Predictive value of high residual platelet reactivity by flow cytometry for outcomes of ischemic stroke patients on clopidogrel therapy.

High residual platelet reactivity (HRPR) assessed by multiple tests has been associated with worse clinical outcomes. However, the clinical impact of HRPR assessed by flow cytometry is unknown. The aim of this study was to validate the predictive value of HRPR measured by flow cytometry for clinical outcomes in ischemic stroke patients during clopidogrel therapy. Overall, 198 consecutive patients with ischemic stroke taking clopidogrel underwent platelet function testing on flow cytometer including adenosine diphosphate (ADP)-induced platelet aggregation (PAg) and platelet activation markers (CD62P, CD63, and PAC-1). Poor outcome was defined as poor prognosis and ischemic events during 12-month follow-up. By receiver operating characteristic curve analysis, residual platelet reactivity assessed by flow cytometry was able to distinguish between patients with and without poor outcomes, when platelet inhibition was evaluated with ADP-PAg (area under the curve [AUC], .77; 95% confidence interval [CI], .69-.84; P < .001), CD62P (AUC, .73; 95% CI, .64-.81; P < .001), CD63 (AUC, .72; 95% CI, .64-.80; P < .001), and PAC-1 (AUC, .70; 95% CI, .62-.78; P < .001). The prevalence of HRPR was 25.8% for ADP-PAg, 32.8% for CD62P, 41.4% for CD63, and 56.1% for PAC-1. The multiple logical regression analysis demonstrated that HRPR was an independent predictor of poor outcomes (ADP-PAg: odds ratio [OR] 13.03, 95% CI 5.66-29.98, P < .001; CD62P: OR 8.55, 95% CI 3.94-18.57, P < .001; CD63: OR 8.74, 95% CI 3.89-19.64, P < .001; PAC-1: OR 4.23, 95% CI 1.98-9.08). In conclusion, HRPR, assessed by flow cytometry, is able to detect ischemic stroke patients at increased risk of 12-month poor outcomes on clopidogrel treatment.

Systemic Immune-Inflammation Index is a Prognostic Predictor for Patients With Acute Ischemic Stroke Treated With Intravenous Thrombolysis.

OBJECTIVE: To investigate whether baseline systemic immune-inflammation index (SII) is associated with 3-month poor prognosis and early neurological outcomes in patients with acute ischemic stroke treated with intravenous thrombolysis. PATIENTS AND METHODS: A total of 221 consecutive patients were enrolled in the retrospective study. The primary endpoints were poor functional outcomes or death at 3 months. Secondary endpoints were early neurological deterioration (END) or symptomatic intracerebral hemorrhage within 24 hours. Receiver operating characteristic curve analyses was performed to assess the overall discriminative ability of SII in predicting the 4 endpoints. We also performed the Spearman correlation test to evaluate the relationship between SII and stroke severity. Univariable and multivariable logistic regression analyses were performed to evaluate the associations between SII and endpoints. RESULTS: The cutoff values of SII were 504.99×10 9 /L for predicting a 3-month poor prognosis (sensitivity, 70.9% and specificity, 69.6%), 524.47×10 9 /L for predicting 3-month death (sensitivity, 78.9% and specificity, 59.9%) and 504.99×10 9 /L for predicting END (sensitivity, 70.7% and specificity, 62.6%), respectively. A positive association between SII and the National Institutes of Health Stroke Scale was observed ( rs = 0.306, P < 0.001). Multivariable analyses indicated that SII was independently associated with 3-month poor prognosis [odds ratio (OR) = 5.384; 95% CI: 2.844-10.193; P < 0.001], 3-month death (OR = 2.592, 95% CI: 1.046-6.421, P = 0.040) and END (OR = 3.202, 95% CI: 1.796-5.707, P < 0.001). CONCLUSION: Increased baseline SII was associated with END and 3-month poor outcomes, and may act as a potential prognostic predictor for acute ischemic stroke patients treated with intravenous thrombolysis.

[Impact of adding folic acid, vitamin B(12) and probucol to standard antihypertensive medication on plasma homocysteine and asymmetric dimethylarginine levels of essential hypertension patients].

