Juan F. Arenillas

Matrix Metalloproteinase-9 Pretreatment Level Predicts Intracranial Hemorrhagic Complications After Thrombolysis in Human Stroke

Background—Matrix metalloproteinase (MMP) expression is related to blood brain barrier disruption after cerebral ischemia. Moreover, MMP inhibitors reduce hemorrhagic transformation (HT) after embolic ischemia in tissue plasminogen activator (t-PA)–treated animals. We aimed to correlate plasmatic MMP levels with the appearance of intracranial bleeding complications in stroke patients treated with t-PA. Methods and Results—Serial MMP-2 and MMP-9 determinations were performed (ELISA, ng/mL) in 41 strokes involving the middle cerebral artery territory in patients who received t-PA within 3 hours of stroke onset. Blood samples were obtained at baseline (pretreatment) and at 12 and 24 hours after symptom onset. Hemorrhagic events were classified according to CT criteria (petechial hemorrhagic infarctions [HI, 1 to 2] and large parenchymal hemorrhages [PH, 1 to 2]). Brain CT scan was obtained at 48 hours or when a neurological worsening occurred. HT was present in 36.5% of the patients (24.4% HI and 12.1% PH). MMP-2 values were unrelated to any subtype of HT. The highest baseline MMP-9 level (normal range <97 ng/mL) corresponded to patients who later developed a PH (PH: 270.2±87.8, non-HT: 126.3±127.5, HI: 94.6±88.7;P =0.047). A graded response was found between mean baseline MMP-9 levels and the degree of bleeding (HI-1=37.4; HI-2=111.0; PH-1=202.5; PH-2=337.8). Baseline MMP-9 was the most powerful predictor of PH appearance in the multiple logistic regression model (OR= 9.62; CI 1.31 to 70.26;P =0.025). Conclusions—Baseline MMP-9 level predicts PH appearance after t-PA treatment. Therefore, we suggest that MMP determination may increase the safety profile for thrombolysis and, in the future, anti-MMP drugs might be combined with t-PA to prevent hemorrhagic complications.

Microbubble Administration Accelerates Clot Lysis During Continuous 2-MHz Ultrasound Monitoring in Stroke Patients Treated With Intravenous Tissue Plasminogen Activator

BACKGROUND AND PURPOSE We sought to evaluate the effects of administration of microbubbles (MBs) on the beginning, speed, and degree of middle cerebral artery (MCA) recanalization during systemic thrombolysis and continuous 2-MHz pulsed-wave transcranial Doppler (TCD) monitoring. METHODS We evaluated 111 patients with acute stroke attributable to MCA occlusion treated with intravenous tissue plasminogen activator (tPA). Thirty-eight patients were treated with tPA plus continuous 2-hour TCD monitoring plus 3 doses of 2.5 g (400 mg/mL) of galactose-based MBs given at 2, 20, and 40 minutes after tPA bolus (MB group). These patients were compared with 73 patients who were allocated to receive tPA plus continuous 2-hour TCD ultrasound (US) monitoring (tPA/US group) or tPA plus placebo monitoring (tPA group), most of whom were enrolled in a previous study of US-enhanced thrombolysis. The beginning, degree, and time to maximum completeness of recanalization during the first 2 hours of tPA bolus were recorded. RESULTS Median prebolus National Institutes of Health Stroke Scale (NIHSS) score was 18. Eighty patients (72%) had a proximal and 31 (28%) a distal MCA occlusion on TCD. Thirty-seven patients (33%) received tPA/US, 38 (34%) received tPA/US/MB, and 36 (32%) were treated with tPA alone. Stroke severity, time to treatment, location of MCA occlusion, and presence of carotid artery disease were similar among groups. Two-hour recanalization was seen in 14 (39%), 25 (68%), and 27 patients (71%) in the tPA, tPA/US, and tPA/US/MB groups, respectively (P=0.004). Two-hour complete recanalization rate was significantly (P=0.038) higher in the tPA/US/MB group (54.5%) compared with tPA/US (40.8%) and tPA (23.9%) groups. The time to beginning of recanalization after tPA bolus was 26+/-18 minutes in the tPA/US group and 19+/-12 minutes in the tPA/US/MB group (P=0.12). Four patients (3.6%) experienced symptomatic intracranial hemorrhage: 2 (5.5%), 1 (2.7%), and 1 patient (2.6%) who received tPA only, tPA/US, and tPA/US/MB, respectively, experienced symptomatic intracranial hemorrhage. At 24 hours, 31%, 41%, and 55% of tPA, tPA/US, and tPA/US/MB improved >4 points in the NIHSS score. CONCLUSIONS Administration of MBs induces further acceleration of US-enhanced thrombolysis in acute stroke, leading to a more complete recanalization and to a trend toward better short- and long-term outcome.

