Nuclear Magnetic Resonance-Based Metabolomics to Predict Early and Late Adverse Outcomes in Ischemic Stroke Treated with Intravenous Thrombolysis.

Metabolic perturbations and inflammatory mediators play a fundamental role in both early and late adverse post-acute ischemic stroke outcomes. Using data from the observational MAGIC (MArker bioloGici nell'Ictus Cerebrale) study, we evaluated the effect of 130 serum metabolic features, using a nuclear magnetic spectroscopy approach, on the following outcomes: hemorrhagic transformation at 24 h after stroke, non-response to intravenous thrombolytic treatment with the recombinant tissue plasminogen activator (rt-PA), and the 3 month functional outcome. Blood circulating metabolites, lipoproteins, and inflammatory markers were assessed at the baseline and 24 h after rt-PA treatment. Adjusting for the major determinants for unfavorable outcomes (i.e., age, sex, time onset-to-treatment, etc.), we found that acetone and 3-hydroxybutyrate were associated with symptomatic hemorrhagic transformation and with non-response to rt-PA; while 24 h after rt-PA, levels of triglycerides high-density lipoprotein (HDL) and triglycerides low-density lipoprotein (LDL) were associated with 3 month mortality. Cholesterol and phospholipids levels, mainly related to smaller and denser very low-density lipoprotein (VLDL) and LDL subfractions were associated with 3 month poor functional outcomes. We also reported associations between baseline 24 h relative variation (Δ) in VLDL subfractions and ΔC-reactive protein, Δinterleukin-10 levels with hemorrhagic transformation. All observed metabolic changes reflect a general condition of energy failure, oxidative stress, and systemic inflammation that characterize the development of adverse outcomes.

Analysis of Metabolite and Lipid Association Networks Reveals Molecular Mechanisms Associated with 3-Month Mortality and Poor Functional Outcomes in Patients with Acute Ischemic Stroke after Thrombolytic Treatment with Recombinant Tissue Plasminogen Activator.

Here, we present an integrated multivariate, univariate, network reconstruction and differential analysis of metabolite-metabolite and metabolite-lipid association networks built from an array of 18 serum metabolites and 110 lipids identified and quantified through nuclear magnetic resonance spectroscopy in a cohort of 248 patients, of which 22 died and 82 developed a poor functional outcome within 3 months from acute ischemic stroke (AIS) treated with intravenous recombinant tissue plasminogen activator. We explored differences in metabolite and lipid connectivity of patients who did not develop a poor outcome and who survived the ischemic stroke from the related opposite conditions. We report statistically significant differences in the connectivity patterns of both low- and high-molecular-weight metabolites, implying underlying variations in the metabolic pathway involving leucine, glycine, glutamine, tyrosine, phenylalanine, citric, lactic, and acetic acids, ketone bodies, and different lipids, thus characterizing patients' outcomes. Our results evidence the promising and powerful role of the metabolite-metabolite and metabolite-lipid association networks in investigating molecular mechanisms underlying AIS patient's outcome.

Blood-brain barrier leakage and hemorrhagic transformation: The Reperfusion Injury in Ischemic StroKe (RISK) study.

