Asymmetric and symmetric dimethylarginine as markers of endothelial dysfunction in cerebrovascular disease: A prospective study.

BACKGROUND AND AIM: Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) have been proposed as mediators of endothelial dysfunction. In this study, we aimed to investigate the diagnostic and prognostic role of ADMA and SDMA in acute cerebrovascular disease. METHODS AND RESULTS: A prospective case-control study was performed, enrolling 48 patients affected by ischemic stroke with no cardioembolic origin, 20 patients affected by TIA, 40 subjects at high cardiovascular risk and 68 healthy subjects. ADMA levels were significantly lower in high-risk subjects (18.85 [11.78-22.83] µmol/L) than in patients with brain ischemic event, both transient (25.70 [13.15-40.20] µmol/L; p = 0.032) and permanent (24.50 [18.0-41.33] µmol/L; p = 0.001). SDMA levels were different not only between high-risk subjects and ischemic patients, but also between TIA and stroke patients, reaching higher levels in TIA group and lower levels in stroke group (1.15 [0.90-2.0] vs 0.68 [0.30-1.07] µmol/L; p < 0.001). SDMA was also correlated with short-term prognosis, with lower levels in case of adverse clinical course, evaluated by type of discharge (p = 0.009) and need of prolonged rehabilitation (p = 0.042). CONCLUSIONS: The present study highlights the relationship between l-arginine, ADMA, SDMA and acute cerebrovascular events. Therefore, our results suggested a potential role of SDMA as a specific marker of transient ischemic damage and as a short-term positive prognostic marker.

Prognostic value of serum albumin to creatinine ratio in patients undergoing carotid artery stenting.

BACKGROUND: We aimed to investigate the prognostic value of serum albumin-to-creatinine ratio (sACR) in carotid artery stenting (CAS) patients regarding in-hospital and 5-year outcomes. METHODS: This is a retrospective study. Baseline characteristics were compared between patients by admission albumin to creatinine ratio and categorized accordingly: T1, T2 and T3. 609 patients were included in the study. Serum albumin and creatinine levels at hospital admission were used to calculate the sACR. The primary endpoint was all-cause mortality. MACE consisted of stroke, transient ischemic attack (TIA), myocardial infarction (MI) and death. All follow-up data were obtained from electronic medical records or by interview. The study was terminated after 60 months of follow-up. RESULTS: Serum albumin levels were found to be significantly lower in T1, while creatinine was found to be significantly higher in T1. T1 has the lowest sACR while T3 has the highest. In hospital, ipsilateral stroke, major stroke, MI and death were significantly higher in T1. In long-term outcomes, ipsilateral stroke, major stroke, and death were significantly higher in T1. CONCLUSIONS: Low sACR values at hospital admission was independently associated with in-hospital and long-term mortality and major stroke in patients underwent CAS.

Serum sortilin as a predictor of stroke in patients with intermediate carotid artery stenosis.

BACKGROUND: Sortilin was an important molecular protein involved in the pathogenesis of atherosclerosis. Besides, serum sortilin was associated with adverse cerebrovascular events. Atherosclerotic stenosis in the carotid artery is a major etiology for ischemic stroke. The risk of stroke in patients with intermediate carotid artery stenosis (CAS) was unknown. Hence, the aim of the present study was to evaluate the relationship between serum sortilin levels and stroke in patients with intermediate CAS. METHODS: A total of 195 intermediate CAS patients were included in this cross-sectional study. The patients were divided into two groups as symptomatic (N = 95) and asymptomatic (N = 100) patients. Patients with a transient ischemic attack (TIA), retinal ischemic event, or ischemic stroke resulting from the narrowed carotid artery were considered to be symptomatic. Serum sortilin concentrations were measured using the enzyme-linked immunosorbent assay. RESULTS: Serum sortilin level was significantly higher in the symptomatic group than in the severe asymptomatic group (1.53 ± 0.25 ng/mL vs 1.34 ± 0.19 ng/mL, p < 0.001). Besides, high serum sortilin levels (odds ratio = 4.91, 95% confidence intervals 1.24-19.51, p = 0.023) were identified as independent predictors of symptomatic carotid plaque. In the receiver operating characteristic curve analysis, serum sortilin levels higher than 1.34 ng/mL predicted stroke/TIA with a sensitivity of 66.3% and a specificity of 67% (AUC = 0.725, p < 0.001). CONCLUSIONS: Serum sortilin level is increased in the presence of symptomatic intermediate CAS and may have clinical value in the management of patients with carotid artery disease.

