Association of Urine Albumin-Creatinine Ratio and Cystatin C-Based Estimated GFR with Outcomes in Patients with Ischemic Stroke.

BACKGROUND/AIMS: Data about the independent and combined effects of cystatin C-based estimated glomerular filtration rate (eGFRcys) and albuminuria on the risk of poor outcome in stroke patients are limited. The aim was to elucidate how these two renal markers affect the clinical outcomes after ischemic stroke separately and jointly. METHODS: The study subjects consisted of 10,197 patients with ischemic stroke from the third China National Stroke Registry. The study outcomes were all-cause mortality, poststroke disability, recurrence of stroke, and cardiocerebral vascular disease (CVD) composite events. Cox proportional hazard models and multivariable logistic regression model were applied to evaluate the effects of eGFRcys and urine albumin-creatinine ratio (ACR) on these outcomes. RESULTS: Both reduced eGFRcys and increased ACR were independently associated with higher incidences of all-cause death and poststroke disability (p < 0.01). Mildly decreased eGFRcys (60-89 mL/min/1.73 m2) is associated with increased risk of all-cause death and poststroke disability in the presence of high-normal ACR (10-29 mg/g). Patients with both eGFRcys <45 mL/min/1.73 m2 and ACR ≥30 mg/g at baseline had a 6.8-fold risk for all-cause mortality and 3.6-fold risk for poststroke disability, compared with patients with eGFRcys of 90-119 mL/min/1.73 m2 and ACR <10 mg/g. In addition, increased ACR was associated with recurrent stroke and CVD composite event, while reduced eGFRcys showed no relationship with these outcomes. CONCLUSIONS: Both decreased eGFRcys and albuminuria are independent risk factors for all-cause death and poststroke disability. Combining the two markers is useful for improving risk stratification even in those without chronic kidney disease.

Elevated Urinary Titin and its Associated Clinical Outcomes after Acute Stroke.

INTRODUCTION: Urinary titin is a biomarker of muscle atrophy, which is a serious complication after stroke. However, there are currently no clinical data regarding urinary titin in stroke patients. METHODS: Consecutive stroke patients admitted to the stroke care unit were included. Spot urine samples were collected immediately after admission, and on days 3, 5, and 7. The primary outcome was the trend of urinary titin in patients after acute stroke. The secondary outcomes included the association between the peak urinary titin level and the modified Rankin Scale (mRS) score, the National Institutes of Health Stroke Scale (NIHSS) score, and the Barthel index (BI) upon hospital discharge. Multivariate analysis was adjusted for age, sex, NIHSS at admission, and the peak urinary titin to predict poor outcome (mRS 3-6). RESULTS: Forty-one patients were included (29 male; age, 68 ± 15 years), 29 had ischemic stroke, 8 had intracerebral hemorrhage, and 4 had subarachnoid hemorrhage. The levels of urinary titin on days 1, 3, 5, and 7 were 9.9 (4.7-21.1), 16.2 (8.6-22.0), 8.9 (4.8-15.2), and 8.7 (3.6-16.2) pmol/mg Cr, respectively. The peak urinary titin level was associated with the mRS score (r = 0.55, p < 0.01), the NIHSS score (r = 0.72, p < 0.01), and the BI (r = -0.59, p < 0.01) upon hospital discharge. In multivariate analysis, the peak urinary titin was associated with poor outcome (p = 0.03). CONCLUSIONS: Urinary titin rapidly increased after stroke and was associated with impaired functional outcomes at hospital discharge.

Potential Metabolite Biomarkers for Acute Versus Chronic Stage of Ischemic Stroke: A Pilot Study.

