Harumitsu Nagoya

A Peroxisome Proliferator-Activated Receptor-γ Agonist Reduces Infarct Size in Transient but not in Permanent Ischemia

Background and Purpose— Activators of peroxisome proliferator-activated receptor-&ggr; (PPAR&ggr;), a member of the PPAR family, increase levels of CuZn-superoxide dismutase (SOD) in cultured endothelium, suggesting a mechanism by which it may exert its protective effect within the brain. These properties raise the question of whether a PPAR&ggr; agonist may be neuroprotective in models of ischemia without reperfusion, in which oxidative injury is less prevalent. Methods— In 2 groups of rats, 90 minutes of middle cerebral artery (MCA) occlusion was followed by 1 day of reperfusion, with 1 group receiving pioglitazone (a PPAR&ggr; agonist) starting 72 hours before MCA occlusion (MCAO) and continuing through the day of occlusion, whereas the other group received vehicle only. In 2 comparable groups, the MCA was occluded permanently. One day after occlusion, the animals were tested neurologically and infarct volumes were calculated. In a separate group, rats were treated with pioglitazone or vehicle for 4 days. Tissue was obtained from the cortex and the striatum 2 hours into reperfusion after 90 minutes of MCAO, and the tissue was examined for CuZn-SOD by Western blot. Results— Results show a significant reduction in infarct size in the treated rats, with transient MCAO but not permanent MCAO. There was also an improvement in neurological score in the treated animals after transient MCAO. The level of CuZn-SOD was increased in the cortex in treated animals. Conclusions— These data, which show that a PPAR&ggr; agonist reduces infarct size in transient but not permanent MCAO, suggest that the role of PPAR&ggr; is specific to events occurring during reperfusion. Our data point to CuZn-SOD as the mediator of this neuroprotection.

Nitric Oxide Production during Cerebral Ischemia and Reperfusion in eNOS- and nNOS-Knockout Mice

The purpose of this study was to clarify the kinetics of nitric oxide (NO) induced by either endothelial NO synthase (eNOS) or neuronal NO synthase (nNOS) after transient global forebrain ischemia. We investigated NO production and ischemic changes to hippocampal CA1 neurons in eNOS knockout (-/-) mice and nNOS (-/-) mice during cerebral ischemia and reperfusion. NO production was continuously monitored by in vivo microdialysis. Global forebrain ischemia was produced by occlusion of both common carotid arteries for 10 minutes. Levels of nitrite (NO(2)(-)) and nitrate (NO(3)(-)), as NO metabolites, in dialysate were determined using the Griess reaction. Two hours after the start of reperfusion, animals were perfused with 4% paraformaldehyde. Hippocampal CA1 neurons were divided into three phases (severely ischemic, moderately ischemic, surviving), and the ratio of surviving neurons to degenerated neurons was calculated as the survival rate. The relative cerebral blood flow (rCBF) was significantly higher in nNOS (-/-) mice than in control mice after reperfusion. Levels of NO(3)(-) were significantly lower in eNOS (-/-) mice and nNOS (-/-) mice than in control mice during ischemia and reperfusion. NO(3)(-) levels were significantly lower in nNOS (-/-) mice than in eNOS (-/-) mice after the start of reperfusion. Survival rate tended to be higher in nNOS (-/-) mice than in control mice, but not significantly. These in vivo data suggest that NO production in the striatum after reperfusion is closely related to activities of both nNOS and eNOS, and is mainly related to nNOS following reperfusion.

