Abstract Background and aims Leptomeningeal collateral (LMC) circulation helps preserve brain tissue during acute ischemic stroke (AIS), with poor collateral status predicting worse outcomes. This study assessed the association between asymmetric dimethylarginine (ADMA), LMCs, infarct volume, and oxidative stress in 101 AIS patients with large vessel occlusion within 6h or wake-up stroke. Methods LMC status was graded using the Menon score (poor, intermediate, or good) on CT angiography, and recanalization was assessed by the modified Thrombolysis in Cerebral Infarction score. Serum ADMA, NADPH oxidase 2 (NOX2), and nitric oxide (NO) levels were measured at admission (<6h, T0), 24h (T1), and 48h (T2). Results Among patients, 43.1% had good, 35.3% intermediate, 21.6% poor LMC status. Higher admission ADMA levels were significantly associated with poor LMC at T0 (p=0.028) and more severe neurological deficits at T1 and T2 (p=0.005, p=0.008). ADMA levels increased over time (p=0.046), and correlated with NOX2 at T1 (p<0.001). Rising NOX2 was associated with increased neutrophils (p=0.013) and decreased lymphocytes (p=0.006). Conclusions ADMA may impair endothelial function by reducing NO availability and enhancing NOX2-driven oxidative stress. These findings support a role for the ADMA-NO-NOX2 axis in limiting collateral circulation. Targeting this axis may represent a therapeutic strategy to improve outcomes in AIS. Conflict of interest Manuela De Michele: nothing to disclose

Good leptomeningeal collaterals (LMCs) after large vessel occlusion (LVO) extend the time window for endovascular therapy. The mechanisms regulating LMC activation are not fully understood. The aim of this study was to investigate the potential role of two vasoactive molecules endothelin-1 (ET-1)—a vasoconstrictor agent—and nitric oxide (NO)—a vasodilator agent—in the regulation of post-stroke LMCs. Ischemic stroke patients within 6 h of LVO were included. Collateral status was assessed using the Menon scoring system based on computed tomography angiography scans. Patients were accordingly divided into three groups: poor, intermediate, and good LMCs. Recanalization was evaluated using the modified thrombolysis in cerebral infarction (mTICI) score. Serum levels of ET-1 and NO were measured at three time points: T0 (<6 h), T1 (24 h), and T2 (48 h). A total of 105 patients were enrolled (mean age 76 ± 12.8 years): 44 with good (46.2%), 36 with intermediate (37.8%), and 22 with poor LMCs (23.1%). NO values decreased, whereas ET-1 values increased from T0 to T1 in all groups of patients. No significant association was found between serum ET-1 levels and collateral status. Higher ET-1 levels at T1 correlated with poor outcome regardless of the LMC status or the degree of recanalization (p = 0.030). A significant linear positive correlation was revealed at T0 between high levels of ET-1 and the neutrophil count (Spearman’s rho = 0.236, p = 0.035). Subgroup analysis showed a significant inverse correlation at T1 between NO and the collateral score (Spearman’s rho = −0.251, p = 0.021). Although we observed no significant association between LMC score and serum ET-1 concentrations, at 24 h higher ET-1 serum levels were predictive of poor outcome and higher NO levels were correlated with poor collateral status. These findings may indicate an inadequate microvascular reperfusion, possibly due to ET-1-mediated vasoconstriction, neutrophil activation, and NO-mediated oxidative stress, suggesting their potential role in the no-reflow phenomenon.

Leptomeningeal collateral (LMC) circulation helps preserve brain tissue during acute ischemic stroke (AIS), with poor collateral status predicting worse outcomes. This study assessed the association between asymmetric dimethylarginine (ADMA), LMCs, infarct volume, and oxidative stress in 101 AIS patients with large vessel occlusion within 6h or wake-up stroke. LMC status was graded using the Menon score on CT angiography (categorized as poor, intermediate, or good), and recanalization was assessed by the modified Thrombolysis in Cerebral Infarction score. Serum ADMA and NOX2 levels were measured at admission (< 6h, T0), 24h (T1), and 48h (T2). Among patients, 43.1% had good, 35.3% intermediate, 21.6% poor LMC status. Higher admission ADMA levels were significantly associated with poor LMC (p = 0.028) and more severe neurological deficits at T1 and T2 (p = 0.005, p = 0.008). ADMA levels increased over time (p = 0.046), and correlated with NOX2 at T1 (p < 0.001). Rising NOX2 was associated with increased neutrophils (p = 0.013) and decreased lymphocytes (p = 0.006). ADMA likely impairs endothelial function by reducing nitric oxide availability and enhancing NOX2-driven oxidative stress. Statin use was associated with lower NOX2 levels. These findings support a role for the ADMA-NO-NOX2 axis in limiting collateral circulation. Targeting this axis may represent a therapeutic strategy to improve outcomes in AIS.