BACKGROUND: Metabolome profiling is used to identify biomarkers for acute ischemic stroke (AIS). Previous studies compared metabolite profiles in AIS and healthy controls, which did not account for factors that affect metabolome (genetics, medications). This pilot project evaluates the change in metabolite concentrations between the acute and chronic stage of stroke in the same cohort in order to minimize other factors impact. METHODS: We performed global metabolome profile on serum of 20 and urine of 12 stroke patients in acute (72 hours) and chronic (3-5.2 months) stage and compared relative peak values using Wilcoxon and orthogonal partial least squares discriminant analysis methods. Chronic stage metabolite concentrations were considered baseline. We performed analysis to identify significantly overrepresented pathways using MetaboAnalyst. RESULTS: Three serum metabolites asparagine (P = .045), tyrosine (P = .015), and xylose (P = .003) had significantly higher concentrations in acute stage. Seven out of top 10 serum metabolites ranked by Wilcoxon test P value were related to amino acid (AA) metabolism. Two urine metabolites glycine (P = .03) and acetylcarnitine (P = .05) had significantly different concentrations in the acute stage. Five of the top 10 urine metabolites related to AA metabolism. We identified 6 significant pathways after false discovery rate correction that were upregulated in the acute stage: (1) Aminoacyl-tRNA synthesis, (2) nitrogen, (3) alanine, aspartate, and glutamate, (4) branched-chain AA, (5) arginine and proline, and (6) phenylalanine metabolism. CONCLUSION: Longitudinal study design confirms that AA metabolism heavily involved in the pathophysiology of acute brain ischemia. Prospective longitudinal studies with a higher number of participants are needed to establish useful stroke biomarkers.

Early renal dysfunction and fibroblast growth factor-23 in patients with small vessel disease-related stroke.

Interactions between cerebral small vessel disease (CSVD) and renal dysfunction (RD) have been reported, but previous studies were mostly retrospective and limited to measurements of estimated glomerular filtration rate (eGFR). In this prospective, longitudinal study of patients with CSVD-related recent small subcortical infarcts (RSSI), we aimed at a comprehensive exploration of markers of early RD and their association with microvascular brain damage. We investigated 101 stroke patients (mean age: 60.2 ± 10.7 years) with an MRI-confirmed RSSI who underwent follow-up brain MRI 15 months post-stroke. Besides serum creatinine and eGFR, we assessed urinary Albumin-Creatinine Ratio and fibroblast growth factor-23 (FGF-23). RD was classified according to recent Kidney Disease: Improving Global Outcomes criteria. We identified 24 patients with RD, only six patients revealed an eGFR <60 mL/min/1.73 m². RSSI patients with RD more often had severe white matter hyperintensities (WMH, 58% vs. 36%, p = 0.04). CSVD progression was not dependent on RD. However, patients in the highest FGF-23 quartile more frequently had new microangiopathic lesions on follow-up MRI (50% vs. 21%, p = 0.03). Early RD was found in a quarter of RSSI patients and associated with WMH severity, but not CSVD progression. High FGF-23 indicates an increased risk for ongoing microvascular brain damage, warranting further studies.

The role of blood pressure in risk of ischemic and hemorrhagic stroke in type 1 diabetes.

BACKGROUND: Hypertension is one of the strongest risk factors for stroke in the general population, while systolic blood pressure has been shown to independently increase the risk of stroke in type 1 diabetes. The aim of this study was to elucidate the association between different blood pressure variables and risk of stroke in type 1 diabetes, and to explore potential nonlinearity of this relationship. METHODS: We included 4105 individuals with type 1 diabetes without stroke at baseline, participating in the nationwide Finnish Diabetic Nephropathy Study. Mean age at baseline was 37.4 ± 11.9 years, median duration of diabetes 20.9 (interquartile range 11.5-30.4) years, and 52% were men. Office systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured. Based on these pulse pressure (PP) and mean arterial pressure (MAP) were calculated. Strokes were classified based on medical and autopsy records, as well as neuroimaging. Cox proportional hazard models were performed to study how the different blood pressure variables affected the risk of stroke and its subtypes. RESULTS: During median follow-up time of 11.9 (9.21-13.9) years, 202 (5%) individuals suffered an incident stroke; 145 (72%) were ischemic and 57 (28%) hemorrhagic. SBP, DBP, PP, and MAP all independently increased the risk of any stroke. SBP, PP, and MAP increased the risk of ischemic stroke, while SBP, DBP, and MAP increased the risk of hemorrhagic stroke. SBP was strongly associated with stroke with a hazard ratio of 1.20 (1.11-1.29)/10 mmHg. When variables were modeled using restricted cubic splines, the risk of stroke increased linearly for SBP, MAP, and PP, and non-linearly for DBP. CONCLUSIONS: The different blood pressure variables are all independently associated with increased risk of stroke in individuals with type 1 diabetes. The risk of stroke, ischemic stroke, and hemorrhagic stroke increases linearly at blood pressure levels less than the current recommended treatment guidelines.

