An Embolic Stroke in a Patient With PROC p.Lys193del.

We report a 58-year-old woman who suddenly developed brain infarction with weakness of the left lower extremity and left perioral dysesthesia during postoperative tamoxifen therapy for breast cancer and prednisolone therapy for rheumatoid arthritis. Diffusion-weighted images detected multiple areas of hyperintensity in the posterior circulation system of the brain. Despite extensive examinations, we could not identify any embolic sources except hypoplasia of the right vertebral artery. We found decreased activity of protein C against its antigen level (activity: 59% versus antigen: 122%) with enhanced activity of coagulation factor VIII (178%) and von Willebrand factor (285%). DNA sequencing identified trinucleotide deletion of the PROC gene leading to 1 amino acid deletion at Lys-193 (p.Lys193del). We speculate that the PROC gene polymorphism may have participated in tamoxifen- and prednisolone- associated hypercoagulable state, leading to development of an embolic stroke in this patient.

Atrial Cardiopathy and Nonstenosing Large Artery Plaque in Patients With Embolic Stroke of Undetermined Source.

Background and Purpose- Atrial cardiopathy and atherosclerotic plaque are two potential mechanisms underlying embolic strokes of undetermined source (ESUS). The relationship between these two mechanisms among ESUS patients remains unclear. A better understanding of their association may inform targeted secondary prevention strategies. Methods- We examined the association between atrial cardiopathy and atherosclerotic plaque in the NAVIGATE ESUS trial (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source), which enrolled 7213 patients with recent ESUS during 2014 to 2017. For this analysis, we included patients with data on left atrial dimension, location of brain infarction, and cervical large artery plaque. The variables of primary interest were left atrial diameter and cervical plaque ipsilateral to brain infarction. Secondary markers of atrial cardiopathy were premature atrial contractions on Holter monitoring and newly diagnosed atrial fibrillation. For descriptive purposes, left atrial enlargement was defined as ≥4.7 cm. Multivariable logistic regression was used to examine the association between atrial cardiopathy markers and ipsilateral plaque after adjustment for age, sex, body mass index, hypertension, diabetes mellitus, current smoking, and hyperlipidemia. Results- Among 3983 eligible patients, 235 (5.9%) had left atrial enlargement, 939 (23.6%) had ipsilateral plaque, and 94 (2.4%) had both. Shared risk factors for left atrial enlargement and ipsilateral plaque were male sex, white race, hypertension, tobacco use, and coronary artery disease. Despite shared risk factors, increasing left atrial dimension was not associated with ipsilateral plaque after adjustment for covariates (odds ratio per cm, 1.1 [95% CI, 1.0-1.2]; P=0.08). We found no consistent associations between secondary markers of atrial cardiopathy and ipsilateral plaque. Conclusions- In a large population of patients with ESUS, we did not observe a notable association between atrial cardiopathy and atherosclerotic plaque, and few patients had both conditions. These findings suggest that atrial cardiopathy and atherosclerotic plaque may be distinct, nonoverlapping risk factors for stroke among ESUS patients.

D-dimer and C-reactive Protein as Potential Biomarkers for Diagnosis of Trousseau's Syndrome in Patients with Cerebral Embolism.

BACKGROUND: Differentiating stroke due to Trousseau's syndrome from other types of cerebral embolism is challenging, especially in patients with occult cancer. The current study aimed to determine predicting factors and biomarkers of stroke due to Trousseau's syndrome. METHODS: This retrospective study comprised 496 consecutive patients with acute cerebral embolism, including 19, 85, 310, and, 82 patients with stroke due to Trousseau's syndrome, artery-to-artery embolism, cardioembolic stroke, and embolic stroke with undetermined source, respectively. All patients were evaluated within 72 hours of onset. The clinical characteristics, laboratory findings, and patterns on diffusion-weighted magnetic resonance imaging (DWI) were compared among the groups. RESULTS: Plasma D-dimer and C-reactive protein (CRP) levels were significantly higher in the Trousseau's syndrome than in the other causes of cerebral embolism. Multivariate analyses demonstrated that female sex, multiple lesions on DWI, high D-dimer and CRP levels, and low platelet and low brain natriuretic peptide levels were independent predictors that could distinguish Trousseau's syndrome from the other causes of cerebral embolism. The cutoff values of D-dimer and CRP to identify stroke due to Trousseau's syndrome was 2.68 µg/mL fibrinogen equivalent units and .29 mg/dL, respectively. CONCLUSIONS: The elevated D-dimer and CRP levels on admission in addition to specific clinical features may be useful for diagnosis of Trousseau's syndrome in patients with cerebral embolism.

