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Background: Accumulating data suggest blood biomarkers could inform stroke etiology., Objective: The purpose of this study was to investigate the performance of multiple blood biomarkers in elucidating stroke etiology with a focus on new-onset atrial fibrillation (AF) and cardioembolism., Methods: Between January and December 2017, information on clinical and laboratory parameters and stroke characteristics was prospectively collected from ischemic stroke patients recruited from the National University Hospital, Singapore. Multiple blood biomarkers (N-terminal pro-brain natriuretic peptide [NT-proBNP], d-dimer, S100β, neuron-specific enolase, vitamin D, cortisol, interleukin-6, insulin, uric acid, and albumin) were measured in plasma. These variables were compared with stroke etiology and the risk of new-onset AF and cardioembolism using multivariable regression methods., Results: Of the 515 ischemic stroke patients (mean age 61 years; 71% men), 44 (8.5%) were diagnosed with new-onset AF, and 75 (14.5%) had cardioembolism. The combination of 2 laboratory parameters (total cholesterol ≤169 mg/dL; triglycerides ≤44.5 mg/dL) and 3 biomarkers (NT-proBNP ≥294 pg/mL; S100β ≥64 pg/mL; cortisol ≥471 nmol/l) identified patients with new-onset AF (negative predictive value [NPV] 90%; positive predictive value [PPV] 73%; area under curve [AUC] 85%). The combination of 2 laboratory parameters (total cholesterol ≤169 mg/dL; triglycerides ≤44.5 mg/dL) and 2 biomarkers (NT-proBNP ≥507 pg/mL; S100β ≥65 pg/mL) identified those with cardioembolism (NPV 86%; PPV 78%; AUC 87%). Adding clinical predictors did not improve the performance of these models., Conclusion: Blood biomarkers could identify patients with increased likelihood of cardioembolism and direct the search for occult AF., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Atrial fibrillation (AF) is associated with an increased risk of thromboembolism, which can be significantly reduced with anticoagulant treatment. Key goals in the clinical management of AF are the identification of patients at high risk for developing AF and accurate stratification of the risk of stroke and systemic embolic events (S/SEE) as well as treatment-related major bleeding., Content: In this review, we describe the expanding evidence regarding the use of circulating biomarkers for predicting the risks of both incident AF and its clinically important complications of S/SEE and treatment-related major bleeding. We also review emerging biomarker-based scores for assessing these risks., Summary: Patients with AF undergo progressive cardiac structural remodeling, which may precede the onset of the arrhythmia. Abnormal concentrations of circulating biomarkers reflecting the underlying pathophysiologic mechanisms of hemodynamic stress (i.e., natriuretic peptides), inflammation (i.e., C-reactive protein), and myocardial fibrosis identify patients at higher risk of developing AF. Circulating biomarkers can also be used to identify patients with AF who are at greatest risk for developing S/SEE or major bleeding. In particular, biomarkers of hemodynamic stress, myocardial injury (i.e., cardiac troponin), and coagulation activity (i.e., D-dimer) are key indicators of thromboembolic risk, and cardiac troponin and growth-differentiation factor-15 are strongly associated with risk of anticoagulant-related major bleeding. The biomarker-based age, biomarker, clinical history (ABC)-stroke and ABC-bleeding risk scores improve risk stratification for S/SEE and major bleeding, respectively, when compared with traditional clinical risk scores like the CHA2DS2-VASc and HAS-BLED scores., (© American Association for Clinical Chemistry 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The novel coronavirus (severe acute respiratory syndrome CoV-2 [SARS-CoV-2]), also known as COVID-19, is a single-stranded enveloped RNA virus that created a Public Health Emergency of International Concern in January 2020, with a global case burden of over 15 million in just 7 months. Infected patients develop a wide range of clinical manifestations-typically presenting with fever, cough, myalgia, and fatigue. Severely ill patients may fall victim to acute respiratory distress syndrome, acute heart injuries, neurological manifestations, or complications due to secondary infections. These critically ill patients are also found to have disrupted coagulation function, predisposing them to consumptive coagulopathies, and both venous and thromboembolic complications. Common laboratory findings include thrombocytopenia, elevated D-dimer, fibrin degradation products, and fibrinogen, all of which have been associated with greater disease severity. Many cases of pulmonary embolism have been noted, along with deep vein thrombosis, ischemic stroke, myocardial infarction, and systemic arterial embolism. The pathogenesis of coronavirus has not been completely elucidated, but the virus is known to cause excessive inflammation, endothelial injury, hypoxia, and disseminated intravascular coagulation, all of which contribute to thrombosis formation. These patients are also faced with prolonged immobilization while staying in the hospital or intensive care unit. It is important to have a high degree of suspicion for thrombotic complications as patients may rapidly deteriorate in severe cases. Evidence suggests that prophylaxis with anticoagulation may lead to a lower risk of mortality, although it does not eliminate the possibility. The risks and benefits of anticoagulation treatment should be considered in each case. Patients should be regularly evaluated for bleeding risks and thrombotic complications.

Background: Troponin is a marker of cardiac ischemia and is elevated in about 30% of stroke patients. We investigated if the elevation of troponin during an acute stroke code is associated with a cardioembolic source., Methods: We performed a retrospective chart review of patients evaluated for acute strokes from July 2014 to March 2018. Patients included in the study were all given intravenous alteplase, had blood drawn for troponins during the acute stroke code and had confirmation of a new stroke on neuroimaging during hospitalization. Patients who were on dialysis or had a glomerular filtration rate of less than or equal to 40 ml/minutes on initial laboratory evaluation were excluded. Stroke etiology was classified into noncardioembolic (NCE) and cardioembolic (CE), according to Trial of Org 10172 in Acute Stroke Treatment criteria. The NCE group was compared with the CE group with respect to troponin levels. Troponin was considered as a dichotomous categorical variable, with a cut-off point at greater than or equal to.05 ng/ml., Results: 144 patients met the inclusion criteria. In our cohort, 40.74% of patients in the CE group had troponin levels of greater than or equal to .05 ng/mL compared to 12.22% in NCE group. A troponin level of greater than or equal to.05 ng/ml obtained during a stroke code showed a significant difference between cardioembolic and noncardioembolic strokes (OR, 4.94; 95% CI, 2.15-11.35; P < .001), with high specificity (87.78%) but low sensitivity (40.74%) to exclude noncardioembolic stroke., Conclusions: A troponin level of greater than or equal to .05 ng/ml obtained during a stroke code showed a significant difference between CE and NCE strokes. This finding may have implications for clinical workup, and patients with admission troponin levels of greater than or equal to .05 ng/mL may need further clinical investigations to look for a cardioembolic source. A troponin level of greater than or equal to .05 ng/ml may prompt a more thorough search for a cardioembolic source in cases in which such a source is not identified on initial evaluation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A relevant part of embolic strokes of undetermined source (ESUS) is assumed to be cardiogenic. As shown previously, certain biomarkers of endothelial pathology are related to atrial fibrillation (AF). In this long-term follow-up study, we aimed to investigate whether these biomarkers are associated with subsequently diagnosed AF and with atrial cardiopathy. In 98 patients who suffered ischemic stroke of known and unknown origin L-arginine, Asymmetric (ADMA) and Symmetric Dimethylarginine (SDMA) have been measured on follow-up at least one year after index stroke. Stroke-diagnostics were available for all patients, including carotid Intima-Media-Thickness (CIMT) and comprehensive echocardiography studies. CIMT was larger in AF- compared with ESUS-patients (P < 0.001), independently from CHA 2 DS 2 VASC in the regression analysis (P = 0.004). SDMA-values were stable over time (P < 0.001; r = 0.788), whereas for ADMA moderate correlation with the initial values could be found (P = 0.007; r = 0.356). According to Kaplan-Meier-analyses, AF-detection rates were associated with CIMT (P = 0.003) and SDMA (P < 0.001). SDMA correlated with left atrial volume-index within the whole collective (P = 0.003, r = 0.322) and within the ESUS-subgroup (P = 0.003; r = 0.446). These associations were independent from CHA 2 DS 2 VASC and renal function in the regression analysis (P = 0.02 and P = 0.005, respectively). In conclusion, these results highlight SDMA and CIMT as potential markers of atrial cardiopathy and AF in ESUS-patients.