Increased Spot Urine Albumin-to-Creatinine Ratio and Stroke Incidence: A Systematic Review and Meta-Analysis.

OBJECTIVE: This study aimed to clarify the association between an increased spot urine albumin-to-creatinine ratio (UACR) and the risk of stroke. METHODS: We performed a systematic review and meta-analysis of cohort studies, case-control studies, and ancillary data randomized controlled trials (RCTs), which were treated as cohorts in this study, and estimated the association between albuminuria, as measured with the UACR, and the risk of stroke. We performed a comprehensive search of PubMed, Embase, and the Cochrane Library and conducted a systematic review and cumulative meta-analysis of cohort studies with a cross-sectional with prospective design in which stroke incidence was reported and the baseline UACR was measured. Ancillary data from RCTs were also included as part of the cohort study. We studied the characteristics of the participants, quality scores and risk ratios (RR, with confidence intervals, CI) of stroke associated with normal and high UACRs, and we synthesized the data via a meta-analysis. RESULTS: Twelve eligible studies including a total of 32,888 participants and 3,944 cases of stroke were identified. A high UACR (>30 mg/mmol) increased the risk of stroke by 1.67 times (RR: 1.67, 95% CI: 1.49-1.86, P<0.001 I2 = 26%). The results were not different between Asian and non-Asian patients (RR: 1.64, 95% CI: 1.41-1.91, P<0.001, I2 = 23% compared with RR: 1.67, 95% CI: 1.50-1.85, P<0. 00, I2 = 39%) or between subgroups classified by old age (RR: 1.61, 95% CI: 1.39-1.88, P<0.001, I2 = 34% compared with RR: 1.68, 95% CI: 1.52-1.87, P<0.001, I2 = 13%). A sensitivity analysis did not significantly change the results. CONCLUSION: The incidence of stroke increased significantly in the high UACR group compared with the normal UACR group. The UACR could be a clinical addition for the early indication of high-risk stroke patients.

Mass spectrometry-based urinary metabolomics for the investigation on the mechanism of action of Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. leaves against ischemic stroke in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: As a traditional Chinese medicine, Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. leaves (ESL) can treat ischemic, neurasthenia, and hypertension diseases. However, only few studies have been conducted on the mechanism of action of ESL for ischemic disease treatment. AIM OF THE STUDY: This study aimed to discover the potential biomarkers in the rats caused by ischemic stroke and build a gene-enzyme-biomarker network to explore the mechanism of ESL treatment on ischemic stroke further. MATERIALS AND METHODS: The urinary metabolomics strategy was developed by combining UPLC-Q-TOF/MS with multivariate data analysis. The gene-enzyme-biomarker network was built by Cytoscape 3.6.0 on the basis of the potential biomarkers filtered out via urinary metabolomic analysis. Then, the potential target enzymes of ESL in the treatment of ischemic stroke were selected for further validation analysis via the ELISA kits. RESULTS: A total of 42 biomarkers associated with ischemic stroke have been identified, among which 38 species can be adjusted by ESL, including 5'-methylthioadenosine, prostaglandin A2, l-methionine, aldosterone, 11b-hydroxyprogesterone, prostaglandin E3, dehydroepiandrosterone, taurine, 5-methoxyindoleacetate, and p-cresol glucuronide. These biomarkers were involved in several metabolic pathways, including taurine and hypotaurine, arachidonic acid, cysteine and methionine, steroid hormone biosynthesis, tryptophan, and tyrosine metabolism pathways. The gene-enzyme-biomarker network was built, and three predicted target proteins, including cyclooxygenase-2 (COX-2), monoamine oxidase (MAO), and nitric oxide synthase (NOS), were selected as the potential target enzymes for ESL in ischemic stroke treatment. CONCLUSIONS: All results showed that ESL can play a therapeutic role in treating ischemic stroke through different pathways. This study will provide an overall view of the mechanism underlying the action of ESL against ischemic stroke.

A NMR-Based Metabonomics Approach to Determine Protective Effect of a Combination of Multiple Components Derived from Naodesheng on Ischemic Stroke Rats.

