal cut-off point of total bilirubin for the lowest risk of ischemic stroke was 17.0 µmol/L.ConclusionsTotal bilirubin levels are nonlinearly associated with initial ischemic stroke in patients with non-valvular atrial fibrillation.

Baseline Serum Bilirubin and Risk of First Stroke in Hypertensive Patients.

BackgroundData on the association between serum bilirubin and the risk of stroke are limited and inconclusive. We aimed to evaluate the association between serum bilirubin and the risk of first stroke and to examine any possible effect modifiers in hypertensive patients.Methods and ResultsOur study was a post hoc analysis of the CSPPT (China Stroke Primary Prevention Trial). A total of 19 906 hypertensive patients were included in the final analysis. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% CIs for the risk of first stroke associated with serum bilirubin levels. The median follow‐up period was 4.5 years. When serum total bilirubin was assessed as tertiles, the adjusted HR of first ischemic stroke for participants in tertile 3 (12.9–34.1 μmol/L) was 0.75 (95% CI, 0.59–0.96), compared with participants in tertile 1 (<9.3 μmol/L). When direct bilirubin was assessed as tertiles, a significantly lower risk of first ischemic stroke was also found in participants in tertile 3 (2.5–24.8 μmol/L) (adjusted HR, 0.77; 95% CI, 0.60–0.98), compared with those in tertile 1 (<1.6 μmol/L). However, there was no significant association between serum total bilirubin (tertile 3 versus 1: adjusted HR, 1.45; 95% CI, 0.89–2.35) or direct bilirubin (tertile 3 versus 1: adjusted HR, 1.27; 95% CI, 0.76–2.11) and first hemorrhagic stroke.ConclusionsIn this sample of Chinese hypertensive patients, there was a significant inverse association between serum total bilirubin or direct bilirubin and the risk of first ischemic stroke.

Individual and Combined Associations of Fasting Serum Lipids with Incident Risk of First Ischemic Stroke: A Chinese Community-Based Nested Case-Control Study

Background: Dyslipidemia is a well-recognized risk factor of cardiovascular diseases. But its role in first ischemic stroke (IS) remains perplexing. Our study evaluated individual and combined associations of specific types of fasting blood lipids with first IS. Methods: The study sample population was drawn from a community-based cohort study of hypertension in Lianyuangang and Rongcheng, China, using a nested case-control design, including 2463 identified first IS cases and 2463 controls, matched by age±1 year, sex and region . Conditional logistic regression was used to estimate odds ratios (OR) and 95% confident intervals (CI) of first IS, after adjustment for pertinent covariates. Findings: High-density lipoprotein cholesterol (HDL-C) was inversely associated with first IS (adjusted OR: 0·91; 95% CI: 0·85-0·98; P=0·014). A positive association between triglycerides (TG) and first IS (aOR:1·10; 95% CI: 1·02-1·17; P=0·007) was found. There was a positive but non-significant association between low-density lipoprotein cholesterol (LDL-C) and first IS (aOR:1·04; 95% CI:0·97-1·12; P=0·239). When LDL-C or TG was combined with HDL-C for analysis, a significant risk association with first IS was found among those with low HDL (< 53·0 mg/dL) and high LDL-C (≥138·1 mg/dL) (aOR: 1·66; 95%CI: 1·19-2·31; P=0·003) or those with low HDL (< 53·0 mg/dL) and high TG (≥140·8 mg/dL) (aOR: 1·47; 95%CI: 1·17-1·84; P<0·001). Interpretation: In this Chinese hypertensive population, higher HDL-C was a significant protective factor, while higher TG was a significant risk factor. And elevated LDL-C and TG were no longer associated with first IS in the presence of higher HDL-C. These results, if further confirmed, underscore the importance of optimizing HDL-C levels, likely higher than the current clinical threshold, in the primary prevention of IS. Funding: The study was funded by the following: the National Key Research and Development Program [2016YFE0205400, 2018ZX09739, 2018ZX09301034003], the Science and Technology Planning Project of Guangzhou, China [201707020010]; the Science, Technology and Innovation Committee of Shenzhen [JSGG20170412155639040, GJHS20170314114526143, JSGG20180703155802047]; the Economic, Trade and Information Commission of Shenzhen Municipality [20170505161556110, 20170505160926390], the Jiangxi Outstanding Person Foundation [20192BCBL23024], Major projects of the Science and Technology Department, Jiangxi [20171BAB205008];the Key Disciplines Group Construction Project of Pudong Health Bureau of Shanghai (Grant No. PWZxq2017-08) and the National Nature Science Foundation of China (Grant No. 81601010, 81960074, 81500233). Declaration of Interests: The authors have no conflicts of interest to declare. Ethics Approval Statement: This study was approved by the Ethics Committee of the Institute of Biomedicine, Anhui Medical University, Hefei, China, the Ethics Committee of Lianyungang Precision Health Institute, and the Ethics Committee of the Lianyungang Center for Advanced Research in Cardiovascular Diseases. All participants provided written informed consent.