Matrix Metalloproteinase Expression After Human Cardioembolic Stroke Temporal Profile and Relation to Neurological Impairment

Background and Purpose— Uncontrolled expression of matrix metalloproteinases (MMPs) can result in tissue injury and inflammation. In animal models of cerebral ischemia, the expression of MMP-2 and MMP-9 was significantly increased. However, their role in human stroke in vivo remains unknown. Therefore, we sought to determine the temporal profile of MMP expression in patients with acute ischemic stroke and to investigate its relationship to stroke severity, location of arterial occlusion, and total infarct volume. Methods— Serial MMP-2 and MMP-9 determinations were made in 39 patients with cardioembolic strokes that involved the middle cerebral artery territory by means of enzyme-linked immunosorbent assay. Blood samples, transcranial Doppler recordings, and National Institutes of Health Stroke Scale (NIHSS) scores were obtained at baseline and at 12, 24, and 48 hours after stroke onset. Infarct volume was measured with CT scanning at 48 hours. Results— No correlation was found between MMP-2 and NIHSS score at any time point, although a close relation appeared between mean MMP-9 and final NIHSS score (r =0.486, P =0.002). MMP-9 value was the only factor associated with the final NIHSS score in the multiple logistic regression model (OR 4.54, 95% CI 1.5 to 13.75). A cut-point of MMP-9 142.18 ng/mL had a positive predictive value of 94.4% to assess a patient’s NIHSS (<8 or ≥8) by the end of the study. Final MMP-2 and MMP-9 levels were significantly lower when recanalization occurred (528±144.3 versus 681.4±239.2 ng/mL, P =0.031 for MMP-2; 110.2±100.9 versus 244.8±130 ng/mL, P =0.004 for MMP-9). A positive correlation was found between mean MMP-9 and infarct volume (r =0.385, P =0.022). Conclusions— MMPs are involved in the acute phase of human ischemic stroke. MMP-9 levels are associated with neurological deficit, middle cerebral artery occlusion, and infarct volume.

Effects of Admission Hyperglycemia on Stroke Outcome in Reperfused Tissue Plasminogen Activator-Treated Patients

Background and Purpose— We sought to investigate the impact of hyperglycemia before reperfusion on long-term outcome in patients treated with intravenous tissue plasminogen activator (tPA). Methods— Of 268 consecutive patients with a nonlacunar middle cerebral artery (MCA) stroke evaluated at <3 hours after onset, 73 (27.2%) received intravenous tPA. Serum glucose was determined at baseline before tPA administration. Hyperglycemia was defined as a glucose level >140 mg/dL. National Institutes of Health Stroke Scale (NIHSS) scores were obtained at baseline and 24 hours. Transcranial Doppler monitoring of recanalization and reocclusion was conducted during the first 24 hours. Total infarct volume was measured on CT at day 5 to 7. Modified Rankin Scale was used to assess outcome at 3 months. Results— Median NIHSS score was 17. At baseline, 31 patients (42.5%) were hyperglycemic and 42 (57.5%) normoglycemic. Early reperfusion (<6 hours) occurred in 43 patients (58.9%). Admission blood glucose correlated negatively with the degree of neurological improvement at 24 hours in reperfused (r =−0.43;P =0.019) but not in nonreperfused (r =−0.20;P =0.21) tPA-treated patients. Increased age (P =0.014), history of diabetes mellitus (P =0.043), admission glucose >140 mg/dL (P =0.002), and early reocclusion (P =0.004) were factors associated with poor outcome among reperfused patients. A logistic regression modeling revealed that only admission glucose value >140 mg/dL (odds ratio, 8.4; 95% CI, 1.76 to 40.02;P =0.005) emerged as an independent predictor of poor outcome despite tPA-induced recanalization. In patients with 6-hour persistent MCA occlusion, baseline NIHSS score >15 points (P =0.011) and proximal MCA occlusion (P =0.039) were variables associated with poor outcome on univariate analysis. In a logistic regression model, only NIHSS score >15 points (odds ratio, 11.9; 95% CI, 1.48 to 97.1;P =0.032) remained as an independent predictor of poor outcome and functional dependence at 3 months in nonreperfused tPA-treated patients. Conclusions— Hyperglycemia before reperfusion may in part counterbalance the beneficial effect of early restoration of blood flow, which translates into a worse outcome in hyperglycemic patients despite tPA-induced recanalization.