Naodesheng (NDS) is a widely used traditional Chinese medicine (TCM) prescription for the treatment of ischemic stroke. A combination of 10 components is derived from NDS. They are: Notoginsenoside R1, ginsenoside Rg1, ginsenoside b1, ginsenoside Rd, hydroxysafflor yellow A, senkyunolide I, puerarin, daidzein, vitexin, and ferulic acid. This study aimed to investigate the protective effect of the ten-component combination derived from NDS (TCNDS) on ischemic stroke rats with a middle cerebral artery occlusion (MCAO) model by integrating an NMR-based metabonomics approach with biochemical assessment. Our results showed that TCNDS could improve neurobehavioral function, decrease the cerebral infarct area, and ameliorate pathological features in MCAO model rats. In addition, TCNDS was found to decrease plasma lactate dehydrogenase (LDH) and malondialdehyde (MDA) production and increase plasma superoxide dismutase (SOD) production. Furthermore, 1H-NMR metabonomic analysis indicated that TCNDS could regulate the disturbed metabolites in the plasma, urine, and brain tissue of MCAO rats, and the possible mechanisms were involved oxidative stress, energy metabolism, lipid metabolism, amino acid metabolism, and inflammation. Correlation analysis were then performed to further confirm the metabolites involved in oxidative stress. Correlation analysis showed that six plasma metabolites had high correlations with plasma LDH, MDA, and SOD. This study provides evidence that an NMR-based metabonomics approach integrated with biochemical assessment can help to better understand the underlying mechanisms as well as the holistic effect of multiple compounds from TCM.

Salt and cardiovascular disease in PURE: A large sample size cannot make up for erroneous estimations.

The latest Prospective Urban Rural Epidemiology (PURE) study claims that salt reduction should be confined to settings where its intake exceeds 12.7 g/day and that eating less than 11.1 g/day of salt could increase cardiovascular risk. More specifically, Mente et al. suggested that (a) salt intake was positively associated with stroke only when it exceeded 12.7 g/day, (b) salt intake was inversely associated with myocardial infarction and total mortality, and (c) these associations were largely independent of blood pressure. These provocative findings challenge the robust evidence on the role of salt reduction in the prevention of cardiovascular disease and call into question the World Health Organization's global recommendation to reduce salt intake to less than 5 g/day. However, Mente et al.'s re-analysis of the PURE data has several severe methodological problems, including erroneous estimations of salt intake from a single spot urine using the problematic Kawasaki formula. As such, these implausible results cannot be used to refute the strong evidence supporting the benefits of salt reduction for the general population worldwide.

Gender differences in the association of syndecan-4 with myocardial infarction: The population-based Tromsø Study.

BACKGROUND AND AIMS: Cardiovascular disease is a common cause of morbidity and mortality, with gender differences in pathophysiology. The endothelial glycocalyx maintains vascular integrity, and glycocalyx shedding reflects endothelial dysfunction and early atherosclerosis. Syndecan-1 and -4 are components of the glycocalyx, and increased serum levels indicate glycocalyx damage. We hypothesised that increased serum syndecan-1 and -4 were independently associated with myocardial infarction (MI), ischaemic stroke and all-cause mortality in men and women from a general population. METHODS: Using a case-cohort design, we included 1495 participants from the Tromsø Study 2001-02. Syndecan-1 and -4 were measured in serum. Baseline variables also included age, gender, cardiovascular risk factors and urinary albumin-creatinine ratio (ACR). Hazard ratios were assessed using multivariable Cox regression models. RESULTS: Between baseline in 2001-02 and December 2007 fatal or non-fatal MI was experienced by 328 and ischaemic stroke by 191 subjects, and 423 participants died. Syndecan-4 was independently associated with MI (hazard ratio per 10 ng/mL increase 1.32; 95% confidence interval 1.06-1.63), but not ischaemic stroke and mortality, and the associations were unchanged by adjustment for urinary ACR. Interaction between syndecan-4 and sex was borderline significant, and in gender-specific analysis, syndecan-4 was associated with MI in women only. Syndecan-1 was not associated with any endpoint. CONCLUSIONS: Syndecan-4 was associated with incident MI, and the association was stronger in women than in men. This suggests a link between endothelial glycocalyx shedding and coronary heart disease in women. Use of syndecan-4 as a risk marker in clinical setting needs further investigation.