Leptomeningeal collateral (LMC) circulation helps preserve brain tissue during acute ischemic stroke (AIS), with poor collateral status predicting worse outcomes. This study assessed the association between asymmetric dimethylarginine (ADMA), LMCs, infarct volume, and oxidative stress in 101 AIS patients with large vessel occlusion within 6 h or wake-up stroke. LMC status was graded using the Menon score (poor, intermediate, or good) on CT angiography, and recanalization was assessed by the modified Thrombolysis in Cerebral Infarction score. Serum ADMA, NADPH oxidase 2 (NOX2), and nitric oxide (NO) levels were measured at admission (< 6 h, T0), 24 h (T1), and 48 h (T2). Among patients, 43.1% had good, 35.3% intermediate, 21.6% poor LMC status. Higher admission ADMA levels were significantly associated with poor LMC at T0 (p = 0.028) and more severe neurological deficits at T1 and T2 (p = 0.005, p = 0.008). ADMA levels increased over time (p = 0.046), and correlated with NOX2 at T1 (p < 0.001). Rising NOX2 was associated with increased neutrophils (p = 0.013) and decreased lymphocytes (p = 0.006). ADMA may impair endothelial function by reducing NO availability and enhancing NOX2-driven oxidative stress. These findings support a role for the ADMA-NO-NOX2 axis in limiting collateral circulation. Targeting this axis may represent a therapeutic strategy to improve outcomes in AIS.

Background: In patients with atrial fibrillation who suffered an ischemic stroke while on treatment with nonvitamin K antagonist oral anticoagulants, rates and determinants of recurrent ischemic events and major bleedings remain uncertain. Methods: This prospective multicenter observational study aimed to estimate the rates of ischemic and bleeding events and their determinants in the follow-up of consecutive patients with atrial fibrillation who suffered an acute cerebrovascular ischemic event while on nonvitamin K antagonist oral anticoagulant treatment. Afterwards, we compared the estimated risks of ischemic and bleeding events between the patients in whom anticoagulant therapy was changed to those who continued the original treatment. Results: After a mean follow-up time of 15.0±10.9 months, 192 out of 1240 patients (15.5%) had 207 ischemic or bleeding events corresponding to an annual rate of 13.4%. Among the events, 111 were ischemic strokes, 15 systemic embolisms, 24 intracranial bleedings, and 57 major extracranial bleedings. Predictive factors of recurrent ischemic events (strokes and systemic embolisms) included CHA 2 DS 2 -VASc score after the index event (odds ratio [OR], 1.2 [95% CI, 1.0–1.3] for each point increase; P =0.05) and hypertension (OR, 2.3 [95% CI, 1.0–5.1]; P =0.04). Predictive factors of bleeding events (intracranial and major extracranial bleedings) included age (OR, 1.1 [95% CI, 1.0–1.2] for each year increase; P =0.002), history of major bleeding (OR, 6.9 [95% CI, 3.4–14.2]; P =0.0001) and the concomitant administration of an antiplatelet agent (OR, 2.8 [95% CI, 1.4–5.5]; P =0.003). Rates of ischemic and bleeding events were no different in patients who changed or not changed the original nonvitamin K antagonist oral anticoagulants treatment (OR, 1.2 [95% CI, 0.8–1.7]). Conclusions: Patients suffering a stroke despite being on nonvitamin K antagonist oral anticoagulant therapy are at high risk of recurrent ischemic stroke and bleeding. In these patients, further research is needed to improve secondary prevention by investigating the mechanisms of recurrent ischemic stroke and bleeding.

Background and Purpose- Despite treatment with oral anticoagulants, patients with nonvalvular atrial fibrillation (AF) may experience ischemic cerebrovascular events. The aims of this case-control study in patients with AF were to identify the pathogenesis of and the risk factors for cerebrovascular ischemic events occurring during non-vitamin K antagonist oral anticoagulants (NOACs) therapy for stroke prevention. Methods- Cases were consecutive patients with AF who had acute cerebrovascular ischemic events during NOAC treatment. Controls were consecutive patients with AF who did not have cerebrovascular events during NOACs treatment. Results- Overall, 713 cases (641 ischemic strokes and 72 transient ischemic attacks; median age, 80.0 years; interquartile range, 12; median National Institutes of Health Stroke Scale on admission, 6.0; interquartile range, 10) and 700 controls (median age, 72.0 years; interquartile range, 8) were included in the study. Recurrent stroke was classified as cardioembolic in 455 cases (63.9%) according to the A-S-C-O-D (A, atherosclerosis; S, small vessel disease; C, cardiac pathology; O, other causes; D, dissection) classification. On multivariable analysis, off-label low dose of NOACs (odds ratio [OR], 3.18; 95% CI, 1.95-5.85), atrial enlargement (OR, 6.64; 95% CI, 4.63-9.52), hyperlipidemia (OR, 2.40; 95% CI, 1.83-3.16), and CHA2DS2-VASc score (OR, 1.72 for each point increase; 95% CI, 1.58-1.88) were associated with ischemic events. Among the CHA2DS2-VASc components, age was older and presence of diabetes mellitus, congestive heart failure, and history of stroke or transient ischemic attack more common in patients who had acute cerebrovascular ischemic events. Paroxysmal AF was inversely associated with ischemic events (OR, 0.45; 95% CI, 0.33-0.61). Conclusions- In patients with AF treated with NOACs who had a cerebrovascular event, mostly but not exclusively of cardioembolic pathogenesis, off-label low dose, atrial enlargement, hyperlipidemia, and high CHA2DS2-VASc score were associated with increased risk of cerebrovascular events.