Timing of Spontaneous Recanalization and Risk of Hemorrhagic Transformation in Acute Cardioembolic Stroke

Background and Purpose The relationship between reperfusion and hemorrhagic transformation (HT) remains uncertain. Therefore, we aimed to clarify the relationship between the time course of recanalization and the risk of HT in patients with cardioembolic stroke studied within 6 hours of symptom onset. Methods Fifty-three patients with atrial fibrillation and nonlacunar stroke in the middle cerebral artery (MCA) territory admitted within the first 6 hours after symptom onset were prospectively studied. Serial TCD examinations were performed on admission and at 6, 12, 24, and 48 hours. CT was performed within 6 hours after stroke onset and again at 36 to 48 hours. Results Proximal and distal MCA occlusions were detected in 32 patients (60.4%) and 18 patients (34%), respectively. Early spontaneous recanalization occurring within 6 hours was identified in 10 patients (18.8%). Delayed recanalization (>6 hours) occurred in 28 patients (52.8%). HT on CT scan was detected in 17 patients (32%) within the first 48 hours. Only large parenchymal hemorrhage (PH2) was significantly associated with an increase (P =0.038, Kruskal-Wallis test) in the National Institutes of Health Stroke Scale (NIHSS) score compared with the other subtypes of HT. Univariate analysis revealed that an NIHSS score of >14 on baseline (P =0.001), proximal MCA occlusion (P =0.004), hypodensity >33% of the MCA territory (P =0.012), and delayed recanalization occurring >6 hours of stroke onset (P =0.003) were significantly associated with HT. With a multiple logistic regression model, delayed recanalization (OR 8.9; 95% CI 2.1 to 33.3) emerged as independent predictor of HT. Conclusions Delayed recanalization occurring >6 hours after acute cardioembolic stroke is an independent predictor of HT.

Thrombolysis-Related Hemorrhagic Infarction A Marker of Early Reperfusion, Reduced Infarct Size, and Improved Outcome in Patients With Proximal Middle Cerebral Artery Occlusion

Background and Purpose— The role of early and delayed recanalization after thrombolysis in the development of hemorrhagic transformation (HT) subtypes remains uncertain. We sought to explore the association between the timing of recanalization and HT risk in patients with proximal middle cerebral artery (MCA) occlusion treated with intravenous recombinant tissue plasminogen activator (rtPA) <3 hours of stroke onset and to investigate the relationship between HT subtypes, infarct volume, and outcome. Methods— Thirty-two patients with acute stroke caused by proximal MCA occlusion treated with rtPA <3 hours of symptom onset were prospectively studied. Serial transcranial Doppler examinations were performed on admission and at 6, 12, 24, and 48 hours. Presence and type of HT were assessed on CT at 36 to 48 hours. Modified Rankin scale was used to assess outcome at 3 months. Results— Early and delayed recanalization was identified in 17 patients (53.1%) and 8 patients (25%), respectively. HT was detected in 14 patients (43.7%): 4 (12.5%) with hemorrhagic infarction (HI1), 5 (15.6%) with HI2, 3 (9.3%) with parenchymal hematoma (PH1), and 2 (6.8%) with PH2. Distribution of HT subtypes differed significantly (P =0.025), depending on the time to artery reopening. Eight of 9 (89%), 1 of 5 (20%), and 8 of 18 (44.4%) with HI1-HI2, with PH1-PH2, and without HT, respectively, recanalized in <6 hours. Delayed recanalization was observed in 1 patient with HI1-HI2 (11%), 4 with PH1-PH2 (80%), and 3 without HT (16.6%). Neurological improvement was significantly (P <0.001) more frequent in patients with HI1-HI2 (88%) than in those without HT (39%). Infarct volume was significantly (P <0.031) lower in patients with HI1-HI2 (51.4±42 cm3) than in patients with PH1-PH2 (83.8±48 cm3) and those without HT (98.4±84 cm3, P =0.021). The modified Rankin scale score was significantly lower in HI1-HI2 compared with PH1-PH2 patients (1.9±1.1 versus 4.6±1.2, P <0.001) and with those without HT (1.9±1.1 versus 3.5±2.0, P =0.009.). Conclusions— Thrombolysis-related HI (HI1-HI2) represents a marker of early successful recanalization, which leads to a reduced infarct size and improved clinical outcome.