Association between haemoglobin A1c and cerebral microbleeds in community-based stroke-free individuals: A cross-sectional study.

AIMS: The association between haemoglobin A1c (HbA1c) and cerebral microbleeds (CMBs) remains unclear. We aimed to investigate the association between HbA1c and CMBs in community-based individuals without stroke or transient ischaemic attack (TIA) and whether the association differs between individuals with and without diabetes mellitus (DM). MATERIALS AND METHODS: All individuals were recruited from a community in Beijing, China, from January 2015 to September 2019. All individuals completed a questionnaire and underwent blood tests and brain magnetic resonance imaging. A susceptibility-weighted imaging sequence was acquired to detect CMBs, which were defined as small, round and low-signal lesions with <10 mm diameter. The association between HbA1c and CMBs was analysed using multivariable logistic regression adjusted for demographics, medical history and blood sample test results. Subgroup analyses stratified by history of DM were performed. RESULTS: Of 544 recruited individuals, 119 (21.88%) had CMBs. HbA1c was independently associated with CMBs (odds ratio [OR], 1.51; 95% confidence interval [CI], 1.03-2.22). In 87 individuals with DM, multivariable logistic analysis showed that HbA1c was significantly associated with CMBs (OR, 1.67; 95% CI, 1.04-2.69), whereas in individuals without DM, no significant association was observed between HbA1c and CMBs (OR, 1.07; 95% CI, 0.50-2.30). CONCLUSIONS: HbA1c was associated with CMBs in individuals without stroke or TIA, particularly in individuals with DM, suggesting that the status of glycaemic control warrants attention for the prevention of CMBs. It would be beneficial to manage HbA1c specifically to control the risk of CMBs, especially in individuals with DM.

Diagnostic and Prognostic Blood Biomarkers in Transient Ischemic Attack and Minor Ischemic Stroke: An Up-To-Date Narrative Review.

INTRODUCTION: Early diagnosis and correct risk stratification in patients with transient ischemic attack (TIA) and minor ischemic stroke (MIS) is crucial for the high rate of subsequent disabling stroke. Although highly improved, diagnosis and prognostication of TIA/MIS patients remain still based on clinical and neuroimaging findings, with some inter-rater variability even among trained neurologists. OBJECTIVES: To provide an up-to-date overview of diagnostic and prognostic blood biomarkers in TIA and MIS patients. MATERIAL AND METHODS: We performed a bibliographic search on PubMed database with last access on July 10th 2021. More than 680 articles were screened and we finally included only primary studies on blood biomarkers. RESULTS: In a narrative fashion, we discussed about blood biomarkers investigated in TIA/MIS patients, including inflammatory, thrombosis, neuronal injury and cardiac analytes, antibodies and microRNAs. Other soluble molecules have been demonstrated to predict the risk of recurrent cerebrovascular events or treatment response in these patients. A rapid point of care assay, combining the determination of different biomarkers, has been developed to improve triage recognition of acute cerebrovascular accidents. CONCLUSIONS: The implementation of blood biomarkers in the clinical management of TIA/MIS could ameliorate urgent identification, risk stratification and individual treatment choice. Large prospective and longitudinal studies, adopting standardized sampling and analytic procedures, are needed to clarify blood biomarkers kinetic and their relationship with TIA and minor stroke etiology.

sTWEAK is a leukoaraiosis biomarker associated with neurovascular angiopathy.