Prediction of myocardial infarction, stroke and cardiovascular mortality with urinary biomarkers of oxidative stress: Results from a large cohort study.

BACKGROUND: Oxidative stress contributes to endothelial dysfunction and is involved in the pathogenesis of cardiovascular diseases (CVD). However, large population-based cohort studies are sparse and biomarkers of oxidative stress have not been evaluated for CVD risk prediction so far. METHODS: The associations of urinary oxidized guanine/guanosine (OxGua) levels (including 8-hydroxy-2'-deoxyguanosine (8-OHdGuo)) and 8-isoprostane levels with myocardial infarction, stroke and CVD mortality were examined in a population-based cohort of 9949 older adults from Germany with 14 years of follow-up in multivariable adjusted Cox proportional hazards models. RESULTS: Both OxGua and 8-isoprostane levels were associated with CVD mortality independently from other risk factors (hazard ratio (HR) [95% confidence interval] of top vs. bottom tertile: 1.32 [1.06; 1.64] and 1.58 [1.27; 1.98], respectively). Moreover, CVD mortality risk prediction was significantly improved when adding the two biomarkers to the European Society of Cardiology's Systematic Coronary Risk Evaluation (ESC SCORE) tool. The area under the curve (AUC) increased from 0.739 to 0.752 (p = 0.001). In addition, OxGua levels were associated with stroke incidence (HR for 1 standard deviation increase: 1.07 [1.01; 1.13]) and 8-isoprostane levels were associated with fatal stroke incidence (HR of top vs. bottom tertile: 1.77 [1.09; 2.89]). With respect to myocardial infarction, associations were observed for both biomarkers in obese subjects (BMI ≥ 30 kg/m2). CONCLUSIONS: These results from a large cohort study add evidence to the involvement of an imbalanced redox system to the etiology of CVD. In addition, 8-isoprostane and OxGua measurements were shown to be useful for an improved CVD mortality prediction.

Abnormal admission kidney function predicts higher mortality in stroke patients.

OBJECTIVE: To investigate the impact of abnormal kidney function on stroke outcome. METHODS: This was a retrospective cohort of stroke patients admitted to King Abdulaziz University Hospital in Kingdom of Saudi Arabia between 2010 and 2014. Serum creatinine and urine protein were collected at admis-sion. We defined proteinuria as urine protein dipstick >/=+1. Estimated glomerular filtration (eGFR) rate was calculated by Modification of Diet in Renal Disease Study equation in mL/min/1.73m2. Abnormal kidney disease was defined as Creatinine>126 mg/dl or eGFR<60. Clinical characteristics and outcomes including one-year mortality and 30-day readmission were compared between patients with versus (vs.) without abnormal kidney function and/or proteinuria. RESULTS: Out of 548 patients, 507 had creatinine measurement at admission and 193 patients had ab-normal kidney function. These patients tended to be older (median age 67 years vs. 60.5 for those with normal kidney function), men (66.7% vs. 54.3%), and hypertensive (96% vs. 88%). Diabetes prevalence did not differ between the 2 groups. Proteinuria was not associ-ated with future mortality. Abnormal kidney function was a significant predictor of post-stroke one-year mortality (adjusted OR=2.5, 95% CI=1.4 to 4.6; p-value=0.003). CONCLUSION: Abnormal kidney function doubled the risk of one-year mortality post stroke in our cohort. High-risk groups, including older hypertensive men, could be targeted for aggressive moni-toring and early treatment of risk factors.

Urinary cadmium concentration and the risk of ischemic stroke.