BACKGROUND AND PURPOSE: In patients with acute ischemic stroke treated with reperfusion therapy we aimed to evaluate whether pretreatment blood-brain barrier (BBB) leakage is associated with subsequent hemorrhagic transformation (HT). METHODS: We prospectively screened patients with acute ischemic stroke treated with intravenous thrombolysis and/or endovascular treatment. Before treatment, each patient received computed tomography (CT), CT angiography, and CT perfusion. We assessed pretreatment BBB leakage within the ischemic area using the volume transfer constant (Ktrans ) value. Our primary outcome was relevant HT, defined as hemorrhagic infarction type 2 or parenchymal hemorrhage type 1 or 2. We evaluated independent associations between BBB leakage and HT using logistic regression, adjusting for age, sex, baseline stroke severity, Alberta Stroke Program Early CT Score (ASPECTS) ≥ 6, treatment type, and onset-to-treatment time. RESULTS: We enrolled 171 patients with available assessment of BBB leakage. The patients' mean (±SD) age was 75.5 (±11.8) years, 86 (50%) were men, and the median (interquartile range) National Institutes of Health Stroke Scale score was 18 (12-23). A total of 32 patients (18%) received intravenous thrombolysis, 102 (60%) underwent direct endovascular treatment, and 37 (22%) underwent both. Patients with relevant HT (N = 31;18%) had greater mean BBB leakage (Ktrans 0.77 vs. 0.60; p = 0.027). After adjustment in the logistic regression model, we found that BBB leakage was associated both with a more than twofold risk of relevant HT (odds ratio [OR] 2.50; 95% confidence interval [CI] 1.03-6.03 per Ktrans point increase; OR 2.34; 95% CI 1.06-5.17 for Ktrans values > 0.63 [mean BBB leakage value]) and with symptomatic intracerebral hemorrhage (OR 4.30; 95% CI 1.13-13.77 per Ktrans point increase). CONCLUSION: Pretreatment BBB leakage before reperfusion therapy was associated with HT, and may help to identify patients at risk of HT.

Small vessel disease and biomarkers of endothelial dysfunction after ischaemic stroke.

INTRODUCTION: Although pathogenesis of small vessel disease is poorly understood, increasing evidence suggests that endothelial dysfunction may have a relevant role in development and progression of small vessel disease. In this cross-sectional study, we investigated the associations between imaging signs of small vessel disease and blood biomarkers of endothelial dysfunction at two different time points in a population of ischaemic stroke patients. PATIENTS AND METHODS: In stroke patients treated with intravenous thrombolysis, we analysed blood levels of von Willebrand factor, intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and vascular endothelial growth factor. Three reviewers independently assessed small vessel disease features using computed tomography. At baseline and 90 days after the index stroke, we tested the associations between single and combined small vessel disease features and levels of blood biomarkers using linear regression analysis adjusting for age, sex, hypertension, diabetes, smoke. RESULTS: A total of 263 patients were available for the analysis. Mean age (±SD) was 69 (±13) years, 154 (59%) patients were male. We did not find any relation between small vessel disease and endothelial dysfunction at baseline. At 90 days, leukoaraiosis was independently associated with intercellular adhesion molecule-1 (ß = 0.21; p = 0.016) and vascular cell adhesion molecule-1 (ß = 0.22; p = 0.009), and lacunes were associated with vascular endothelial growth factor levels (ß = 0.21; p = 0.009) whereas global small vessel disease burden was associated with vascular endothelial growth factor (ß = 0.26; p = 0.006). DISCUSSION: Leukoaraiosis and lacunes were associated with endothelial dysfunction, which could play a key role in pathogenesis of small vessel disease. CONCLUSIONS: Small vessel disease features and total burden were associated with endothelial dysfunction 90 days after the stroke, whereas there was no relation during the acute phase. Our results suggest that endothelial dysfunction, particularly vascular endothelial growth factor, is involved in pathological process of small vessel disease.

Small Vessel Disease Is Associated with Tissue Inhibitor of Matrix Metalloproteinase-4 After Ischaemic Stroke.