Background: Visceral infarctions appear to be more common in patients with embolic stroke subtypes, but their relation to troponin elevation remains uncertain., Methods: Among patients with acute ischemic stroke enrolled in the Cornell AcutE Stroke Academic Registry (CAESAR) from 2011 to 2016, we included those with troponin measured within 24 hours from stroke onset and a contrast-enhanced abdominal computed tomographic scan within 1 year of admission. A troponin elevation was defined as a value exceeding our laboratory's upper limit of normal (.04 ng/ mL) in the absence of a clinically recognized acute ST-segment elevation myocardial infarction. Visceral infarction was defined as a renal or splenic infarction as ascertained by a single radiologist blinded to patients' other characteristics. Multivariable logistic regression was used to evaluate the association between elevated troponin and visceral infarction., Results: Among 2116 patients registered in CAESAR from 2011 to 2016, 153 patients had both a troponin assay and a contrast-enhanced abdominal computed tomographic scan, of whom 33 (21%) had an elevated troponin and 22 (14%) had a visceral infarction. The prevalence of visceral infarction was higher among patients with an elevated troponin (30%; 95% confidence interval [CI], 16%-49%) than among patients without an elevated troponin (10%; 95% CI, 5%-17%) (P = .003). After adjustment for demographics and comorbidities, we found a significant association between elevated troponin and visceral infarction (odds ratio, 3.9; 95% CI, 1.5-10.4)., Conclusions: Among patients with acute ischemic stroke, elevated troponin was associated with visceral infarction. Our results demonstrate that poststroke troponin elevation may indicate the presence of underlying embolic sources., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Previous reports have suggested that direct oral anticoagulants exert a prothrombolytic effect against intracardiac thrombi. We hypothesized that these anticoagulants may also help recanalize occluded intracranial arteries via prothrombolytic effects. In this study, we evaluated the effects of rivaroxaban, a direct oral anticoagulant, on fibrin emboli within the cerebrocortical microvessels in a mouse model of embolic stroke. Fibrin emboli prepared ex vivo were injected into the common carotid artery of male C57BL/6 mice, and embolization in the microvessels on the brain surface was observed through a cranial window. Oral administration of rivaroxaban was initiated a week before injection of the emboli. The number and sizes of the emboli were measured at two time points: immediately after and 3 h after the embolus injection in the rivaroxaban-treated mice (n =6) and untreated mice (n =7). The rates of recanalization and change in the embolus size were analyzed between the two groups. Complete recanalization was observed only in the rivaroxaban group (three mice in the rivaroxaban group compared with none in the control group). A significantly higher rate of reduction of the embolus size was observed in the rivaroxaban group than in the control group (P=0.0216). No significant differences between the two groups were observed in the serum levels of the following coagulation markers: thrombin-antithrombin III complexes, D-dimers, or plasmin-α2-plasmin inhibitor complex. Our findings indicate that rivaroxaban may promote reduction in the size of stagnated fibrin emboli in cerebrocortical microvessels in cases of embolic stroke.

Background: Gastric adenocarcinoma (GAC) is the third deadliest malignant neoplasm worldwide, mostly because of late disease diagnosis, low chemotherapy response rates, and an overall lack of tumor biology understanding. Therefore, tools for prognosis and prediction of treatment response are needed. Quantification of circulating tumor cells (CTCs) and circulating tumor microemboli (CTM) and their expression of biomarkers has potential clinical relevance. Our aim was to evaluate CTCs and CTM and their expression of HER2 and plakoglobin in patients with nonmetastatic GAC, correlating the findings to clinicopathological data., Materials and Methods: CTC enrichment was performed with isolation by size of epithelial tumor cells, and the analysis was performed with immunocytochemistry and microscopy. Two collections were made: one at diagnosis (55 samples before neoadjuvant treatment) and one after surgery and before adjuvant therapy (33 samples)., Results: A high detection rate of CTCs (90%) was observed at baseline. We evaluated HER2 expression in 45/55 biopsy samples and in 42/55 CTC samples, with an overlap of 36 subjects. Besides the good agreement observed for HER2 expression in primary tumors and paired CTCs for 36 cases (69.4%; κ = 0.272), the analysis of HER2 in CTCs showed higher positivity (43%) compared with primary tumors (11%); 3/5 patients with disease progression had HER2-negative primary tumors but HER2-positive CTCs. A significant CTC count drop in follow-up was seen for CTC-HER2-positive cases (4.45 to 1.0 CTCs per mL) compared with CTC-HER2-negative cases (2.6 to 1.0 CTCs per mL). The same was observed for CTC-plakoglobin-positive cases (2.9 to 1.25 CTCs per mL)., Conclusion: CTC analysis, including their levels, plakoglobin, and HER2 expression, appears to be a promising tool in the understanding the biology and prognosis of GAC., Implications for Practice: The analysis of circulating tumor cell levels from the blood of patients with gastric adenocarcinoma, before and after neoadjuvant treatment, is useful to better understand the behavior of the disease as well as the patients more likely to respond to treatment., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

The management of anticoagulant therapy (OAT) in patients with factor VII (FVII) deficiency is a very challenging clinical issue, as warfarin further reduces FVII levels, thus potentially increasing bleeding risk. On the other hand, the International Normalized Ratio test is misleading in such patients, as they do not reflect the actual level of global inhibition of the coagulation system. We report here three cases of patients with a moderate FVII deficiency and receiving direct oral anticoagulants (DOAC) for prevention of cardioembolism in atrial fibrillation. Of note, two of them experienced a treatment failure while on warfarin, while DOAC treatment was not associated with thrombotic or hemorrhagic adverse events. DOAC are very attractive for the management of OAT in FVII deficient patients, because they do not require monitoring by tests affected by the inherited defect, and their mechanism of action is FVII-independent., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: To investigate the roles of microembolus and plasma D-dimer in evaluating the warfarin anticoagulant therapy efficacies for patients with atrial fibrillation (AF)., Methods: Fifty-six AF patients were treated with aspirin antiplatelet therapy (Group ASP) and forty AF patients were treated with warfarin anticoagulant therapy (Group WAR). The microemboli and plasma D-dimer in these two groups were monitored and compared before and after treatment., Results: Group ASP had 21 and 17 cases with positive microemboli before and after treatment, respectively, and there was no significant difference in the detection rate of microemboli before and after treatment; Group WAR had 14 and 5 cases with positive microemboli before and after treatment, respectively, and the detection rate of microemboli was significantly reduced after treatment. The levels of plasma D-dimer in the two groups were significantly reduced after treatment (327±73 µg/L vs 235±61 µg/L and 313±81 µg/L vs 170±67 µg/L, respectively, P<0.05), among which the reduction level in Group WAR was more significant., Conclusions: Microemboli and D-dimer can be used as the indicators for evaluating the embolism risk and therapeutic efficacies in AF patients.

Background: MicroRNAs (miRNA) are a class of small, endogenous (17-25 nucleotide) noncoding ribonucleic acids implicated in the transcriptional and post-transcriptional regulation of gene expression. This study examines stroke-specific miRNA expression in large vessel territory cardioembolic stroke., Methods: Peripheral blood was collected from controls and ischemic stroke patients 24 hours after stroke onset. Whole blood miRNA was isolated and analyzed for differential expression. A total of 16 patients with acute middle cerebral artery territory strokes of cardioembolic origin were included in this pilot study. MiRNA profiling was conducted by miRCURY LNA™ microRNA Array., Results: In patients with cardioembolic stroke, significant differential expression of 14 miRNAs was observed when compared to controls. Ten of these miRNA had not previously been associated with ischemic stroke (miR-664a-3p, -2116-5pp, -4531, -4765-5p, -647, -4709-3p, -4742-3p, -5584-3p, -4756-3p, and -5187-3p). Subanalysis of severe strokes (NIHSS > 10) identified an additional 5 differentially expressed miRNA. No significant effects of sex or tissue plasminogen activator treatment were seen on miRNA expression., Conclusions: Ischemic stroke patients show a differential miRNA expression profile as compared to controls. These new associations between circulating miRNAs and ischemic stroke may help to refine stroke subtype diagnosis and identify novel therapeutic miRNA targets for the treatment of ischemic stroke., (Copyright © 2018. Published by Elsevier Inc.)