Arterial Stiffness and Indices of Left Ventricular Diastolic Dysfunction in Patients with Embolic Stroke of Undetermined Etiology.

PURPOSE: The study is aimed at identifying echocardiographic and circulating biomarkers as well as hemodynamic indices of embolic stroke of undetermined etiology (ESUS) in patients aged <65. METHODS: We prospectively investigated 520 patients with confirmed ischemic stroke and selected those 65 patients who were diagnosed with ESUS (age 54 (47-58) years, 42% male). An additional 36 without stroke but with a similar risk profile were included as a control group (age 53 (47-58) years, 61% male). All patients underwent echocardiography, noninvasive assessment of hemodynamic parameters using a SphygmoCor tonometer (AtCor Med., Australia), and measurements of selected biomarkers. RESULTS: ESUS patients and controls were well matched for baseline characteristics including blood pressure and left ventricular ejection fraction (LVEF). Compared to controls, patients with ESUS had lower mean early diastolic (E') and systolic (S') mitral annular velocities and a higher ratio of the peak velocity of early diastolic transmitral flow to the peak velocity of early diastolic mitral annular motion (all p < 0.01). The peak velocity flow in the late diastole (A wave) value and LV mass indexed to the body surface area (LVMI) (g/m2) were higher in the ESUS group than in the control group (both p < 0.01). The isovolumetric relaxation time (IVRT) was longer and the mean left atrial volume index (LAVI) was higher in ESUS patients compared to the control group. Parameters of arterial stiffness such as augmentation pressure, augmentation index, and augmentation index adjusted to a heart rate of 75 bpm (AIx75) were higher in ESUS patients compared to controls (p < 0.05). Patients in the ESUS group had higher levels of asymmetric dimethylarginine, interleukin 6, and N-terminal probrain natriuretic peptide (NT-proBNP, all p < 0.05) than those in the control group. In multivariate analysis, the following factors were significantly associated with the presence of ESUS: AIx75 (odds ratio (OR) 1.095, 95% confidence interval (CI) 1.004-1.194; p = 0.04), IVRT (OR 1.045, 95% CI: 1.009-1.082; p = 0.014), LAVI (OR 1.3, 95% CI: 1.099-1.537; p = 0.002), and NT-proBNP (OR 1.003, 95% CI: 1.001-1.005; p = 0.005). CONCLUSIONS: Increased arterial stiffness and indices of diastolic dysfunction as well as a higher NT-proBNP level are significantly associated with ESUS. These parameters require further scrutiny over time to understand their impact on the development of symptomatic heart failure. The ClinicalTrials.gov identifier is NCT03377465.

Plasma Osteoprotegerin Correlates with Stroke Severity and the Occurrence of Microembolic Signals in Patients with Acute Ischemic Stroke.

BACKGROUND: Instability of atherosclerotic plaques is associated with the occurrence of stroke. Microembolic signals (MESs) are an indicator of unstable plaque. A relationship between plasma osteoprotegerin (OPG) and ischemic stroke has already been identified. The aim of this study was to investigate whether plasma OPG levels have a relationship with MESs and to evaluate the feasibility of OPG as a biomarker of stroke severity and occurrence of MESs. METHODS: Our study consisted of 127 patients with large artery atherosclerosis stroke and 56 controls. Patients were classified into subgroups based on stroke severity and the occurrence of MESs. MES-monitoring was performed for 60 min using transcranial Doppler within 72 h of stroke onset. Stroke severity at admission was assessed by the National Institutes of Health Stroke Scale. RESULTS: Plasma OPG levels were significantly associated with stroke, MESs, and stroke severity at admission (adjusted OR [95% CI]: 1.002 [1.001-1.003] p < 0.001; 1.002 [1.001-1.003] p = 0.001; 1.001 [1.000-1.002] p = 0.028). When plasma OPG levels were used to determine the stroke severity, the area under the receiver-operating characteristic curve (AUC) was 0.734 (95% CI: 0.625-0.843) based on a cutoff value of 1998.44 pg/ml; the sensitivity and specificity of this test were 80.6% and 65.6%, respectively. Furthermore, when the levels of OPG were used to distinguish the presence of MESs, the AUC was 0.766 (95% CI: 0.672-0.860); the cutoff value was 2107.91 pg/ml. The sensitivity of this cutoff value was 68.8% and the specificity was 73.7%. CONCLUSIONS: Plasma OPG levels correlate with stroke severity and the occurrence of MESs.