Significance of Clinical–Diffusion Mismatch in Hyperacute Cerebral Infarction

In recent years, patient selection for intravenous tissue plasminogen activator (t-PA) therapy based on clinical-diffusion mismatch (CDM) has been closely examined. We investigated the relationship between prognosis and CDM in patients with hyperacute cerebral infarction within 3 hours of onset and compared CDM with diffusion-perfusion mismatch (DPM). Of 122 patients with hyperacute cerebral infarction who visited the hospital within 3 hours of onset between April 2007 and November 2008, 85 patients with cerebral infarction in the anterior circulation who underwent head magnetic resonance imaging diffusion-weighted imaging (DWI)/magnetic resonance angiography (MRA) (51 men and 34 women; average age, 74 ± 10 years) were enrolled. Seventeen of these patients underwent CT perfusion imaging. CDM-positive cases were those with a National Institute of Health Stroke Scale (NIHSS) score ≥ 8 and a DWI-Alberta Stroke Program Early CT Score (DWI-ASPECTS) ≥ 8; CDM-negative cases were those with an NIHSS score ≥ 8 and an ASPECTS-DWI < 8. The other patients were classified as belonging to the NIHSS score < 8 group. Of the 32 CDM-positive cases, 10 received t-PA infusion. These patients had markedly higher modified Rankin Scale scores 90 days after onset compared with the 22 patients who did not receive t-PA infusion. The 8 CDM-positive cases included 4 DPM-positive cases and 4 DPM-negative cases, and a discrepancy was confirmed between CDM and DPM. In all DPM-positive cases, MRA confirmed lesions in major intracranial arteries. CDM may enable more accurate prediction of outcomes in patients with hyperacute cerebral infarction. In addition, the combination of CDM findings and MRA findings (stenosis or occlusion in major intracranial arteries) may be an alternative to DPM for determining the indications for IV t-PA therapy in patients with hyperacute cerebral infarction.

The CHA(2)DS(2)-VASc score reflects clinical outcomes in nonvalvular atrial fibrillation patients with an initial cardioembolic stroke.

BACKGROUND Whether the CHA(2)DS(2)-VASc score reflects severity or clinical outcomes in patients with an initial cardioembolic stroke associated with nonvalvular atrial fibrillation (NAVF) was investigated. METHODS This study included 327 patients hospitalized between April 2007 and March 2012 for an initial cardioembolic stroke associated with NVAF with no history of stroke. The National Institutes of Health Stroke Scale (NIHSS) score on admission and clinical outcome (modified Rankin Scale [mRS] score after 90 days) were retrospectively evaluated according to the CHA(2)DS(2)-VASc score. RESULTS CHA(2)DS(2)-VASc scores were 0, 3.1%; 1, 9.1%; 2, 24.5%; 3, 26%; 4, 20.8%; 5, 14.4%; and 6, 2.1%. The median NIHSS scores for CHA(2)DS(2)-VASc scores of 0-6 were 4.5, 8, 8, 10, 11, 17, and 23, respectively. Severity differed according to the CHA(2)DS(2)-VASc score. The clinical outcomes according to the CHA(2)DS(2)-VASc scores were as follows: score 0, mRS scores of 0-2 (80%) and 3-6 (20%); score 1, mRS scores of 0-2 (80%) and 3-6 (20%); score 2, mRS scores of 0-2 (64%) and 3-6 (36%); score 3, mRS scores of 0-2 (48%) and 3-6 (52%); score 4, mRS scores of 0-2 (28%) and 3-6 (72%); score 5, mRS scores of 0-2 (26%) and 3-6 (74%); and score 6, mRS scores of 0-2 (29%) and 3-6 (71%). The clinical outcome worsened as the CHA(2)DS(2)-VASc score increased. On logistic regression analysis, age, NIHSS score on admission, and thrombolytic therapy were related to a clinical outcome. CONCLUSIONS The severity of NVAF-induced initial cardioembolic stroke increased with higher CHA(2)DS(2)-VASc scores, and the outcomes were poor. The present study suggests that the CHA(2)DS(2)-VASc score may be useful not only for the evaluation of stroke risk but also for the prediction of clinical outcomes after stroke.

Takotsubo cardiomyopathy associated with top of the basilar artery syndrome

JO N 3087 clinical symptoms such as chest pain or dyspnea were absent. Echocardiography revealed apical hypokinesia (Figs. 1 D and E). Within half a day, the troponin level decreased to within the normal range and CK-MB did not increase throughout the clinical course. Levels of noradrenaline and BNP on day 6 were high (609 and 117 pg/ml, respectively), although they could not be measured upon admission. Apical akinesis was normalized on day 10. We diagnosed this patient with Takotsubo cardiomyopathy. Atrial fibrillation did not occur at any time during the clinical course and the patient’s history did not include any coagulation disorders. Only ischemic stroke was identified as a possible cause of the Takotsubo cardiomyopathy, since neither prior psychological/physical stress nor pheochromocytoma was found. The diagnostic findings and the clinical course suggested that stroke-related stress caused the Takotsubo cardiomyopathy. Acute therapy with heparin and glycerol was administered to prevent stroke progression. Brain CT on day 2 showed an infarct of the contralateral thalamus (Figs. 1 F and G). A 3D-CT angiogram on day 3 revealed no occlusion of the basilar artery (Fig. 1 H) and ECG on day 10 showed obvious negative T waves in leads I, II, III, aVF and V26. Consciousness improved within 1 week and the patient was transferred to a rehabilitation center on day 19. Takotsubo cardiomyopathy is a rare syndrome that was originally described in 1990 in Japan [1]. The Japanese name is derived from its gross similarity to an antique octopus (tako) trap (tsubo), which is shaped like an ampulla. Takotsubo cardiomyopathy usually affects elderly women with prior emotional, psychological or physical stress. It often resembles acute coronary Yuji Kato Hidetaka Takeda Daisuke Furuya Harumitsu Nagoya Ichiro Deguchi Norio Tanahashi