Background: LncRNAs play an essential role in a variety of diseases. Zinc finger antisense 1 (ZFAS1), a newly identified lncRNA, is a transcript antisense to the 5' end of the gene Znfx1. The purpose of this study was to aim to compare the levels of ZFAS1 between ischemic stroke (IS) and healthy control subjects and explore its potential role as a noninvasive biomarker in the diagnosis of IS., Methods:  A total of 176 patients and 111 healthy controls were included in the study. RT-qPCR was performed to detect the expression of ZFAS1., Results: The results showed that level of ZFAS1 in IS patients was significantly lower than controls ( P  = 0.0002). Furthermore, we found that the ZFAS1 levels in large-artery atherosclerosis (LAA) strokes were significantly downregulated than those in non-LAA strokes and controls. Meanwhile, ZFAS1 levels in the small vessel occlusion (SVO) group were lower than those in cardioembolism (CE) ( P  = 0.0197) and controls ( P  = 0.0041). Multinomial logistic regression analyses showed that the expression of ZFAS1 was not associated with the CE ( P  = 0.185) and SVO ( P  = 0.268) stroke groups, while lower ZFAS1 levels ( P  < 0.003, adjusted OR = 0.218, 95% CI: 0.079-0.597) showed significant associations with increased probability of having LAA strokes, compared to control subjects. The receiver operating characteristic curve analyses indicated that the sensitive of ZFAS1 was 89.39% in differentiating LAA strokes from controls., Conclusion: These results suggest that ZFAS1 might be used as a potential noninvasive biomarker for the diagnosis of LAA stroke.

Embolus Analogues (EAs) can provide understanding of the mechanical characteristics of blood clots of cardiac origin. Bovine EAs (n = 29) were fabricated with varying concentrations of thrombin (0-20 NIHU/ml blood). Histological staining confirmed that EA composition compared sufficiently with human samples reported in literature. EAs were mechanically described under seven testing conditions: tensile, compression, shear wave ultrasound elastography (SWE), parallel plate rheometry, indentation, creep and relaxation. The Young modulus of bovine EAs in tension varied from 7 kPa (5% strain) to 84 kPa (50% strain). The compressive Young modulus increased with increasing thrombin concentration, which was in agreement with the SWE results. There was no significant difference in Young modulus throughout the clot (p < 0.05). The EAs displayed a non-linear response under parallel plate rheometry, creep and stress relaxation. The 3rd order Mooney-Rivlin constitutive equation and Standard Linear Solid model were used to fit the non-linear stress-strain response and time-dependent properties, respectively. This is the first study in which bovine EAs, with and without addition of thrombin, are histologically and mechanically described with corresponding proposed constitutive equations. The equations and experimental data determined can be applied for future numerical and experimental testing of mammalian EAs and cardiac source clots.

Background: The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been shown to be valuable prognostic markers for a variety of pathological conditions including solid tumors, sepsis, and others. However, the prognostic values of the NLR and PLR in patients with acute mesenteric arterial embolism (AMAE) and acute mesenteric arterial thrombosis (AMAT) have not been elucidated. The aim of this study was to determine the predictive value of the NLR and PLR for poor prognosis in patients with AMAE and AMAT., Methods: A total of 137 patients with AMAE (n = 77) or AMAT (n = 60) were divided into a poor outcome group (cases of intestinal necrosis or death) and a better outcome group (cases without intestinal necrosis who survived successfully), according to prognosis. Neutrophil, platelet, and lymphocyte counts were recorded before pharmacotherapy or surgery. The NLR and PLR were calculated, and logistic regression analysis was performed to test their prognostic values., Results: The cutoff values for NLR and PLR were 11.05 and 156.26, respectively. The PLR was linearly associated with the NLR (R = 0.769, P < 0.001). NLR (odds ratio [OR] = 6.835, 95% confidence interval [CI] = 2.282-20.469, P = 0.001), PLR (OR = 4.871, 95% CI = 1.627-14.587, P = 0.005), and coronary heart disease (OR = 3.388, 95% CI = 1.156-9.929, P = 0.026) were found to be independent prognostic factors for the patients., Conclusions: NLR ≥ 11.05, PLR ≥ 156.26, and coronary heart disease were shown to be risk factors for poor prognosis in patients with AMAE and AMAT. According to these factors, patients can be divided into 3 prognostic groups: good, NLR < 11.05 with PLR < 156.26; moderate, NLR < 11.05 with PLR ≥ 156.26 or NLR ≥ 11.05 with PLR < 156.26; and poor, NLR ≥ 11.05 with PLR ≥ 156.26., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Antiphospholipid (aPL) antibodies may activate platelets and contribute to vegetation growth and embolisation in infective endocarditis (IE). We aimed to determine the value of aPL as predictors of embolic events (EE) in IE., Methods: We studied 186 patients with definite IE (Duke-Li criteria, all types of IE) from the Nanc-IE prospective registry (2007-2012) who all had a frozen blood sample and at least one imaging procedure to detect asymptomatic or confirm symptomatic EE. Anticardiolipin (aCL) and anti-β 2 -glycoprotein I (β 2 GPI) antibodies (IgG and IgM) were assessed after the end of patients' inclusion. The relationship between antibodies and the detection of EE after IE diagnosis were studied with Kaplan-Meier and Cox multivariate analyses., Results: At least one EE was detected in 118 (63%) patients (52 cerebral, 95 other locations) after IE diagnosis in 80 (time interval between IE and EE diagnosis: 5.9±11.3 days). At least one aPL antibody was found in 31 patients (17%).Detection of EE over time after IE diagnosis was more frequent among patients with anti-β 2 GPI IgM (log-rank P=0.0036) and that of cerebral embolisms, among patients with aCL IgM and anti-β 2 GPI IgM (log-rank P=0.002 and P<0.0001, respectively).Factors predictive of EE were anti-β 2 GPI IgM (HR=3.45 (1.47-8.08), P=0.0045), creatinine (2.74 (1.55-4.84), P=0.0005) and vegetation size (2.41 (1.41-4.12), P=0.0014). Those of cerebral embolism were aCL IgM (2.84 (1.22-6.62), P=0.016) and anti-β 2 GPI IgM (4.77 (1.79-12.74), P=0.0018)., Conclusion: The presence of aCL and anti-β 2 GPI IgM was associated with EE, particularly cerebral ones, and could contribute to assess the embolic risk of IE., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Coronary embolism is the underlying cause of 3% of acute coronary syndromes but is often not considered in the differential of acute coronary syndromes. It should be suspected in the case of high thrombus burden despite a relatively normal underlying vessel or recurrent coronary thrombus. Coronary embolism may be direct (from the aortic valve or left atrial appendage), paroxysmal (from the venous circulation through a patent foramen ovale), or iatrogenic (following cardiac intervention). Investigations include transesophageal echocardiography to assess the left atrial appendage and atrial septum and continuous electrocardiographic monitoring to assess for paroxysmal atrial fibrillation. The authors review the historic and contemporary published data about this important cause of acute coronary syndromes. The authors propose an investigation and management strategy for work-up and anticoagulation strategy for patients with suspected coronary embolism., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Elevated cardiac troponin is a marker of cardiac disease and has been recently shown to be associated with embolic stroke risk. We hypothesize that early elevated troponin levels in the acute stroke setting are more prevalent in patients with embolic stroke subtypes (cardioembolic and embolic stroke of unknown source) as opposed to noncardioembolic subtypes (large-vessel disease, small-vessel disease, and other)., Methods: We abstracted data from our prospective ischemic stroke database and included all patients with ischemic stroke during an 18-month period. Per our laboratory, we defined positive troponin as ≥0.1 ng/mL and intermediate as ≥0.06 ng/mL and <0.1 ng/mL. Unadjusted and adjusted regression models were built to determine the association between stroke subtype (embolic stroke of unknown source and cardioembolic subtypes) and positive and intermediate troponin levels, adjusting for key confounders, including demographics (age and sex), clinical characteristics (hypertension, hyperlipidemia, diabetes mellitus, renal function, coronary heart disease, congestive heart failure, current smoking, and National Institutes of Health Stroke Scale score), cardiac variables (left atrial diameter, wall-motion abnormalities, ejection fraction, and PR interval on ECG), and insular involvement of infarct., Results: We identified 1234 patients, of whom 1129 had admission troponin levels available; 10.0% (113/1129) of these had a positive troponin. In fully adjusted models, there was an association between troponin positivity and embolic stroke of unknown source subtype (adjusted odds ratio, 4.46; 95% confidence interval, 1.03-7.97; P =0.003) and cardioembolic stroke subtype (odds ratio, 5.00; 95% confidence interval, 1.83-13.63; P =0.002)., Conclusions: We found that early positive troponin after ischemic stroke may be independently associated with a cardiac embolic source. Future studies are needed to confirm our findings using high-sensitivity troponin assays and to test optimal secondary prevention strategies in patients with embolic stroke of unknown source and positive troponin., (© 2017 American Heart Association, Inc.)