Association between systolic blood pressure and first ischemic stroke in the Chinese older hypertensive population.

ObjectiveThis study aimed to evaluate the association between systolic blood pressure (SBP) and first ischemic stroke in older people with hypertension in the community.MethodsThis retrospective cohort study included 3315 residents who were hypertensive and older than 60 years in Guangdong, China.ResultsA total of 1475 men and 1840 women aged 71.41±7.20 years were included. All subjects had a median follow-up duration for 5.5 years and 206 subjects reached the endpoint. The prevalence of first ischemic stroke increased with a higher SBP. SBP expressed as a continuous variable (hazard ratio [HR], 1.01; 95% confidence interval [CI], 1.00–1.02) and categorical variable (HRs, 1.00, 1.06, 1.17, 1.39, and 1.60 for increasing blood pressure from < 120–≥150 mmHg), was significantly associated with a higher risk of first ischemic stroke. Moreover, a fully adjusted model indicated an obvious increased risk in the SBP ≥150 mmHg group (HR, 1.60; 95% CI, 1.15–2.71) and the SBP 140–149 mmHg group (HR, 1.39; 95% CI, 1.01–2.39).ConclusionsHigh SBP was independently associated with the risk of first ischemic stroke in hypertensive residents in the community aged older than 60 years. SBP ≥140 mmHg increases the risk of first ischemic stroke.

Abstract TP184: High-Density Lipoprotein Cholesterol Levels Inversely Associated With First Ischemic Stroke in a Chinese Hypertensive Population

Background and Purpose: Lipid levels are established risk factors for ischemic heart disease, but uncertainty persists about the relevance of lipids for first ischemic stroke (IS). The goal of this study was to evaluate whether lipid profiles are risk factors for first IS in a Chinese hypertensive population. Methods: Our study population was selected from 300,000 individuals registered from 2016-2018 in the Lianyungang and Rongcheng “H-type hypertension prevention and control public service project”. Hypertensive patients with stroke data from the Chinese centers for disease control and prevention (CDC, 2013-2018) who had complete records (physical exam, questionnaire, and biological samples) were selected as cases. We used a nested case-control study design and matched 3615 ischemic stroke cases with an equal number of controls (hypertensive patients without stroke) for age±1 years, sex, and village. The crude and adjusted risks of first ischemic stroke were estimated by ORs and 95% CIs using conditional logistic regression, with or without adjustment for pertinent covariates. Results: Participants with first IS had higher blood pressure, body mass index, fasting glucose, triglycerides, and low-density lipoprotein cholesterol. High-density lipoprotein cholesterol (HDL-C) was significantly and inversely associated with IS risk (OR, 0.71; 95% CI: 0.61-0.82). When HDL was assessed as quartiles, the lowest quartile was used as reference, a significantly lower risk for IS was found in the highest quartile (HDL-C ≥ 1.8mmol/L: OR, 0.70; 95% CI: 0.59-0.82). There was a significant positive association between TG and the risk of IS (per SD increment; OR, 1.13; 95% CI, 1.07-1.20). Consistently, a significantly higher risk of first IS was found in quartile 4 (≥1.8 mmol/L: OR, 1.41; 95% CI, 1.20-1.65) compared with those in quartile 1 (&lt;0.9 mmol/L). Conclusions: HDL-C levels inversely associated with first IS. These results differ from existing evidence from western populations, highlighting potential differences in Chinese populations. These differences can be attributed to multiple factors, including genetics, diet and lifestyle and call for further study to investigate potential explanatory mechanisms.