OBJECTIVES: To examine the association between urinary cadmium levels and the incidence of ischemic stroke and to explore possible effect modifications. METHODS: A case-cohort study was designed nested in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, including 680 adjudicated incident cases of ischemic stroke and 2,540 participants in a randomly selected subcohort. Urinary creatinine-corrected cadmium concentration was measured at baseline. Multivariable-adjusted hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were estimated with the Barlow weighting method for the Cox proportional hazards regression model. RESULTS: The median urinary cadmium concentration was 0.42 (interquartile range 0.27-0.68) µg/g creatinine. After adjustment for potential confounders, urinary cadmium was associated with increased incidence of ischemic stroke (quintile 5 vs quintile 1: HR 1.50, 95% CI 1.01-2.22, p for trend = 0.02). The observed association was more pronounced among participants in the lowest serum zinc tertile (tertile 3 vs tertile 1: HR 1.82, 95% CI 1.06-3.11, p for trend = 0.004, p for interaction = 0.05) but was attenuated and became nonsignificant among never smokers (tertile 3 vs tertile 1: never smokers: HR 1.27, 95% CI 0.80-2.03, p for trend = 0.29; ever smokers: HR 1.60, 95% CI 1.06-2.43, p for trend = 0.07, p for interaction = 0.51). CONCLUSIONS: Findings from this study suggest that cadmium exposure may be an independent risk factor for ischemic stroke in the US general population. Never smoking and maintaining a high serum zinc level may ameliorate the potential adverse effects of cadmium exposure.

Arsenic Exposure in Relation to Ischemic Stroke: The Reasons for Geographic and Racial Differences in Stroke Study.

BACKGROUND AND PURPOSE: The purpose of this case-cohort study was to examine urinary arsenic levels in relation to incident ischemic stroke in the United States. METHODS: We performed a case-cohort study nested within the REGARDS (REasons for Geographic and Racial Differences in Stroke) cohort. A subcohort (n=2486) of controls was randomly sampled within region-race-sex strata while all incident ischemic stroke cases from the full REGARDS cohort (n=671) were included. Baseline urinary arsenic was measured by inductively coupled plasma-mass spectrometry. Arsenic species, including urinary inorganic arsenic and its metabolites monomethylarsonic acid and dimethylarsinic acid, were measured in a random subset (n=199). Weighted Cox's proportional hazards models were used to calculate hazard ratios and 95% confidence intervals of ischemic stroke by arsenic and its species. RESULTS: The average follow-up was 6.7 years. Although incident ischemic stroke showed no association with total arsenic or total inorganic arsenic, for each unit higher level of urinary monomethylarsonic acid on a log-scale, after adjustment for potential confounders, ischemic stroke risk increased ≈2-fold (hazard ratio=1.98; 95% confidence interval: 1.12-3.50). Effect modification by age, race, sex, or geographic region was not evident. CONCLUSIONS: A metabolite of arsenic was positively associated with incident ischemic stroke in this case-cohort study of the US general population, a low-to-moderate exposure area. Overall, these findings suggest a potential role for arsenic methylation in the pathogenesis of stroke, having important implications for future cerebrovascular research.

Practical Application of Biogenic Amine Profiles for the Diagnosis of Patients with Ischemic Stroke.

BACKGROUND: Ischemic stroke (IS) is still one of the major issues in medicine. Still, early diagnosis and misdiagnosis remain the main barriers for proper patient treatment and follow-up. Exploring new potential diagnostic biomarkers for IS is relevant to decrease patient morbidity and the occurrence of poststroke diseases. Biomedical analysis could bring new light to the background of IS and-in such a way-propose new bioanalytical tools for the early diagnosis, prognostication, and monitoring of IS. MATERIALS AND METHODS: This research aimed to present a discussion on the employment of biogenic amines (BAs), as well as their precursory amino acids and main metabolites, as a new panel of biomarkers for IS. Preliminary patient data were presented and the patients were described with respect to their clinical history and examination records, as well as scientific data gained from the liquid extraction-capillary electrophoresis determination of BAs in the patients' urine samples. RESULTS: The results showed the potential of BA screening using the developed sample preparation and analysis methods in urine during IS, and this will be further studied on a more numerous group of patients with IS to reveal the usefulness of BAs as a new panel of biomarkers for early IS diagnosis and prognostication. CONCLUSIONS: To our best knowledge, this methodology for the first time has been used for the simultaneous analysis of multiple small molecular biomarkers. In addition, the factors that might influence the determination of BAs in real samples were pointed out.

Differential Impact of Serial Measurement of Nonplatelet Thromboxane Generation on Long-Term Outcome After Cardiac Surgery.

