Cerebral Microembolic Signals Research Articles

Cerebral microembolic signal burden during pulsed field ablation: preliminary results from robotically-assisted transcranial doppler and magnetic resonance imaging

Abstract Funding Acknowledgements Type of funding sources: None. Background Transcranial Doppler (TCD) has been used to monitor the burden of cerebral microembolic signals (MESs) during atrial fibrillation (AF) ablation. MES burden is considered a surrogate marker for stroke risk and has never been reported during AF ablation with pulsed field ablation (PFA). Purpose To assess the MES burden during AF ablation with point-by-point radiofrequency (RF) versus single-shot PFA. Methods Fifteen consecutive paroxysmal and persistent AF patients underwent catheter ablation via either single-shot (2000V) PFA [n=7, median age: 56yo (range:53-73), 85.7% males] or point-by point (45W) RF [n=8, median age: 58yo (range 56-74), 62.6% males] under uninterrupted oral anticoagulation and a periprocedural ACT≥300s. Peri-procedural TCD was performed via a robotically-assisted ultrasound system, which includes an Artificial Intelligence-powered robotic headset designed to automate signal acquisition and reduce interoperator variability of TCD findings (Figure 1). Ablation-related asymptomatic cerebral embolism (CE) was assessed via diffusion-weighted imaging (DWI) sequences at magnetic resonance imaging (MRI) performed 24-48h post-ablation. Results Among the 7 PFA patients, the median number of applications to achieve PV isolation was 35 (range:33-42). Five (71.4%) patients showed multiple MESs clustered in a shower-like pattern (Figure 2). The overall number of MES-showers was 51 [median: 9 (range:8-15)] and they were temporally correlated with a PFA application. Shower formation was more common after a PFA application to the right superior pulmonary vein [(PV); 19 cases (37.3%)], followed by the right inferior PV [16 cases (31.4%)], the left inferior PV [14 cases (27.5%)], and the left superior PV [2 cases (3.9%)]. A single shower-like pattern was documented among the 8 RF patients, following a stem-pop while ablating at the right inferior PV antrum. There were no procedure-related complications and none of the 15 patients showed any post-ablation neurological symptoms. The mean time from ablation to MRI was 29±4hours; DWI imaging revealed no acute cerebral microembolic lesions. Conclusion PFA generated a relevant number of MESs frequently clustered in short-lasting shower-like patterns. The composition of MESs, their exact mechanism of formation, and the impact on neurological outcomes are unknown and will be addressed in future studies.

Determination of cerebral blood flow velocity and microembolic signals in essential thrombocytosis by transcranial doppler ultrasonography

ABSTRACT Objectives The goal of treatment in essential thrombocytosis (ET) is to prevent vascular complications such as thrombosis and hemorrhage. This study aimed to evaluate the risk of cerebrovascular microembolism in ET patients due to detection of microembolic signals (MES) and measure cerebral blood flow velocity (CBFV) by Transcranial Doppler (TCD) ultrasonography. Material and Methods In this prospective case-control study, forty patients with diagnosed ET and age and sex-matched forty healthy controls were examined by the TCD sonography. Results The ET group had a higher rate of MES (8/40) in the right MCA than that in the control group (none), as measured by TCD. Five patients had MES at the left MCA compared to that in no subjects in the control group. The comparison of the ET and control groups in terms of CBFV parameters showed significantly lower end-diastolic FV at the right MCA in the ET group compared to that in the control group (p < 0.05). On the other hand; both pulsatility and resistance indices in the right and left MCA and the ratios of systolic to diastolic blood flow rates in the right and left MCA were significantly higher in the ET group than that in the control group. Discussion This study revealed that MES seems to be more common in patients with ET despite treatment. We could suggest that ET patients should be monitored more closely to address the potential risk of developing a cerebrovascular disease, which can be estimated by detection MES and raised CBFV, combine antiplatelet therapies to standard treatments.