Goals: This study aimed to determine whether the plasma levels of free fatty acid (FFA) are associated with ischemic lesion characteristics in nonarterial-origin embolic stroke., Materials and Methods: We prospectively recruited 254 patients with acute cerebral infarction caused by cardioembolic stroke (CES, n=121) or with embolic stroke of undetermined source (ESUS, n=133). Plasma levels of FFA were measured during the acute stage (median of 2days after stroke onset). Acute ischemic lesions on diffusion-weighted imaging were measured in terms of size, composition, and pattern. Transthoracic echocardiography parameters were evaluated in all patients., Findings: Plasma levels of FAA were not different in CES and ESUS patients (mEq/L, 0.78±0.52 vs. 0.67±0.61, P=0.120). Echocardiography parameters, including left atrium volume index and E/e', were higher, and the ischemic lesion volume was larger in patients with CES than in those with ESUS. The ischemic lesion volume and the proportion of patients with mixed (small and large) and large cortical lesions increased with FFA quartile in both CES and ESUS groups. In a multivariable analysis, FFA level (coefficient, 5.249; standard error, 3.447; P=0.001), atrial fibrillation (coefficient, 7.673; standard error, 1.855; P<0.001), and fasting glucose (coefficient, 0.104; standard error, 0.023; P<0.001) were associated with ischemic lesion volume in nonarterial-origin embolic stroke., Conclusion: Elevated plasma FFA levels are associated with larger ischemic lesion volumes and a higher prevalence of large cortical infarcts in patients with nonarterial-origin embolic stroke regardless of the presence of a high-risk cardioembolic source., (Copyright © 2017. Published by Elsevier B.V.)

Background: The impact of different types of extracranial bleeding events on health-related quality of life and health-state utility among patients with atrial fibrillation is not well understood., Methods and Results: The ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) Trial compared edoxaban with warfarin with respect to the prevention of stroke or systemic embolism in atrial fibrillation. Data from the EuroQol-5D (EQ-5D-3L) questionnaire, prospectively collected at 3-month intervals for up to 48 months, were used to estimate the impact of different categories of bleeding events on health-state utility over 12 months following the event. Longitudinal mixed-effect models revealed that major gastrointestinal bleeds and major nongastrointestinal bleeds were associated with significant immediate decreases in utility scores (-0.029 [-0.044 to -0.014; P <0.001] and -0.029 [-0.046 to -0.012; P =0.001], respectively). These effects decreased in magnitude over time, and were no longer significant for major nongastrointestinal bleeds at 9 months, but remained borderline significant for major gastrointestinal bleeds at 12 months. Clinically relevant nonmajor and minor bleeds were associated with smaller but measurable immediate impacts on utility (-0.010 [-0.016 to -0.005] and -0.016 [-0.024 to -0.008]; P <0.001 for both), which remained relatively constant and statistically significant over the 12 months following the bleeding event., Conclusions: All categories of bleeding events were associated with negative impacts on health-state utility in patients with atrial fibrillation. Major bleeds were associated with relatively large immediate decreases in utility scores that gradually diminished over 12 months; clinically relevant nonmajor and minor bleeds were associated with smaller immediate decreases in utility that persisted over 12 months., Clinical Trial Registration: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00781391., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background and Aim of the Study: The study aim was to investigate the safety and effects of fasting during Ramadan on the International Normalized Ratio (INR) in patients with mechanical cardiac valves., Methods: A total of 105 patients admitted to the authors' hospital between June and October 2015, who had history of prosthetic valve replacement, was investigated. The patients were allocated to two groups: those fasting during Ramadan (n = 42) and those not fasting (n = 63). All patients were examined by a cardiologist, and the clinical findings and complaints for the past three months were evaluated. The INR, complete blood count (CBC) and a basic biochemical panel were monitored for all patients., Results: The mean corpuscular volume (MCV) of the fasting group was significantly higher than that of the non- fasting group (87.59 ± 6.39 (μm3) versus 84.28 ± 6.387 (μm3); p = 0.011). Other CBC parameters and basic biochemical values did not differ significantly different between groups. Neither were significant differences noted in INR values during Ramadan (fasting group 2.87 ± 0.97; non-fasting group 2.73 ± 0.78; p = 0.50) and at routine control one month later (fasting group 3.07 ± 1.55; non-fasting group 2.94 ± 1.03; p = 0.601). No significant differences related to increased rates of hospitalization, valvular dysfunction on echocardiography, thrombus, embolism, bleeding and clinical complaints were identified between the groups., Conclusions: Fasting during Ramadan had no adverse effects on the INR of patients, and appears to be safe for patients with mechanical prosthetic cardiac valves.

Thromboembolic events are one of the world's leading causes of death among patients. Embolus or clot formations have several etiologies including paraneoplastic, post-surgery, cauterization, transplantation, or extracorporeal circuits. Despite its medical significance, little progress has been made in early embolus detection, screening and control. The aim of our study is to test the utility of the in vivo photoacoustic (PA) flow cytometry (PAFC) technique for non-invasive embolus detection in real-time. Using in vivo PAFC, emboli were non-invasively monitored in the bloodstream of two different mouse models. The tumor-free mouse model consisted of two groups, one in which the limbs were clamped to produce vessel stasis (7 procedures), and one where the mice underwent surgery (7 procedures). The melanoma-bearing mouse model also consisted of two groups, one in which the implanted tumor underwent compression (8 procedures), and one where a surgical excision of the implanted tumor was performed (8 procedures). We demonstrated that the PAFC can detect a single embolus, and has the ability to distinguish between erythrocyte-rich (red) and leukocyte/platelet-rich (white) emboli in small vessels. We show that, in tumor-bearing mice, the level of circulating emboli was increased compared to tumor-free mice (p = 0.0013). The number of circulating emboli temporarily increased in the tumor-free control mice during vessel stasis (p = 0.033) and after surgical excisions (signed-rank p = 0.031). Similar observations were noted during tumor compression (p = 0.013) and after tumor excisions (p = 0.012). For the first time, it was possible to detect unlabeled emboli in vivo non-invasively, and to confirm the presence of pigmented tumor cells within circulating emboli. The insight on embolus dynamics during cancer progression and medical procedures highlight the clinical potential of PAFC for early detection of cancer and surgery-induced emboli to prevent the fatal thromboembolic complications by well-timed therapy.

