Shortened Activated Partial Thromboplastin Time Is Associated With Acute Ischemic Stroke, Stroke Severity, and Neurological Worsening.

BACKGROUND: The role played by hemostasis in the pathogenesis of ischemic strokes is still controversial. The activated partial thromboplastin time (APTT) measures the time necessary to generate fibrin from initiation of the intrinsic pathway. In the present study, we looked for a possible association of ischemic strokes with the shortened APTT. METHODS: The study population consisted of 154 patients with acute ischemic strokes who had been admitted from December 2013 to December 2014 to the Department of Neurology, Chiayi Chang Gung Memorial Hospital, and 71 control subjects with no history of stroke. RESULTS: In a univariate risk analysis, shortened APTT was associated with an odds ratio (OR) for acute ischemic strokes of up to 1.86 (95% confidence interval [CI], 1.06-3.29, P = .031). In a multivariate analysis using a logistic regression model including age, sex, hypertension, diabetes mellitus, and shortened APTT, shortened APTT was still found to significantly add to the risk of ischemic stroke (OR = 2.12 with 95% CI, 1.13-3.98, P = .020). Shortened APTT was also associated significantly with neurological worsening (OR = 3.72 with 95% CI 1.03-13.5, P = .046). As for stroke severity, shortened APTT was associated with an OR for moderate/severe stroke of up to 3.42 (95% CI, 1.53-7.61, P = .003). CONCLUSION: Shortened APTT is a prevalent and independent risk factor for ischemic stroke, stroke severity, and neurological worsening after acute stroke.

Comparisons of outcomes in stroke subtypes after intravenous thrombolysis.

The purpose of this study was to analyze the outcomes and complications between stroke subtypes after intravenous thrombolysis. A total of 471 patients with acute ischemic stroke after intravenous thrombolysis from January 2007 to April 2014 were enrolled and classified according to the Trial of Org 10172 in Acute Stroke Treatment. A multivariate logistic regression model was used to evaluate the outcomes and complications among stroke subtypes after adjusting for baseline variables. Of the 471 patients, 117 (25.1 %) had large-artery atherosclerosis (LAA), 148 (31.8 %) had cardioembolism (CE), 82 (17.6 %) had small vessel disease (SVD), 119 (25.5 %) had undetermined etiology, and 5 (1.1 %) had other determined etiology. The patients with SVD had the mildest initial stroke severity and highest ratio of good and favorable outcomes, whereas those with CE had a higher rate of symptomatic intracranial hemorrhage (sICH) than those with SVD. After adjusting for confounding factors, the ratio of favorable outcome in the patients with SVD stroke was higher than in those with LAA. SVD was associated with a significantly lower rate of any hemorrhage compared to other stroke subtypes, whereas there were no differences in sICH or mortality between stroke subtypes. A lower initial National Institutes of Health Stroke Scale score was associated with good and favorable outcomes, and lower rates of sICH and mortality. The patients with SVD after intravenous thrombolysis had better outcomes and a lower rate of hemorrhage even after adjusting for confounding factors. Stroke severity was an independent factor associated with better functional outcomes, sICH and mortality.

Factor VIII levels are associated with ischemic stroke, stroke subtypes and neurological worsening.

The role played by hemostasis in the pathogenesis of ischemic stroke is still controversial. In the present study, we looked for a possible association of ischemic stroke with the high clotting activity of factor VIII (FVIII). The study population consisted of 116 patients with acute ischemic stroke who had been admitted between September 2013 and September 2014 to the Department of Neurology, Chiayi Chang Gung Memorial Hospital, and 76 control subjects with no history of stroke. FVIII levels were higher in stroke patients as compared to controls (127.5 ± 52.5 vs. 108.4 ± 49.0 IU/dL; P = 0.012). In a univariate risk analysis, FVIII at levels above 150 IU/dL was associated with an odds ratio (OR) for ischemic stroke of up to 2.55 (95% CI, 1.20-5.42, P = 0.013). In a multivariate analysis using a logistic regression model including age, hypertension, low density lipoprotein cholesterol level, estimated glomerular filtration rate, and high FVIII (< 150 IU/dL), high FVIII was still found to significantly add to the risk of ischemic stroke (OR = 3.26 with 95% CI, 1.38-7.68, P = 0.007). As for the stroke subtypes, mean FVIII level was significantly higher in patients with cardioembolic stroke than patients with noncardioembolic stroke (156.0 ± 51.5 IU/dL vs. 124.3 ± 51.9 IU/dL). High levels of FVIII were also associated significantly with neurological worsening (OR = 3.66 with 95% CI, 1.24-10.82, P = 0.019). A high plasma level of FVIII is a prevalent and independent risk factor for ischemic stroke and neurological worsening after acute stroke.