Simultaneous assessment of plaque morphology, cerebral micro-embolic signal status and platelet biomarkers in patients with recently symptomatic and asymptomatic carotid stenosis

The relationship between plaque morphology, cerebral micro-embolic signals (MES) and platelet biomarkers in carotid stenosis patients warrants investigation. We combined data from two prospective, observational studies to assess carotid plaque morphology and relationship with cerebral MES and platelet biomarkers in patients with recently symptomatic (≤4 weeks of transient ischaemic attack (TIA)/ischaemic stroke) versus asymptomatic carotid stenosis. Plaque morphology on ultrasound was graded with Grey-Scale Median (GSM) and Gray–Weale (GW) scoring. Bilateral transcranial Doppler ultrasound classified patients as ‘MES+ve’ or ‘MES-ve’. Full blood counts were analysed and flow cytometry quantified CD62P and CD63 expression, leucocyte-platelet complexes and reticulated platelets. Data from 42 recently symptomatic carotid stenosis patients were compared with those from 36 asymptomatic patients. There were no differences in median GSM scores between symptomatic and asymptomatic patients (25 vs. 30; P = 0.31) or between MES+ve vs. MES-ve symptomatic patients (36 vs. 25; P = 0.09). Symptomatic patients with GSM-echodense plaques (GSM ≥25) had higher platelet counts (228 vs. 191 × 109/L), neutrophil–platelet (3.3 vs. 2.7%), monocyte–platelet (6.3 vs. 4.55%) and lymphocyte–platelet complexes (2.91 vs. 2.53%) than ‘asymptomatic patients with GSM-echodense plaques’ (P ≤ 0.03). Recently, symptomatic carotid stenosis patients with ‘GSM-echodense plaques’ have enhanced platelet production/secretion/activation compared with their asymptomatic counterparts. Simultaneous assessment with neurovascular imaging and platelet biomarkers may aid risk-stratification in carotid stenosis.

‘On-treatment platelet reactivity’ under both high and low shear stress conditions and relationship with cerebral micro-embolic signals in asymptomatic and symptomatic carotid stenosis: Results from the HaEmostasis In carotid STenosis(HEIST) study. (P1.3-066)

‘On-treatment platelet reactivity’ under both high and low shear stress conditions and relationship with cerebral micro-embolic signals in asymptomatic and symptomatic carotid stenosis: Results from the HaEmostasis In carotid STenosis(HEIST) study. (P1.3-066)

Abstract WP113: Evidence of Ongoing Platelet Activation in Micro-emboli Negative Recently Symptomatic versus Asymptomatic Carotid Stenosis

Introduction: Cerebral microembolic signals (MES) predict increased stroke risk in carotid stenosis however micro-emboli negative symptomatic patients also demonstrate increased risk compared to asymptomatic patients. Enhanced platelet activation may contribute to this risk disparity. Methods: We performed a prospective, observational analytical study assessing platelet counts, platelet activation status, and the relationship between platelet activation and MES in asymptomatic versus symptomatic moderate (≥50-69%) or severe (≥70-99%) carotid stenosis. Full blood count measurements were performed, and whole-blood flow cytometry used to quantify platelet surface activation marker expression (CD62P and CD63) and circulating leucocyte-platelet complexes. Bilateral simultaneous Transcranial Doppler (TCD) ultrasound monitoring of the middle cerebral arteries was performed to classify patients’ MES status. Results: Complete TCD data from 28 asymptomatic patients were compared with 35 symptomatic patients in the ‘early phase’ (≤4 weeks) and 30 of these patients in the ‘late phase’ (≥3 months) after TIA/ischaemic stroke. The %MES positive patients were higher in early symptomatic (31.4%; P = 0.027), but not in late symptomatic (6.7%; P = 0.996) vs. asymptomatic patients (7.1%). There were no significant differences in platelet counts, mean platelet volume, %CD62P or %CD63 expression between early/late symptomatic and asymptomatic MES negative patients (P&gt;0.05). There were however, a significantly higher %circulating lymphocyte-platelet complexes in early symptomatic vs. asymptomatic patients (2.7% vs. 2.17%;P=0.02) Discussion: 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 carotid stenosis.

Assessment of ‘on-treatment platelet reactivity’ and relationship with cerebral micro-embolic signals in asymptomatic and symptomatic carotid stenosis