[Platelet inhibition in patients with coronary, cerebral and peripheral macroangiopathy : What, when and how long?] / Thrombozytenaggregationshemmer bei koronarer, zerebraler und peripherer Makroangiopathie : Was, wann, wie lange?

BACKGROUND: Inhibition of platelet aggregation can reduce the rate of vascular events in patients with coronary artery disease, carotid artery stenosis and symptomatic peripheral arterial disease. The choice of platelet inhibitors in monotherapy and combination therapy as well as the duration of dual platelet inhibition depend on the clinical situation and individual patient characteristics. GOAL: The present review summarizes the latest data from clinical trials and recommendations regarding platelet inhibition in coronary, cerebral and peripheral arterial disease. DATA: A large number of randomized trials on platelet inhibition in different clinical situations have been performed, allowing evidence-based recommendations on the choice of drugs and duration of treatment. Moreover, new guidelines of European professional societies on platelet inhibition in patients with coronary, cerebral and peripheral arterial disease have been recently published. CONCLUSION: Based on latest randomized trials and major society guidelines, a number of recommendations on platelet inhibition in stable coronary artery disease, after stent implantation, after acute coronary syndromes and in cerebral and peripheral arterial disease can be made.

Biomarkers of cerebral microembolic signals.

Stroke is a major cause of mortality and morbidity around the world. Microembolic signals (MES), as the markers of unstable atherosclerotic plaque, can predict the occurrence and prognosis of ischemic stroke (IS). MES can also assess the efficacy of antithrombotic agents and predict the recurrence probability of IS. Unstable plaques are the main source of MES; thus, numerous biomarkers of atherosclerotic plaque instability are highly likely to predict the presence of MES. This study aims to review recent biomarker candidates for MES or microembolism. Current research indicates that the following are independent markers for positive MES: high level of serum soluble P-selectin, chemokine (C-X-C motif) ligand 16 (CXCL16) and fibrinogen, high neutrophil count, reduced ratio of CD4+CD25high regulatory T cells (Tregs) and the C allele of tumor necrosis factor receptor superfamily member 11B (TNFRSF11B) rs3102735. However, a more integrated profile of biomarkers for MES is needed to improve the stratification of patients with carotid stenosis and enhance the effectiveness of therapeutic interventions and prevention for IS.

Quantification of Lipid Filtration and the Effects on Cerebral Injury During Cardiopulmonary Bypass.

BACKGROUND: Lipid microemboli (LME) are formed in pericardial suction blood which, when returned to the cardiopulmonary bypass (CPB) circuit, can pass through filter materials and are returned to the arterial cannula. LME have been observed to enter all major organs and have been associated with small capillary arteriolar dilatations in the brains of patients who have died after CPB. However, a causal relationship showing correlation between LME and organ dysfunction has not been demonstrated, or whether removal of LME results in improved organ function. METHODS: A prospective, single center, randomized controlled trial examined 30 patients (15 per group) undergoing coronary artery bypass grafting using CPB with or without a lipid-depleting filter. The effects of LME filtration on neurocognitive injury were assessed using neuron-specific enolase (NSE). RESULTS: The study group showed a significant reduction in LME after filtration of the pericardial suction blood (p < 0.001), whereas the control group exhibited a significant rise in LME (p < 0.001). There was a significant reduction in peak NSE release (p = 0.013) and significant attenuation throughout the postoperative period (p = 0.002). Correlation and regression analyses showed a significant relationship between the number of LME post-CPB and peak NSE release (r = 0.42, p = 0.02). CONCLUSIONS: Several methods of LME filtration have been proposed, but none provided a suitable, efficacious method for use within the clinical setting. The RemoweLL CPB system removes significant numbers of LME from the cardiotomy suction. Furthermore, LME correlate to the release of a known marker of neurologic injury.