Treatment Outcomes of Tissue Plasminogen Activator Infusion for Branch Atheromatous Disease

BACKGROUND The objective of this study was to evaluate treatment outcomes of tissue plasminogen activator (t-PA) infusion for hyperacute branch atheromatous disease (BAD) within 3 hours after onset. METHODS A total of 152 BAD patients with lenticulostriate artery (LSA) or paramedian pontine artery (PPA) territory infarcts (LSA 114; PPA 38) were hospitalized between April 2007 and June 2012. Of these, 21 BAD patients (LSA 19; PPA 2) arrived at the hospital within 3 hours after onset, and, among these, 8 patients who received t-PA infusion (.6 mg/kg) were included in this study. All BAD patients who received t-PA infusion had LSA territory infarcts. RESULTS Six of 8 patients (75%) had improvement of neurologic findings within 60 minutes after t-PA infusion, but neurologic findings deteriorated within 24 hours in 4 of these patients (67%). In all patients with deterioration, diffusion-weighted imaging after 24 hours revealed infarct expansion. One patient (13%) had symptomatic intracranial hemorrhage. After 3 months, the modified Rankin Scale (mRS) score was 0 to 2 in 6 patients (75%) and 3 to 6 in 2 patients (25%). CONCLUSIONS With t-PA infusion for BAD, symptoms transiently improved, but the rate of symptom deterioration was high. The outcome after 3 months was relatively good.

Relationship of Obesity to Recanalization after Hyperacute Recombinant Tissue-Plasminogen Activator Infusion Therapy in Patients with Middle Cerebral Artery Occlusion

BACKGROUND This was a retrospective analysis of factors related to recanalization after hyperacute recombinant tissue-plasminogen activator (rt-PA) infusion therapy in patients with middle cerebral artery occlusion. METHODS Of the 50 patients (39 males and 11 females; mean age 70 ± 11 years) with cerebral infarction who were able to undergo diffusion-weighted magnetic resonance imaging (MRI)/magnetic resonance angiography (MRA) of the head within 24 hours of starting rt-PA infusion therapy while hospitalized at our center between April 2007 and October 2010, 23 patients (18 males and 5 females; mean age 71 ± 9.4 years) with hyperacute cerebral infarction with findings of obstruction in the proximal segment of the middle cerebral artery (MCA-M1) served as subjects. RESULTS Of the 23 patients with MCA occlusion, 13 (57%) were recanalized. Analysis of factors related to recanalization revealed a significant difference (P = .019) for obesity (body mass index >25 kg/m(2)), with significantly more obese patients in the nonrecanalized group than in the recanalized group. The study revealed no significant differences in other factors between the 2 groups. CONCLUSIONS The results suggest that obesity may be involved in recanalization after hyperacute rt-PA infusion therapy in patients with MCA occlusion.