Interaction of serum vitamin B 12 and folate with MTHFR genotypes on risk of ischemic stroke

We evaluated the interaction of serum folate and vitamin B12 with methylenetetrahydrofolate reductase (MTHFR) C677T genotypes on the risk of first ischemic stroke and on the efficacy of folic acid treatment in prevention of first ischemic stroke. A total of 20,702 hypertensive adults were randomized to a double-blind treatment of daily enalapril 10 mg and folic acid 0.8 mg or enalapril 10 mg alone. Participants were followed up every 3 months. Median values of folate and B12 concentrations at baseline were 8.1 ng/mL and 280.2 pmol/L, respectively. Over a median of 4.5 years, among those not receiving folic acid, participants with baseline serum B12 or serum folate above the median had a significantly lower risk of first ischemic stroke (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.57-0.96), especially in those with MTHFR 677 CC genotype (wild-type) (HR, 0.49; 95% CI, 0.31-0.78). Folic acid treatment significantly reduced the risk of first ischemic stroke in participants with both folate and B12 below the median (2.3% in enalapril-folic acid group vs 3.6% in enalapril-only group; HR, 0.62; 95% CI, 0.46-0.86), particularly in MTHFR 677 CC carriers (1.6% vs 4.9%; HR, 0.24; 95% CI, 0.11-0.55). However, TT homozygotes responded better with both folate and B12 levels above the median (HR, 0.28; 95% CI, 0.10-0.75). The risk of first ischemic stroke was significantly higher in hypertensive patients with low levels of both folate and B12. Effect of folic acid treatment was greatest in patients with low folate and B12 with the CC genotype, and with high folate and B12 with the TT genotype.

A U-shaped association between serum betaine and incident risk of first ischemic stroke in hypertensive patients.

Betaine (a micronutrient) has important biological functions (e.g., preventing premature apoptosis and serving as a methyl donor). We investigated the association between baseline serum betaine and the incident risk of first stroke in hypertensive patients. We conducted a nested case-control study, including 622 patients with first stroke (including 502 ischemic stroke, 118 hemorrhagic stroke and 2 uncertain type of stroke) and 622 matched controls from the China Stroke Primary Prevention Trial (CSPPT). The study was conducted from May 2008 to August 2013. The study outcomes included first stroke and its subtypes: first ischemic and hemorrhagic stroke. There was a U-shaped association between baseline serum betaine and the risk of first ischemic stroke. The risk of first ischemic stroke decreased with the increment of betaine (per 10μmol/L increase: OR, 0.87; 95%CI: 0.77-0.99) in patients with betaine <77.7μmol/L, while the risk of first ischemic stroke increased with the betaine increment (OR, 1.17; 95%CI: 1.01-1.36) in patients with betaine ≥77.7μmol/L. However, there was no significant association between serum betaine and risk of first hemorrhagic stroke (per 10μmol/L increase: OR, 0.98; 95%CI: 0.82-1.17). There was a U-shaped association between baseline betaine levels and the risk of first ischemic stroke in hypertensive patients, with a turning point at about 77.7μmol/L. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00794885.

Characteristics of Children with Abnormal TCD in the Modern Era: Results from the Displace Consortium