Evidence for periprocedural antiplatelet therapy, heparinization and bridging of coumarin therapy in carotid revascularization.

Thromboembolism prevention is a crucial factor determining both the natural outcome and outcome of intervention of stenotic atherosclerotic carotid artery pathology. Roughly 80% of all natural course cerebral ischemic events are caused by thromboembolism, versus 20% due to hemodynamic insufficiency. The risk of periprocedural cerebral (micro-) thromboembolization during carotid revascularization is considered to be even higher, with a higher rate in carotid artery stenting (CAS) as compared to carotid endarterectomy (CEA). Guidelines on CEA and CAS are unanimous in advising perioperative continuation of antiplatelet therapy (APT) for all patients to prevent thromboembolization without specification of the type of APT. Recommendations on dual antiplatelet (DAPT) therapy are inconsistent. Bridging vitamin K antagonists (VKA) perioperative with unfractionated heparin (UFH) or low-molecular weight heparins (LMWHs) might not be necessary for CAS, while CEA-specific data is lacking. No data are available on the use and position of direct-acting oral anticoagulants (DOACs) for CEA or CAS. Guidelines on treatment of carotid artery disease currently do not provide information on perioperative heparinization. There are several monitoring tools to detect perioperative micro-embolic signals during intervention or new cerebral white matter lesions following CEA or CAS. Transcranial Doppler ultrasonography (TDU) and diffusion weighed imaging (DWI) might be used to assess these (secondary) outcome measurements. The use of platelet function testing (PFT) to tailor APT might contribute to finding the therapeutic place of stronger APT and new APT regimen. Periprocedural antiplatelet and anticoagulation therapy for carotid revascularization still lacks solid evidence and guidelines do not yet cover the full spectrum of anticoagulants and procedural steps. This review aims to cover and discuss the full spectrum of available antiplatelet and anticoagulant drugs and therapies available for thromboembolism prevention during all crucial steps of revascularization and specify the need to know topics to be addressed in future research.

Non-high-density lipoprotein cholesterol and the development of coronary heart disease and stroke subtypes in a general Japanese population: the Hisayama Study.

BACKGROUND AND PURPOSE: It has not been fully determined whether non-high-density lipoprotein cholesterol (non-HDLC) levels are involved in vascular events, especially stroke, in general Asian populations. We evaluated the association between non-HDLC levels and the risk of type-specific cardiovascular disease in a prospective cohort study in Japan. METHODS: A total of 2452 community-dwelling Japanese subjects aged≥40 years were followed prospectively for 24 years. RESULTS: The age- and sex-adjusted incidence of coronary heart diseases (CHD) significantly increased with elevating non-HDLC levels (P for trend<0.001), but no such association was observed for ischemic and hemorrhagic strokes. With regard to ischemic stroke subtypes, the age- and sex-adjusted incidence of lacunar infarction significantly increased with elevating non-HDLC levels (P for trend<0.01), and such tendency was seen for atherothrombotic infarction (P for trend=0.098), while a significant inverse association was observed for cardioembolic infarction (P for trend=0.007). After adjustment for confounders, namely, age, sex, diabetes, body mass index, systolic blood pressure, electrocardiogram abnormalities, current drinking, current smoking, and regular exercise, the associations remained significant for CHD [adjusted hazard ratio (HR) for a 1 standard deviation of non-HDLC concentrations=1.17, 95% confidence interval (CI)=1.02 to 1.35], atherothrombotic infarction (adjusted HR=1.39, 95% CI=1.09 to 1.79), and cardioembolic infarction (adjusted HR=0.64, 95% CI=0.47 to 0.85). CONCLUSIONS: Our findings suggest that elevated non-HDLC levels are a significant risk factor for the development of atherothrombotic infarction as well as CHD but reduce the risk of cardioembolic infarction in the general Japanese population.