OBJECTIVE: Leukoaraiosis (LA) refers to white matter lesions of undetermined etiology associated with the appearance and worsening of vascular pathologies. The aim is to confirm an increased frequency and intensity of LA in symptomatic patients with neurovascular pathology compared with asymptomatic subjects, and its association with circulating serum levels of soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK). METHODS: An observational study was conducted in which two groups of patients were compared. Group I (N = 242) comprised of asymptomatic subjects with arterial hypertension and/or diabetes or with a history of transient ischemic attacks, and Group II (N = 382) comprised patients with lacunar stroke or deep hemispheric intracerebral hemorrhage (ICH) of hypertensive origin. Serum levels of sTWEAK were analyzed and correlated with prevalence and intensity of LA according to the Fazekas scale. RESULTS: The prevalence of LA was higher in symptomatic (85.1%) versus asymptomatic patients (62.0%). Logistic regression model showed a significant relation of LA with neurovascular pathologies (OR: 2.69, IC 95%: 1.10-6.59, p = 0.003). When stratified according to the Fazekas scale, LA of grade II (OR: 3.53, IC 95%: 1.10-6.59, p = 0.003) and specially grade III (OR: 4.66, 95% CI: 1.09-19.84, p = 0.037) showed correlation with neurovascular pathologies. Increased sTWEAK levels were found in the symptomatic group in all LA grades (p < 0.0001), and associated with 5.06 times more risk of presenting clinical symptoms (OR: 5.06, 95% CI: 2.66-9.75, p < 0.0001). INTERPRETATION: LA showed a higher prevalence in patients with symptomatic lacunar stroke or deep hemispheric ICH. There is an association between sTWEAK levels and LA degree.

Atherogenic Dyslipidemia and Residual Vascular Risk After Stroke or Transient Ischemic Attack.

BACKGROUND AND PURPOSE: Notwithstanding the current guideline-based management, patients with stroke retain a substantial risk of further vascular events. We aimed to assess the contribution of atherogenic dyslipidemia (AD) to this residual risk. METHODS: This was a prospective observational study, in which 792 patients (mean age, 70.1 years; male, 60.2%) with acute ischemic stroke (n=710) or transient ischemic attack (n=82) within 1 week of onset were consecutively enrolled and followed for 1 year. AD was defined as having both elevated levels of triglycerides ≥150 mg/dL and low HDL-C (high-density lipoprotein cholesterol) <40 mg/dL in men or <50 mg/dL in women, under fasting conditions. The primary outcome was a composite of major adverse cardiovascular events, including nonfatal stroke, nonfatal acute coronary syndrome, and vascular death. RESULTS: The prevalence of AD was 12.2%. Patients with AD more often had intracranial artery stenosis than those without (42.3% versus 24.1%; P=0.004), whereas no differences were observed in the prevalence of extracranial artery stenosis (17.7% versus 12.9%; P=0.62) or aortic plaques (33.3% versus 27.0%; P=0.87). At 1 year, patients with AD were at a greater risk of major adverse cardiovascular events (annual rate, 24.5% versus 10.6%; hazard ratio [95% CI], 2.33 [1.44-3.80]) and ischemic stroke (annual rate, 16.8% versus 8.6%; hazard ratio [95% CI], 1.84 [1.04-3.26]) than those without AD. When patients were stratified according to baseline LDL-C (low-density lipoprotein cholesterol) level, AD was predictive of major adverse cardiovascular events among those with LDL-C ≥100 mg/dL (n=509; annual rate, 20.5% versus 9.6%; P=0.036) as well as those with LDL-C <100 mg/dL (n=283; annual rate, 38.6% versus 12.4%; P<0.001). CONCLUSIONS: AD is associated with intracranial artery atherosclerosis and a high residual vascular risk after a stroke or transient ischemic attack. AD should be a promising modifiable target for secondary stroke prevention. Registration: URL: https://upload.umin.ac.jp; Unique identifier: UMIN000031913.

Profile of reticulated platelets in the early, subacute and late phases after transient ischemic attack or ischemic stroke.

Information regarding the profile of reticulated platelets (RP) in ischemic cerebrovascular disease (CVD) patients is limited. Data from two prospective, observational, case-control studies were combined to compare the %RP using whole blood flow cytometry in patients ≤ 4 weeks of TIA/stroke onset (baseline, N = 210), and 14 ±7 days (14d, N = 182) and ≥ 90 days (90d, N = 145) after starting or changing antiplatelet therapy with healthy controls (N = 34). There were no differences in median %RP between the overall CVD patient population at baseline or 14d vs. controls (P ≥ 0.2). However, the median %RP was significantly higher in CVD patients overall at 90d (P = .036), and in the subgroup of patients with "lacunar" TIA/ischemic stroke at baseline (P = .04) and at 90d (P = .01), but not at 14d (P = .06) vs. controls. There were no significant differences in the median %RP between other TIA/stroke subgroups and controls (P ≥ 0.05). Elevated circulating reticulated platelets, as a marker of increased platelet production/turnover, may occur following an ischemic event in a well-phenotyped TIA/ischemic stroke population overall, but may precede symptom onset at least in the subgroup with small vessel occlusion. These data improve our understanding of the profile of reticulated platelets in CVD patients.