Low baseline urine creatinine excretion rate predicts poor outcomes among critically ill acute stroke patients.

Urinary creatinine excretion rate (CER) is an established marker of muscle mass. Low CER has been linked to poor coronary artery disease outcomes, but a link between CER and acute stroke prognosis has not been previously explored. We prospectively collected data from patients with acute stroke (ischemic or hemorrhagic) within 24 hours from symptom onset in a Neurological and Neurosurgery Intensive Care Unit in Taiwan. Baseline CER (mg/d) was calculated by urine creatinine concentration in morning spot urine multiplies 24-hour urine volume on the second day of admission. Patients were divided into 3 tertiles with highest, middle, and lowest CER. Primary endpoint was poor outcome defined as modified Rankin Scale 3-6 at 6 months. Among 156 critically ill acute stroke patients meeting study entry criteria, average age was 67.9 years, and 83 (53.2%) patients had ischemic stroke. Patients with lowest CER (vs. highest CER) had a high risk of poor outcome at 6-month after adjustment (odds ratio 4.96, 95% confidence interval 1.22 to 20.15, p value = 0.025). In conclusion, low baseline CER, a marker of muscle mass, was independently associated with poor 6-month outcome among critically ill acute stroke patients. We speculate that preservation of muscle mass through exercise or protein-energy supplement might be helpful for improving prognosis in severe stroke patients.

Perfusion-diffusion Mismatch Predicts Early Neurological Deterioration in Anterior Circulation Infarction without Thrombolysis.

Perfusion-diffusion mismatch in magnetic resonance imaging (MRI) represents the non-core hypoperfused area in acute ischemic stroke. The mismatch has been used to predict clinical response after thrombolysis in acute ischemic stroke, but its role for predicting early neurological deterioration (END) in acute ischemic stroke without thrombolysis has not been clarified yet. In this study, we prospectively recruited 54 patients with acute non-lacunar ischemic stroke in anterior circulation without thrombolysis. All patients received the first perfusion MRI within 24 hours from stroke onset. Target mismatch profile was defined as a perfusion-diffusion mismatch ratio ≥ 1.2. END was defined as an increase of ≥ 4 points in the National Institute of Health Stroke Scale (NIHSS) score within 72 hours. There were 13 (24.1%) patients developing END, which was associated with larger infarct growth (p = 0.002), worse modified Rankin Scale (p = 0.001) and higher mortality rate at 3 months (p = 0.025). Target mismatch profiles measured by T(max) ≥ 4, 5 and 6 seconds were independent predictors for END after correcting initial NIHSS score. Among the 3 T(max) thresholds, target mismatch measured by T(max) ≥ 6 seconds had the highest odd's ratio in predicting END (p < 0.01, odd's ratio = 17), with an 80% sensitivity and a 79.5% specificity. In conclusion, perfusion-diffusion mismatch could identify the patients at high risk of early clinical worsening in acute ischemic stroke without thrombolysis.

Genetic polymorphism of LDLR (rs688) is associated with primary intracerebral hemorrhage.

Intracranial hemorrhage is the third most common cause of cerebrovascular disease. Some polymorphisms that affect clotting factors increase the risk of thrombosis. However, few reports have analyzed the effect of polymorphisms on the hemostatic state in bleeding disorders. The low-density lipoprotein receptor (LDLR) has been shown to contribute to factor VIII (FVIII) homeostasis, which represents a link between LDLR and hemostasis. FVIII plays a pivotal role in the coagulation cascade. Patients with high levels of FVIII are at an increased risk of arterial and venous thrombosis. On the other hand, patients with insufficient FVIII tend to bleed excessively, such as in hemophilia A. In a previous study, analysis of the genetic LDLR variant rs688 provided evidence suggesting that genetic polymorphisms of rs688 are associated with thrombotic cardiovascular diseases. The current study aimed to investigate the potential role of rs688 in primary intracerebral hemorrhage (PICH). This genetic association study was conducted within an isolated Taiwanese population (447 PICH patients and 430 controls). Genotypes C/C and C/T were used as the reference genotypes, and the genotype T/T was found to be associated with a 73% decreased risk of PICH. The preliminary evidence suggests that genetic polymorphisms of LDLR are associated with PICH.

Mutual effect of rs688 and rs5925 in regulating low-density lipoprotein receptor splicing.