Ultrasound destruction of air microemboli as a novel approach to brain protection in cardiac surgery.

OBJECTIVE: Evaluation of a novel approach to eliminate air microemboli from extracorporeal circulation via ultrasonic destruction. DESIGN: In vitro proof-of-concept study. SETTING: Research laboratory. PARTICIPANTS: None. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: An extracorporeal circulation device was filled with human blood circulating at 3 L/min. Air bubbles were injected into the system. For bubble destruction, the blood in the tubing system was repeatedly insonated for 3 minutes using a therapeutic 60-kHz device, with variation of intensity and duty cycle settings, ranging from 0.2 W/cm² to 1.0 W/cm² and from duty cycle 60% to continuous wave (CW). Number and diameter of air microemboli were counted upstream and downstream of the ultrasound device by a 2-channel microemboli Doppler detector. For safety assessment, circulating blood was insonated continuously for 2 hours at 0.8 W/cm² CW and compared with circulation without insonation; and standard blood parameters were analyzed. Without treatment, 1,313 to 1,580 emboli were detected upstream, diameter ranging between 10 and 130 µm. Ultrasound treatment eliminated up to 87% of all detected bubbles in cw application (p<0.01) and showed comparable effects at intensities from 0.4 W/cm² to 1.0 W/cm² cw. Bubbles sized>15 µm almost were eliminated completely (p<0.001). Pulsed wave application rendered inferior results (p>0.05). No relevant changes of blood parameters were observed compared with control circulation. CONCLUSIONS: Ultrasound destruction of air emboli is a very efficient method to reduce number and size of emboli. Within the limits of safety assessment, the authors could not detect relevant side effects on standard blood parameters.

Increased platelet activation in early symptomatic vs. asymptomatic carotid stenosis and relationship with microembolic status: results from the Platelets and Carotid Stenosis Study.

BACKGROUND: Cerebral microembolic signals (MES) may predict increased stroke risk in carotid stenosis. However, the relationship between platelet counts or platelet activation status and MES in symptomatic vs. asymptomatic carotid stenosis has not been comprehensively assessed. SETTING: University teaching hospitals. METHODS: This prospective, pilot observational study assessed platelet counts and platelet activation status, and the relationship between platelet activation and MES in asymptomatic vs. early (≤ 4 weeks after TIA/stroke) and late phase (≥ 3 months) symptomatic moderate or severe (≥ 50%) carotid stenosis patients. Full blood count measurements were performed, and whole blood flow cytometry was used to quantify platelet surface activation marker expression (CD62P and CD63) and circulating leucocyte-platelet complexes. Bilateral simultaneous transcranial Doppler ultrasound monitoring of the middle cerebral arteries was performed for 1 h to classify patients as MES positive or MES negative. RESULTS: Data from 31 asymptomatic patients were compared with 46 symptomatic patients in the early phase, and 35 of these patients were followed up to the late phase after symptom onset. The median platelet count (211 vs. 200 × 10(9)  L(-1) ; P = 0.03) and the median percentage of lymphocyte-platelet complexes was higher in early symptomatic than asymptomatic patients (2.8 vs. 2.4%; P = 0.001). The percentage of lymphocyte-platelet complexes was higher in early symptomatic than in asymptomatic patients with ≥ 70% carotid stenosis (P = 0.0005) and symptomatic patients recruited within 7 days of symptom onset (P = 0.028). Complete TCD data were available in 25 asymptomatic, 31 early phase symptomatic and 27 late phase symptomatic patients. Twelve per cent of asymptomatic vs. 32% of early phase symptomatic (P = 0.02) and 19% of late phase symptomatic patients (P = 0.2) were MES positive. Early symptomatic MES-negative patients had a higher percentage of lymphocyte-platelet complexes than asymptomatic MES-negative patients (2.8 vs. 2.3%; P = 0.0085). DISCUSSION: Recently, symptomatic carotid stenosis patients have had higher platelet counts (potentially reflecting increased platelet production, mobilization or reduced clearance) and platelet activation status than asymptomatic patients. MES were more frequently detected in early symptomatic than asymptomatic patients, but the differences between late symptomatic and asymptomatic groups were not significant. Increased lymphocyte-platelet complex formation in recently symptomatic vs. asymptomatic MES-negative patients indicates enhanced platelet activation in this early symptomatic subgroup. Platelet biomarkers, in combination with TCD, have the potential to aid risk-stratification in asymptomatic and symptomatic carotid stenosis patients.