Program of Rehabilitative Exercise and Education to Avert Vascular Events After Non-Disabling Stroke or Transient Ischemic Attack (PREVENT Trial): A Randomized Controlled Trial.

BACKGROUND: Non-disabling stroke (NDS) and transient ischemic attack (TIA) herald the possibility of future, more debilitating vascular events. Evidence is conflicting about potency of exercise and education in reducing risk factors for second stroke. METHODS: Three-site, single-blinded, randomized controlled trial with 184 participants <3 months of NDS or TIA (mean age, 65 years; 66% male) randomized to usual care (UC) or UC + 12-week program of exercise and education (PREVENT). Primary (resting systolic blood pressure) and secondary outcomes (diastolic blood pressure [DBPrest], high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], total cholesterol [TC], TC/HDL, triglycerides, fasting glucose, and body mass index) were assessed at baseline, post-intervention, and 6- and 12-month follow-up. Peak oxygen consumption (VO2peak) was measured at baseline, post-intervention, 12-month assessments. RESULTS: Significant between-group differences at post-intervention favored PREVENT group over UC: DBPrest (mean difference [MD]: -3.2 mmHg, 95% confidence interval [CI]: -6.3, -.2, P = .04) and LDL-C (MD: -.31 mmol/L, 95% CI: -.42, -.20, P = .02). Trends of improvement in PREVENT group were noted in several variables between baseline and 6-month follow-up but not sustained at 12-month follow-up. Of note, VO2 peak did not change over time in either group. CONCLUSION: Impact of PREVENT on vascular risk factor reduction was more modest than anticipated, possibly because several outcome variables approximated normative values at baseline and training intensity may have been sub-optimal. Further investigation is warranted to determine when exercise and education programs are viable adjuncts to pharmaceutical management for reduction of risk factors for second stroke.Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: #NCT00885456.

Serum anti-SERPINE1 antibody as a potential biomarker of acute cerebral infarction.

The presence of disease-specific antigens and autoantibodies in the sera of patients with atherosclerosis-related diseases has been widely reported and is considered to result from inflammation of the arterial wall and the involvement of immune factors. The aim of this study was to identify a novel antibody in patients with ischemic stroke by serological identification of antigens using recombinant cDNA expression cloning from patients who had a transient ischemic attack (TIA). We identified the serpin peptidase inhibitor, clade E member 1 (SERPINE1), as a candidate antigen. The serum anti-SERPINE1 antibody levels quantified using amplified luminescent proximity homogeneous assay-linked immunosorbent assay were significantly higher in patients with ischemic stroke, including those with acute cerebral infarction (aCI), TIA, and chronic cerebral infarction, than in healthy donors. The antibody levels were strongly associated with old age, female sex, and presence of hypertension, diabetes mellitus, and cardiovascular disease. Age and intima-media thickness of the carotid artery were positively correlated with antibody levels, which suggests that SERPINE1 may reflect the progression of atherosclerosis. In a multivariate analysis, SERPINE1 antibody level was an independent predictor of aCI. Thus, the serum levels of anti-SERPINE1 antibody could potentially serve as a biomarker of atherothrombotic infarction.

Hemoglobin Concentration and Clinical Outcomes After Acute Ischemic Stroke or Transient Ischemic Attack.

