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Sinus P-wave abnormalities have been associated stroke in people with atrial fibrillation (AF). The majority of AF-related strokes occur from left atrial appendage (LAA) thromboembolism. Dysfunction of the left atrium (LA) and left atrial appendage (LAA) can increase rates of thromboembolic stroke. We studied whether abnormal P wave terminal force in V1 (aPTFV1) is associated with decreased LAA ejection velocity (LAAV) on transesophageal echocardiography (TEE).We conducted a retrospective cross-sectional study reviewing patients at a tertiary care medical center who underwent TEE in sinus rhythm and had an interpretable sinus ECG within 12 months of TEE. Participants were excluded for complex congenital heart disease, age18, cardiac transplantation, and chronic atrial pacing. Logistic regression analysis was used to estimate the odds ratios of LAAV40 cm/s for aPTFV1.In our final cohort of 169 patients (28% of which had LAAV40), the multivariate odds ratio of aPTFV1 for LAAV40 cm/s after adjustment for CHAAbnromal P-wave terminal force in lead V1 is associated with low LAAV after adjustment for potential confounders. Future research is needed for validation of our findings and determination of clinical utility.

Background Left ventricular thrombus (LVT) may develop in systolic heart failure or after acute myocardial infarction. The current recommendations support the use of vitamin K antagonists (VKAs) for the treatment of LVT. Limited data exist regarding the use of direct oral anticoagulants (DOACs) in patients with LVT. This meta-analysis aims to investigate the efficacy and safety of DOACs versus VKAs for LVT. Methods We performed a comprehensive literature search using PubMed, Embase, and Cochrane Library databases through November 2020 for all studies that evaluated the efficacy and safety of DOACs versus VKAs in patients with LVT. The primary outcomes were LVT resolution, overall thromboembolic events, and thromboembolic stroke. The secondary outcomes were major bleeding and all-cause mortality. Pooled risk ratio (RR) and 95% confidence intervals (CIs) were obtained by the Mantel-Haenszel method within a random-effects model. Heterogeneity was assessed by I2 statistic. Results A total of 11 studies including 2153 patients with LVT on anticoagulation (570 on DOACs vs. 1583 on VKAs) were included. LVT resolution was significantly higher in DOACs compared with VKAs [RR: 1.18 (95% CI: 1.04-1.35); P = 0.01, I2 = 25%]. However, no significant difference existed between DOACs and VKAs regarding overall thromboembolic events [RR: 1.10 (95% CI: 0.75-1.62); P = 0.61, I2 = 0%] and thromboembolic stroke [RR: 0.63 (95% CI: 0.39-1.02); P = 0.06, I2 = 0%]. Major bleeding [RR: 1.00 (95% CI: 0.66-1.51); P = 0.99, I2 = 4%] and all-cause mortality [RR: 0.84 (95% CI: 0.50-1.43); P = 0.53, I2 = 0%] were similar between the 2 groups. Conclusions DOACs seem to be more efficacious in achieving LVT resolution compared with VKAs. However, there was no significant difference between the 2 groups in thromboembolic events, major bleeding, and all-cause mortality. Randomized controlled trials are needed to confirm our findings.

Atrial fibrillation (AF) is the most common sustained arrhythmia, with an estimated prevalence in the U.S.of 6.1 million. AF increases the risk of a thromboembolic stroke in five-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function in AF remains unknown. We have recently identified protein phosphatase 1 subunit 12c (PPP1R12C) as a key molecule targeting myosin light-chain phosphorylation in AF. Objective: We hypothesize that the overexpression of PPP1R12C causes hypophosphorylation of atrial myosin light-chain 2 (MLC2a), thereby decreasing atrial contractility in AF. Methods and Results: Left and right atrial appendage tissues were isolated from AF patients versus sinus rhythm (SR). To evaluate the role of the PP1c-PPP1R12C interaction in MLC2a de-phosphorylation, we utilized Western blots, co-immunoprecipitation, and phosphorylation assays. In patients with AF, PPP1R12C expression was increased 3.5-fold versus SR controls with an 88% reduction in MLC2a phosphorylation. PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF. In vitro studies of either pharmacologic (BDP5290) or genetic (T560A), PPP1R12C activation demonstrated increased PPP1R12C binding with both PP1c and MLC2a, and dephosphorylation of MLC2a. Additionally, to evaluate the role of PPP1R12C expression in cardiac function, mice with lentiviral cardiac-specific overexpression of PPP1R12C (Lenti-12C) were evaluated for atrial contractility using echocardiography, versus wild-type and Lenti-controls. Lenti-12C mice demonstrated a 150% increase in left atrium size versus controls, with reduced atrial strain and atrial ejection fraction. Also, programmed electrical stimulation was performed to evaluate AF inducibility in vivo. Pacing-induced AF in Lenti-12C mice was significantly higher than controls. Conclusion: The overexpression of PPP1R12C increases PP1c targeting to MLC2a and provokes dephosphorylation, associated with a reduction in atrial contractility and an increase in AF inducibility. All these discoveries suggest that PP1 regulation of sarcomere function at MLC2a is a main regulator of atrial contractility in AF.