Small vessel disease (SVD) is frequent in aging and stroke patients. Inflammation and remodeling of extracellular matrix have been suggested as concurrent mechanisms of SVD. We investigated the relationship between imaging features of SVD and circulating metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in patients with ischaemic stroke. In patients treated with intravenous thrombolysis, we took blood samples before intravenous thrombolysis and 90 days after the acute stroke and analysed levels of MMPs and TIMPs. We assessed leukoaraiosis, number of lacunes and brain atrophy on pre-treatment CT scan and graded global SVD burden combining such features. We investigated associations between single features, global SVD and MMPs and TIMPs at baseline and at follow-up, retaining univariate statistically significant associations in multivariate linear regression analysis and adjusting for clinical confounders. A total of 255 patients [mean (±SD) = 68.6 (± 12.7) years, 154 (59%) males] were included, 107 (42%) had no signs of SVD; 47 (19%) had from moderate to severe SVD burden. A total of 107 (42%) patients had no signs of SVD; 47 (19%) had from moderate to severe SVD burden. After adjustment, only TIMP-4 proved associations with SVD features. Brain atrophy was associated with baseline TIMP-4 (ß = 0.20;p = 0.019) and leukoaraiosis with 90 days TIMP-4 (ß = 0.19; p = 0.013). Global SVD score was not associated with baseline TIMP-4 levels (ß = 0.10; p = 0.072), whereas was associated with 90 days TIMP-4 levels (ß = 0.21; p = 0.003). Total SVD burden was associated with higher TIMP-4 levels 90 days after stroke, whereas was not during the acute phase. Our results support a biological relationship between SVD grade and TIMP-4.

Blood Biomarkers of Parenchymal Damage in Ischemic Stroke Patients Treated With Revascularization Therapies.

PURPOSE: Postischemic reperfusion injury may exacerbate cerebral damage and capillary dysfunction, leading to brain edema (BE), hemorrhagic transformation (HT), necrosis, and injury from free radicals with subsequent infarct growth (IG). Several plasmatic biomarkers involved in the ischemic cascade have been studied in relation to radiological and clinical outcomes of reperfusion injury in ischemic stroke with heterogeneous results. This article provides a brief overview of the contribution of circulating biomarkers to the pathophysiology of parenchymal damage in ischemic stroke patients treated with revascularization therapies. METHODS: We included full reports with measurements of plasma markers in patients with acute ischemic stroke treated with revascularization therapies. FINDINGS: Our research included a large number of observational studies investigating a possible role of circulating biomarkers in the development of parenchymal damage after acute stroke treatments. To make the results clearer, we divided the review in 4 sections, exploring the relation of different biomarkers with each of the indicators of parenchymal damage (HT, BE, IG, recanalization). DISCUSSION AND CONCLUSION: Definite conclusions are difficult to draw because of heterogeneity across studies. However, our review seems to confirm an association between some circulating biomarkers (particularly matrix metalloproteinase-9) and occurrence of parenchymal damage in ischemic stroke patients treated with revascularization therapies.

Reperfusion Injury after ischemic Stroke Study (RISKS): single-centre (Florence, Italy), prospective observational protocol study.

INTRODUCTION: Treatments aiming at reperfusion of the acutely ischaemic brain tissue may result futile or even detrimental because of the so-called reperfusion injury. The processes contributing to reperfusion injury involve a number of factors, ranging from blood-brain barrier (BBB) disruption to circulating biomarkers. Our aim is to evaluate the relative effect of imaging and circulating biomarkers in relation to reperfusion injury. METHODS AND ANALYSIS: Observational hospital-based study that will include 140 patients who had ischaemic stroke, treated with systemic thrombolysis, endovascular treatment or both. BBB disruption will be assessed with CT perfusion (CTP) before treatment, and levels of a large panel of biomarkers will be measured before intervention and after 24 hours. Relevant outcomes will include: (1) reperfusion injury, defined as radiologically relevant haemorrhagic transformation at 24 hours and (2) clinical status 3 months after the index stroke. We will investigate the separate and combined effect of pretreatment BBB disruption and circulating biomarkers on reperfusion injury and clinical status at 3 months. Study protocol is registered at http://www.clinicaltrials.gov (ClinicalTrials.gov ID: NCT03041753). ETHICS AND DISSEMINATION: The study protocol has been approved by ethics committee of the Azienda Ospedaliero Universitaria Careggi (Università degli Studi di Firenze). Informed consent is obtained by each patient at time of enrolment or deferred when the participant lacks the capacity to provide consent during the acute phase. Researchers interested in testing hypotheses with the data are encouraged to contact the corresponding author. Results from the study will be disseminated at national and international conferences and in medical thesis. TRIAL REGISTRATION NUMBER: NCT03041753.