Coagulation markers may improve monitoring the risk of stroke and bleeding in patients with atrial fibrillation (AF) during anticoagulant treatment. We examined baseline levels of D-dimer and their association with stroke, cardiovascular death and major bleeding in 6,202 AF patients randomised to dabigatran or warfarin in the RE-LY trial. The effects of treatment on serial levels of D-dimer and coagulation factor (F) VIIa in 2,567 patients were also analysed. Baseline D-dimer levels were related to the rate of stroke/systemic embolism (SEE) with 0.64 % in the lowest quartile (Q1, as reference) (D-dimer < 298 µg/l), 1.38 % Q2 (D-dimer 298-473 µg/l), 1.71 % Q3 (D-dimer 474-822 µg/l) and 2.00 % in Q4 (D-dimer > 822 µg/l) (p=0.0007). Similar associations were shown for cardiovascular death and major bleeding. Addition of baseline D-dimer to established clinical risk factors improved prediction of stroke/SEE, cardiovascular death and major bleeding (C-index increased from 0.66 to 0.68, 0.71 to 0.73 and 0.66 to 0.67, respectively). Dabigatran provided a greater reduction of D-dimer levels than warfarin regardless of baseline anticoagulant treatment. On-treatment levels of FVIIa were markedly reduced by warfarin (median 12.1-13.8 mU/ml) but significantly higher with dabigatran (median 39.4-49.0 mU/ml) at all-time points. Dabigatran is associated with greater reduction in D-dimer without the pronounced reduction of FVIIa seen with warfarin. These different effects on the coagulation system might explain the better efficacy and less intracranial bleeding observed with dabigatran compared with warfarin.

Background: Distal coronary embolization (DCE) of thrombotic material occurs frequently during percutaneous interventions for acute myocardial infarction and can alter coronary flow grades. The significance of DCE on infarct size and myocardial function remains unsettled. The aims of this study were to evaluate the effects of DCE sufficient to cause no-reflow on infarct size, cardiac function and ventricular remodeling in a porcine acute myocardial infarction model., Methods and Results: Female Yorkshire pigs underwent 60 min balloon occlusion of the left anterior descending coronary artery followed by reperfusion and injection of either microthrombi (prepared from autologous porcine blood) sufficient to cause no-reflow (DCE), or saline (control). Animals were sacrificed at 3 h (n = 5), 3 days (n = 20) or 6 weeks (n = 20) post-AMI. Cardiovascular magnetic resonance (CMR), serum troponin-I, and cardiac gelatinase (MMP) and survival kinase (Akt) activities were assessed. At 3d, DCE increased infarct size (CMR: 18.8% vs. 14.5%, p = 0.04; serum troponin-I: 13.3 vs. 6.9 ng/uL, p < 0.05) and MMP-2 activity levels (0.81 vs. 0.49, p = 0.002), with reduced activation of Akt (0.06 versus 0.26, p = 0.02). At 6 weeks, there were no differences in infarct size, ventricular volume or ejection fraction between the two groups, although infarct transmurality (70% vs. 57%, p< 0.04) and ventricular thinning (percent change in mid anteroseptal wall thickness:-25.6% vs. 0.7%, p = 0.03) were significantly increased in the DCE group., Conclusions: DCE increased early infarct size, but without affecting later infarct size, cardiac function or ventricular volumes. The significance of the later remodelling changes (ventricular thinning and transmurality) following DCE, possibly due to changes in MMP-2 activity and Akt activation, merits further study.

Background: Atrial fibrillation (AF) is a major risk factor for stroke and systemic embolism. Trials comparing warfarin with non-vitamin K oral anticoagulants (NOACs) have demonstrated that, when compared with warfarin, the NOACs are at least as effective in preventing stroke, although detailed analyses characterizing systemic embolic events (SEEs) are lacking., Methods and Results: We performed a prespecified analysis in 21,105 patients with AF enrolled in the ENGAGE AF-TIMI 48 trial, which compared 2 once-daily regimens of edoxaban with warfarin for the prevention of stroke and SEE. Of 1,016 patients who met the primary end point, 67 (6.6%) experienced an SEE of which 13% were fatal. Of 73 total SEEs (including recurrent events), 85% involved the extremities, and 41% required a surgical or percutaneous intervention. There were 23 (0.12%/year) SEEs with warfarin versus 15 with higher dose edoxaban (0.08%/year; hazard ratio vs warfarin 0.65; 95% CI 0.34-1.24; P = .19) and 29 with lower dose edoxaban (0.15%/year; hazard ratio vs warfarin 1.24; 95% CI 0.72-2.15; P = .43). In a meta-analysis of 4 warfarin-controlled phase 3 AF trials, NOACs significantly reduced the risk of SEE by 37% (relative risk 0.63; 95% CI 0.43-0.91; P = .01)., Conclusion: Although considerably less frequent than stroke, systemic embolism is associated with significant morbidity and mortality in patients with AF. Although the overall number of events was too small to show a significant difference in the risk of SEE between edoxaban and warfarin, a meta-analysis of all the NOAC trials demonstrates that NOACs significantly reduce the risk of SEE compared with warfarin., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Myxomas are the most common primary heart tumors and are closely associated with embolic events. Cardiac myxomas typically arise from the interatrial septum at the border of the fossa ovalis in the left atrium. Any other location is considered atypical. Embolism, one of the complications of myxoma, is associated with high morbidity and mortality. The aim of this study was to investigate the risk factors for embolism in patients with cardiac myxoma., Material and Methods: In this retrospective study, a cohort of 162 patients with cardiac myxomas was surgically treated between January 1998 and June 2014 at 3 cardiac centers in China. Preoperative data, including platelet count, sex, age, and the tumor (size, location, surface, and attachment), were compared between embolic and non-embolic groups of patients., Results: No significant differences in vascular risk factors were seen between the 2 groups. However, the percentage of higher platelet count (>300 × 10(9)/L) and mean platelet volume in the embolic group were significantly higher than in the non-embolic group (P=0.0356, and 0.0113, respectively). Irregular surface and atypical location of the myxomas were also independently associated with increased risk of embolic complications., Conclusions: Tumor location, macroscopic appearance, mean platelet volume, and high platelet count are strong risk factors for embolic events in patients with cardiac myxomas.

We hypothesised that increased on-admission and follow-up mean platelet volume (MPV) levels would correlate with adverse outcomes in patients with infective endocarditis (IE). A total of 108 consecutive patients were grouped into two according to median MPV level (≤ 8.6 and > 8.6 fL). Patients with MPV level of > 8.6 fL had a significantly higher rate of end-stage renal disease, Staphylococcus aureus infection, higher CRP levels, embolic events and in-hospital mortality compared to patients with MPV levels ≤ 8.6 fL. In multivariable Cox regression analysis, previous history of IE, S. aureus infection, end-stage renal disease, depressed LVEF, early surgical intervention, vegetation size ≥ 10 mm, presence of perivalvular abscess, higher on-admission platelet count, CRP and MPV levels emerged as independent predictors of in-hospital unfavourable outcomes. Patients with embolic events and in-hospital mortality revealed an incremental trend for MPV levels compared to patients without any adverse events. Our study results suggest that both on-admission and follow-up MPV levels may be a simple and available biomarker for risk stratification of IE patients.

We report 2 similar cases of embolic myocardial infarction due to thrombus on a mechanical prosthesis despite anticoagulation therapy. In our first case, aspiration of the thrombus was performed successfully. Our second patient was given medical treatment with target international normalized ratio values between 3.5 and 4.0., (© The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Background: Platelet activation appears to play an important role in thromboembolic complications of infective endocarditis (IE). Mean platelet volume (MPV) is a potentially useful marker of platelet activity and a quick and easy determinant of thrombotic risk. Hence the aim of this study was to investigate the baseline platelet volume indices (MPV and platelet distribution width [PDW]) in IE patients who developed embolic events in the follow-up period and who did not., Methods: The study group consisted of 76 consecutive patients (female: 55, male: 21, mean age: 26 years old, ranged: 8-64 years) with definite IE according to Duke Criteria. Thirty four healthy subjects, who were age and gender adjusted, served as the control group. The mean duration of hospital stay was 44 days., Results: Among the IE patients, 13 (13/76, 17.1%) had major embolic events. Significantly larger vegetations were observed in patients with embolic events as compared to non-embolic group (1.4 vs. 1.0 cm, p = 0.03). MPV at hospital admission was higher in patients who had embolic events in the follow-up period compared to both those who did not and the control subjects (10.62 ± 1.13 vs. 9.25 ± 0.97 and 8.93 ± 0.82 fL, p < 0.001, respectively). Similarly, the patients with embolic events had increased PDW compared to the non-embolic ones and the control group (16.31 ± 2.42 vs. 14.35 ± 1.97 and 14.04 ± 1.82%, p < 0.001, respectively)., Conclusions: The present study demonstrated that IE patients with embolic events had increased MPV and PDW values, compared to non-embolics. Future prospective studies with standardized measurements may clarify the clinical role of platelet volume indices in thrombo-embolic complications of IE.