IntroductionThe relationship between on-treatment platelet reactivity and cerebral micro-embolic signals (MES) is unknown, and has not been previously simultaneously assessed in asymptomatic and symptomatic carotid stenosis patients. MethodsConsecutive eligible patients with ≥50% asymptomatic or recently symptomatic carotid stenosis (≤4weeks following TIA/ischaemic stroke) were recruited to this pilot study. Symptomatic patients were followed up to the ‘late’ phase (≥3months) following symptom onset or carotid intervention; longitudinal data were analysed from symptomatic patients with data available at both time-points. Platelet function/reactivity was assessed with the PFA-100® to measure collagen-ADP (C-ADP) and collagen-epinephrine (C-EPI) closure times in citrate-anticoagulated whole blood. Bilateral simultaneous 1-hour transcranial Doppler ultrasound (TCD) monitoring of the middle cerebral arteries was performed to classify patients as MES +ve or MES −ve. Results31 patients with ≥50% asymptomatic and 46 with early symptomatic carotid stenosis or occlusion were included. 35 symptomatic patients were followed up to the late phase (23 following carotid intervention). Prevalence of ‘high on-treatment platelet reactivity’ (HTPR) on the C-EPI cartridge did not differ between asymptomatic and symptomatic patients overall, but was lower in ‘symptomatic post-intervention’ than asymptomatic patients on aspirin monotherapy (10% vs. 50%; p=0.03). The prevalence of HTPR on the C-EPI cartridge decreased between the early and late phases in symptomatic patients (63% vs. 34%; p=0.017), including those on aspirin monotherapy (p=0.016). There were no significant differences in HTPR status between asymptomatic vs. early or late symptomatic MES +ve or MES −ve patients. DiscussionCarotid interventional treatment, presumably in combination with resolution of the acute phase response, may decrease the prevalence of HTPR in patients with recently symptomatic carotid stenosis over time. Preliminary subgroup analysis suggests that successful intervention may reduce the prevalence of aspirin-HTPR in symptomatic patients to lower levels than asymptomatic medically-treated patients on aspirin monotherapy. Larger, longitudinal studies are warranted to reassess the impact of more intensive secondary preventive treatment on ex vivo platelet function at different levels of shear stress in carotid stenosis patients.

Transcranial Doppler Monitoring in Carotid Endarterectomy: A Systematic Review and Meta-analysis.

To evaluate the efficacy of intraoperative transcranial Doppler monitoring in predicting perioperative strokes after carotid endarterectomy (CEA). An electronic search of PubMed, Embase, and Web of Science databases was conducted for studies on transcranial Doppler monitoring in CEA published from January 1970 through September 2015. All titles and abstracts were independently screened on the basis of predetermined inclusion criteria, which included randomized clinical trials and prospective or retrospective cohort reviews, patients who underwent CEA with intraoperative transcranial Doppler monitoring (either middle cerebral artery velocity [MCAV] or cerebral microembolic signals [MES]) and postoperative neurologic assessments up to 30 days after the surgery, and studies including an abstract, published in English on adult humans 18 years and older with a sample size of 50 or greater. A total of 25articles with a sample population of 4705 patients were analyzed. Among the study patients, 189 developed perioperative strokes. Transcranial Doppler monitoring (either MCAV or MES) showed specificity of 72.7% (95% confidence interval [CI], 61.2%-81.8%) and sensitivity of 56.1% (95% CI, 46.8%-65.0%) for predicting perioperative strokes. Intraoperative MCAV changes during CEA showed strong specificity of 84.1% (95% CI, 74.4%-90.6) and sensitivity of 49.7% (95% CI, 40.6%-58.8) for predicting perioperative strokes. Patients with perioperative strokes are 4 times more likely to have had transcranial Doppler changes (either MCAV or MES) during CEA compared to patients without strokes. Simultaneous MCAV and MES monitoring by transcranial Doppler sonography and combined intraoperative monitoring of transcranial Doppler sonography with somatosensory evoked potentials and electroencephalography during CEA to predict perioperative stroke could not be evaluated because of a lack of clinical studies combining these measures.

Inhibition of Factor XIa Reduces the Frequency of Cerebral Microembolic Signals Derived from Carotid Arterial Thrombosis in Rabbits.