Atrial fibrillation (AF) is the most common cardiac arrythmia and a major cause of stroke, heart failure, sudden death, and cardiovascular morbidity. AF increases risk of thromboembolic stroke via stasis in the left atrium and subsequent embolization to the brain. In patients with acute ischemic stroke, it is essential that clinicians undertake careful investigation to search for AF. In these patients, up to 23.7% eventually are found to have underlying AF. Oral anticoagulation is effective in prevention of strokes secondary to AF, reducing overall stroke numbers by approximately 64%. Left atrial appendage occlusion is promising for prevention of stroke in AF.

Objectives We demonstrate the feasibility and safety of robotics-assisted left atrial appendage clip exclusion in clinical practice. Methods Analysis of a single center robotics-assisted left atrial appendage clip exclusion experience using an epicardial linear clip device in patients with atrial fibrillation with high-risk of thromboembolic stroke and intolerance to oral anticoagulants. Results During the period from December 2017 to September 2020, we performed 42 robotics-assisted left atrial appendage clip exclusions in response to increased risk of bleeding in patients with atrial fibrillation and intolerance to oral anticoagulants. The average congestive heart failure, hypertension, age, diabetes, stroke, and vascular disease score was 5.2 ± 1.6 and hypertension, abnormal liver or kidney function, stroke, bleeding, labile international normalized ratio, elderly, drugs (aspirin, other antiplatelets, or anticoagulants) score was 4.5 ± 0.9. No patients died intraoperatively or within 30 days, or due to conversion to thoracotomy, intraoperative complications, or failure to apply the clip satisfactorily. The procedure was successfully completed despite pericardial adhesions in 2 patients with prior coronary bypass grafts and 3 with postpericarditis scars. Intraoperative transesophageal echocardiography was performed in 38 out of 42 patients; satisfactory exclusion with left atrial appendage stump

Multiple randomized controlled trials and many real-world evidence studies have consistently shown that non-vitamin K antagonist oral anticoagulants (NOACs) are preferable to vitamin K antagonists for thromboembolic stroke prevention in the majority of patients with atrial fibrillation (AF). However, their role in the management of patients with AF and comorbidities, as well as in other patient populations with a high risk of stroke, such as patients with prior embolic stroke of undetermined source (ESUS) and those with atherosclerosis, is less clear. There is now increasing evidence suggesting that NOACs have a beneficial effect in the prevention of stroke in patients with AF and comorbidities, such as renal impairment and diabetes. In addition, while studies investigating the efficacy and safety of NOACs for the prevention of secondary stroke in patients with a history of ESUS demonstrated neutral results, subanalyses suggested potential benefits in certain subgroups of patients with ESUS. One NOAC, rivaroxaban, has also recently been found to be effective in reducing the risk of stroke in patients with chronic cardiovascular disease including coronary artery disease and peripheral artery disease, further broadening the patient groups that may benefit from NOACs. In this article, we will review recent evidence for the use of NOACs across the stroke spectrum in detail, and discuss the progress and future prospects in the different stroke areas.

Tissue type Plasminogen Activator (tPA), named alteplase (Actilyse®) under its commercial form, is currently the only pharmacological treatment approved during the acute phase of ischemic stroke, used either alone or combined with thrombectomy. Interestingly, the commercial recombinant tPA (rtPA) contains two physiological forms of rtPA: the single chain rtPA (sc-rtPA) and the two-chains rtPA (tc-rtPA), with differential properties demonstrated in vitro. Using a relevant mouse model of thromboembolic stroke, we have investigated the overall effects of these two forms of rtPA when infused early after stroke onset (i.e. 20 min) on recanalization, lesion volumes, alterations of the integrity of the blood brain barrier and functional recovery. Our data reveal that there is no difference in the capacity of sc-rtPA and tc-rtPA to promote fibrinolysis and reperfusion of the tissue. However, compared to sc-rtPA, tc-rtPA is less efficient to reduce lesion volumes and to improve functional recovery, and is associated with an increased opening of the blood brain barrier. These data indicate better understanding of differential effects of these tPA forms might be important to ultimately improve stroke treatment.

The aim of this study was to compare outcomes of the full maze procedure with left atrial appendage closure (LAAc) as concomitant procedures for atrial fibrillation (AF) in patients undergoing cardiovascular surgery. A total of 151 patients (88 men, 62 women) underwent elective AF surgery concomitantly with cardiovascular surgery from April 2005 to December 2019. The mean age at time of operation was 70 years and the mean follow-up period was 5.2 ± 3.8 years. Patients were divided into two groups according to the procedure performed: the maze group (n = 87) and the LAAc group (n = 63). Patients in the LAAc group were significantly older and had more comorbidities than those in the maze group. The operative mortality rate was significantly higher in the LAAc group. There was no difference in the rate of freedom from cardiac-related death between the groups (p = 0.86). Furthermore, there was no difference in the 5-year rate of freedom from thromboembolic stroke between the maze group and the LAAc group (p = 0.17). However, the 5-year rate of freedom from heart failure was significantly higher in the maze group compared with the LAAc group (100% vs. 86% ± 6%, respectively; p = 0.006). Patients undergoing the maze procedure had good operative and long-term results, suggesting that this procedure should be performed if indicated. Concomitant LAAc may be effective for preventing thromboembolic stroke in patients with AF if they have no indication for the maze procedure.