Inflammatory and metalloproteinases profiles predict three-month poor outcomes in ischemic stroke treated with thrombolysis.

Inflammatory mediators and metalloproteinases are altered in acute ischemic stroke (AIS) and play a detrimental effect on clinical severity and hemorrhagic transformation of the ischemic brain lesion. Using data from the Italian multicenter observational MAGIC (MArker bioloGici nell'Ictus Cerebrale) Study, we evaluated the effect of inflammatory and metalloproteinases profiles on three-month functional outcome, hemorrhagic transformation and mortality in 327 patients with AIS treated with intravenous thrombolys in according to SITS-MOST (Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy) criteria. Circulating biomarkers were assessed at baseline and 24 h after thrombolysis. Adjusting for age, sex, baseline glycemia and National Institute of Health Stroke Scale, history of atrial fibrillation or congestive heart failure, and of inflammatory diseases or infections, baseline alpha-2macroglobulin (A2M), baseline serum amyloid protein (SAP) and pre-post tissue-plasminogen activator (tPA) variations (Δ) of metalloproteinase 9, remained significantly and independently associated with three-month death [OR (95% CI):A2M:2.99 (1.19-7.53); SAP:5.46 (1.64-18.74); Δmetalloproteinase 9:1.60 (1.12-2.27)]. The addition of baseline A2M and Δmetalloproteinase 9 or baseline SAP and Δmetalloproteinase 9 (model-2 or model-3) to clinical variables (model-1) significantly improved the area under curve for prediction of death [model-2 with A2M: p = 0.0205; model-3 with SAP: p = 0.001]. In conclusion, among AIS patients treated with thrombolysis, circulating A2M, SAP and Δmetalloproteinase 9 are independent markers of poor outcome. These results may prompt controlled clinical research about agents antagonizing their effect.

Leukoaraiosis, intracerebral hemorrhage, and functional outcome after acute stroke thrombolysis.

OBJECTIVE: To perform a systematic review and pooled meta-analysis of published studies to assess whether the presence of leukoaraiosis on neuroimaging before treatment with thrombolysis (IV or intra-arterial) is associated with an increased risk of symptomatic intracerebral hemorrhage (sICH) or poor functional outcome. METHODS: We included studies of patients with acute ischemic stroke, treated with IV or intra-arterial thrombolysis, which assessed functional outcome (3-month modified Rankin Scale [mRS]) or sICH in relation to leukoaraiosis on pretreatment neuroimaging (CT or MRI). We used random-effects models to calculate pooled relative risks (RR) of sICH and poor functional outcome (mRS ≥ 2) for any vs no leukoaraiosis (using any rating scale) and for no to mild vs moderate to severe leukoaraiosis (using the Van Swieten or Fazekas Schmidt scale). RESULTS: We identified 15 studies (total n = 6,967). For sICH outcome, the RR was 1.65 (n = 5,551; 95% confidence interval [CI] 1.26-2.16, p = 0.001) with an absolute risk (AR) increase of 2.5% for any leukoaraiosis vs none. The RR was 2.4 (n = 4,192; 95% CI 1.83-3.14, p = 0.001) with an AR increase of 6.2% for moderate to severe vs no to mild leukoaraiosis. For poor functional outcome; the RR was 1.30 (n = 3,401; 95% CI 1.19-1.42, p = 0.001) with an AR increase of 15.4% for any leukoaraiosis vs none. The RR was 1.31 (n = 3,659; 95% CI 1.22-1.42, p = 0.001) with an AR increase of 17.5% for moderate to severe vs no to mild leukoaraiosis. No statistical heterogeneity was noted for any of the analyses. CONCLUSIONS: Leukoaraiosis presence and severity are consistently associated with an increased risk of sICH and poor functional outcome after IV or intra-arterial thrombolysis for acute ischemic stroke.