Factor XI (FXI) is an integral component of the intrinsic pathway of the coagulation cascade and plays a critical role in thrombus formation. Because its role in the pathogenesis of cerebral microembolic signals (MES) is unclear, this study used a potent and selective small molecule inhibitor of FXIa, compound 1, to assess the effect of FXI blockade in our recently established preclinical model of cerebral MES induced by FeCl3 injury of the carotid artery in male New Zealand White rabbits. Ascending doses of compound 1 were evaluated simultaneously for both carotid arterial thrombosis by a Doppler flowmeter and MES in the middle cerebral artery by a transcranial Doppler. Plasma drug exposure and pharmacodynamic responses to compound 1 treatment were also assessed. The effective dose for 50% inhibition (ED50) of thrombus formation was 0.003 mg/kg/h compound 1, i.v. for the integrated blood flow, 0.004 mg/kg/h for reduction in thrombus weight, and 0.106 mg/kg/h for prevention of MES. The highest dose, 3 mg/kg/h compound 1, achieved complete inhibition in both thrombus formation and MES. In addition, we assessed the potential bleeding liability of compound 1 (5 mg/kg/h, i.v., >1250-fold ED50 levels in arterial thrombosis) in rabbits using a cuticle bleeding model, and observed about 2-fold (not statistically significant) prolongation in bleeding time. Our study demonstrates that compound 1 produced a robust and dose-dependent inhibition of both arterial thrombosis and MES, suggesting that FXIa blockade may represent a novel therapeutic strategy for the reduction in MES in patients at risk for ischemic stroke.

High Extent of Intracranial Carotid Artery Calcification Is Associated with Downstream Microemboli in Stroke Patients

Intracranial arterial calcification (ICAC) is frequently detected on head computed tomography and has been found to be associated with ischemic stroke by recent clinical studies. Based on a hospital-based study, we aimed to compare the occurrence of cerebral microembolic signals (MES) among stroke patients with different degrees of ICAC, which may indicate the potential mechanisms linking ICAC and ischemic stroke in intracranial atherosclerosis patients. This is a post-hoc analysis of our previous clinical study in 2005-2007, recruiting consecutive ischemic stroke patients with middle cerebral artery territory infarctions and good temporal window for MES monitoring. The degrees of ICAC in the Circle of Willis, especially calcification in the ipsilateral intracranial internal carotid artery (iICA), were evaluated both qualitatively and quantitatively on unenhanced head computed tomography. Among the 68 recruited patients, MES was detected in 26 patients (38.24%). The overall degree of ICAC in the Circle of Willis was similar between patients with and without MES. For calcification in ipsilateral iICA, the presence of MES was more frequent in the high extent group (widest arc of calcification ≥90°) than in the low extent group (54.2% versus 29.5%, P = .046). Logistic regression found that a high extent ipsilateral iICA calcification was an independent risk factor of MES (odds ratio: 3.134; 95% confidence interval, 1.029-9.543; P = .044). MES is frequently detected in patients with a high extent of ipsilateral iICA calcification, which suggests that a high extent of iICA calcification indicates artery vulnerability and accounts for the occurrence of microemboli in the corresponding artery.

A rabbit model of cerebral microembolic signals for translational research: preclinical validation for aspirin and clopidogrel

Essentials Microembolic signal (MES) is an independent predictor of stroke risk in patients. A rabbit model of cerebral microembolic signals was established. Therapeutic efficacy was demonstrated for aspirin and clopidogrel on microembolic signals. Potential translational value of this preclinical model of MES was demonstrated. Objectives Cerebral microembolic signals (MESs) detected by transcranial Doppler (TCD) ultrasound constitute an independent predictor of stroke risk and prognosis. The aim of this study was to develop a novel preclinical model of MESs to facilitate translational research. Methods A clinical TCD ultrasound machine was used to detect MESs in the cerebral circulation of New Zealand White rabbits. Technical feasibility was assessed for the measurement of MESs in the middle cerebral artery (MCA) by TCD. FeCl3 -induced carotid arterial thrombosis was optimized for the generation of endogenous microemboli. Ascending doses of two antithrombotic agents (aspirin and clopidogrel) were evaluated individually and in combination for their effects on both arterial thrombosis and MESs in a 30% FeCl3 -induced carotid arterial thrombosis model, along with ex vivo functional assays. Results Dose-dependent FeCl3 -induced arterial thrombosis studies showed that 30% FeCl3 resulted in the most consistent and reproducible MESs in the MCA (3.3 ± 0.7 MESs h(-1) ). Ascending-dose studies showed that the effective doses for 50% inhibition (ED50 ) of thrombus formation, based on integrated blood flow and thrombus weight, respectively, were 3.1 mg kg(-1) and 4.2 mg kg(-1) orally for aspirin, and 0.3 mg kg(-1) and 0.28 mg kg(-1) orally for clopidogrel. The ED50 values for MES incidence were 12.7 mg kg(-1) orally for aspirin, and 0.25 mg kg(-1) orally for clopidogrel. Dual treatment with aspirin (5 mg kg(-1) ) and clopidogel (0.3 mg kg(-1) ) resulted in significant reductions in cerebral MESs (P < 0.05) as compared with monotherapy with either agent. Conclusions Our study demonstrated the successful establishment of the MES model in rabbits, and it may provide translational value for MESs and ischemic stroke research.