The recent clinical trial (DAWN) suggests that recanalization treatment may be beneficial up to 24 h after stroke onset, thus re-opening avenues for development of new therapeutic strategies. Unfortunately, there is a continuous failure of drugs in clinical trials and one of the major reasons proposed for this translational roadblock is the animal models. Therefore, the purpose of this study was to validate a new thromboembolic stroke rat model that mimics the human pathology, and that can be used for evaluating new strategies to save the brain in conditions compatible with recanalization. Stroke was induced by injection of thrombin into the middle cerebral artery. Recombinant tissue-type plasminogen activator (rt-PA) or saline was administrated at 1 h/4 h after stroke onset, and outcome was evaluated after 24 h. Induced ischemia resulted in reproducible cortical brain injuries causing a decrease in neurological function 24 h after stroke onset. Early rt-PA treatment resulted in recanalization, reduced infarct size and improved neurological functions, while late rt-PA treatment showed no beneficial effects and caused hemorrhagic transformation in 25% of the rats. This validated and established model’s resemblance to human ischemic stroke and high translational potential, makes it an important tool in the development of new therapeutic strategies for stroke.

Recent studies reported that the new coronavirus disease (COVID-19) invades the central or peripheral nervous system by various mechanisms including angiotensin converting enzyme-2 receptors, blood-brain barrier injury, and immune injury. The possibility that COVID-19 can occur due to the mechanism of thromboembolic stroke, as a result central nervous system, was confirmed by brain images and laboratory test. What we need to note is that COVID-19 can also appear as a focal neurological defect. In addition, if the COVID-19 patient has a high D-dimer and an inflammatory maker, clinicians must be aware of multiple thromboembolic strokes as well as the occurrence of ischemic stroke caused by large vessel stroke.

Background Elderly patients with atrial septal defect (ASD) often present with chronic atrial fibrillation and large left to right shunt. This study reports the experience of left atrial appendage (LAA) and ASD closure in patients with significant ASD and chronic atrial fibrillation. Methods We report six consecutive elderly patients with chronic atrial fibrillation and significant ASD who underwent LAA and fenestrated ASD closure from January 1, 2014 until December 31, 2019. All periprocedural and long-term (>1 year) outcomes were reported. Results Six patients (male: 33.3%; mean age: 66.8 ± 3.3 years) were included. Mean CHADS2 , CHA2 DS2 -VASc , and HAS-BLED scores were 2.33 ± 0.82, 3.83 ± 0.75, and 1.83 ± 0.75. Four patients underwent simultaneous procedure, while two patients underwent a staged procedure. Procedural success was achieved in all patients. Total occlusion was achieved during LAA occlusion without device embolization prior to ASD closure. Patients who underwent simultaneous procedure had a shorter total hospital stay and lower total hospital stay. During a follow-up period of 32.8 ± 19.4 months, both the devices were well seated. No device-related thrombosis or erosion reported. All patients remained in atrial fibrillation. No patients experienced any thromboembolic stroke or transient ischemic attack. Conclusions LAA and ASD closure is feasible and can be safely performed in the same seating in elderly patients with a significant ASD.

Background Arterial thoracic outlet syndrome is a rare condition characterized by a subclavian artery pathology associated with a bone abnormality. It is rarely associated with thromboembolic stroke. The mechanism of cerebral embolism associated with thoracic outlet syndrome have rarely been demonstrated. We present here a fully studied case with a high probability of reverse flow embolism. Case presentation A 24-year-old man with a known arterial thoracic outlet syndrome presented with a right cerebral posterior artery brain infarction. An ultrasound examination depicted the compression of the right subclavian artery in the scalene defile with a post stenotic aneurysm and the presence of a floating thrombus in this aneurysm. There was a reverse flow during diastole in this aneurysm. Anticoagulation was carried out with the disappearance of the floating thrombus with no new clinical or brain MRI event. Corrective surgery of this thoracic outlet syndrome was performed one month after stroke. Conclusion Very few cases of stroke in arterial thoracic outlet syndrome have been described with thorough dynamic vascular imaging. To our knowledge, this is the fourth reported case that advocates for a reverse flow embolism mechanism in stroke associated with thoracic outlet syndrome, and the first to realize an extensive ultrasound and doppler workup.