Magnetic Resonance Imaging Investigation of Secondary Degeneration of the Mesencephalic Substantia Nigra After Cerebral Infarction

Secondary degeneration of the mesencephalic substantia nigra after cerebral infarction is widely known to occur in animal experiments, but has yet to be sufficiently investigated in human cerebral infarction. This study investigated the background and features of patients exhibiting secondary degeneration of the mesencephalic substantia nigra. The subjects comprised 43 patients admitted to our hospital for cerebral infarction between April 2007 and October 2010 showing secondary degeneration of the mesencephalic substantia nigra on cranial magnetic resonance imaging (MRI). We investigated clinical disease type, location of vascular occlusion, lesion site, and time from onset of symptoms to lesion identification by MRI. The clinical disease type was cardiogenic embolism in 29 patients (67%), atheromatous embolism (artery to artery) in 8 patients (19%), embolism (origin unknown) in 2 patients (5%), infarction after coil embolization for internal carotid aneurysm in 1 patient (2%), arterial dissection in 2 patients (5%), and vasculitis due to Takayasu disease in 1 patient (2%). Magnetic resonance angiography (MRA) identified the occluded vessel as the internal carotid artery in 19 patients (44%), the middle cerebral artery (M1) in 20 patients (47%), and the middle cerebral artery (M2) in 3 patients (7%); MRA was not performed in 1 patient (2%). The cerebral infarctions were striatal in 7 patients (16%) and striatal and cortical in 36 patients (84%). Hyperintense regions in the mesencephalic substantia nigra were observed in all patients after 7-28 days (mean, 13.3 days) on diffusion-weighted imaging or fluid-attenuated inversion recovery and T2-weighted MRI. Most patients with secondary degeneration of the substantia nigra demonstrated clinical disease comprising vascular occlusion of the internal carotid artery or the neighborhood of the middle cerebral artery, which was envisaged to cause a sudden drop in brain circulation across a wide area. Striatal infarctions were observed in all patients. Secondary degeneration of the substantia nigra appeared at 1-4 weeks after onset and disappeared after several months.

Clinical Review of 28 Patients with Basilar Artery Occlusion

BACKGROUND We retrospectively analyzed factors related to the outcomes of patients with basilar artery occlusion. METHODS Twenty-eight patients with basilar artery occlusion admitted to our hospital within 24 hours after onset between April 2007 and December 2010 were included. We investigated parameters related to outcome, such as coexisting disease, clinical type, clinical severity at admission, the site of occlusion and the infarction lesion, the collateral flow from posterior communicating artery, therapy, and time to therapy after onset. RESULTS Of 28 patients with basilar artery occlusion, good outcomes occurred in 6 patients (21%) and poor outcomes occurred in 22 patients (79%). Clinical severity on admission was significantly different between the 2 groups. Three of 5 patients with percutaneous transluminal angioplasty achieved recanalization. Two of 3 cases with recanalization resulted in poor outcomes. CONCLUSIONS Clinical severity on admission was the determinant factor of functional prognosis in patients with basilar artery occlusion.

Additional endovascular therapy in patients with acute ischemic stroke who are nonresponsive to intravenous tissue plasminogen activator: usefulness of magnetic resonance angiography-diffusion mismatch.

BACKGROUND In patients who are not responsive to intravenous tissue plasminogen activator (IV t-PA), the present study aimed to report recanalization rates, the incidence of hemorrhagic transformation (HT), and clinical outcomes of additional endovascular therapy (AET), and to investigate the usefulness of magnetic resonance angiography-diffusion mismatch (MDM) in a selection of patients eligible for AET. METHODS Fifty-eight patients who received IV t-PA therapy because of intracranial major artery occlusion between April 2007 and November 2010 were divided into 2 groups: 18 patients in the AET group and 21 patients in the IV t-PA nonresponders group. The remaining 19 patients were responders to IV t-PA and therefore not eligible for this study. Recanalization rates, HT incidence, and 3-month outcomes were assessed, and the relationship between MDM and clinical outcome was examined. RESULTS A 3-month modified Rankin Scale (mRS) score of 0 to 3 was seen more frequently in the AET group (72% in the AET group v 29% in the nonresponder group; P = .01). Serious outcomes (3-month mRS of 5-6) were seen significantly less often in the AET group (17%) than in the nonresponder group (57%; P = .019). There were no differences in the incidence of HT. In the AET group, reappraisal considering MDM revealed a significantly higher rate of a 3-month mRS of 0 to 3 in the MDM-positive group compared to the MDM-negative group (86% v 25%, respectively; P = .044). Serious outcomes were observed significantly less frequently in the MDM-positive group compared to the MDM-negative group (0% v 75%, respectively; P = .005). CONCLUSIONS AET for nonresponders to IV t-PA was safe, improved recanalization rates, and led to better prognoses. MDM was a very good predictor of improved prognosis in a selection of eligible patients for AET after IV t-PA.