Acute Hyperglycemia State Is Associated With Lower tPA-Induced Recanalization Rates in Stroke Patients

Background and Purpose— Hyperglycemia (HG) has a deleterious effect in stroke patients by accelerating ischemic brain damage; moreover, its antifibrinolytic effect may also influence reperfusion. We aimed to study the effect of acute/chronic HG on tissue-type plasminogen activator (tPA)–induced recanalization. Methods— We studied 139 consecutive stroke patients with documented intracranial artery occlusion treated with intravenous tissue-type plasminogen activator (tPA). Admission glucose levels were recorded (in mg/dL). The existence of previous chronic HG was determined by plasma levels of glycosylated hemoglobin (HbA1c, %) and fructosamine (in &mgr;mol/L). Transcranial Doppler monitoring assessed complete recanalization 2 hours after tPA bolus. National Institutes of Health Stroke Scale (NIHSS) scores were obtained at baseline and 48 hours. Results— On admission, the median NIHSS score was 18 and mean glucose value was140±63 mg/dL. At 2 hours, 32% of patients(n=44) achieved complete recanalization. Patients who recanalized showed lower admission glucose levels (127 vs 146 mg/dL; P=0.039) but no differences in HbA1c (6.3% vs 6.3%; P=0.896) or fructosamine (292 vs 293 &mgr;mol/L; P=0.957) were observed. Other variables associated with recanalization were initial distal middle cerebral artery occlusion (P=0.011) and platelet count (P=0.015). Patients with an admission glucose level >158 mg/dL had lower recanalization rates (16% vs 36.1%; P=0.035) and a higher NIHSS score at 48 hours (7 vs 14.5; P=0.04). After adjustment for stroke etiology, age, and risk factors, the only independent predictors on admission of no recanalization were glucose value >158 mg/dL (odds ratio [OR], 7.3; 95% confidence interval [CI], 1.3 to 42.3; P=0.027), proximal middle cerebral artery occlusion (OR, 2.6; 95% CI, 1.1 to 6.5; P=0.034), and platelet count <219 000/mL (OR, 2.6; 95% CI, 1.1 to 6.1; P=0.029). Conclusions— In tPA-treated patients, the acute but not chronic HG state may hamper the fibrinolytic process, delaying reperfusion of the ischemic penumbra. Early measures to reduce HG may favor early recanalization.

The Increase of Circulating Endothelial Progenitor Cells After Acute Ischemic Stroke Is Associated With Good Outcome

Background and Purpose— Increased circulating endothelial progenitor cells (EPC) have been associated with a low cardiovascular risk and may be involved in endothelial cell regeneration. The present study was designed to evaluate the prognostic value of EPC in acute ischemic stroke. Methods— Forty-eight patients with a first-ever nonlacunar ischemic stroke were prospectively included in the study within 12 hours of symptoms onset. Stroke severity was evaluated by the National Institutes of Health Stroke Scale, and functional outcome was assessed at 3 months by the modified Rankin Scale (mRS). Infarct volume growth between admission and days 4 to 7 was measured on multiparametric MRI. EPC colonies were defined as early outgrowth colony-forming unit-endothelial cell (CFU-EC). The increment of CFU-EC was quantified during the first week and defined as the absolute difference between the number of CFU-EC at day 7 and admission. The influence of CFU-EC increase on good functional outcome (mRS ≤2) and infarct growth was analyzed by logistic regression and linear models. Results— Patients with good outcome (n=25) showed a higher CFU-EC increment during the first week (median [quartiles], 23 [11, 36] versus −3 [−7, 1], P<0.0001) compared with patients with poor outcome. CFU-EC increment ≥4 during the first week was associated with good functional outcome at 3 months (odds ratio, 30.7; 95% CI, 2.4 to 375.7; P=0.004) after adjustment for baseline stroke severity, ischemic volume and thrombolytic treatment. For each unit increase in the CFU-EC the mean reduction in the growth of infarct volume was 0.39 (0.03 to 0.76) mL (P=0.033). Conclusions— The increase of circulating EPC after acute ischemic stroke is associated with good functional outcome and reduced infarct growth. These findings suggest that EPC might participate in neurorepair after ischemic stroke.