BACKGROUND: Systemic thromboxane generation, not suppressible by standard aspirin therapy and likely arising from nonplatelet sources, increases the risk of atherothrombosis and death in patients with cardiovascular disease. In the RIGOR (Reduction in Graft Occlusion Rates) study, greater nonplatelet thromboxane generation occurred early compared with late after coronary artery bypass graft surgery, although only the latter correlated with graft failure. We hypothesize that a similar differential association exists between nonplatelet thromboxane generation and long-term clinical outcome. METHODS AND RESULTS: Five-year outcome data were analyzed for 290 RIGOR subjects taking aspirin with suppressed platelet thromboxane generation. Multivariable modeling was performed to define the relative predictive value of the urine thromboxane metabolite, 11-dehydrothromboxane B2 (11-dhTXB2), measured 3 days versus 6 months after surgery on the composite end point of death, myocardial infarction, revascularization or stroke, and death alone. 11-dhTXB2 measured 3 days after surgery did not independently predict outcome, whereas 11-dhTXB2 >450 pg/mg creatinine measured 6 months after surgery predicted the composite end point (adjusted hazard ratio, 1.79; P=0.02) and death (adjusted hazard ratio, 2.90; P=0.01) at 5 years compared with lower values. Additional modeling revealed 11-dhTXB2 measured early after surgery associated with several markers of inflammation, in contrast to 11-dhTXB2 measured 6 months later, which highly associated with oxidative stress. CONCLUSIONS: Long-term nonplatelet thromboxane generation after coronary artery bypass graft surgery is a novel risk factor for 5-year adverse outcome, including death. In contrast, nonplatelet thromboxane generation in the early postoperative period appears to be driven predominantly by inflammation and did not independently predict long-term clinical outcome.

The impact of acute kidney injury on in-hospital mortality in acute ischemic stroke patients undergoing intravenous thrombolysis.

INTRODUCTION: Acute kidney injury (AKI) increases the risk of death in acute ischemic stroke (AIS) patients. Intravenous thrombolytic therapy (iv. rt-PA) seems to be the most effective treatment for AIS patients. The effects of AKI on iv. rt-PA treated AIS cases is less studied. Our paper addresses this issue. METHODS: 45 consecutive stroke patients treated with iv. rt-PA (median age = 64 years; 29 male) and 59 age and sex matched controls not eligible for iv. rt-PA have been enrolled in our study. Subjects were followed-up until hospital release or death (median follow up time = 12 days). RESULTS: The prevalence of AKI did not differ between iv. rt-PA treated patients and controls (35.5% vs. 33.89%). In both groups, AKI was associated with increased in-hospital mortality: 50.0% vs. 3.4% p<0.0001 (in the rt-PA treated), and 45% vs. 30.7% (in controls). AKI iv. rt-PA treated patients had a significantly higher risk of in hospital mortality as compared to the no-AKI iv. rt-PA treated (HR = 15.2 (95%CI [1.87 to 124.24]; P = 0.011). In a Cox-multivariate model, the presence of AKI after iv. rt-PA remained a significant factor (HR = 8.354; p = 0.041) influencing the in-hospital mortality even after correction for other confounding factors. The independent predictors for AKI were: decreased eGFR baseline and elevated serum levels of uric acid at admission, (the model explained 60.2% of the AKI development). CONCLUSIONS: The risk of AKI was increased in AIS patients. Thrombolysis itself did not increase the risk of AKI. In the iv. rt-PA patients, as compared to non-AKI, those which developed AKI had a higher rate of in-hospital mortality. The baseline eGFR and the serum uric acid at admission were independent predictors for AKI development in the iv. rt-PA treated AIS patients.

Values of vanillylmandelic acid and homovanillic acid in the urine as potential prognostic biomarkers in ischaemic stroke patients.