Background: Stroke is one of the most devastating complications of sickle cell anemia (SCA). In 1998, the Stroke Prevention Trial in Sickle Cell Anemia (STOP), demonstrated that a high-risk group of children with SCA could be identified using Transcranial Doppler ultrasound(TCD) and that chronic red cell transfusion therapy (CRCT) could reduce the risk of first ischemic stroke in this group by over 90% (Adams, et al NEJM 1998).At STOP studyenrollment, 9.7% of children with SCA were identified as having an abnormal TCD. Baby HUG, (NCT00006400), an NHLBI supported phase III trial showed that severe anemia in SCA was associated with elevated white blood cell (WBC) and higher TCD velocities (Lebensburger, et al Blood 2010 ). It is unclear if lower hemoglobin (Hb) and/or higher WBC are causative of elevated TCD velocities or correlative biomarkers. As new disease therapies become available, it is important to know the current rate of abnormal TCD and characteristics of those patients. The DISPLACE (Dissemination and Implementation Looking at the Care Environment) project is a multicenter, NHLBI-funded study whose primary purpose is to identify barriers to implementation of stroke screening in SCA and test novel methods for improving outcomes. DISPLACE is a 3-part study: retrospective assessment of current practice, qualitative review of barriers and facilitators to screening and a cluster-randomized intervention implementation project to improve stroke screening. Part 1 of the study showedthat TCD screening rates varied widely among institutions ranging from 30-75.2% (mean 48.4%, median 47%). We are now reporting on the rate of abnormal TCD and the characteristics and outcomes of patients with abnormal TCD. Methods: DISPLACE is a consortium of 28 US centers. Each site performed a rigorous retrospective chart review of children with SCA aged 2-16 years from 2012-2016. To be eligible for inclusion, children must have been seen at their institution at least 2x during the study period and have confirmation of SCA. A custom electronic data capture (EDC) system facilitated entry of de-identified data including demographics, TCD and MRI results, medications, transfusions, and laboratory values. For children with SCA who had TCD or central nervous system imaging prior to 2012, these results were also entered into the EDC. TCD results were recorded in the EDC as normal, conditional or abnormal based on their institutional interpretation. Labs and vitals were entered for each patient in closest proximity to each TCD. Confirmation and adjudication of each abnormal TCD and associated outcomes were performed. Stroke status was also recorded as well as presence or absence of CRCT. Results: In total, 5247 children with SCA are included in the database of whom 5225 should have received a TCD. Of this cohort, 4210 children (80.6%) had at least one TCD recorded in the database. Within this group, 207 (4.9%) of children had an abnormal TCD and 816 (19.4%) had a conditional TCD. For those children who underwent TCD during the study (2012-2016) period, there were 105 (2.9%) abnormal TCD and 501 (13.6%) conditional TCD (Table 1). The mean age of children at the time of abnormal TCD was 6.6 years (range 2-16 yr). The majority of children were &lt;10 yr at first abnormal TCD. Over 30% of patients with an abnormal TCD were identified as receiving hydroxyurea.The mean Hb associated with an abnormal TCD was 7.8 +/- 1.1g/dl (range 5.7-10.6) and the mean WBC was 13 x109/L+/- 3.6 (range 3.9-23.4) (Table 2). Of the 105 patients with abn TCD during the study period, 18% had a stroke. Of the total 5247 patients in the database, 3093 (59%) had been prescribed hydroxyurea (HU) and 999 (19%) were prescribed CRCT. CRCT was prescribed most often for abnormal TCD (37%) or secondary stroke prevention (31%). Discussion: DISPLACE is the largest contemporary cohort of children with SCA. The incidence of abnormal TCD in the DISPLACE cohort is significantly lower than at randomization in the STOP study. The number of children receiving CRCT is higher than expected which may partly account for the decrease in frequency of abnormal TCD. Many patients with abnormal TCD were receiving HU when their TCD was abnormal and were started on CRCT. Additionally, while the outcomes of children with conditional TCD are still being evaluated, many of those children reverted to normal TCD without intervention. These data may also help us redefine the use and interventions needed for abnormal TCD. Disclosures Kanter: NHLBI: Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc.: Consultancy; SCDAA: Membership on an entity's Board of Directors or advisory committees; Guidepoint Global: Consultancy; GLG: Consultancy; Sangamo: Consultancy, Honoraria; Modus: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Imara: Consultancy; Cowen: Consultancy; Jeffries: Consultancy; Medscape: Honoraria; Rockpointe: Honoraria; Peerview: Honoraria. Adams:GBT: Consultancy, Other: consultancy to companies GBT and Blueburd Bio; Bluebird: Consultancy.