The most common causes of ischaemic stroke are represented by carotid artery atherosclerotic disease (CAAD) and atrial fibrillation. While oral anticoagulants substantially reduce the incidence of thromboembolic stroke (< 1%/year), the rate of ischaemic stroke and other cardiovascular disease events in patients with CAAD remains high, ranging from 8.4 to 18.1 events per 100 patient-years. Similar to any other atherosclerotic disease, anti-thrombotic therapies are proposed for CAAD to reduce stroke and other cardiovascular events. The 2017 European Society of Cardiology (ESC)/European Society for Vascular Surgery (ESVS) guidelines recommend for patients with asymptomatic CAAD ≥60% the use of aspirin 75 to 100 mg once daily or clopidogrel 75 mg once daily at the exception of patient at very high bleeding risk. For patients with symptomatic CAAD ≥50%, the use of aspirin 75 to 100 mg once daily or clopidogrel 75 mg once daily is recommended. New perspectives for anti-thrombotic therapy for the treatment of patients with CAAD come from the novel dual pathway strategy combining a low-dose anticoagulant (i.e. rivaroxaban) and aspirin that may help reduce long-term ischaemic complications in patients with CAAD. This review summarizes current evidence and recommendations for the anti-thrombotic management of patients with symptomatic or asymptomatic CAAD or those undergoing carotid revascularization.

Author(s): Ford, James S.; Holmes, James F.; Jones, Russell F. | Abstract: Introduction: There is a growing body of literature detailing coronavirus 2019 (COVID-19) cardiovascular complications and hypercoagulability, although little has been published on venous or arterial thrombosis risk.Case Report: In this report, we present a single case of cardioembolic stroke in the setting of COVID-19 related myocarditis, diagnosed via cardiac magnetic resonance imaging and echocardiography. COVID-19 infection was confirmed via a ribonucleic acid polymerase chain reaction assay.Conclusion: Further research is needed to evaluate the hypercoagulable state of patients with COVID-19 to determine whether prophylactic anticoagulation may be warranted to prevent intracardiac thrombi and cardioembolic disease in patients with COVID-19 related myocarditis.

Tissue reperfusion is a serious therapeutic strategy of ischemic stroke in addition to recanalization. In this work, we aimed to establish new urokinase-based therapeutics in order to dissolve large vessel thrombus together with microthrombi for stroke implications. Formulations consisted of free urokinase (UK), polyethylene glycol–crosslinked urokinase nanogel (PEG-UK), and a 1:1 mixture of UK and PEG-UK (PEG-UK+UK) were tested both in vitro and in vivo. In vitro experiments confirmed the pH-dependent release of PEG-UK in the PEG-UK+UK formulation. It was activated at pH 6.50, an environmental pH in the infarct brain tissue, owing to the dynamic crosslink property of PEG-UK. In vivo tests on a thromboembolic stroke rat model showed that the formulations containing UK, i.e., free UK and PEG-UK+UK, demonstrated better neurological scores and smaller infarction volumes within the time window, in which the PEG-UK+UK formulation relatively performed better. On the other hand, the formulations containing PEG-UK, i.e., PEG-UK and PEG-UK+UK, gained sufficient thrombolytic efficiency beyond the time window. Further investigation on the mechanism revealed that PEG-UK could reduce microthrombus in distal microcirculation, and its destructive effect was also less than that of free UK. The PEG-UK+UK formulation actually provided a “dual targeting” delivery of UK to both the large vessels and the microcirculation, which was beneficial to the treatment of cerebral ischemic stroke both within and beyond the therapeutic time window.

A patient undergoes intracranial stent insertion for stent-assisted coiling of a basilar tip aneurysm and left middle cerebral artery aneurysm. A flow diverting stent is also placed across an anterior communicating artery aneurysm. Prior to the procedure, the patient takes dual antiplatelet medications, being aspirin and clopidogrel. Because of the concern regarding in-stent thrombus and thromboembolic complications related to intracranial stenting and the high rate of clopidogrel resistance, preoperative platelet function testing (PFT) was undertaken to ensure platelet inhibition. In this case, PFT was performed on a platelet function analyser which demonstrated platelet inhibition. Ten days following the procedure, the patient represented with thromboembolic stroke. Repeat PFT performed with whole blood impedance aggregometry and despite full medication compliance demonstrated clopidogrel resistance. Clopidogrel was then ceased and prasugrel commenced. This case demonstrates the importance of appropriate platelet inhibition in patients with intracranial stents and the controversy surrounding PFT.

Background and importance Anticoagulants are one of the therapeutic groups most frequently involved in drug related problems in the emergency services. However, the therapeutic management and the impact of assistance for those anticoagulated patients who suffer a stroke episode are not known. Aim and objectives To describe the therapeutic management and healthcare impact of patients with atrial fibrillation treated with oral anticoagulants (OAT) admitted in an emergency services due to a thromboembolic stroke. Material and methods This was a retrospective observational study. Adult patients (>18 years old) with atrial fibrillation receiving treatment with OAT admitted for cardioembolic stroke were included (January 2017–June 2019). Anticoagulant dosing prior to the stroke episode was evaluated. The modified Rankin Scale (mRS) score and National Institutes of Health Stroke Scale (NIHSS) score at admission and discharge, anticoagulant treatment prescribed after the episode and number of consultations to the emergency department in the year after hospital discharge were recorded. Results Thirty-two patients were included (mean Age 75.2 (11.8) years): 22 (68.7%) were treated with vitamin K antagonists (VKA) and 10 (31.2%) with direct oral anticoagulants (DOACs). Eleven (34.4%) patients had a mRS score of 0 prior to the episode, 6 (18.8%) had a score of 1, 13 (40.6%) a score of 2 and 2 (6.2%) a score >2. The median score on the NIHSS scale at admission was 14 points (IQR 10–20) and 1 (0–7) point at discharge. Five (15.6%) patients died during hospitalisation. Among patients receiving VKA treatment, 13 (59.1%) had an international normalised ratio of Conclusion and relevance A significant percentage of patients treated with DOACs suffering from stroke were under dosed. Consultations after discharge were frequent in this group of patients. Our results open the door to the design of multicentre studies that will allow us to verify the best anticoagulation strategies in this group of patients. References and/or acknowledgements No conflict of interest.