Apixaban Inhibits Cerebral Microembolic Signals Derived from Carotid Arterial Thrombosis in Rabbits.

Cerebral microembolic signal (MES) is an independent predictor of stroke risk and prognosis. The objective of this study is to assess the effects of apixaban, as a representative of the novel oral anticoagulant class, on a rabbit model of cerebral MES. A clinical transcranial Doppler ultrasound instrument was used to assess MESs in the middle cerebral artery in a 30% FeCl3-induced carotid arterial thrombosis model in male New Zealand White rabbits. Ascending doses of apixaban were evaluated as monotherapy and in combination with aspirin on both arterial thrombosis and MES. Pharmacokinetic and pharmacodynamic responses were also evaluated. The effective dose for 50% inhibition (ED50) of thrombus formation for monotherapy was 0.04 mg/kg per hour apixaban, i.v. (0.03 μM plasma exposure) for the integrated blood flow, 0.13 mg/kg per hour apixaban (0.10 μM plasma exposure) for thrombus weight, and 0.03 mg/kg per hour apixaban (0.02 μM plasma exposure) for MES. Dual treatment with aspirin (5 mg/kg, PO) and apixaban (0.015 mg/kg per hour, i.v.) resulted in a significant reduction in cerebral MES (P < 0.05) compared with monotherapy with either agent. Pharmacokinetic analysis of apixaban and pharmacodynamic assays using activated partial thromboplastin time (aPTT) and prothrombin time (PT) for apixaban- and arachidonic acid-induced platelet aggregation for aspirin were used to confirm the exposure-response relationships. In summary, our study demonstrates that apixaban in a concentration-dependent manner inhibits both arterial thrombosis and MES, suggesting a potential association between factor Xa (FXa) blockade and the reduction in MES in patients at risk of ischemic stroke.

Influence of Clinical Parameters and Anticoagulation on Intraprocedural Cerebral Microembolic Signals during Pulmonary Vein Isolation.

ObjectiveWe had the objective to determine the impact of clinical parameters and anticoagulation status on cerebral microembolic signals (MES) during pulmonary vein isolation (PVI) for atrial fibrillation (AF).BackgroundThromboembolism and stroke are the most feared complications of PVI. MES can help to evaluate embolic burden. It is unknown whether clinical parameters have an impact on embolic risk during PVI.MethodsIn this retrospective analysis we investigated the impact of clinical parameters, including the CHADS2- and CHA2DS2-VASc-score, pulmonary vein variants and echocardiographic parameters on MES rates in patients that underwent PVI using three different ablation approaches (radiofrequency ablation (iRF), pulmonary vein ablation catheter (PVAC) with deactivated electrode pair 1 or 5 (PVAC-red) or PVAC without deactivation (PVAC-all).Results118 AF patients (61±12 years) were included between 2011 and 2013 (Median: 489 MES during PVI). Patients were more likely to have more MES (within 4th quartile) with the PVAC-all approach (60.7% vs. 25.0% (iRF) vs. 14.3% (PVAC-red) respectively (p<0.001). Patients with oral anticoagulation (OAC) pre-ablation were more likely to have lower MES-counts (1st-3rd quartile); (65.6% vs. 35.7%; p = 0.005). Additionally, patients with lower MES counts (1st-3rd quartile) had significantly higher INR values than those in the 4th quartile (1.78 vs. 1.09; p = 0.029). 2 patients developed a potentially thromboembolic event during the procedure.ConclusionClinical predictors of cerebral emboli and stroke do not correlate with cerebral embolic burden during PVI. Pre-ablation OAC and increased INR values correlate with decreased MES-rates. Therefore, it might be beneficial to perform PVI with pre-ablation anticoagulation even in low risk patients.