Baseline Serum Bilirubin and Risk of First Stroke in Hypertensive Patients

Background: Data concerning the association between serum bilirubin and the risk of stroke is limited and inconclusive. We aimed to evaluate the association between serum bilirubin and the risk of first stroke, and examine any possible effect modifiers in hypertensive patients. Methods: Our analyses included a total of 19,906 hypertensive patients from the China Stroke Primary Prevention Trial (CSPPT). In the CSPPT, a total of 20,702 hypertensive patients without major cardiovascular diseases were randomly assigned to a double-blind, daily treatment with either 10mg enalapril and 0·8mg folic acid or 10 mg enalapril alone. The median treatment duration was 4·5 years. Findings: There was a significant inverse association between serum total bilirubin (TBiL) (per-SD increment; HR, 0·90; 95%CI: 0·81, 0·99) or direct bilirubin (DBiL) (HR, 0·83; 95%CI: 0·74, 0·93) and the risk of first ischemic stroke. When TBiL and DBiL were assessed as tertiles, the adjusted HR for first ischemic stroke for participants in tertile 3 was 0·74 (95%CI: 0·58, 0·93) for TBiL and 0·73 (95%CI: 0·57, 0·93) for DBiL, compared with those in tertile 1. Furthermore, the serum DBiL-first ischemic stroke association was significantly stronger in participants without the use of antiplatelet drugs during the treatment period (vs. with antiplatelet drugs usage; P-interaction=0·033). However, there was no significant association between serum TBiL or DBiL and first hemorrhagic stroke. Interpretation: In Chinese hypertensive patients, there was a significant inverse association between serum DBiL and the risk of first ischemic stroke, especially among those without antiplatelet drugs usage during the treatment period. Funding Statement: The study was supported by funding from the following: the National Key Research and Development Program [2016YFE0205400, 2018ZX09739, 2018ZX09301034003]; the National Natural Science Foundation of China [81730019, 81973133]; the Science and Technology Planning Project of Guangzhou, China [201707020010]; the Science, Technology and Innovation Committee of Shenzhen [JSGG20170412155639040, GJHS20170314114526143]; the Economic, Trade and Information Commission of Shenzhen Municipality [20170505161556110, 20170505160926390]; the President Foundation of Nanfang Hospital, Southern Medical University [2017C007, 2018Z009]; the Outstanding Youths Development Scheme of Nanfang Hospital, Southern Medical University [2017J009]. Declaration of Interests: Dr. Xiping Xu reports grants from the National Key Research and Development Program [2016YFE0205400, 2018ZX09739, 2018ZX09301034003], the Science and Technology Planning Project of Guangzhou, China [201707020010], the Science, Technology and Innovation Committee of Shenzhen [JSGG20170412155639040, GJHS20170314114526143], and the Economic, Trade and Information Commission of Shenzhen Municipality [20170505161556110, 20170505160926390]. Dr. Xianhui Qin reports grants from the National Natural Science Foundation of China [81730019, 81973133], and the Outstanding Youths Development Scheme of Nanfang Hospital, Southern Medical University [2017J009]. Dr. Youbao Li reports grants from the President Foundation of Nanfang Hospital, Southern Medical University [2017C007, 2018Z009]. No other disclosures were reported. Ethics Approval Statement: The parent study (the CSPPT: Clinical Trials. gov, NCT00794885) and the current study were approved by the Ethics Committee of the Institute of Biomedicine, Anhui Medical University, Hefei, China (FWA assurance number: FW1263). All participants provided written informed consent. The data that support the findings of this study will be available from the corresponding authors upon request, after the request is submitted and formally reviewed and approved by the Ethics Committee of the Institute of Biomedicine, Anhui Medical University.