Background Anemia or low hemoglobin can increase the risk of stroke. However, the association between hemoglobin and outcomes after stroke is uncertain. In this study, we aimed to investigate the association between hemoglobin and clinical outcomes, including mortality, poor functional outcome, stroke recurrence, and composite vascular events at 1 year. Methods and Results We included the patients diagnosed with acute ischemic stroke or transient ischemic attack from the Third China National Stroke Registry. We used the Cox model for mortality, stroke recurrence, and composite vascular events and the logistic model for the poor functional outcome to examine the relationship between hemoglobin and clinical outcomes. In addition, we used the restricted cubic spline to evaluate the nonlinear relationship. This study included 14 159 patients with acute ischemic stroke or transient ischemic attack. After adjusted for potential cofounders, both anemia and high hemoglobin were associated with the higher risk of mortality (hazard ratio [HR], 1.73; 95% CI, 1.39-2.15; HR, 2.71; 95% CI, 1.95-3.76) and poor functional outcome (odds ratio [OR], 1.36; 95% CI, 1.18-1.57; OR, 1.42; 95% CI, 1.07-1.87). High hemoglobin, but not anemia, increased the risk of stroke recurrence (HR, 1.37; 95% CI, 1.05-1.79) and composite vascular events (HR, 1.41; 95% CI, 1.08-1.83). There was a U-shaped relationship between hemoglobin and mortality and poor functional outcome. Conclusions Abnormal hemoglobin was associated with a higher risk of all-cause mortality, poor functional outcome, stroke recurrence, and composite vascular events. More well-designed clinical studies are needed to confirm the relationship between hemoglobin and clinical outcomes after stroke.

Association Between Plasma Trimethyllysine and Prognosis of Patients With Ischemic Stroke.

Background Trimethyllysine, a trimethylamine N-oxide precursor, has been identified as an independent cardiovascular risk factor in acute coronary syndrome. However, limited data are available to examine the role of trimethyllysine in the population with stroke. We aimed to examine the relationship between plasma trimethyllysine levels and stroke outcomes in patients presenting with ischemic stroke or transient ischemic attack. Methods and Results Data of 10 027 patients with ischemic stroke/transient ischemic attack from the CNSR-III (Third China National Stroke Registry) and 1-year follow-up data for stroke outcomes were analyzed. Plasma levels of trimethyllysine were measured with mass spectrometry. The association between trimethyllysine and stroke outcomes was analyzed using Cox regression models. Mediation analysis was performed to examine the mediation effects of risk factors on the associations of trimethyllysine and stroke outcomes. Elevated trimethyllysine levels were associated with increased risk of cardiovascular death (quartile 4 versus quartile 1: adjusted hazard ratio [HR], 1.72; 95% CI, 1.03-2.86) and all-cause mortality (quartile 4 versus quartile 1: HR, 1.97; 95% CI, 1.40-2.78) in multivariate Cox regression model. However, no associations were found between trimethyllysine and nonfatal stroke recurrence or nonfatal myocardial infarction. Trimethyllysine was associated with cardiovascular death independent of trimethylamine N-oxide. Both estimated glomerular filtration rate and hs-CRP (high-sensitivity C-reactive protein) had significant mediation effects on the association of trimethyllysine with cardiovascular death, with a mediation effect of 37.8% and 13.4%, respectively. Conclusions Elevated trimethyllysine level is associated with cardiovascular death among patients with ischemic stroke/transient ischemic attack. Mediation analyses propose that trimethyllysine contributes to cardiovascular death through inflammation and renal function, suggesting a possible pathomechanistic link.

Cardiac Troponin and Recurrent Major Vascular Events after Minor Stroke or Transient Ischemic Attack.

OBJECTIVE: This study was undertaken to investigate whether high-sensitivity cardiac troponin T (hs-cTnT) is associated with major adverse cardiovascular events (MACE) in patients with minor stroke or transient ischemic attack (TIA), and whether this association differs after risk stratification based on the Age, Blood Pressure, Clinical Features, Duration of Symptoms, Diabetes (ABCD2 ) score. METHODS: INSPiRE-TMS was a randomized controlled trial allocating patients with minor stroke or TIA to an intensified support program or conventional care. In this post hoc analysis, participants were categorized using hs-cTnT levels (5th generation; Roche Diagnostics, Manheim, Germany; 99th percentile upper reference limit [URL] = 14ng/l). Vascular risk was stratified using the ABCD2 score (lower risk = 0-5 vs higher risk = 6-7). Cox proportional hazard regression was performed using covariate adjustment and propensity score matching (PSM) for the association between hs-cTnT and MACE (stroke/nonfatal coronary event/vascular death). RESULTS: Among 889 patients (mean age = 70 years, 37% female), MACE occurred in 153 patients (17.2%) during a mean follow-up of 3.2 years. hs-cTnT was associated with MACE (9.3%/yr, >URL vs 4.4%/yr, ≤URL, adjusted hazard ratio [HR] = 1.63 [95% confidence interval (CI) = 1.13-2.35], adjusted HR [Q4 vs Q1 ] = 2.57 [95% CI = 1.35-4.97], adjusted HR [log-transformed] = 2.31 [95% CI = 1.37-3.89]). This association remained after PSM (adjusted HR = 1.76 [95% CI = 1.14-2.72]). There was a significant interaction between hs-cTnT and ABCD2 category for MACE occurrence (pinteraction  = 0.04). In the lower risk category, MACE rate was 9.5%/yr in patients with hs-cTnT > URL, which was higher than in those ≤URL (3.8%/yr) and similar to the overall rate in the higher risk category. INTERPRETATION: hs-cTnT levels are associated with incident MACE within 3 years after minor stroke or TIA and may help to identify high-risk individuals otherwise deemed at lower risk based on the ABCD2 score. If confirmed in independent validation studies, this might warrant intensified secondary prevention measures and cardiac diagnostics in stroke patients with elevated hs-cTnT. ANN NEUROL 2021;90:901-912.