Emerging evidence indicates combination therapy with anticoagulants and antiplatelet agents for atrial fibrillation (AF) will be increasingly required. Numerous studies compare the efficacy and cost-effectiveness of anticoagulation alone in AF, i. e., non-vitamin K oral anticoagulants (NOACs) vs. warfarin. However, the addition of antiplatelet agents with their potential for decreasing thromboembolic stroke counter-balanced by an increased bleeding risk has received less attention. Thus, we evaluated the cost–utility of this combination therapy. We obtained event estimates from our recent meta-analysis of four randomized clinical trials designed to compare NOACs with warfarin in patients with AF. We examined patient subgroups within each trial that received antiplatelet therapy in addition to anticoagulation. Utilities were derived from the literature and cost estimates from the German health-care system. A decision tree was constructed and populated with these parameters. We used a 1-year time horizon because combination therapy is not recommended beyond this time. We calculated the incremental cost–effectiveness ratio (ICER) per quality-adjusted life-year (QALY). The derived ICER was 13,168.50 € per QALY. NOAC prices exerted considerable influence on the calculation. Nevertheless, there is potential for ICER shifts in favor of warfarin, e.g., if warfarin-mediated anticoagulation control is improved and thereby adverse events decrease. Conversely, if NOAC adherence decreases, adverse events could increase. The derived ICER was 13,168.50 € per QALY, consistent with NOACs being cost-effective vs. warfarin when anticoagulation is used with antiplatelet agents. Nevertheless, country-, practice-, and patient-related factors influence the ICER. Our cost–utility calculation should be used a starting point for decision-making.

Background and purpose The recent literature suggests that a cardiac origin in ischaemic stroke is more frequent than previously assumed. However, it is not always clear which patients benefit from additional cardiac investigations if obvious cardiac pathology is absent.Methods A single-center retrospective observational study was performed with 7454 consecutive patients admitted to the intensive care unit after cardiac surgery in the period 2006-2015 and who had postoperative brain imaging. Cerebral imaging was studied for the occurrence of stroke including subtype and involved vascular territory. It was assumed that all perioperative thromboembolic strokes are of cardiac origin. Data obtained from a hospital cohort of consecutive patients who received a diagnosis of ischaemic stroke were used for comparison. Results Thromboembolic stroke occurred in 135 cardiac surgery patients in 56 (41%) of whom the posterior cerebral circulation was involved. In the control group, 100 out of 503 strokes (20%) were located in the posterior cerebral circulation. The relative risk for a posterior location for stroke after cardiac surgery compared to patients with ischaemic stroke without prior cardiac surgery was 2.09; 95% confidence interval 1.60-2.72.Conclusions Thromboembolic stroke after cardiac surgery occurs twice as often in the posterior cerebral circulation compared to ischaemic strokes in the general population. If confirmed in general stroke cohorts, the consequence of this finding may be that in patients with an ischaemic stroke that involves the posterior cerebral circulation the chance of a cardiac origin is increased and therefore might trigger additional cardiac investigations such as long-term heart rhythm monitoring or echocardiography.

The recent success of endovascular stroke treatment has heralded a new era in the management of acute ischemic stroke (AIS) with significantly improved outcome for patients. A large number of patients may be amenable to this new treatment and as the evidence expands the number of patients eligible for mechanical thrombectomy continues to increase. Recent evidence suggests that the time window for treatment can be extended up to 24 h after symptom onset for patients with anterior circulation strokes; however, many clinicians and medical professionals may not be aware of these recent changes and it is important that they are kept up-to-date with this rapidly evolving treatment. This review provides an overview of the recent successful trials and highlights important steps that should be instituted in order to achieve rapid reperfusion and optimize the outcome for ischemic stroke patients. It also looks at the remaining controversies facing the field of thrombectomy. A short summary of each of these contentious areas is provided and the current state of the art.