Serum Bilirubin and Risk of First Stroke in Hypertensive Patients

Background: Identification of novel risk factors is essential to further lower stroke risk. Data concerning the relation of serum bilirubin levels with the risk of stroke are limited. We sought to evaluate the association between serum bilirubin and the risk of first stroke in hypertensive patients. Methods: Our analyses included a total of 19,906 hypertensive patients from the China Stroke Primary Prevention Trial (CSPPT). In the CSPPT, a total of 20,702 hypertensive patients without major cardiovascular diseases were randomly assigned to a double-blind, daily treatment with either 10mg enalapril and 0·8mg folic acid or 10 mg enalapril alone. The median treatment duration was 4·5 years. Findings: There was a significant inverse association between serum total bilirubin (TBiL) (per-SD increment; HR, 0·90; 95%CI: 0·81-0·99) or direct bilirubin (DBiL) (HR, 0·83; 95%CI: 0·74-0·93) and the risk of first ischemic stroke. Consistently, when TBiL was assessed as tertiles, the adjusted HR for participants in tertile 3 was 0·74 (95%CI: 0·58-0·93), when compared with those in tertile 1. When DBiL was assessed as tertiles, a significantly lower risk of first ischemic stroke was also found in participants in tertile 3 (HR, 0·73; 95%CI: 0·57-0·93) compared with those in tertile 1. However, there was no significant association between serum TBiL (per-SD increment; HR, 1·15; 95%CI: 0·96, 1·38) or DBiL (HR, 1·10; 95%CI: 0·91-1·33) and first hemorrhagic stroke. Interpretation: Our data showed a significant inverse association between serum TBiL or DBiL levels and the risk of first ischemic stroke among Chinese hypertensive adults. Funding: The study was supported by funding from the following: the National Key Research and Development Program, the National Natural Science Foundation of China; the Science and Technology Planning Project of Guangzhou, China; the Science, Technology and Innovation Committee of Shenzhen, China. Declaration of Interest: Dr. Yong Huo reports grants from the National Key Research and Development Program [2016YFC0903103]. Dr. Yimin Cui reports grants from the National Key Research and Development Program [2016YFC0904900]. Dr. Xiping Xu reports grants from the National Key Research and Development Program [2016YFE0205400, 2018ZX09739, 2018ZX09301034003], the Science and Technology Planning Project of Guangzhou, China [201707020010], and the Science, Technology and Innovation Committee of Shenzhen [JSGG20170412155639040, GJHS20170314114526143]. Dr. Xianhui Qin reports grants from the National Natural Science Foundation of China [81730019]. Ethical Approval: Both the CSPPT and the current study were approved by the Ethics Committee of the Institute of Biomedicine, Anhui Medical University, Hefei, China (FWA assurance number: FW1263).

Serum levels of Trimethylamine-N-oxide in patients with ischemic stroke.

Objective: Accumulating evidence suggests that Trimethylamine-N-oxide (TMAO), a gut microbial metabolite, is implicated in the pathogenesis of many cardiovascular diseases. The aim of the present study was to investigate the serum levels of TMAO in Chinese patients with ischemic stroke.Method: In the present study, 255 consecutive patients with first-ever acute ischemic stroke and 255 age and gender-matched healthy volunteers were included for testing serum TMAO. Stroke severity was determined by the NIH Stroke Scale (NIHSS). The stroke severity was dichotomized as minor (NIHSS ≤ 5) and moderate-to-high clinical severity (NIHSS > 6).Results: The serum levels of TMAO in stroke ranged from 0.5 to 18.3 μM, with a median value of 5.8 (interquartile range (IQR), 3.3–10.0) μM, which was higher than in those controls (3.9; IQR, 2.6–6.1 μM). The median level of TMAO in those patients was significantly lower than in those moderate-to-high stroke patients (4.1 μM [IQR, 2.8–6.2] vs. 9.1 μM [5.1–11.0]; P<0.001). In univariate and multivariable models, the unadjusted risk of moderate-to-high stroke was increased by 31% (odds ratio (OR) = 1.31 [95% confidence interval (CI): 1.21–1.42], P<0.001) and 22% (OR = 1.22; 95% CI = 1.08–1.32; P<0.001), when TMAO was increased each by 1 μM. Based on the receiver operating characteristic (ROC) curve, the optimal cut-off value of serum level of TMAO as an indicator for screening of moderate-to-high stroke was estimated to be 6.6 μM, which yielded a sensitivity of 69.3 % and a specificity of 79.0%, with the area under the curve at 0.750 (95% CI, 0.687–0.812).Conclusions: Higher TMAO levels were associated with increased risk of first ischemic stroke and worse neurological deficit in Chinese patients.

Benign neoplasm of the heart increases the risk of first ischemic stroke: a population-based cohort study.