Abstract 523: Factor XIIa: New Insights on Chemical Tractability and Target Indications From a Potent and Selective Tool Inhibitor

FXII is an emerging target for thrombosis, yet several questions remain to be addressed. Firstly, from drug discovery perspective, level of enzyme occupancy needed for efficacy (which largely dictates potency and selectivity requirement for small molecule inhibitors) is unclear, as most reported active site inhibitors have some level of off-target activities. Secondly, from disease treatment perspective, it is unclear whether FXIIa inhibition will be a safe strategy for stroke treatment or prevention, as it was recently reported that FXIIa inhibition destabilized the subocclusive thrombi in a plaque rupture model. In this presentation, we set out to address these questions using a previously described molecule, Inf4mut15. We generated the human albumin (HA)-Inf4mut15 fusion protein (Mut-inf) for our studies. In vitro Mut-inf displayed comparable potency as the widely used wild-type HA-Infestin4 (WT-inf) (human FXIIa Ki = 73 and 120 pM, respectively). Both infs acted as competitive reversible active site inhibitors of FXIIa, with no binding to FXII zymogen, hence same mode of action as certain small molecule inhibitors. Mut-inf, however, was much more selective against plasmin compared to WT-inf (20,000- and 75-fold Ki separation, respectively), consistent with results from the functional tPA-induced TEG assay, where Ly60 was reduced dose-dependently by WT- but not Mut-inf. Mut-inf aPTT doubling concentration was 15 uM and FXIIa Ki in 30% plasma was 3.5 nM. Calculated enzyme occupancy for Mut-inf for doubling human aPTT is thus 99.9%. In the rabbit model of cerebral microembolic signals (MES) induced by FeCl 3 injury of the carotid artery, treatment with vehicle (n=7), WT-, and Mut-inf (1mg/kg and n=5 each) produced arterial thrombus of 6.0±0.4, 1.9±0.6, and 0.2±0.1 mg, respectively; incidence of MES detected in the middle cerebral artery was 4.1±1.3, 1.8±0.6, and 0.0±0.0, respectively. In summary, our studies demonstrated that very high enzyme occupancy will be required for achieving a putative aPTT doubling target in human for FXIIa active site inhibitors, highlighting the challenge with the small molecule modality. Our MES studies suggest that targeting FXII may offer a safe strategy for stroke prevention and/or other thromboembolic disorders.

Increased thrombin generation potential in symptomatic versus asymptomatic moderate or severe carotid stenosis and relationship with cerebral microemboli

IntroductionThe importance of thrombin generation in the pathogenesis of TIA or stroke and its relationship with cerebral microembolic signals (MES) in asymptomatic and symptomatic carotid stenosis has not been comprehensively...

Increased endothelial activation in recently symptomatic versus asymptomatic carotid artery stenosis and in cerebral microembolic‐signal‐negative patient subgroups

von Willebrand factor propeptide (VWF:Ag II) is potentially a more sensitive marker of acute endothelial activation than von Willebrand factor antigen (VWF:Ag). These biomarkers have not been simultaneously assessed in asymptomatic versus symptomatic carotid stenosis patients. The relationship between endothelial activation and cerebral microembolic signals (MESs) detected on transcranial Doppler ultrasound is unknown. In this multicentre observational analytical study, plasma VWF:Ag and VWF:Ag II levels in patients with ≥50% asymptomatic carotid stenosis were compared with those from patients with ≥50% symptomatic carotid stenosis in the 'early' (≤4weeks) and 'late' (≥3months) phases after transient ischaemic attack or ischaemic stroke. Endothelial activation was also longitudinally assessed in symptomatic patients during follow-up. Transcranial Doppler ultrasound monitoring classified patients as MES-positive or MES-negative. Data from 31 asymptomatic patients were compared with those from 46 early symptomatic and 35 late phase symptomatic carotid stenosis patients, 23 of whom had undergone carotid intervention. VWF:Ag II levels were higher in early (12.8μg/ml; P<0.001), late (10.6μg/ml; P=0.01) and late post-intervention (10.6μg/ml; P=0.038) symptomatic patients than asymptomatic patients (8.9μg/ml). VWF:Ag levels decreased in symptomatic patients followed up from the early to late phase after symptom onset (P=0.048). Early symptomatic MES-negative patients had higher VWF: Ag II levels (13.3 vs. 9.0μg/ml; P<0.001) than asymptomatic MES-negative patients. Endothelial activation is enhanced in symptomatic versus asymptomatic carotid stenosis patients, in early symptomatic versus asymptomatic MES-negative patients, and decreases over time in symptomatic patients. VWF:Ag II levels are a more sensitive marker of endothelial activation than VWF:Ag levels in carotid stenosis. The potential value of endothelial biomarkers and concurrent cerebral MES detection at predicting stroke risk in carotid stenosis warrants further study.