[What is the current use of vitamin K antagonists in the elderly?]. / Quelle place reste-t-il aux AVK dans la fibrillation atriale du sujet âgé ?

With the recent marketing of the new oral anticoagulants (NOAC), the future of vitamin k antagonist (VKA) needs to be redefined. VKAs are drugs with a narrow therapeutic margin and a high iatrogenic risk that requires a close biological monitoring. Their efficacy has been proven for atrial fibrillation in numerous populations, especially in the elderly. Their side effects and interactions are well known. The measurement of the level of anticoagulation is possible and reliable using the INR (international normalized ratio) and an antidote is usable in case of emergency. The NOAC are at least as effective as VKA with slightly less side-effects especially cerebral hemorrhage, and they do not require biological monitoring. However, data on efficacy and side-effects of NOAC rely mainly on phase III clinical trials that did not particularly target polypathologic and frail populations. In these populations, we therefore have more "real life" information on VKA than NOAC. But studies on NOAC are currently conducted among these populations. A conservative approach would be to maintain VKA to older patients with stable INR. Lastly VKA are the only anticoagulant usable in case of severe renal failure and valvular fibrillation.

Continuous brain tissue oxygenation monitoring in the management of pediatric stroke.

BACKGROUND: Direct invasive monitoring of brain tissue oxygenation (PbtO(2)) has been routinely utilized to predict cerebral ischemia and to prevent secondary injury in patients with traumatic brain injury (TBI) and vasospasm secondary to subarachnoid hemorrhage (SAH). The safety and utility of these devices in the pediatric population have been examined in a few small studies. No studies, however, have examined the use of PbtO(2) monitoring in stroke patients. METHODS: Retrospective chart review of the first two consecutive, critically ill pediatric patients in the pediatric intensive care unit requiring brain tissue oxygen monitoring for newly diagnosed cerebral ischemia. ICP, CPP, PbtO(2), SaO(2), BP, and RR were all continually monitored during their care and were retrospectively collected and reviewed. RESULTS: We present two pediatric stroke patients managed in a critical care setting with PbtO(2) monitoring in addition to ICP, MAP, CPP, and SaO(2). Both patients had multiple events of low brain tissue oxygen (PbtO(2) <20 torr), independent of abnormal values in other monitoring parameters, which required physician intervention. No new ischemic damage occurred after PbtO(2) monitoring began in either patient. CONCLUSIONS: There is currently inadequate data to support the application of PbtO(2) monitoring in children with stroke to prevent progressive ischemia and to improve outcome. However, the positive results for these two patients support the need for further study in this area.

[The role of platelets in atherosclerosis, diabetes mellitus, and chronic kidney disease. An attempt at explaining the TREAT study results]. / Die Rolle der Thrombozyten bei Atherosklerose, Diabetes mellitus und chronischer Niereninsuffizienz : Ein Versuch, die Resultate der TREAT-Studie zu erklären.

Erythropoiesis-stimulating agents (ESA) are used to treat renal anemia. The TREAT study (Trial to Reduce Cardiovascular Events with Aranesp Ther- apy) of diabetic patients with chronic kidney disease (CKD) found that the risk of stroke was significantly higher than in the control arm. This raises the question as to what causes this phenomenon. Platelets may play a crucial role in this context. Atherogenesis involves complex interactions between platelets and monocytes (platelet-monocyte crosstalk) and with endothelial cells. Platelets are activated in cases of diabetes mellitus, especially. During atherogenesis, partial functions of platelets other than those inhibited by aspirin, as a cyclooxygenase inhibitor, or by adenosine diphosphate receptor P2Y(12)antagonists, such as thienopyridines, are of relevance. During platelet-monocyte crosstalk, specifically, an important role is played by adhesion receptors such as selectins and integrins. In addition, ESA cause platelet activation by direct and indirect mechanisms. Antagonistic thereto is a renal bleeding tendency in cases of severe CKD, due to platelet dysfunction, which can be remedied with appropriate renal replacement therapy and administration of ESA in order to reach a hemoglobin (Hb) level of 10 g/dl. However, if the Hb level exceeds 10 g/dl, the even stronger platelet activation caused by ESA, combined with the activation caused by diabetes, leads to a prothrombotic state, which in patients with severe atherosclerosis can result in acute atherothrombotic complications, in the genesis of which platelets play a key role. This would be one hypothesis for explaining the increased incidence of strokes in the TREAT study.