Pathological coagulation parameters may reflect life-threatening hemorrhagic or thromboembolic diseases but may also be a laboratory result without any clinical significance, result from in vitro phenomena or preanalytical errors. This article gives an overview of potential pitfalls in coagulation diagnostics, lists the differential diagnoses of pathological coagulation parameters and describes further steps in the diagnostic approach to clarify pathological results. The focus lies on coagulation parameters that are frequently determined in routine clinical investigations, e.g. platelet count, prothrombin time, activated partial thromboplastin time (aPTT) and fibrinogen. Besides heparin, fondaparinux, danaparoid, and vitamin K antagonists, direct factor Xa inhibitors and direct thrombin inhibitors are nowadays available for therapeutic anticoagulation. This article gives an overview of the influence of anticoagulants on coagulation parameters which depends on the dose, the time of the last administration, as well as the method used for the determination of coagulation parameters. Moreover, common reasons for elevation of the fibrin degradation product D-dimer are presented. The clinical utility of D-dimer assays is limited by their poor specificity. Elevated D-dimer concentrations can be found in various diseases and also under normal physiological circumstances (e.g. in the elderly). Thus, the most useful clinical application of D-dimer is evidence of normal values to essentially rule out venous thromboembolism.

Background: D-dimer is related to adverse outcomes in arterial and venous thromboembolic diseases., Objectives: To evaluate the predictive value of D-dimer level for stroke, other cardiovascular events, and bleeds, in patients with atrial fibrillation (AF) treated with oral anticoagulation with apixaban or warfarin; and to evaluate the relationship between the D-dimer levels at baseline and the treatment effect of apixaban vs. warfarin., Methods: In the ARISTOTLE trial, 18 201 patients with AF were randomized to apixaban or warfarin. D-dimer was analyzed in 14 878 patients at randomization. The cohort was separated into two groups; not receiving vitamin K antagonist (VKA) treatment and receiving VKA treatment at randomization., Results: Higher D-dimer levels were associated with increased frequencies of stroke or systemic embolism (hazard ratio [HR] [Q4 vs. Q1] 1.72, 95% confidence interval [CI] 1.14-2.59, P = 0.003), death (HR [Q4 vs. Q1] 4.04, 95% CI 3.06-5.33) and major bleeding (HR [Q4 vs. Q1] 2.47, 95% CI 1.77-3.45, P < 0.0001) in the no-VKA group. Similar results were obtained in the on-VKA group. Adding D-dimer level to the CHADS2 score improved the C-index from 0.646 to 0.655 for stroke or systemic embolism, and from 0.598 to 0.662 for death, in the no-VKA group. D-dimer level improved the HAS-BLED score for prediction of major bleeds, with an increase in the C-index from 0.610 to 0.641. There were no significant interactions between efficacy and safety of study treatment and D-dimer level., Conclusion: In anticoagulated patients with AF, the level of D-dimer is related to the risk of stroke, death, and bleeding, and adds to the predictive value of clinical risk scores. The benefits of apixaban were consistent, regardless of the baseline D-dimer level., (© 2014 International Society on Thrombosis and Haemostasis.)

Background: Time in therapeutic range (TTR) is a standard quality measure of the use of warfarin. We assessed the relative effects of rivaroxaban versus warfarin at the level of trial center TTR (cTTR) since such analysis preserves randomized comparisons., Methods and Results: TTR was calculated using the Rosendaal method, without exclusion of international normalized ratio (INR) values performed during warfarin initiation. Measurements during warfarin interruptions >7 days were excluded. INRs were performed via standardized finger-stick point-of-care devices at least every 4 weeks. The primary efficacy endpoint (stroke or non-central nervous system embolism) was examined by quartiles of cTTR and by cTTR as a continuous function. Centers with the highest cTTRs by quartile had lower-risk patients as reflected by lower CHADS2 scores (P<0.0001) and a lower prevalence of prior stroke or transient ischemic attack (P<0.0001). Sites with higher cTTR were predominantly from North America and Western Europe. The treatment effect of rivaroxaban versus warfarin on the primary endpoint was consistent across a wide range of cTTRs (P value for interaction=0.71). The hazard of major and non-major clinically relevant bleeding increased with cTTR (P for interaction=0.001), however, the estimated reduction by rivaroxaban compared with warfarin in the hazard of intracranial hemorrhage was preserved across a wide range of threshold cTTR values., Conclusions: The treatment effect of rivaroxaban compared with warfarin for the prevention of stroke and systemic embolism is consistent regardless of cTTR.

Objective: To determine whether the plasma level of free fatty acid (FFA) could be associated with recurrent stroke in cardioembolic (CE) stroke patients., Methods: We analyzed data from 669 acute ischemic stroke patients and examined the association between FFA concentration and recurrent stroke in CE stroke patients compared with non-CE stroke patients., Results: The baseline plasma FFA concentration (mEq/L) was approximately 1.5-fold higher in CE stroke patients (1.01 ± 0.63) than in non-CE stroke patients (0.72 ± 0.51). Multivariate logistic analysis showed that an increased level of FFA was significantly associated with CE stroke (hazard ratio [HR] 2.124, confidence interval [CI] 1.492-3.024). During the mean follow-up period of 25.4 months, a total of 56 (8.4%) patients experienced a stroke recurrence. The recurrence rate did not differ between patients with CE (10.5%) and non-CE (8.0%) stroke (p = 0.396). In CE stroke patients, an elevated baseline FFA concentration was independently associated with stroke recurrence (HR 2.711, CI 1.056-6.959). However, there was no association between FFA and stroke recurrence in non-CE stroke patients., Conclusion: In this retrospective registry-based observational study, CE stroke seemed to be associated with elevated plasma level of FFA. In addition, the present study suggested that an elevated FFA concentration could be a useful indicator for predicting recurrent stroke in CE stroke patients.

Objectives: The aim of this study was to investigate the value of plasma D-dimer (DD) levels for predicting systemic embolism in patients with infective endocarditis (IE)., Study Design: A total of 42 patients (mean age: 46±16 years; 78% males) with IE were included. Clinical, laboratory and echocardiographic findings of the patients were evaluated., Results: Increased plasma DD levels were determined in 13 patients with systemic embolism (p=0.016). Moreover, when patients were divided in two groups as DD >500 ng/dl and DD <500 ng/dl, systemic embolism was increased in the DD >500 ng/dl group (p=0.036). Receiver operating characteristics (ROC) curve analysis was performed to detect the best cut-off value of DD in the prediction of systemic embolism. DD >425 ng/dl yielded an area under the curve (AUC) value of 0.735 (95% CI 0.560-0.909, p=0.016). DD >425 ng/dl demonstrated a sensitivity of 77% and specificity of 62% for the prediction of clinical embolism. Hematocrit (r=-0.31, p=0.045), platelet count (r=-0.40, p=0.009), albumin (r=-0.37, p=0.026), and globulin (r=0.38, p=0.028) levels were correlated with DD levels., Conclusion: Plasma DD levels are increased in patients with IE who suffered from clinically significant systemic embolism. Further studies are needed to determine the predictive value of DD levels for clinically silent systemic embolism.