The novel direct oral anticoagulants (NOACs) represent a major advance in oral anticoagulant therapy and are replacing vitamin K antagonists as the preferred options for many indications. Given in fixed doses without routine laboratory monitoring, they have been shown to be at least as effective in reducing thromboembolic stroke as dose-adjusted warfarin in phase 3 randomized trials and less likely to cause hemorrhagic stroke. Pharmacokinetic and/or pharmacodynamic subanalyses of the major NOAC trials in patients with atrial fibrillation have established relationships between clinical characteristics, and drug levels and/or pharmacodynamic responses with both efficacy and safety. Based on these analyses, pharmaceutical manufacturers and regulatory authorities have provided contraindications and dosing recommendations based on clinical characteristics that are associated with drug levels and/or pharmacodynamic responses, stroke reduction, and bleeding risk to optimize the risk-benefit profile of the NOACs in the real world. The current fixed-dosing strategy of NOACs has triggered discussions about the potential value of laboratory monitoring and dose adjustment in customizing drug exposure to further improve the safety and efficacy of the NOACs in patients with atrial fibrillation. As there is neither high-quality evidence nor consensus about the potential role of laboratory monitoring and dose adjustment for the NOACs, a Cardiac Research Safety Consortium "Think Tank" meeting was held at the American College of Cardiology Heart House in December 2015 to discussions these issues. This manuscript reports on the deliberations and the conclusions reached at that meeting.

The study focuses the dose administration of dabigatran to avoid the deaths due to hemorrhagic complications and thromboembolic stroke in clinics worldwide. To target the issue, a novel emerging acoustic technology, namely ''Quartz Crystal Microbalance with Dissipation'' (QCM-D) has been applied, while the acoustic assays namely ''activated Partial Thromboplastin Time'' (aPTT) and ''Prothrombinase complex-induced Clotting Test'' (PiCT) have been compared with the standard methods in parallel. Both techniques have been applied to 300 samples, including 220 plasma samples of patients suffering coagulation disorders and 80 plasma samples of non-patients. In comparison, the coagulation times of the acoustic aPTT and PiCT yielded an excellent correlation with the standard methods with in analytical standard deviation limits. Finally, the acoustic aPTT assay is the ''gold standard'' for a dose administration of the new oral anticoagulant, where the Δf/ΔΓ ratio of the acoustic assay demonstrates that dabigatran with FEIBA 50 combination could be a safe remedy to avoid the deaths in clinics.

Aim and objective: Atrial fibrillation (AF), a major cause of thromboembolic stroke, is under-detected. Our aim was to compare the established pathway of AF detection, reporting to point-of-treatment decision, with a pilot pathway coordinated by the clinical nurse specialists (CNS) for stroke in Qatar. Methods: The established system uses traditional holter monitors, attached by a technician. The report is sent to cardio-electrophysiology physicians, and then uploaded onto electronic records. The piloted stroke system used a cardiac monitoring device capable of prolonged recording. The device is calibrated, downloaded, reviewed and uploaded onto electronic records by the CNS. Results: 319 holters were requested during the 6-month pilot period, 217 via the stroke cardiac monitor service (SCMS) and 102 via the hospital holter monitor service (HHMS). Sixty-two percent of the SCMS reports were attached within 24 hours of admission compared to 31% of the HHMS reports. The reports were available within 48 hours in 2% of patients in the HHMS as compared to 76% with SCMS. The time from detachment to the consultant's decision was 2.6 days in SCMS versus 18.4 days in the HHMS. Conclusion: Utilising the skills of the CNS team for the application, interpretation and reporting provided a more efficient service with improved initiation of anticoagulation treatment for patients.

Resection of the left atrial appendage (LAA) to prevent recurrent arterial emboli in patients with atrial fibrillation was first suggested more than 60 years ago. Longer-term follow-up from randomized studies of the safety and efficacy of transcatheter LAA occlusion has recently been completed; data from large, observational cohorts are being reported. These recent data provide further insights into procedural safety with current techniques and the ability of LAA closure to reduce thromboembolic stroke compared with warfarin anticoagulation. This review summarizes the latest data regarding transcatheter LAA occlusion, focusing on larger prospective studies and further analyses of seminal clinical trials.

During acute brain ischemia, α2-antiplasmin markedly enhances brain injury, blood brain barrier breakdown and matrix metalloproteinase-9 (MMP-9) expression. Although α2-antiplasmin inhibits fibrin thrombus-degradation, and MMP-9 is a collagen-degrading enzyme altering blood brain barrier, both have similar deleterious effects on the ischemic brain. We examined the hypothesis that MMP-9 is an essential downstream mediator of α2-antiplasmin’s deleterious effects during brain ischemia. Middle cerebral artery thromboembolic stroke was induced in a randomized, blinded fashion in mice with increased blood levels of α2-antiplasmin. There was a robust increase in MMP-9 expression (immunofluorescence) in the ischemic vs. the non-ischemic hemisphere of MMP-9(+/+) but not MMP-9(−/−) mice, 24 h after stroke. Brain swelling and hemorrhage were significantly increased in the ischemic vs. the non-ischemic hemisphere of MMP-9(+/+) mice. By comparison to MMP-9(+/+) mice, the ischemic hemispheres of MMP-9(−/−) mice showed a ~6-fold reduction in brain swelling (p