Microemboli from cardiopulmonary bypass are associated with a serum marker of brain injury.

An increasing number of reports surrounding neurologic injury in the setting of cardiac surgery has focused on utilizing biomarkers as intermediate outcomes. Previous research has associated cerebral microemboli and neurobehavioral deficits with biomarkers. A leading source of cerebral microemboli is the cardiopulmonary bypass (CPB) circuit. This present study seeks to identify a relationship between microemboli leaving the CPB circuit and a biomarker of neurologic injury. We enrolled 71 patients undergoing coronary artery bypass grafting at a single institution from October 14, 2004 through December 5, 2007. Microemboli were monitored using Power-M-Mode Doppler in the inflow and outflow of the CPB circuit. Blood was sampled before and within 48 hours after surgery. Neurologic injury was measured using S100beta (microg/L). Significant differences in post-operative S100beta relative to microemboli leaving the circuit were tested with analysis of variance and Kruskal-Wallis. Most patients had increased serum levels of S100beta (mean .25 microg/L, median .15 microg/L) following surgery. Terciles of microemboli measured in the outflow (indexed to the duration of time spent on CPB) were associated with elevated levels of S100beta (p = .03). Microemboli leaving the CPB circuit were associated with increases in postoperative S100beta levels. Efforts aimed at reducing microembolic load leaving the CPB circuit should be adopted to reduce brain injury.

Low levels of plasma soluble receptor for advanced glycation end products are associated with severe leukoaraiosis in acute stroke patients.

A secreted isoform of the receptor for advanced glycation end products (RAGE), soluble RAGE (sRAGE), can neutralize the adverse effects of RAGE signaling by acting as a decoy. RAGE signaling contributes to the development of diabetic microangiopathy, however few studies have addressed pivotal roles of RAGE signaling in acute stroke. We examined plasma sRAGE levels associated with clinical features in acute stroke patients. Plasma sRAGE was measured in 482 patients (318 men; mean age 71 years) admitted within three days of stroke onset. Median values of sRAGE were significantly different among stroke subtypes (p=0.001); 1010 pg/ml in atherothrombotic infarction, 933 pg/ml in lacunar, 1280pg/ml in cardioembolic infarction, 1050 pg/ml in other types of infarctions, and 943 pg/ml in primary intracerebral hemorrhage. Severe leukoaraiosis on brain MR images, high NIHSS scores on admission, cigarette smoking, and normal estimated glomerular filtration rate were significantly associated with low sRAGE levels (p<0.05). The low level of sRAGE was associated with severe leukoaraiosis, reflecting long-standing presence of hypertensive angiopathy. Kidneys play a role in the removal of sRAGE. RAGE signaling can contribute to the deterioration of neuronal damage under severe leukoaraiosis, result in a high NIHSS score on admission in acute stroke patients, especially those with smoking habits.

Low molecular weight heparin significantly reduces embolisation after carotid endarterectomy--a randomised controlled trial.