OBJECTIVE: To investigate the impact of adding folic acid, vitamin B(12) and probucol to standard antihypertensive medication on plasma homocysteine (Hcy) and asymmetric dimethylarginine (ADMA), serum NO and eNOS of essential hypertensive patients. METHOD: A total of 120 patients with hypertension were randomly divided to three groups (n = 40 each): group 1 (standard medication), group 2 (adding folic acid 5 mg/day and vitamin B(12) 500 µg twice daily) and group 3 (adding folic acid 5 mg/day and vitamin B(12) 500 µg twice daily and probucol 500 mg twice daily). Plasma Hcy and ADMA, serum NO and eNOS levels were observed at baseline, 2 and 12 weeks after various therapy. RESULTS: In group 1, concentrations of plasma Hcy [(23.06 ± 14.15) µmol/L, (23.67 ± 12.31) µmol/L, (23.25 ± 11.64) µmol/L], ADMA [(0.21 ± 0.12) µmol/L, (0.23 ± 0.13) µmol/L, (0.21 ± 0.09) µmol/L] and serum NO [(64.14 ± 15.07) µmol/L, (65.29 ± 15.04) µmol/L, (65.32 ± 13.58) µmol/L], eNOS [(20.02 ± 4.50) µg/L, (20.79 ± 4.03) µg/L, (19.82 ± 5.70) µg/L] remained unchanged during the 12 weeks therapy (all P > 0.05). In group 2, concentrations of plasma Hcy [(12.54 ± 6.49) µmol/L] and ADMA[(0.18 ± 0.07) µmol/L] were significantly decreased after the treatment of 12 weeks than the treatment baseline value [(21.51 ± 7.82) µmol/L, (0.20 ± 0.12) µmol/L] and 2 weeks value[(19.38 ± 8.14) µmol/L, (0.21 ± 0.12) µmol/L], however the concentrations of serum NO and eNOS showed contrary results of the Hcy and ADMA's. (all P < 0.05). In group 3, similar changes occurred at 2 weeks after therapy (P < 0.05 2 weeks vs. baseline and 12 weeks vs. 2 weeks). Plasma ADMA level was positively correlated with Hcy at baseline (r = 0.546, P < 0.05). CONCLUSIONS: Supplementation of folic acid, VitB(12) and/or probucol helps to improve endothelial function and reduce plasma Hcy and ADMA levels in patients with hypertension.

Clinical and MRI features about two types of silent cerebral small-vessel disease in type-2 diabetes mellitus: a retrospective cross-sectional study in a tertiary hospital.

Background: The present study aimed to evaluate the frequency of silent cerebral small-vessel disease, especially lacunes and white matter hyperintensities, in patients with or without the impaired glucose tolerance (IGT) and type-2 diabetes mellitus, and to characterize the diabetes-correlated factors related to silent cerebral small-vessel disease. Methods: This is a retrospective cross-sectional study. Totally 698 patients were included in this study, from January 2014 to December 2019, among which 270 patients were included in the diabetes mellitus group, 106 patients were included in the IGT group, and 322 patients were included in the Control group. All patients underwent magnetic resonance imaging to investigate the silent cerebral small-vessel disease: the lacunes and the white matter hyperintensities. All the baseline information and diabetes-related factors, such as glycated hemoglobin level, insulin usage, etc., were collected. Then correlation analysis and regression analysis were used to explore the correlation between diabetes with related risk factors and silent cerebral small-vessel disease. Results: Lacunes and white matter hyperintensities were more common in the diabetes mellitus group than in the IGT group and the Control group, with an occurrence of lacunes of 83.3% vs. 70.8% vs. 70.4% (P=0.003), respectively, and an occurrence of white matter hyperintensities of 41.1% vs. 24.5% vs. 31.1% (P=0.003), respectively. The occurrence of lacunes was correlated with the duration of diabetes mellitus [odds ratio (OR) =1.483, 95% confidence interval (CI): 1.082-2.031, P=0.009] and the age (OR =1.141, 95% CI: 1.102-1.180, P<0.001), while white matter hyperintensities were independently correlated only with the age (OR =1.124, 95% CI: 1.094-1.155, P<0.001). Conclusions: Lacunes and white matter hyperintensities, are more common in the diabetes mellitus patients than in the IGT patients or in the other patients. The occurrence of lacunes was correlated with the duration of diabetes mellitus and the age, while the occurrence of white matter hyperintensities was independently correlated with the age.

Relationship Between Type 2 Diabetes and White Matter Hyperintensity: A Systematic Review.