Leukoaraiosis and lacunes are associated with poor clinical outcomes in ischemic stroke patients treated with intravenous thrombolysis.

BACKGROUND: The effect of preexisting small vessel disease on outcomes of patients with ischemic stroke treated with i.v. thrombolysis is not fully understood. AIM: We aim to investigate the effect of combined leukoaraiosis and lacunes as detected on unenhanced brain computer tomography at baseline on clinical outcomes after i.v. thrombolysis. METHODS: We analyzed data from the Canadian Alteplase for Stroke Effectiveness Study. Small vessel disease was assessed on baseline computer tomography rating for leukoaraiosis and lacunes. We dichotomized the burden of small vessel disease to "absent or moderate" and "severe." Clinical outcomes at 90 days included excellent outcome (mRS = 0-1), good outcome (mRS = 0-2), and the occurrence of symptomatic intracerebral hemorrhage. Sensitivity analysis was performed on two age groups (≤80 versus >80). We ran logistic regression adjusting for confounders to evaluate independent effect of small vessel disease on outcomes. RESULTS: There were 820 patients with available brain computer tomography with mean age (±SD) of 71.3 (±13.2), 455 (55.5%) were male. Of these, 123 (15%) patients had severe small vessel disease at baseline. Age group analysis revealed significant associations of small vessel disease only in patients aged ≤80. After adjustment for confounders, presence of severe small vessel disease reduced the chances of both excellent (OR = 0.42, 95% CI = 0.24-0.74) and good outcome (OR = 0.35, 95% CI = 0.21-0.58) and with an increased risk of symptomatic intracerebral hemorrhage (OR = 5.91; 95% CI = 2.40-14.57). CONCLUSION: When considered together as radiological expressions of small vessel disease, presence and severity of severe leukoaraiosis and lacunes on baseline computer tomography scan are associated with poor clinical outcomes in patients treated with i.v. thrombolysis.

Branch Atheromatous Disease: A Clinically Meaningful, Yet Unproven Concept.

BACKGROUND: In 1989, Louis Caplan first used the term branch atheromatous disease (BAD) to describe an occlusion or stenosis at the origin of a deep penetrating artery of the brain, associated with a microatheroma or a junctional plaque, and leading to an internal capsule or pontine small infarct. BAD remained an understudied concept for decades. In recent years, the increasing diffusion of high-resolution magnetic resonance imaging (HRMRI) techniques brought new attention to the BAD debate. We have reviewed clinical studies dealing with BAD-related stroke checking whether a univocal definition of BAD existed, as well as to what extent were consistently associated clinical and imaging features reported. SUMMARY: We conducted a search of the available literature published up to October 20, 2015 via PubMed using the following search terms: 'branch atheromatous disease,' 'intracranial branch atheromatous disease,' 'cerebral branch atheromatous disease,' combined with 'stroke.' Forty-six articles were included. We found discrepant definitions and a large variation among clinical features reported in BAD-related stroke patients: among others, a consistent association between BAD and any specific vascular risk factor profile was not detected. Despite this, early neurological deterioration (END) was consistently reported to occur frequently in such patients, although no clear-cut rate range or specific predictor or mechanism of progression was established. In a majority of the studies reporting imaging data, BAD diagnosis was not based on the selective site or type of arterial walls changes, but was inferred based on the vascular territory, size and/or shape of the ischemic lesion. Following the concept that these changes are seated proximally along the perforator artery, differently from to lipohyalinosis changes located distally, the consequent ischemic lesion was hypothesized to be larger in BAD than in lacunar infarcts. However, across reviewed studies, there was little consistency on the dimensional cutoff used to define BAD-related infarcts. In the last few years, a still limited number of studies using HRMRI techniques is providing preliminary proofs that atheromatous changes causing selective remodeling in the parent vessel and extending through the proximal segment of perforating vessel may subtend BAD. KEY MESSAGES: Our literature search showed the lack of a clear-cut definition of BAD, although BAD-related strokes were consistently considered a high risk of END. The use of high-resolution imaging techniques in the assessment of small subcortical strokes may represent the cornerstone in the perspective to better delimiting the boundaries of BAD as a nosological entity.