OBJECTIVES: The administration of unfractionated heparin (UFH) prior to carotid clamping during carotid endarterectomy (CEA) transiently increases the platelet aggregation response to arachidonic acid (AA) despite the use of aspirin. We hypothesized that this phenomenon might be reduced by using low molecular weight heparin (LMWH) resulting in fewer emboli in the early post-operative period. METHODS: 183 aspirinated patients undergoing CEA were randomised to 5000 IU UFH (n=91) or 2500 IU LMWH (dalteparin, n=92) prior to carotid clamping. End-points were: transcranial Doppler (TCD) measurement of embolisation, effect on bleeding and platelet aggregation to AA and adenosine 5'-diphosphate (ADP). RESULTS: Patients randomised to UFH had twice the odds of experiencing a higher number of emboli in the first 3h after CEA, than those randomised to LMWH (p=0.04). This was not associated with increased bleeding (mean time from flow restoration to operation end: 23 min (UFH) vs. 24 min (LMWH), p=0.18). Platelet aggregation to AA increased significantly following heparinisation, but was unaffected by heparin type (p=0.90). The platelets of patients randomised to LMWH exhibited significantly lower aggregation to ADP compared to UFH (p<0.0001). CONCLUSIONS: Intravenous LMWH is associated with a significant reduction in post-operative embolisation without increased bleeding. The higher rate of embolisation seen with UFH may be mediated by increased platelet aggregation to ADP, rather than to AA.

Transcranial Doppler and acoustic pressure fluctuations for the assessment of cavitation and thromboembolism in patients with mechanical heart valves.

The formation and collapse of vapor-filled bubbles near a mechanical heart valve is called cavitation. Such microbubbles are suspected to have strong pro-coagulant effects. Therefore, cavitation may be a contributing factor to the pro-thrombotic effects of mechanical valves. Herein, we systematically review the available evidence linking cavitation and thrombosis. We also critically appraise the potential usefulness of transcranial Doppler and other new non-invasive diagnostic methods to study cavitation and cerebral embolism in mechanical valve patients. Experimental studies indicate that cavitation microbubbles cause platelet aggregation, complement-activation, fibrinolysis, release of tissue-factor, and endothelial damage. Administration of 100% oxygen to mechanical valve patients during transcranial Doppler examination can transiently decrease the counts of Doppler-detected cerebral microemboli compared with room air. This is associated with removal of most circulating gaseous emboli from cavitation. This method may therefore be applied to the study of cavitation and thromboembolism. Additionally, the analysis of high-frequency acoustic-pressure fluctuations detected from the implosion of cavitation bubbles is a promising method for assessment of cavitation in vivo; however, this requires further development. A better understanding of cavitation is important in order to adequately investigate its role in the overall pro-thrombotic effects in mechanical valve patients. Such studies may allow establishing guidelines for new valve designs.

Fibrinogen and high-sensitive C-reactive protein as serologic predictors for perioperative cerebral microembolic lesions after carotid endarterectomy.

BACKGROUND: Neurologic deficit caused by cerebral ischemia defines the outcome of carotid endarterectomy (CEA). Although few patients have clinically evident neurologic deficit, diffusion-weighted imaging (DWI) presents a number of cases with ischemic brain lesions. This study should elucidate preoperative risk factors for perioperative microemboli that cause brain infarction. METHODS: We studied 183 patients (58 women, 69.2 +/-12.7 years; 125 men, 69.3 +/- 8.9 years) with high-degree carotid artery stenosis. DWI was performed before and after CEA to analyze new cerebral ischemia. Blood samples were obtained before operation to measure fibrinogen and C-reactive protein (CRP), and preoperative high-sensitive CRP (hsCRP) was analyzed in 30 consecutive patients. RESULTS: Postoperative DWI revealed new ipsilateral ischemic lesions in 41 patients (22.4%), and eight (4.4%) showed new neurologic deficit. Preoperative fibrinogen levels were higher in patients with new lesions (397.6 mg/dL +/- 104.7 mg/dL) than in those without (324.7 mg/dL +/- 74.2 mg/dL, P < .001). Preoperative levels of hsCRP were also higher in patients with new lesions (7.9 mg/dL +/- 5.2 mg/dL) than in those without (2.8 mg/dL +/- 2.6 mg/dL, P = .004). Significant association was found between fibrinogen and CRP (Spearman rho = 0.402; P < .001) as well as hsCRP (Spearman rho = 0.603, P = .003). No association was found between postoperative lesions and CRP (P = .833). CONCLUSION: The present study demonstrates that preoperative levels of fibrinogen and hsCRP are independent determinants for new periprocedural cerebral ischemic lesions caused by microembolic events. There is still not sufficient evidence to recommend measurement of CRP as a prognostic marker for perioperative cerebral lesion.