The aim of this translational, randomized, controlled, blinded preclinical trial was to determine the effect of compound 21 (C21) in embolic stroke. Rats were subjected to embolic-middle cerebral artery occlusion (eMCAO). They received C21 (0.01, 0.03 and 0.06 mg/kg/d) or saline (orally) for five days, with the first-dose given IV at 3 h post-eMCAO. For the time-window study, the optimal-dose of C21 was initiated at 3, 6 or 24 h post-eMCAO and continued for five days. For the combinatorial study, animals received IV-tissue plasminogen activator (tPA) at either 2 or 4 h, with IV-C21 (0.01 mg/kg) or saline at 3 h post-eMCAO and daily thereafter for five days. After performing the behavior tests, brains were collected for analyses. The dose–response study showed significant motor improvements with the lowest-dose (0.01 mg/kg) of C21. In the time-window study, this same dose resulted in improvements when given 6 h and 24 h post-eMCAO. Moreover, C21-treated animals performed better on the novel object recognition test. Neither the single treatment with C21 or tPA (4 h) nor the combination therapy was effective in reducing the hemorrhage or infarct size, although C21 alone lowered sensorimotor deficit scores post-eMCAO. Future studies should focus on the long-term cognitive benefits of C21, rather than acute neuroprotection.

Background It has been suggested that ethnicity can make a significant difference to the likelihood of thromboembolic stroke related to atrial fibrillation. Ethnic differences have been shown to alter inflammatory and haemostatic factors; however, this may all be confounded by differences in cardiovascular risk factors between different ethnicity. The impact of different ethnicities on the thrombogenic profile is not known. The aim of this study was to investigate differences in markers of inflammation, endothelial function and tissue remodelling between Caucasian and Indian populations with supraventricular tachycardia (SVT). Methods Patients with structurally normal hearts undergoing catheter ablation for SVT were studied. This study included 23 Australian (Caucasian) patients from the Royal Adelaide Hospital, Adelaide, Australia and 24 Indian (Indian) patients from the Christian Medical College, Vellore, India. Blood samples were collected from the femoral vein, and right and left atria. Blood samples were analysed for the markers of endothelial function (ADMA, ET-1), inflammation (CD40L, VCAM-1, ICAM-1), and tissue remodelling (MMP-9, TIMP-1) using ELISA. Results The study populations were well matched for cardiovascular risk factors and the absence of structural heart disease. No difference in the echocardiographic measurements between the two ethnicities was found. In this context, there was no difference in markers of inflammation, endothelial function or tissue remodelling between the two SVT populations. Conclusion Caucasian and Indian populations demonstrate similar inflammatory, endothelial function or tissue remodelling profiles. This study suggests a lack of an impact of different ethnicity in these populations in terms of thrombogenic risk.

The COVID-19 pandemic has escalated the occurrence of hypoxia including thrombotic stroke worldwide, for which nitric oxide (NO) therapy seems very promising and translatable. Therefore, various modes/routes of NO-delivery are now being tested in different clinical trials for safer, faster, and more effective interventions against ischemic insults. Intravenous (IV) infusion of S-Nitrosoglutathione (GSNO), the major endogenous molecular pool of NO, has been reported to protect against mechanical cerebral ischemia-reperfusion (IR), however, it has been never tested in any kind of “clinically” relevant thromboembolic stroke models with or without comorbidities and in combination with the thrombolytic reperfusion therapy. Moreover, “IV-effects” of higher dose of GSNO following IR-injury have been contradicted to augment stroke injury. Herein, we tested the hypothesis that nebulization of low-dose GSNO will not alter blood pressure (BP) and will mitigate stroke injury in diabetic mice via enhanced cerebral blood flow (CBF) and brain tissue oxygenation (PbtO2). GSNO-nebulization (200 μg/kgbwt) did not alter BP, but augmented the restoration of CBF, improved behavioral outcomes and reduced stroke injury. Moreover, GSNO-nebulization increased early reoxygenation of brain tissue/PbtO2 as measured at 6.5 h post-stroke following thrombolytic reperfusion, and enervated unwanted effects of late thrombolysis in diabetic stroke. We conclude that the GSNO-nebulization is safe and effective for enhancing collateral microvascular perfusion in the early hours following stroke. Hence, nebulized-GSNO therapy has the potential to be developed and translated into an affordable field therapy against ischemic events including strokes, particularly in developing countries with limited healthcare infrastructure.

Pseudoginsenoside-F11 (PF11), an ocotillol-type ginsenoside, has been reported to exert neuroprotective effects on ischemic stroke induced by permanent and transient middle cerebral artery occlusion in experimental animals. The aim of the present study was to investigate the effect of PF11 on thromboembolic stroke in rats and its possible mechanisms on thromboinflammation. PF11 (4, 12, 36 mg/kg) was injected intravenously (i.v.) once a day for 3 consecutive days to male Wistar rats followed by embolic middle cerebral artery occlusion (eMCAO). The results showed that PF11 significantly reduced the cerebral infarction volume, brain edema and neurological deficits induced by eMCAO. Meanwhile, the thromboinflammation in the ischemic hemisphere was observed at 24 h after eMCAO, as indicated by the increased number of microvascular thrombus and inflammatory response. Moreover, eMCAO resulted in the up-regulation of platelet glycoprotein Ibα (GPIbα) and VI (GPVI), as well as the activation of contact-kinin pathway. Notably, PF11 significantly reversed all these changes. Furthermore, PF11 prevented the eMCAO-induced loss of tight junction proteins and up-regulation of matrix metalloproteinase-9 (MMP-9), thus leading to the alleviation of blood-brain barrier (BBB) damage. In conclusion, the present study revealed that thromboinflammation was induced in the ischemic hemisphere of rats after eMCAO and PF11 exerted marked protective effects against thromboembolic stroke by attenuating thromboinflammation and preventing BBB damage. This research further identifies the potential therapeutic role of PF11 for ischemic stroke.