Background: Activation of the complement system has been proposed to play a role in the pathophysiology of stroke. As the specific involvement of the complement proteins may be influenced by stroke etiology, we compared plasma C3 and C3a levels in patients with cardioembolic (CE) and small vessel disease (SVD) subtypes of ischemic stroke and control subjects and evaluated their association to outcome at three months and two years., Methodology/principal Findings: Plasma C3 and C3a levels in 79 CE and 79 SVD stroke patients, sampled within 10 days and at three months after stroke, and age- and sex-matched control subjects from The Sahlgrenska Academy Study on Ischemic Stroke were measured by ELISA. Functional outcome was assesed with modified Rankin Scale. In the CE group, plasma C3 levels were elevated only in the acute phase, whereas C3a was elevated at both time points. The follow-up phase plasma C3 levels in the upper third were associated with an increased risk of unfavorable outcome at three months (OR 7.12, CI 1.72-29.46, P = 0.007) as well as after two years (OR 8.25, CI 1.61-42.28, P = 0.011) after stroke. These associations withstand adjustment for age and sex. Conversely, three-month follow-up plasma C3a/C3 level ratios in the middle third were associated with favorable outcome after two years both in the univariate analysis (OR 0.19, CI 0.05-0.82, P = 0.026) and after adjustment for age and sex (OR 0.19, CI 0.04-0.88, P = 0.033). In the SVD group, plasma C3 and C3a levels were elevated at both time points but showed no significant associations with outcome., Conclusions: Plasma C3 and C3a levels are elevated after CE and SVD stroke but show associations with outcome only in CE stroke.

Background: There has been debate regarding whether natriuretic peptides can be used as a marker to distinguish cardioembolic (CE) origin of ischemic stroke from other subtypes. Therefore, the aim of this study was to study the value of N-terminal pro B-type natriuretic peptide (NT-proBNP) in differentiating CE from other subtypes of stroke in patients with acute ischemic stroke., Methods: All 125 consecutive patients with acute ischemic stroke in a 1-year period were included. Admission blood samples of all patients were analyzed for the serum level of NT-proBNP. Patients were evaluated for etiology of stroke by imaging modalities and classified based on Trial of Org 10172 in Acute Stroke Treatment criteria. Medical history and risk factors for vascular diseases were also obtained. Receiver operating characteristic (ROC) analysis was used for estimating the diagnostic performance of NT-proBNP levels., Results: Patients were a mean of 67.5 ± 12.6 years of age, and 60 (48%) were men. The most frequent subtype of stroke (57 patients) was CE (45.6%). Levels of NT-proBNP at admission were significantly higher in the CE group (P = .001). After omitting confounding variables, NT-proBNP levels and age were independent predictors of CE stroke subtype. ROC analysis revealed that the diagnostic performance of NT-proBNP levels (area under the curve), optimum cutoff point and its sensitivity and specificity were 0.882 ± 0.031pg/mL, 342 pg/mL, 93%, and 75%, respectively., Conclusions: NT-proBNP has an acceptable diagnostic value in distinguishing CE ischemic stroke from other subtypes. It can be used to differentiate the stroke subtype and facilitate the treatment process in these patients., (Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: Warfarin reduces ischemic stroke in atrial fibrillation, but has numerous limitations. Novel oral anticoagulants provide more predictable anticoagulation with fewer shortcomings., Hypothesis: Novel oral anticoagulants are superior to warfarin to prevent stroke or systemic embolism., Methods: Phase III randomized warfarin-controlled trials enrolling >3000 patients that reported clinical efficacy and safety of novel oral anticoagulants in patients with atrial fibrillation were identified from MEDLINE, Embase, and Cochrane Central Register of Controlled Trials through October 2012. Two reviewers extracted data; differences were resolved by consensus. The end points analyzed were stroke or systemic embolism (primary efficacy composite); all-cause mortality, ischemic stroke, systemic embolism (individually, secondary efficacy); and hemorrhagic stroke, major bleeding (individually, safety). The Mantel-Haenszel method was used to calculate pooled relative risk (RR) and 95% confidence intervals (CI) from fixed-effects (if homogenous) or random-effects models (if heterogeneous)., Results: In 5 studies of 51895 patients, the composite of stroke or systemic embolism (RR: 0.82; 95% CI: 0.69-0.98; P = 0.03) and all-cause mortality (RR: 0.91; 95% CI: 0.85-0.96; P = 0.0026, respectively) were reduced with the novel agents. Factor Xa inhibitors significantly reduced the primary composite (RR: 0.84; 95% CI: 0.74-0.94; P = 0.004) and all-cause mortality (RR: 0.91; 95% CI: 0.84 - 0.98; P = 0.01). Direct thrombin inhibitor achieved results similar to the overall meta-analysis (drug class-outcome interactions P = 0.47 for primary outcome, P = 1.00 for mortality). Compared with warfarin, novel anticoagulants markedly reduced hemorrhagic stroke (RR: 0.51; 95% CI: 0.41-0.64; P < 0.0001)., Conclusions: Novel oral anticoagulants may be superior to warfarin in patients with atrial fibrillation, reducing the composite of stroke or systemic embolism and lowering all-cause mortality. The benefit is largely due to fewer hemorrhagic strokes., (© 2013 Wiley Periodicals, Inc.)

Objective: ω-3 fatty acids, including eicosapentaenoic acid (EPA), prevent ischemic stroke. However, the clinical importance of EPA for ischemic stroke and its subtype has not been fully elucidated., Methods: In a cross-sectional study, we determined whether ω-3 fatty acids were predictive factors for ischemic stroke. We compared common clinical parameters among 65 patients with ischemic stroke and 65 control subjects. The parameters included blood chemistry data; concentrations of EPA, docosahexaenoic acid, and arachidonic acid (AA); EPA/AA ratio; smoking; alcohol intake; fish consumption more than four times per week; and the incidence of underlying diseases. The comparisons were performed using the Mann-Whitney U test, and multiple logistic regression analysis was applied to the significant factors in the non-parametric test. We also applied the same approach to the ischemic stroke subtypes, cardioembolism and large-artery atherosclerosis., Results: In the multiple logistic regression analysis after the Mann-Whitney U test, a lower EPA concentration was one of the significant risk factors for ischemic stroke, as were a lower body mass index, lower high-density lipoprotein cholesterol, and smoking (sensitivity 0.846, specificity 0.831, positive predictive value 0.833). In the analysis of subtypes, a lower EPA/AA ratio and a lower body mass index were the significant risk factors for cardioembolism (sensitivity 0.800, specificity 0.733, positive predictive value 0.750). However, large-artery atherosclerosis was not related to the EPA concentration or the EPA/AA ratio., Conclusions: In this study, the plasma EPA concentration and the EPA/AA ratio were potential predictive risk factors for ischemic stroke, especially for cardioembolism. Further prospective studies are necessary., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The risk of recurrent stroke is likely related to etiology. Therefore it is important to identify which patients are at highest early risk. We evaluated whether selected blood biomarkers may aid in the diagnosis of stroke etiology. We studied consecutive non-lacunar stroke patients between November 2006 and January 2007, and selected undetermined origin strokes. Blood samples were drawn at arrival to test brain natriuretic peptide (BNP), D-dimer, CK-MB, myoglobin, and troponin. Second harmonic transthoracic echocardiography (SHTTE) and ECG-24 h monitoring were also performed within the first 24 h. We evaluated 294 patients with ischemic stroke; 89 had an initial undetermined origin. After a cardiological work-up, 49 were diagnosed as embolic including atrial fibrillation (4), severe aortic arch atheromatosis (24), severe wall abnormalities (12), valve disease (3), dilated cardiomyopathy (1), and patent foramen (5). Higher levels of CK-MB, BNP, and myoglobin were found in patients with embolic source in SHTTE, but only CK-MB >1.5 ng/ml and BNP >64 pg/ml remained as independent predictors: BNP (OR 8.86; CI 95 % 2.79-28.09), CK-MB (OR 6.28; CI 95 % 1.66-23.69). BNP showed specificity of 75 %, sensitivity of 63.4 %, and positive predictive value (PPV) of 75.6 %. CK-MB had specificity of 85 %, sensitivity of 47.9 %, and PPV of 79.3 %. Measuring both biomarkers improves the finding of embolic source, increasing specificity to 95 % and PPV to 88.2 %. High-level CK-MB and BNP during the acute phase of ischemic stroke are associated with an embolic source. Measurement of both biomarkers may improve the diagnosis, guiding the need to perform a heart exploration.