Predictors of Early Arterial Reocclusion After Tissue Plasminogen Activator-Induced Recanalization in Acute Ischemic Stroke

Background and Purpose— We aimed to determine clinical and hemodynamic predictors of early reocclusion (RO) in stroke patients treated with intravenous tissue plasminogen activator (tPA). Methods— We studied 142 consecutive stroke patients with a documented middle cerebral artery (MCA) occlusion treated with intravenous tPA. All patients underwent carotid ultrasound and transcranial Doppler (TCD) examination before tPA bolus. National Institutes of Health Stroke Scale (NIHSS) scores were performed at baseline and serially for <24 hours. TCD monitoring of MCA recanalization (RE) and RO was performed during the first 2 hours after tPA bolus and repeated when clinical deterioration occurred <24 hours after documented RE in absence of intracranial hemorrhage. Results— After 1 hour of tPA administration, RE occurred in 84 (61%) patients (53 partial, 31 complete). Of these, 21 (25%) patients worsened after an initial improvement and 17 (12%) of them showed RO on TCD. RO was identified at a mean time of 65±55 minutes after documented RE. RO was associated (P=0.034) with a lower degree of 24-hour NIHSS score improvement than sustained RE, and a higher modified Rankin scale score at 3 months (P=0.002). Age older than 75 years (P=0.012), previous antiplatelet treatment (P=0.048), baseline NIHSS score >16 points (P=0.009), higher leukocytes count (P=0.042), beginning of RE <60 minutes after tPA bolus (P=0.039), and ipsilateral severe carotid stenosis/occlusion (P=0.001) were significantly associated with RO. In a logistic regression model, NIHSS score >16 at baseline (odds ratio [OR], 7.1; 95% CI, 1.3 to 32) and severe ipsilateral carotid disease (OR, 13.3; 95% CI, 3.2 to 54) remained as independent predictors of RO. Conclusions— Stroke severity and ipsilateral severe carotid artery disease independently predict RO after tPA-induced MCA RE.

Differential Pattern of Tissue Plasminogen Activator–Induced Proximal Middle Cerebral Artery Recanalization Among Stroke Subtypes

Background and Purpose— We aimed to evaluate the timing, speed, and degree of tissue plasminogen activator (tPA)–induced recanalization in patients with proximal middle cerebral artery (MCA) occlusion of different stroke subtypes. Methods— We evaluated 72 patients with acute stroke caused by proximal MCA occlusion treated with intravenous tPA in <3 hours. Transcranial Doppler monitoring of recanalization was conducted during tPA infusion and at 6 hours. Strokes were categorized as large-vessel disease strokes, cardioembolic strokes, or strokes of undetermined origin according to Trial of Org 10172 in Acute Stroke Treatment criteria. Results— During 1-hour tPA infusion, recanalization occurred in 34 patients (47%); 32% showed a sudden, 50% showed a stepwise, and 18% showed a slow pattern of recanalization. One-hour recanalization was more frequent in patients with cardioembolic stroke (59%) compared with large-vessel disease (8%) and undetermined origin (50%) strokes. A cardiac source of emboli was identified in 81% of patients who showed a sudden clot breakup during tPA infusion. Rate of complete recanalization at 6 hours was higher (P =0.006) in patients with cardioembolic stroke (50%) compared with other stroke subtypes (27%). Sudden recanalization was associated (P =0.002) with a higher degree of neurological improvement at 24 hours compared with stepwise, slow, and no recanalization. A graded response in long-term outcome was observed in relation to the speed of clot lysis during tPA administration. Conclusions— We demonstrate that the pattern of tPA-induced MCA recanalization differs among stroke subtypes. Early recanalization was more frequent, faster, and more complete in patients with cardioembolic stroke compared with other stroke subtypes.