BACKGROUND: Suitable biomarkers that have prognostic values are one of the key points of interest in ischaemic stroke. Increased sympathetic nervous system activity in ischaemic stroke causes multiple local and systemic effects that can be detrimental to the outcome. The mechanism of action is increased secretion and activity of catecholamines, whose end metabolic products are vanillylmandelic acid and homovanilic acid. Aim of our study was to determine whether these compounds can be used as potential prognostic biomarkers in ischaemic stroke, as a unique insight into the activity of the sympathetic nervous system. METHODS: Urine samples of 96 patients with ischaemic stroke and transitory ischaemic attacks were analysed. Values of vanillylmandelic and homovanillic acids in urine were tested using liquid chromatography on the first and third day post-stroke. Severity of stroke was determined using the NIHSS scale, while functional outcome was determined using the Modified Rankin Scale. RESULTS: Values of vanillylmandelic and homovanillic acids positively correlated with functional outcome of ischaemic stroke. Favorable outcomes correlated with decreased values, on contrary to increased values, which were associated with unfavourable outcomes. CONCLUSION: Determining the values of these compounds in the urine is an easily available prognostic tool for the ischaemic stroke outcome, while also influencing potential therapeutic changes.

Urine-Specific Gravity-Based Hydration Prevents Stroke in Evolution in Patients with Acute Ischemic Stroke.

BACKGROUND: Early neurological deterioration after ischemic stroke (stroke-in-evolution [SIE]) is associated with poorer outcomes. Previous studies have demonstrated a link between hydration status and the development of SIE. In this study, we tested the hypothesis that rehydration therapy, administered on the basis of urine-specific gravity (USG) findings, might reduce the development of SIE. METHODS: We conducted a single-arm prospective study of patients with acute ischemic stroke with historical controls. For the study group, a USG higher than 1.010 was taken as an indication for rehydration. Control group patients were rehydrated without referring to USG. An increase in National Institutes of Health Stroke Scale (NIHSS) score of 4 or higher within 3 days was defined as having SIE. RESULTS: A total of 445 patients were analyzed, 167 in the study group and 278 in the control group. The proportion of patients who developed SIE was numerically, but not significantly, lower in the study group (5.9%; 10 of 167) compared with the control group (11.5%; 32 of 278). Among patients with a USG higher than 1.010 at admission, the SIE rate was significantly reduced in the study group compared with the control group (6.1% versus 16.0%; P = .021), while the rate of SIE was similar in those with a USG of 1.010 or lower at admission. Multivariate logistic regression analysis confirmed that USG-based hydration was an independent factor associated with reducing SIE. CONCLUSIONS: USG might be a convenient and useful method for guiding fluid therapy in patients with acute ischemic stroke. USG-based hydration reduced the incidence of SIE among patients with a USG higher than 1.010 at admission.

Comparison of Associations of Reduced Estimated Glomerular Filtration Rate With Stroke Outcomes Between Hypertension and No Hypertension.

BACKGROUND AND PURPOSE: We compared the association of low estimated glomerular filtration rate (eGFR) with stroke outcomes among patients with hypertension and without hypertension. METHODS: We used the China stroke registry to identify patients on discharge with the diagnosis of stroke in 2012 and 2013. Low eGFR was defined as <60 mL/min/1.73 m2. Multivariable analysis was used to evaluate the association of low eGFR with 1-year all-cause mortality, recurrent stroke, poor functional outcome defined as 3 to 6 in modified Rankin Scale (mRS), and ordinal mRS, where the interaction of eGFR category and hypertension status was investigated. RESULTS: Of 5082 patients without hypertension, 221 patients (4.4%) had low eGFR, as compared with 1378 patients (8.6%) previously diagnosed with hypertension. In patients without hypertension, the adjusted odds ratios with 95% confidence interval of low eGFR was 1.88 (1.23-2.88) for all-cause mortality, 1.36 (0.66-2.83) for recurrent stroke, 2.14 (1.45-3.16) for poor functional outcome, and 2.07 (1.58-2.70) for ordinal mRS. In patients with hypertension, low eGFR was associated with all stroke outcomes: 1.80 (1.50-2.16) for all-cause mortality, 1.52 (1.20-1.91) for recurrent stroke, 1.30 (1.11-1.52) for poor functional outcome, and 1.31 (1.18-1.46) for ordinal mRS. The significant interaction between eGFR categories and hypertension was only found for poor functional outcome (P=0.046) and ordinal mRS (P=0.002). CONCLUSIONS: Effect of low eGFR on all-cause mortality and recurrent stroke in patients without hypertension was not significantly different from that in patients with hypertension, but low-eGFR patients without hypertension had a higher risk of stroke-related disability than those with hypertension.