Background: Since atherogenesis is related to oxidative stress, our objective was to study the association of oxidative stress markers with the vascular recurrence in non-cardioembolic stroke., Methods: Atherosclerotic and oxidative stress markers were evaluated on admission, in 477 patients suffering from a first non-cardioembolic stroke. Patients were followed at 6 and 12 months after inclusion, recording cardiovascular events. As markers of endothelial oxidative stress we used oxidized LDL, Cu/Zn superoxide dismutase and 8-OH deoxiguanosine. 136 patients were being treated with statins at the moment of serum samples acquisition., Results: Patients who suffered vascular recurrence or vascular-origin death had higher levels of 8-OHDG (40.06 ± 24.70 vs 33.11 ± 15.18;p=0.003). We also found associations between vascular recurrence or vascular origin death and Cu/ZnSOD (OR,1.02; 95%CI,1.00-1.03;p=0.0001) and 8-OHDG (OR,1.12;95%CI,1.08-1.16;p<0.0001) in a subgroup of 333 patients that were not in treatment with statins on admission. We also found associations between 8-OHDG and intima media thickness (IMT) (OR,1.13;95%CI,1.09-1.16;p<0.0001), presence of ipsilatieral stenosis ≥ 50% (OR,1.03;95%CI 1.00-1.05;p=0.007) and other atherosclerotic plaque characteristics., Conclusions: Specific oxidative stress markers were found to be markers of atherosclerosis plaque types and vascular recurrence in non-statins treated patients at admission.

Soluble thrombomodulin (sTM) has been proposed as a potential marker of ischemic stroke. Results from previous studies remain controversial among different populations. We performed an analysis of plasma levels of sTM in Thai patients with acute ischemic stroke and determined whether sTM levels correlate with stroke subtypes, severity, and risk factors. Ninety-three patients and 76 controls were enrolled. Blood samples were obtained within 24 hours after stroke onset. Plasma sTM levels, measured using quantitative enzyme-linked immunosorbent assay, were significantly higher in patients than controls (P < .005), with the mean ± standard deviation (SD) levels of 3.08 ± 1.05 and 2.57 ± 1.15 ng/mL, respectively. Plasma levels of sTM in patients with cardioembolic subtype were significantly higher than in patients with other stroke subtypes, with the mean ± SD levels of 3.79 ± 1.26, 2.38 ± 0.68 (P < .009), and 2.38 ± 0.44 (P < .05) ng/mL for cardioembolism, large artery atherosclerosis, and small artery occlusion, respectively. Plasma sTM levels were not associated with stroke severity and risk factors of stroke; however, there was a slight relationship between high sTM levels and the presence of atrial fibrillation in the patient group. In conclusion, plasma sTM levels were increased in Thai patients with cardioembolic stroke and may be a potential marker during the acute phase.

Objective: At sites of vascular injury, thrombin is an important mediator in thrombus growth and stability. Using microfluidic flow devices as well as patterned surfaces of collagen and tissue factor (TF), we sought to determine the role that fibrin plays in clot stability without interfering with the production of thrombin., Methods and Results: We deployed an 8-channel microfluidic device to study coagulation during corn trypsin inhibitor-treated (XIIa-inhibited) whole blood perfusion over lipidated TF linked to a fibrillar collagen type 1 surface. Clot growth and embolization were measured at initial inlet venous (200 s(-1)) or arterial (1000 s(-1)) wall shear rates under constant flow rate or pressure relief mode in the presence or absence of Gly-Pro-Arg-Pro (GPRP) to block fibrin polymerization. Numerical calculations for each mode defined hemodynamic forces on the growing thrombi. In either mode at inlet venous flow, increasing amounts of TF on the surface led to a modest dose-dependent increase (up to 2-fold) in platelet deposition, but resulted in massive fibrin accumulation (>50-fold) only when exceeding a critical TF threshold. At a venous inlet flow, GPRP led to a slight 20% increase in platelet accumulation (P<0.01) in pressure relief mode with thrombi resisting ≈1500 s(-1) before full channel occlusion. GPRP-treated thrombi were unstable under constant flow rate, where shear forces caused embolization at a maximum shear rate of ≈2300 s(-1) (69 dynes/cm2). In constant flow rate mode, the nonocclusive platelet-fibrin deposits (no GPRP) withstood maximum shear rates of ≈29 000 s(-1) (870 dyne/cm2) at ≈95% of full channel occlusion. For arterial inlet shear rate, embolization was marked for either mode with GPRP present when shear forces reached 87 dynes/cm2 (≈2900 s(-1)). Under constant flow rate, platelet-fibrin deposits (no GPRP) withstood maximums of 2400 dynes/cm2 (80,000 s(-1)) at ≈90% of full channel occlusion prior to embolization., Conclusions: Fibrin increased clot strength by 12- to 28-fold. Under pressure relief mode, ≈2-fold more fibrin was produced under venous flow (P<0.001). These studies define embolization criteria for clots formed with surface TF-triggered thrombin production (±fibrin) under venous and arterial flows.

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with potentially dreadful cardioembolic complications such as stroke. The risk of stroke is stratified based on the patient's comorbid conditions using several scoring systems. Patients are treated with oral anticoagulation using warfarin or aspirin based on their cardioembolic stroke risk. Although warfarin has been the only effective therapy, it is underutilized clinically due to concern for multiple drug-to-drug and drug-to-food interactions and hemorrhagic complications. Dual antiplatelet therapy with aspirin and clopidogrel has been studied as a potential alternative anticoagulant for AF patients; however, the combination of aspirin and clopidogrel was noted to be inferior to warfarin in preventing strokes, with an increased risk of bleeding. As a result, newer anticoagulant agents, including direct thrombin inhibitors, direct and indirect factor Xa inhibitors, and vitamin K antagonists, have been developed and evaluated in AF patients. Results from a recent study demonstrated that high-dose dabigatran, a direct thrombin inhibitor, was superior to warfarin in preventing stroke and systemic embolism with similar bleeding risk. It ultimately received approval by the US Food and Drug Administration for stroke prophylaxis for nonvalvular AF patients. There are several other direct factor Xa inhibitors currently under study. Dabigatran may be considered in AF patients who are intolerant to warfarin or unwilling or unable to follow-up with frequent laboratory monitoring. Other newer anticoagulant agents also provide us with possible suitable alternatives to warfarin, and their clinical use will depend on the results from ongoing studies.

Background: Classification defined in the Trial of Org10172 in Acute Ischaemic Stroke (TOAST) is widely used in trials and practice. Previous studies on pathophysiology suggest a role for endothelial inflammation in atherothrombotic strokes and intracardiac thrombosis in cardioembolic strokes. Data on lacunar and undetermined strokes are limited. The aim of the study was to assess non-specific inflammatory and thrombogenic parameters in patients with ischaemic stroke., Methods: This was a prospective controlled clinical study involving 200 patients with ischaemic stroke and 50 controls. Patients were classified following the TOAST criteria. Plasma levels of fibrinogen, D-dimer, C reactive protein and values for D-dimer/fibrinogen ratio and erythrocyte sedimentation rate were assessed over 48 h after admission. Clinical severity was measured using the National Institutes of Health Stroke Scale and the Oxfordshire Community Stroke Project classification. Patients with severe systemic disorders were excluded., Results: The assessed parameters were significantly higher in patients versus controls. Cardioembolic stroke patients showed increased D-dimer, fibrinogen and D-dimer/fibrinogen ratio. Patients with atherothrombotic stroke showed raised fibrinogen and erythrocyte sedimentation rate. Patients with lacunar and undetermined stroke showed intermediate values of markers. Total anterior cerebral infarction syndrome was related to D-dimer., Discussion: Patients showed analytical modifications during the acute phase of stroke, both related to acute response and mechanism. The results suggest that the biochemical profile may be prothrombotic in patients with cardioembolism and inflammatory in those with atherothrombotic stroke. Patients with lacunar and undetermined stroke showed intermediate profiles. Assessment of the studied parameters is not expensive, widely available and may proportionate information about pathophysiology in stroke patients without severe systemic conditions.