Association of serum levels of antibodies against ALDOA and FH4 with transient ischemic attack and cerebral infarction.

BACKGROUND: Ischemic stroke, including transient ischemic attack (TIA) and acute-phase cerebral infarction (aCI), is a serious health problem in the aging society. Thus, this study aimed to identify TIA and aCI biomarkers. METHODS: In 19 patients with TIA, candidate antigens recognized by serum IgG autoantibodies were screened using a human aortic endothelial cell cDNA library. Through amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA), serum antibody levels against the candidate antigens were examined in healthy donor (HD), TIA, and aCI cohorts (n = 285, 92, and 529). The plasma antibody levels in the Japan Public Health Center-based Prospective Cohort Study (1991-1993) were also examined. RESULTS: The candidate antigens were aldolase A (ALDOA) and fumarate hydratase (FH). In AlphaLISA, patients with TIA or aCI had higher anti-ALDOA antibody (ALDOA-Ab) and anti-FH antibody (FH-Ab) levels than the HDs (P < 0.05). In a multivariate logistic regression analysis, the ALDOA-Ab (odds ratio [OR]: 2.46, P = 0.0050) and FH-Ab (OR: 2.49, P = 0.0037) levels were independent predictors of TIA. According to the case-control study, the ALDOA-Ab (OR: 2.50, P < 0.01) and FH-Ab (OR: 2.60, P < 0.01) levels were associated with aCI risk. In a correlation analysis, both ALDOA-Abs and FH-Abs were well associated with hypertension, coronary heart disease, and habitual smoking. These antibody levels also correlated well with maximum intima-media thickness, which reflects atherosclerotic stenosis. CONCLUSIONS: ALDOA-Abs and FH-Abs can be novel potential biomarkers for predicting atherosclerotic TIA and aCI.

Comparison of VerifyNow, thromboelastography, and PL-12 in patients with minor ischemic stroke or transient ischemic attack.

High on-treatment platelet reactivity (HOPR) is associated with stroke recurrence. It is important to find a reliable method to assess HOPR. We aimed to compare the correlations between VerifyNow™ system, thromboelastography (TEG), and Aggrestar platelet function analyzer (PL-12) on platelet activity in patients with minor ischemic stroke or transient ischemic attack (TIA) after dual antiplatelet therapy for 7 days. About 276 patients were included. Spearman's correlation coefficient and the kappa coefficient were adopted to evaluate associations among the three test methods. An obvious correlation between VerifyNow and TEG on HOPR-ADP (r=0.64, p<0.001) was found. The correlations of HOPR-ADP between PL-12 and the other two platelet function analyzers were moderate (PL-12 versus VerifyNow, r=0.47, p<0.001; PL-12 versus TEG, r=0.25, p<0.001). The correlations of HOPR-AA were limited among these three platelet function analyzers (VerifyNow versus TEG, r=0.09, p=0.14; VerifyNow versus PL-12, r=0.15, p=0.01; PL-12 versus TEG, r=0.10, p=0.09). Correlations among different platelet function analyzers were varied. VerifyNow and TEG were more correlative than PL-12 on HOPR-ADP. The consistence of HOPR-AA was limited among VerifyNow, TEG and PL-12. The proportion of stroke recurrence and composite events in patients with HOPR-ADP assessing by PL-12 was higher than VerifyNow and TEG.

The aptamer BT200 blocks von Willebrand factor and platelet function in blood of stroke patients.