Unbalanced Metalloproteinase-9 and Tissue Inhibitors of Metalloproteinases Ratios Predict Hemorrhagic Transformation of Lesion in Ischemic Stroke Patients Treated with Thrombolysis: Results from the MAGIC Study.

BACKGROUND: Experimentally, metalloproteinases (MMPs) play a detrimental role related to the severity of ischemic brain lesions. Both MMPs activity and function in tissues reflect the balance between MMPs and tissue inhibitors of metalloproteinases (TIMPs). We aimed to evaluate the role of MMPs/TIMPs balance in the setting of rtPA-treated stroke patients. METHODS: Blood was taken before and 24-h after rtPA from 327 patients (mean age 68 years, median NIHSS 11) with acute ischemic stroke. Delta median values of each MMP/TIMP ratio [(post rtPA MMP/TIMP-baseline MMP/TIMP)/(baseline MMP/TIMP)] were analyzed related to symptomatic intracranial hemorrhage (sICH) according to NINDS criteria, relevant hemorrhagic transformation (HT) defined as confluent petechiae within the infarcted area or any parenchymal hemorrhage, stroke subtypes (according to Oxfordshire Community Stroke Project) and 3-month death. The net effect of each MMP/TIMP ratio was estimated by a logistic regression model including major clinical determinants of outcomes. RESULTS: Adjusting for major clinical determinants, only increase in MMP9/TIMP1 and MMP9/TIMP2 ratios remained significantly associated with sICH (odds ratio [95% confidence interval], 1.67 [1.17-2.38], p = 0.005; 1.74 [1.21-2.49], p = 0.003, respectively). Only relative increase in MMP9/TIMP1 ratio proved significantly associated with relevant HT (odds ratio [95% confidence interval], 1.74 [1.17-2.57], p = 0.006) with a trend toward significance for MMP9/TIMP2 ratio (p = 0.007). DISCUSSION: Our data add substantial clinical evidence about the role of MMPs/TIMPs balance in rtPA-treated stroke patients. These results may serve to generate hypotheses on MMPs inhibitors to be administered together with rtPA in order to counteract its deleterious effect.

Effect of the Interaction between Recanalization and Collateral Circulation on Functional Outcome in Acute Ischaemic Stroke.

Identification of patients with acute ischaemic stroke who could most benefit from arterial recanalization after endovascular treatment remains an unsettled issue. Although several classifications of collateral circulation have been proposed, the clinical role of collaterals is still debated. We evaluated the effect of the collateral circulation in relation to recanalization as a predictor of clinical outcome. Data were prospectively collected from 103 patients consecutively treated for proximal middle cerebral or internal carotid artery occlusion. The collateral circulation was evaluated with a novel semiquantitative-qualitative score, the Careggi collateral score (CCS), in six grades. Both CCS and recanalization grades (TICI) were analysed in relation to clinical outcome. A statistical analysis was performed to evaluate the effect of interaction between recanalization and collateral circulation on clinical outcome. Out of the 103 patients, 37 (36.3%) had poor collaterals, and 65 (63.7%) had good collaterals. Patients with good collaterals had lower basal National Institute of Health Stroke Scale (NIHSS), more distal occlusion, smaller lesions at 24h CT scan and better functional outcome. After multivariate analysis, the interaction between recanalization and collateral grades was significantly stronger as a predictor of good outcome (OR 6.87, 95% CI 2.11-22.31) or death (OR 4.66, 95%CI 1.48-14.73) compared to the effect of the single variables. Collaterals showed an effect of interaction with the recanalization grade in determining a favourable clinical outcome. Assessment of the collateral circulation might help predict clinical results after recanalization in patients undergoing endovascular treatment for acute ischaemic stroke.