Graphical abstract, Highlights • The patient had an 11-year medical history. • Rare congenital cardiac malformations were present. • The patient was managed medically and surgically.

Background Patients with atrial fibrillation are at increased risk for thromboembolic stroke originating predominantly in the left atrial appendage. To reduce the risk, the standard of care is anticoagulation. In addition, several devices for exclusion of the left atrial appendage have been developed. Methods PubMed was searched for articles relevant to left atrial appendage management. The resulting articles were reviewed as were relevant articles in their bibliographies. Relevant journals were manually searched for sources. Results Devices are being used for left atrial appendage exclusion by percutaneous and surgical approaches. Their indications, limitations, and outcomes are reviewed. Conclusions Excision and exclusion of the left atrial appendage is safe and as effective as medical management of atrial fibrillation for stroke prevention. The choice of treatment should be made based on patients' anatomy, history, and preference informed by an appropriate left atrial appendage management team.

Nonvalvular atrial fibrillation (AF) is the most common arrhythmia with a prevalence of 1-2% and affects approximately 15-20% of all octogenarians. Patients are at increased risk of thromboembolic stroke, with an overall risk of 5% per year. Thrombi form almost exclusively in the left atrial appendage (LAA), a blind sac-like heterogeneous structure trabeculated by pectinate muscles. In the past five decades, life-long oral anticoagulation (OAC) with vitamin K antagonists (VKA) has been the state-of-the art treatment to prevent stroke and systemic embolism from thrombi in AF. In the last decade, nonvitamin K dependent oral anticoagulants (NOAC) have been shown to be superior to VKA. Given the safety issues of indefinite OAC with either VKA or NOAC, it is plausible to consider left atrial appendage closure (LAAC) as an alternative strategy to prevent death, stroke or other systemic embolization, and bleeding. In recent years, LAAC has been compared to VKA in prospective randomized trials, yielding superior results regarding efficacy and noninferiority regarding safety in the mid-term. This review provides an update on the current state of LAAC in the field of prevention of death, stroke, and bleedings in patients suffering from nonvalvular AF. We elucidate the evidence and limitations of anticoagulation as the classical treatment paradigm, and review devices and techniques for LAAC. Most importantly, the current clinical evidence on efficacy and safety is outlined.

Atrial fibrillation is the most common arrhythmia worldwide, and carries a significantly increased risk of thromboembolic stroke. Initially, vitamin K antagonists were used as stroke prophylaxis; but more recently, a group of drugs known as novel oral anticoagulants have been developed. Apixaban belongs to this group of drugs, and is a factor Xa inhibitor that has emerged as a popular pharmacological agent worldwide. In this review, we will provide an overview of the pivotal trials in the development of apixaban, while also critically evaluating the new emerging real-world data, and discussing the effectiveness, safety, economic viability and future prospects of apixaban and how it impacts on patient outcomes in those with non-valvular atrial fibrillation.

Background Atrial fibrillation (AF) increases the risk of thromboembolic stroke. An oral anticoagulant should be administrated to prevent stroke in patients with moderate stroke risk (ie, CHA 2 DS 2 -VASc score > 2). If the stroke risk is low (i.e. the score = 1), however, antiplatelet agent such as aspirin is widely used. Aspirin can cause peptic ulcer disease (PUD) while its alternative, clopidogrel, theoretically does not. Objective To elucidate the efficacy and safety between aspirin and clopidogrel, a multicenter randomized controlled trial was designed in AF patients with low stroke risk. Methods According to sample size estimation based on previous literature, a total of 1560 AF patients with low stroke risk will be randomly assigned into 4 different groups dependent upon initial esophagogastroduodenoscopy (EGD) results: two mono-antiplatelet treatment groups with either aspirin 100 mg or clopidogrel 75 mg for 1 year; two antiplatelet agent and proton pump inhibitor (PPI) combination groups. Follow-up EGD will be performed at 1 year. Results The clinical follow-up will be performed for 1 year after enrollment. The primary efficacy endpoint is to compare the annual stroke rate between aspirin and clopidogrel treatment groups. The primary safety endpoint is to compare the prevalence of drug-induced gastrointestinal (GI) and intracranial hemorrhage and upper-GI response including PUD based on EGD after 1 year. Conclusions This trial will determine whether clopidogrel is noninferior in stroke prevention and superior in reduction of GI events including PUD to aspirin in AF patients with low stroke risk. ( ClinicalTrials.gov : NCT02960126 ).