The effect of conventional anti-platelet agents is limited in secondary stroke prevention, and their effects are blunted under high shear stress in the presence of increased levels of circulating von Willebrand factor (VWF). VWF is critically involved in thrombus formation at sites of stenotic extracranial/intracranial arteries. A third generation anti-VWF aptamer (BT200) has been generated which could be useful for secondary stroke prevention. To characterize the effects of BT200 in blood of patients with large artery atherosclerosis stroke (LAA). Blood samples were obtained from 33 patients with acute stroke or transient ischemic attack to measure inhibition of VWF activity and VWF-dependent platelet function. Patients who received clopidogrel or dual antiplatelet therapy did not differ in VWF dependent platelet function tests from aspirin treated patients. Of 18 patients receiving clopidogrel with or without aspirin, only 3 had a prolonged collagen adenosine diphosphate closure time, and none of the patients had ristocetin induced aggregation in the target range. BT200 concentration-dependently reduced median VWF activity from 178 to < 3%, ristocetin induced platelet aggregation from 40U to < 10U and prolonged collagen adenosine diphosphate closure times from 93 s to > 300 s. Baseline VWF activity correlated (r = 0.86, p < 0.001) with concentrations needed to reduce VWF activity to < 20% of normal, indicating that BT200 acts in a target concentration-dependent manner. Together with a long half-life supporting once weekly administration, the safety and tolerability observed in an ongoing phase I trial, and the existence of a reversal agent, BT200 is an interesting drug candidate.

Risk factor control after ischemic stroke or transient ischemic attack.

OBJECTIVE: We aimed to estimate the status of risk factor control after ischemic stroke or transient ischemic attack (IS/TIA), and the influence on recurrent stroke in rural communities of northeastern China. METHODS: This population-based, prospective cohort study enrolled adults aged ≥35 years residing in rural northeastern China. We conducted cardiovascular health examinations in 2012-2015 and followed up in 2018 to record any cardiovascular event. Control of risk factors after IS/TIA was determined through a baseline survey. The Cox proportional hazard model was used to evaluate the relationship between uncontrolled risk factors and stroke recurrence. RESULTS: Of the 10,700 participants, 575 were diagnosed with IS/TIA and were included in the analysis. At baseline, the rates of control of risk factors were as follows: fasting plasma glucose (FPG), 81.6%; not currently smoking, 65.7%; and achieving physical activity targets, 61%. Blood pressure (BP), low-density lipoprotein cholesterol (LDL-C), and body mass index (BMI) were poorly controlled (28.3%, 26.3%, and 37.4%, respectively). The rate of stroke recurrence was 12% during a median follow-up of 4.43 years. After adjusting for age, sex, ethnicity, family history of stroke, and current drinking, uncontrolled BP and not achieving physical exercise targets were associated with an increased risk of recurrence (hazard ratios: 2.081, 1.685, respectively; p < .05). Uncontrolled FPG, BMI, or LDL-C and current smoking did not significantly influence recurrent risk (p > .05). CONCLUSIONS: Control of risk factors after IS/TIA needs to be improved in rural communities of northeastern China to prevent recurrence and thus alleviate the public health and economic burden of stroke.

Association of Level and Increase in D-Dimer With All-Cause Death and Poor Functional Outcome After Ischemic Stroke or Transient Ischemic Attack.

Background D-dimer is involved in poor outcomes of stroke as a coagulation biomarker. We aimed to investigate the associations of the level and increase in D-dimer between baseline and 90 days with all-cause death or poor functional outcome in patients after ischemic stroke or transient ischemic attack. Methods and Results We collected data from the CNSRIII (Third China National Stroke Registry) study. The present substudy included 10 518 patients within 7 days (baseline) of ischemic stroke or transient ischemic attack and 6268 patients at 90 days. Poor functional outcome at 1 year was assessed on the basis of the modified Rankin Scale (≥3). Multivariable Cox regression or logistic regression was used to assess the association of D-dimer levels with all-cause death or poor functional outcome. D-dimer levels at 90 days were lower than those at baseline (1.4 µg/mL versus 1.7 µg/mL; P<0.001). Higher baseline D-dimer level was associated with all-cause death (adjusted hazard ratio [HR], 1.77; 95% CI, 1.25-2.52; P=0.001) and poor functional outcome (adjusted odds ratio [OR], 1.49; 95% CI, 1.23-1.80; P<0.001) during 1-year follow-up. Higher D-dimer level at 90 days was also associated with poor outcomes independently. Furthermore, an increase in D-dimer levels between baseline and 90 days was associated with all-cause death (since 90 days to 1 year after index event) (adjusted HR, 1.99; 95% CI, 1.12-3.53; P=0.019) but not with poor functional outcome (adjusted OR, 1.08; 95% CI, 0.82-1.41). Conclusions Our study shows that high level and an increase in D-dimer between baseline and 90 days are associated with poor outcomes in patients after ischemic stroke or transient ischemic attack.