Combined full-dose IV and endovascular thrombolysis in acute ischaemic stroke.

BACKGROUND: There is an increasing trend to treating proximal vessel occlusions with intravenous-inter-arterial (IV-IA) thrombolysis. The best dose of IV tissue plasminogen activator (tPA) remains undetermined. We compared the combination of full-dose IV recombinant tissue plasminogen activator (rtPA) and IA thrombolytic therapy to IA therapy. METHODS: Between 2002 and 2009, we reviewed our computed tomographic angiography database for patients who received full-dose intravenous rtPA and endovascular therapy or endovascular therapy alone for acute ischaemic stroke treatment. Details of demographics, risk factors, endovascular procedure, and symptomatic intracranial haemorrhage were noted. Modified Rankin Scale ≤2 at three-months was used as good outcome. Recanalization was defined as Thrombolysis in Myocardial Ischaemia 2-3 flow on angiography. RESULTS: Among 157 patients, 104 patients received IV-IA treatment and 53 patients underwent direct IA therapy. There was a higher recanalization rate with IV-IA therapy compared with IA alone (71% vs. 60%, P < 0·21) which was driven by early recanalization after IV rtPA. Mortality and independent outcome were comparable between the two groups. Symptomatic intracranial haemorrhage occurred in 8% of patients (12% in the IA group, 7% in the IV-IA group) but was more frequent as the intensity of intervention increased from device alone to thrombolytic drug alone to device plus thrombolytic drug(s). Recanalization was a strong predictor of reduced mortality risk ratio (RR) 0·48 confidence interval95 0·27-0·84) and favourable outcome (RR 2·14 confidence interval95 1·3-3·5). CONCLUSIONS: Combined IV-IA therapy with full-dose intravenous rtPA was safe and results in good recanalization rates without excess symptomatic intracranial haemorrhage. Testing of full-dose IV tPA followed by endovascular treatment in the IMS3 trial is justified.

MMP9 variation after thrombolysis is associated with hemorrhagic transformation of lesion and death.

BACKGROUND AND PURPOSE: Experimentally, matrix metalloproteinases (MMPs) play a detrimental role related to hemorrhagic transformation and severity of an ischemic brain lesion. Tissue-type plasminogen activator (tPA) enhances such effects. This study aimed to expand clinical evidence in this connection. METHODS: We measured MMPs 1, 2, 3, 7, 8, 9, and tissue inhibitors of metalloproteinases 1, 2, 4 circulating level in blood taken before and 24 hours after tPA from 327 patients (mean age, 68.9±12.1 years; median National Institutes of Health Stroke Scale, 11) with acute ischemic stroke. Delta median values ([24 hours post tPA-pre tPA]/pre tPA) of each MMP or tissue inhibitors of metalloproteinase were analyzed across subgroups of patients undergoing symptomatic intracerebral hemorrhage, 3-month death, or 3-month modified Rankin Scale score 3 to 6. RESULTS: Adjusting for major clinical determinants, only matrix metalloproteinase-9 variation proved independently associated with death (odds ratio [95% confidence interval], 1.58 [1.11-2.26]; P=0.045) or symptomatic intracerebral hemorrhage (odds ratio [95% confidence interval], 1.40 [1.02-1.92]; P=0.049). Both matrix metalloproteinase-9 and tissue inhibitors of metalloproteinase-4 changes were correlated with baseline, 24 hours, and 7 days National Institutes of Health Stroke Scale (Spearman P from <0.001 to 0.040). CONCLUSIONS: Our clinical evidence corroborates the detrimental role of matrix metalloproteinase-9 during ischemic stroke treated with thrombolysis, and prompts clinical trials testing agents antagonizing its effects.

The coexistence of heart failure predicts short term mortality, but not disability, in patients with acute ischemic stroke treated with thrombolysis: the Florence area Registry.