White matter (WM) disease is recognized as an important cause of cognitive decline and dementia. White matter lesions (WMLs) appear as white matter hyperintensities (WMH) on T2-weighted magnetic resonance imaging (MRI) scans of the brain. Previous studies have shown that type 2 diabetes (T2DM) is associated with WMH. In this review, we reviewed the literature on the relationship between T2DM and WMH in PubMed and Cochrane over the past five years and explored the possible links among the presence of T2DM, the course or complications of diabetes, and WMH. We found that: (1) Both from a macro- and micro-scopic point of view, most studies support the relationship of a larger WMH and a decrease in the integrity of WMH in T2DM; (2) From the relationship between brain structural changes and cognition in T2DM, the poor performance in memory, attention, and executive function tests associated with abnormal brain structure is consistent; (3) Diabetic microangiopathy or peripheral neuropathy may be associated with WMH, suggesting that the brain may be a target organ for T2DM microangiopathy; (4) Laboratory markers such as insulin resistance and fasting insulin levels were significantly associated with WMH. High HbA1c and high glucose variability were associated with WMH but not glycemic control.

Influence of CYP2C19 polymorphisms on platelet reactivity and clinical outcomes in ischemic stroke patients treated with clopidogrel.

CYP2C19 genetic polymorphisms influence clopidogrel response and clinical outcomes of cardiovascular disease. However, data on their relationship in stroke patients are scarce. We aimed to investigate the influence of CYP2C19 polymorphisms on platelet reactivity and clinical outcomes in ischemic stroke patients treated with clopidogrel. A total of 211 patients were enrolled. All patients were given clopidogrel treatment and underwent CYP2C19 genotyping and platelet function testing by flow cytometry including adenosine diphosphate-induced platelet aggregation (ADP-PAg) and platelet activation markers (PAC-1, CD62P and CD63). The modified Rankin Scale (mRS) was used and ischemic events were evaluated. A total of 129 (61.1%) of the 211 enrolled patients were carriers of CYP2C19 loss-of-function (LOF) alleles (*2, *3). After clopidogrel therapy for 7 days, the levels of ADP-PAg, PAC-1, CD62P and CD63 were higher in carriers than noncarriers. CYP2C19 carriage was associated with more frequent high residual platelet reactivity. CYP2C19 polymorphisms alone could explain 12.9%, 4.3%, 8.9% and 5.5% of the inter-individual variability of ADP-PAg, PAC-1, CD62P and CD63 after clopidogrel treatment, respectively. At 6-month follow-up, 38 (19%) patients were scored poor prognosis and 15 (7.6%) ischemic events were observed. Carriers had poorer prognosis than noncarriers (P=0.025). No significant association of CYP2C19 carriage with ischemic events was found. Multiple regression analysis showed that CYP2C19 carriage was an independent predictor of poor prognosis (odds ratio, 3.01; 95% confidence interval, 1.23-7.38; P=0.016). In conclusion, carriage of the CYP2C19 LOF allele has significant influence on clopidogrel response and prognosis in patients with ischemic stroke.

Supplementation of folic acid and vitamin B12 reduces plasma levels of asymmetric dimethylarginine in patients with acute ischemic stroke.

Increased levels of asymmetric dimethylarginine (ADMA) have been observed in patients with acute ischemic stroke. We aimed to investigate the correlation between ADMA and ischemic stroke, and evaluate the effect of supplementation of folic acid and vitamin B12 on concentrations of ADMA. Patients were randomized into intervention and non-intervention groups within 3 days after symptom onset. Intervention group patients were treated with folic acid (5mg daily) and vitamin B12 (500 µg twice daily) for 12 weeks. ADMA and homocysteine (Hcy) concentrations were measured before treatment (baseline) and 2 and 12 weeks after treatment. The laboratory measures were also collected from healthy controls. Eighty five subjects were enrolled in this study, from whom 72 with complete baseline and follow-up laboratory data were included in the present analysis. Thirty four patients were assigned to the intervention group and 38 patients to the non-intervention group. Sixty people were enrolled as healthy controls. Levels of ADMA and Hcy were raised (p<0.05) in patients with acute ischemic stroke. With supplementation of both folic acid and vitamin B12, the levels of ADMA and Hcy decreased significantly at 2 and 12 weeks (p<0.05). The present study reconfirmed that ADMA can be regarded as a risk biomarker for acute ischemic stroke. We observed that with supplementation of folic acid and vitamin B12, levels of ADMA were decreased in patients with acute ischemic stroke.