Modified phased radiofrequency ablation of atrial fibrillation reduces the number of cerebral microembolic signals

Phased radiofrequency (RF) ablation for atrial fibrillation is associated with an increased number of silent cerebral lesions on magnetic resonance imaging and cerebral microembolic signals (MESs) on transcranial Doppler ultrasound imaging compared with irrigated RF. The increased rate of embolic events may be due to a specific electrical interference of ablation electrodes attributed to the catheter design. The purpose of this study was to elucidate the effect of deactivating the culprit electrodes on cerebral MESs. Twenty-nine consecutive patients (60 ± 11 years, 10 female) underwent their first pulmonary vein isolation using phased RF energy. Electrode pairs 1 or 5 were deactivated to avoid electrical interference between electrodes 1 and 10 ('modified'). Detection of MESs by transcranial Doppler ultrasound was performed throughout the procedure to assess cerebral microembolism. Results were compared with the numbers of MESs in 31 patients ablated using all available electrodes ('conventional') and to 30 patients undergoing irrigated RF ablation of a previous randomized study. Ablation with 'modified' phased RF was associated with a marked decrease in MESs when compared with 'conventional' phased RF (566 ± 332 vs. 1530 ± 980; P < 0.001). This difference was mainly triggered by the reduction of MES during delivery of phased RF energy, resulting in MES numbers comparable to irrigated RF ablation (646 ± 449; P = 0.7). Total procedure duration as well as time of RF delivery was comparable between phased RF groups. Both times, however, were significantly shorter compared with the irrigated RF group (123 ± 28 vs. 195 ± 38; 15 ± 4 vs. 30 ± 9; P < 0.001, respectively). Pulmonary vein isolation with 'modified' phased RF is associated with a decreased number of cerebral microembolism especially during the delivery of ablation impulses, supporting the significance of electrical interference between ablation electrodes 1 and 10. Deactivation of electrode pairs 1 or 5 might increase the safety of this approach without an increase in procedure duration or RF delivery time.

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

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. University teaching hospitals. This prospective, pilot observational study assessed platelet counts and platelet activation status, and the relationship between platelet activation and MES in asymptomatic vs. early (≤4weeks after TIA/stroke) and late phase (≥3months) 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 1h to classify patients as MES positive or MES negative. 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 7days 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). 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.

Transcranial Measurement of Cerebral Microembolic Signals During Pulmonary Vein Isolation

Background— Pulmonary vein isolation has increasingly been used to cure atrial fibrillation, but concerns have recently been raised that subclinical brain damage may occur because of microembolization during these procedures. We compared the occurrence of bubble formation seen on intracardiac echocardiography and the microembolic signals (MESs) detected by transcranial Doppler on the use of different ablation techniques and anticoagulation strategies. Methods and Results— This prospective study included 35 procedures in 34 consecutive patients (age, 52; SD, 12.8 years; female:male 9:25). Pulmonary vein isolation was performed with a cryoballoon and the conventional anticoagulation protocol (activated clotting time &gt;250 s) in 10 procedures (group 1), with a multipolar duty-cycled radiofrequency pulmonary group 2), and with regime a pulmonary vein ablation catheter with an aggressive anticoagulation (activated clotting time &gt;320 s) in 13 procedures (group 3). The mean total numbers of MESs detected during the procedures were 833.7 (SD, 727.4) in group 1, 3142.6 (SD, 1736.4) in group 2, and 2204.6 (SD, 1078.1) in group 3 ( P =0.0005). MESs were detected mostly during energy delivery in the pulmonary vein ablation catheter groups, whereas a relatively even distribution of emboli formation was seen during cryoballoon ablations. A significant correlation was found in all groups between the degree of bubble formation on intracardiac echocardiography and the number of MESs ( P =0.0000). Conclusions— Duty-cycled radiofrequency ablation is associated with significantly more MESs, even when more aggressive anticoagulation is applied. With both techniques most of these microemboli are gaseous in nature.