Inhibitory Effects of P2Y12 Receptor Antagonist on PAR1- and PAR4-AP-Induced Platelet Aggregation in Patients with Stroke or TIA.

OBJECTIVES: The inhibitory effects of P2Y12 receptor antagonist on PAR1- and PAR4-activating peptide (AP)-induced platelet aggregation have not been fully elucidated. The present study aimed to investigate the inhibitory effects of P2Y12 receptor antagonist on PAR1- and PAR4-AP-induced platelet aggregation using platelet-rich plasma (PRP) from individuals including patients with stroke or transient ischemic attack (TIA). MATERIALS AND METHODS: PRP was given to 10 healthy individuals pretreated in vitro with cangrelor, then stimulated with adenosine diphosphate (ADP), PAR4-AP, or PAR1-AP. Moreover, 20 patients were enrolled from 148 consecutive patients with acute ischemic stroke or TIA admitted to our institute between December 2017 and April 2019. PRP obtained from each patient before and >7 days after initiation of clopidogrel was similarly stimulated with these agonists. Platelet aggregation was measured using an automatic coagulation analyzer in all participants. RESULTS: In healthy individuals, ADP- and PAR4-AP-induced platelet aggregations were significantly inhibited depending on the cangrelor concentration in vitro, while PAR1-AP-induced platelet aggregation was slightly inhibited. In patients with stroke or TIA, clopidogrel inhibited ADP-induced platelet aggregation at all concentrations, and significantly inhibited PAR4-AP-induced platelet aggregation at 50 µmol/L of PAR4-AP (p<0.05), especially in 5 patients who showed high reactivity to PAR4-AP. PAR1-AP-induced platelet aggregation was also slightly inhibited. CONCLUSIONS: We showed significant inhibitory effects on PAR4-AP-induced platelet aggregation by clopidogrel in patients with stroke or TIA who had high reactivity to PAR4-AP.

Early neutrophil-to-lymphocyte ratio is a prognostic marker in acute minor stroke or transient ischemic attack.

Intravenous injection of alteplase is recommended for patients with minor disabling and not non-disabling ischemic stroke symptoms within 4.5 h of ischemic stroke symptom onset. However, it is hard for clinicians to distinguish which type of minor ischemic stroke is disabled at an early stage. In this study, we aimed to demonstrate early neutrophil-to-lymphocyte ratio is a prognostic marker in acute minor stroke or transient ischemic attack. 196 patients diagnosed with acute minor stroke or transient ischemic attack within 24 h of symptom onset were enrolled. Patients were divided into three groups according to the neutrophil-to-lymphocyte ratio value (< 2, 2-3, > 3). Clinical, neuroradiological, laboratory and follow-up data were collected from electronic database. Functional outcome was assessed by modified Rankin Scale. Neutrophil-to-lymphocyte ratio associated with functional outcome of 90 days was evaluated by logistic regression analysis, and we used receiver operating characteristic curve analysis to detect the overall predictive accuracy of this marker. Early neutrophil-to-lymphocyte ratio was associated with an increased risk of short-term functional outcome (OR 4.502, 95% CI 1.533-13.046, P = 0.006). The optimal cutoff value of neutrophil-to-lymphocyte ratio for prediction of short-term unfavorable outcome was 2.94 with a sensitivity of 69.6% and a specificity of 77.1% (area under the curve: 0.767, 95% CI 0.691-0.843). Early neutrophil-to-lymphocyte ratio is associated with short-term unfavorable functional outcome in patients with acute minor stroke or transient ischemic attack. Early neutrophil-to-lymphocyte ratio is beneficial for clinicians to distinguish minor disabling ischemic stroke at an early stage.