Analysis of the low-density lipoprotein receptor (LDLR) gene based on the rs688 and rs5925 genetic polymorphisms has provided evidence suggesting that haplotypes related to rs688 and rs5925 are associated with ischemic cerebrovascular diseases. Both rs688 and rs5925 have been empirically identified as exon-splicing enhancers in silico, and rs688 has been shown to be a functional polymorphism that modulates LDLR exon 12 splicing efficiency both in vitro and in vivo. The aim of this study was to evaluate whether rs688 and rs5925 and their haplotypes may alter the splicing efficiency of exons 12 and 13 both in vivo and in vitro. When the minigenes were evaluated for splicing efficiency, we found that converting rs688C to the T allele reduced exon 12 splicing efficiency. In parallel, converting rs688T to the C allele increased the efficiency of exon 12 inclusion. The apparent difference in splicing efficiency was 9.36%±2.58% between the C and T alleles. When rs688C existed in the minigene, the major and minor rs5925 alleles were also sufficient to account for the differences in splicing efficiency of LDLR involving exon 13. The apparent splicing efficiency difference was 5.43%±2.87%. Sequential mutations of rs688 and rs5925 were performed to generate four different haplotypes in the LDLR minigene system. The splicing efficiencies for the haplotypes CC, CT, TC, and TT were 79.60%±1.38%, 76.68%±0.85%, 69.02%±1.79%, and 68.54%±1.38%, respectively. The splicing efficiency of the four haplotype groups differed significantly. In vivo analysis of human leukocyte samples was also compatible with in vitro analysis, indicating a mutual effect between rs688 and rs5925 in regulating LDLR splicing efficiency.

Hemodynamic factors may play a critical role in neurological deterioration occurring within 72 hrs after lacunar stroke.

BACKGROUND: Whether a perfusion defect exists in lacunar infarct and whether it is related to early neurological deterioration (END) is still under debate. The aim of this study was to evaluate whether END in lacunar infarct is related to a perfusion defect using diffusion-weighted imaging (DWI), diffusion tensor imaging (DTI) and perfusion MR imaging. METHODS: One hundred and forty-one consecutive patients had an MRI scan within 30 hours after onset of symptoms and 43 patients with acute lacunar infarct and classic lacunar syndrome were recruited. The MRI sequences included DWI, DTI and cerebral blood flow (CBF) maps to respectively represent the topographic locations of acute infarcts, the corticospinal tract and perfusion defects. The END was defined in reference to the National Institute of Health Stroke Scale (NIHSS) as an increase ≧2 within 72 hours. Cohen's Kappa coefficient was used to examine the reliability between the 2 image readers. A multivariate logistic regression model was constructed adjusting for baseline variables. RESULTS: Ten out of the 43 patients had END. Patients having END was significantly associated with lower chances of favorable and good outcomes at 3 months (p = 0.01 and p = 0.002, respectively). END was predicted when the non-core hypoperfused area overlapped on the corticospinal tract, which is defined as the expected END profile. Cohen's Kappa coefficient between the 2 image readers to define images of expected END profiles was 0.74. In 15 patients with expected END profile, 9 had END clinically, whereas 28 patients had no expected END profile, and only 1 patient had END (p<0.0001). After adjusting for sex, the expected END profile was still associated with END (odds ratio, 42.2; p = 0.002). CONCLUSION: Our study demonstrated that the END in acute lacunar stroke is likely related to the transformation of non-core hypoperfused area into infarction in the anatomy of corticospinal tracts.

Efficacy of folic acid supplementation in cardiovascular disease prevention: an updated meta-analysis of randomized controlled trials.

BACKGROUND: In observational studies, lower serum homocysteine levels are associated with a lower incidence of cardiovascular disease (CVD). However, individual randomized controlled trials (RCTs) have yielded mixed findings regarding the efficacy of therapeutic homocysteine in lowering cardiovascular risk. Our aim was to perform an updated meta-analysis of relevant RCTs to assess the efficacy of folic acid supplementation in the prevention of CVD, coronary heart disease (CHD), and stroke. METHODS: We performed systematic search to identify RCTs reported at least one of the CVD, CHD, or stroke as outcomes. Relative risk (RR) with 95% confidence interval was used as a measure of the association between folic acid supplementation and risk of CVD, CHD, stroke, and all-cause mortality. The analysis was further stratified by factors that could affect the treatment effects. RESULTS: The systematic search identified 26 RCTs enrolling 58,804 participants. Pooling the RRs showed that folic acid supplementation was not associated with any significant change in the risk of CVD (RR 0.98, 0.95 to 1.02; p=0.36), CHD (RR 1.03, 0.98 to 1.08; p=0.23), and all-cause mortality (RR 1.00, 0.96 to 1.04; p=0.92), but was linked to a decreasing trend in stroke risk (RR 0.93, 0.86 to 1.00; p=0.05). In stratified analyses, the only heterogeneity was found for stroke risk reduction among groups with (RR 1.07, 0.92 to 1.25) vs. without (RR 0.88, 0.81 to 0.96) mandatory grain fortification (P for heterogeneity=0.03). CONCLUSIONS: This meta-analysis suggests that there might be a potentially modest benefit of folic acid supplementation in stroke prevention.