Arterial recanalization procedures after ischaemic stroke, are now well-established treatments, within 5 h for systemic thrombolysis, and 6 h for the endovascular treatment. Ischaemic stroke with uncertain time of symptoms onset, account for 14-27% of the cases, the vast majority of which occur just after waking up, thus it is impossible to derive an exact timeline. Accordingly, these patients are frequently not eligible for acute treatment. The results of three recent trials, DAWN, DEFUSE 3, and WAKE-UP, provided the basis for a revolution in the selection of patients eligible for late revascularization, and revealed an increase in the rate of functional independence for these patients at 90 days (mRS 0-2). Advanced neuroimaging techniques have been shown to be of utmost importance in the definition of the cerebral tissue window. A wider application of these imaging techniques and standardization of the parameters of images acquisition would provide for a significant advancement in the management of ischaemic stroke in the emergency setting.

Background: Uncertainties remain about the role of common thrombophilia markers as determinants of the ischemic stroke (IS) risk. Polymorphism His1299Arg in the FV gene, named R2 haplotype (FVHR2), has been poorly investigated. The aim of the present study was to assess the prevalence of common thrombophilia markers and of FVHR2 in a cohort of IS patients compared to a nonmatched group of healthy individuals. Methods: We studied 156 consecutive patients survivors of a first ever IS and 124 healthy controls. All subjects were investigated for the gene polymorphisms factor V (FV) Leiden, prothrombin (PTH) G20210A, MTHFR C677T, and FVHR2. Protein C (PC), protein S (PS), antithrombin (ATIII), and lupus anticoagulant (LAC) activity was measured. Homocysteinemia was assessed within 48 hours and after 30 days from stroke onset. Univariate and multivariate analyses were performed. Results: Compared with controls, patients were significantly older (mean [SD] age, 50.5 [12.9] vs 37.5 [15.5] years, P < .001), less frequently females (48.1% vs 67.7%, P = .001) and had more frequently hyperhomocysteinemia (45.9% vs 11.0%) only in the acute phase (OR 6.899, CI 95% 2.993-15.899; P < .001). No differences were found in the prevalence of FV Leiden, PTH G20210A, and MTHFR C677T between patients and controls, whereas FVHR2 was present in 34/156 (22%) stroke patients and in 5/124 (4%) controls (OR 6.632, 95% CI 2.509-17.535, P < .001). In a multivariate logistic regression analysis, the FVHR2 resulted independently associated with the occurrence of IS (OR 6.071, 95% CI 1.762-20.923; P = .004). Conclusions: In our study, hyperhomocysteinemia was confirmed to be a transient consequence of the thrombotic event. FVHR2 seems to be a possible candidate prothrombotic condition related to arterial IS irrespective of age and sex in an Italian sample population.

Ischaemic stroke is the second leading cause of mortality and disability in the western world. Revascularization interventions are the cornerstone of the acute treatment of this pathology and must be administered as soon as possible after the patient's arrival. They consist of intravenous thrombolysis (IVT) with alteplase, recommended by the guidelines within 4.5 h of the onset of symptoms, and endovascular treatment, recommended within 6 h of the onset of symptoms. The individualized patient selection based on the extent of the mismatch between the penumbra and the ischaemic core allowed to overcome the limits imposed by the rigid time windows, defining a benefit of mechanical revascularization therapies up to 24h from the theoretical onset of symptoms (last time the patient was known to be well) and up to 9 h for IVT since the theoretical onset of symptoms (last time the patient was known to be well). Advanced neuroimaging methods with perfusion studies are a fundamental tool in patient selection. Their spread in the territory, together with a greater availability of neurovascular treatment units are desirable to ensure a fair delivery of treatment to all patients with ischaemic stroke.