BACKGROUND: Thrombolysis in ischemic stroke reduces disability but not mortality. Our aim was to evaluate the predictivity of heart failure (HF) diagnosis on 90-day mortality and disability in stroke patients undergoing thrombolysis. MATERIAL AND METHODS: Hospital records of all consecutive stroke patients treated with thrombolysis at our University Hospital were reviewed. Clinical assessment for HF and echocardiogram were available for all patients according to the thrombolysis institutional protocol. History of HF, LVEF <40%, or BOSTON score ≥ 5 were tested as predictors. RESULTS: Of 130 patients (age 66 ± 14 years, 64.6% males, baseline NIHSS 15.6 ± 8.8), 17 (13.1%) had a history of HF, 16 (12.7%) a BOSTON score ≥ 5, 13 (10.9%) a LVEF <40% and 24 (19.0%) met clinical criteria for HF diagnosis. Ninety-day mortality and incidence of disability were 16.1% and 36.1%, respectively. After adjustment for age, sex, baseline stroke severity and pre-stroke disability, LVEF <40% and clinical diagnosis of HF were predictors of 90-day mortality, (p=0.007 and p=0.037, respectively). CONCLUSION: Clinical diagnosis of HF predicts mortality, but not disability, in acute stroke patients undergoing thrombolysis. Unlike anamnestic record of HF, clinical evaluation of cardiac function, with estimation of LVEF, predicts mortality.

Progressive lacunar stroke: review of mechanisms, prognostic features, and putative treatments.

Lacunar stroke is generally considered to have a fair outcome. However 20-30% of patients with lacunar stroke worsen neurologically in hours or days after onset, reaching eventually an unexpectedly severe disability status. In the field of acute stroke, progressive lacunar stroke remains an important unresolved practice problem, because as yet no treatment does exist proven to prevent or halt progression. Pathophysiology of progression is yet incompletely understood. Hemodynamic factors, extension of thrombosis, excitotoxicity, and inflammation, have been proposed as possible mechanisms of progression. A few clinical studies also aimed at establishing presentation features that may help identifying patients at risk of deterioration. In this paper, we review hypothesized mechanisms of lacunar stroke progression and possible markers of early deterioration. Moreover, based on putative mechanisms and suggestions from reported evidence, we propose a few treatments that seem worthy to be tested by randomized clinical trials.

The safety and efficacy of thrombolysis for strokes after cardiac catheterization.

OBJECTIVES: The purpose of this study was to systematically compare clinical outcomes of patients treated with thrombolysis with those without treatment in a multi-year, multicenter cohort of strokes after cardiac catheterization. BACKGROUND: Ischemic strokes after cardiac catheterization procedures, although uncommon, lead to the morbidity and mortality of thousands of patients each year. Despite the availability of Food and Drug Administration-approved thrombolytic therapy for acute ischemic stroke since 1996, thrombolysis remains unestablished in the setting of cardiac catheterization, owing to unique concerns regarding safety and efficacy. METHODS: Consecutive cases of ischemic stroke after cardiac catheterization were abstracted retrospectively and reviewed by clinicians at 7 major North American academic centers with acute stroke teams. Safety and efficacy outcome measures were pre-defined. RESULTS: A total of 66 cases of ischemic strokes after cardiac catheterization were identified over 3 to 4 years; 12 (18%) were treated with thrombolysis, consisting of 7 intravenous and 5 intra-arterial recombinant tissue plasminogen activator cases. Improvement in stroke symptoms, as measured by the primary efficacy measure of median change in National Institutes of Health Stroke Scale score from baseline to 24 h, was greater in treated versus nontreated cases (p < 0.001). Additional secondary measures of efficacy also showed better outcomes in the treated group. There were no significant differences in bleeding events, defined as symptomatic intracerebral hemorrhage, hemopericardium, or other systemic bleeding resulting in hemodynamic instability or blood transfusions. Mortality rates were also similar. CONCLUSIONS: Thrombolysis might improve early outcomes after post-catheterization strokes and seems safe in this context. Emergent cerebral revascularization should be a routine consideration.