The study aims to investigate the incidence of first ischemic stroke in patients with benign cardiac tumors who did or did not undergo operations. We used the National Health Insurance Research Database of Taiwan to conduct the research. The exposure cohort comprised 587 adult patients with benign cardiac tumors. Each patient was randomly frequency matched by age, index month, and index year with 10 participants from the general population who exhibited no history of benign cardiac tumors before the index date (control group). Cox's proportion hazard regression analyses were conducted to determine the relation between benign cardiac tumors and the risk of ischemic stroke. Based on clinical diagnoses, the prevalence of benign cardiac tumors was 0.004%. Patients with benign cardiac tumors exhibited an increased risk of first ischemic stroke [adjusted hazard ratio: 1.77; (95% confidence interval, 1.20-2.63)], particularly at young ages (adjusted hazard ratio: 22.9, 95% confidence interval: 4.17-126.0). We observed no significant difference in the risk of ischemic stroke between men with and without benign cardiac tumors (adjusted hazard ratio: 1.29, 95% confidence interval: 0.63-2.63). Among patients with benign cardiac tumors, the adjusted hazard ratio of first ischemic stroke was 0.48 (95% confidence interval: 0.23-1.04) in the operation group compared with the nonoperation group. Younger patients (<50 years) with benign cardiac tumors exhibit an increased risk of first ischemic stroke.

Light Chain of Factor VIII Is Sufficient for Accelerating Cleavage of von Willebrand Factor by ADAMTS13 Metalloprotease

We previously demonstrated that coagulation factor VIII (FVIII) accelerates proteolytic cleavage of von Willebrand factor (VWF) by A disintegrin and metalloprotease with thrombospondin type 1 repeats (ADAMTS13) under fluid shear stress. In this study, the structural elements of FVIII required for the rate-enhancing effect and the biological relevance of this cofactor activity are determined using a murine model. An isolated light chain of human FVIII (hFVIII-LC) increases proteolytic cleavage of VWF by ADAMTS13 under shear in a concentration-dependent manner. The maximal rate-enhancing effect of hFVIII-LC is ∼8-fold, which is comparable with human full-length FVIII and B-domain deleted FVIII (hFVIII-BDD). The heavy chain (hFVIII-HC) and the light chain lacking the acidic (a3) region (hFVIII-LCΔa3) have no effect in accelerating VWF proteolysis by ADAMTS13 under the same conditions. Although recombinant hFVIII-HC and hFVIII-LCΔa3 do not detectably bind immobilized VWF, recombinant hFVIII-LC binds VWF with high affinity (K(D), ∼15 nM). Moreover, ultra-large VWF multimers accumulate in the plasma of fVIII(-/-) mice after hydrodynamic challenge but not in those reconstituted with either hFVIII-BDD or hFVIII-LC. These results suggest that the light chain of FVIII, which is not biologically active for clot formation, is sufficient for accelerating proteolytic cleavage of VWF by ADAMTS13 under fluid shear stress and (patho) physiological conditions. Our findings provide novel insight into the molecular mechanism of how FVIII regulates VWF homeostasis.

Insulin Resistance and Risk of Ischemic Stroke Among Nondiabetic Individuals From the Northern Manhattan Study

Whether insulin resistance predicts ischemic stroke (IS) is still a matter of debate. To determine the association between insulin resistance (IR) and risk of first ischemic stroke in a large, multiethnic, stroke-free cohort without diabetes. Prospective, population-based cohort study. Longitudinal epidemiologic study. A cohort of 1509 nondiabetic participants from the Northern Manhattan Study (mean [SD] age, 11 [10] years; 64.2% women; 58.9% Hispanics). Insulin sensitivity, expressed by the homeostasis model assessment (HOMA) of insulin sensitivity (HOMA index=[fasting insulin×fasting glucose]/22.5). Insulin resistance was defined by a HOMA-IR index in the top quartile (Q4). Cox proportional hazards models were used to determine the effect of HOMA-IR on the risk of incident IS, myocardial infarction (MI), vascular death, and combined outcomes (IS, MI, and vascular death). The mean (SD) HOMA-IR was 2.3 (2.1), and Q4 was at least 2.8. During mean follow-up of 8.5 years, vascular events occurred in 180 participants; 46 had fatal or nonfatal IS, 45 had fatal or nonfatal MI, and 121 died of vascular causes. The HOMA-IR Q4 vs less than Q4 significantly predicted the risk of IS only (adjusted hazard ratio, 2.83; 95% confidence interval, 1.34-5.99) but not other vascular events. This effect was independent of sex, race/ethnicity, traditional vascular risk factors, and metabolic syndrome and its components. Insulin resistance estimated using the HOMA is a marker of increased risk of incident stroke in nondiabetic individuals. These findings emphasize the need to better characterize individuals at increased risk for IS and the potential role of primary preventive therapies targeted at IR.