Increased Lymphocyte-Platelet Complex Formation as a Measure of Enhanced Platelet Activation in Recently Symptomatic Versus Asymptomatic 'Microembolic Signal Negative' Carotid Stenosis Patients - Results from the Platelets and Carotid Stenosis (PACS) Study (IN3-2.004)

Objective: We hypothesised that patients with more marked platelet activation would have a greater number of MES in the ipsilateral middle cerebral artery than those with less marked platelet activation. Background Cerebral microembolic signals (MES) may predict increased stroke risk in carotid stenosis patients. However, the relationship between MES and platelet activation status in symptomatic vs asymptomatic carotid stenosis has not been comprehensively assessed. Design/Methods: This pilot, observational analytical study compared MES and platelet activation status in early (≤4 weeks after TIA/stroke) and late phase (≥3 months) symptomatic versus asymptomatic moderate or severe (≥50%) carotid stenosis patients. Whole blood flow cytometry was used to quantify platelet surface activation marker expression (CD62P & CD63) and circulating leucocyte-platelet complexes. Bilateral simultaneous transcranial Doppler ultrasound monitoring of the middle cerebral arteries was performed for 1 hour to classify patients as MES+ve or MES-ve. Results: Complete data were available in 31 early phase symptomatic, 27 late phase symptomatic (19 post-carotid intervention), and 25 asymptomatic carotid stenosis patients. 32% of early phase and 19% of late phase symptomatic patients vs 12% of asymptomatic patients were MES+ve (p ≥ 0.07). Early symptomatic MES-ve patients had higher % lymphocyte-platelet complexes than asymptomatic MES-ve patients (2.8 vs 2.3%; p=0.0085). Within the symptomatic subgroup, CD63 expression was lower in early phase MES+ve than MES-ve patients (5.88 vs 14.5%; p=0.0028), but higher in late phase MES+ve than MES-ve patients (12.8 vs 10.0%; p=0.023). Conclusions: Increased lymphocyte-platelet complex formation in recently symptomatic compared with asymptomatic MES-ve patients indicates enhanced platelet activation status in this early symptomatic subgroup. The lack of statistically significant differences in 9MES positivity9 between early symptomatic and asymptomatic patients may reflect a type II error. Larger longitudinal studies are needed to determine whether platelet biomarkers aid risk-stratification in patients with symptomatic and asymptomatic carotid stenosis. Disclosure: Dr. Kinsella has nothing to disclose. Dr. Tobin has nothing to disclose. Dr. Tierney has nothing to disclose. Dr. Feeley has nothing to disclose. Dr. Egan has nothing to disclose. Dr. Collins has nothing to disclose. Dr. Coughlan has nothing to disclose. Dr. O9Neill has nothing to disclose. Dr. Harbison has nothing to disclose. Dr. Doherty has received personal compensation for activities with UCB Pharamaceuticals, Eiasi, and Jansen-Cilag. Dr. Madhavan has nothing to disclose. Dr. Moore has nothing to disclose. Dr. O9Neill has nothing to disclose. Dr. Murphy has nothing to disclose. Dr. Saqqur has nothing to disclose. Dr. Hamilton has nothing to disclose. Dr. Mccabe has nothing to disclose.

Surgery for atrial fibrillation: recent progress and future perspective

Development and introduction of radiofrequency ablation devices allowed the maze procedures to be performed safely and easily, further enabling off-pump pulmonary vein isolation through a mini-thoracotomy or thoracoscope. The effects of the maze procedure include prevention of stroke and other complications related to atrial fibrillation, improved cardiac performance, and relief of symptoms. Indications for the maze procedure have been discussed on the basis of the evidence. Pulmonary vein isolation has been shown to be effective in most patients with paroxysmal atrial fibrillation and can be performed with endocardial catheter ablation and minimally invasive epicardial ablation. These two modalities should be compared in terms of the success rate, occurrence of cerebral microembolic signals, capability of additional lesions indicated for persistent or long-standing persistent atrial fibrillation, and closure of the left atrial appendage. Noncontinuous or nontransmural lines of conduction block as a result of incomplete ablation can result in recurrence of atrial fibrillation and induction of atrial tachycardia. Intraoperative verification of conduction block across the ablation lines is recommended to prevent these complications. Volume reduction of the enlarged left atrium or a boxlesion to isolate the entire posterior left atrium may be effective in patients with a dilated left atrium, but the potentially impaired atrial transport function should be considered. Mapping of active ganglionated plexi and their ablation may improve the outcome of the procedure, but the long-term effect on atrial fibrillation and autonomic nerve activities should be examined.