Multicenter Study of Intravenous Recombinant Tissue Plasminogen Activator Infusion around Hiroshima, Japan: The Hiroshima Acute Stroke Retrospective and Prospective Registry Study.

OBJECTIVE: Approximately 10 years have passed since intravenous (IV) recombinant tissue plasminogen activator therapy was approved in Japan. The aim of this retrospective study was to identify the effectiveness and safety of IV alteplase therapy with the Japanese original dose around Hiroshima via consideration of the patients' backgrounds, examination findings, and outcomes. METHODS: All consecutive patients with ischemic stroke who received IV alteplase therapy between October 2005 and October 2010 were registered. RESULTS: Four hundred twenty-nine patients with ischemic stroke (172 female [40.1%], mean age 73.7 ± 11.8 years) were registered. The proportion of patients over 75 years old was 51.5% (221 patients). The median National Institutes of Health Stroke Scale (NIHSS) scores at admission were 13 (interquartile range, 9-19), and the NIHSS scores 24 hours after alteplase infusion were 8 (interquartile range, 3-15). The proportion of intracerebral hemorrhage within the initial 36 hours was 20.2% (86 patients). After the multivariate regression analysis, a history of hypertension (odds ratio = 4.14; 95% confidence interval, 1.32-14.79; P = .01) and no recanalization (odds ratio = 10.10; 95% confidence interval, 3.03-39.33; P < .0001) were independently associated with a modified Rankin Scale (mRS) score of 2 or higher at 3 months. Patients over 75 years old were not significantly associated with an intracerebral hemorrhage within the initial 36 hours and an mRS score of 2 or higher at 3 months. CONCLUSIONS: The results of our study demonstrated that IV alteplase therapy with the Japanese original dose was effective and exhibited a safety profile similar to other studies. Moreover, we should not hesitate to IV alteplase therapy simply because of advanced age.

Alpha2-macroglobulin as a promising biomarker for cerebral small vessel disease in acute ischemic stroke patients.

Alpha2-macroglobulin is a protease inhibitor that enhances procoagulant properties via the neutralization of plasmin, plasminogen activators and metalloproteinases. Additionally, alpha2-macroglobulin is thought to be involved in inflammatory reactions as a carrier protein for interleukin-6 (IL-6). The objective of this study was to evaluate the usefulness of alpha2-macroglobulin as a biomarker for cerebrovascular diseases. Patients with acute ischemic stroke (n = 159; 93 male and 66 female, 71.6 ± 10.3 years) and patients with no previous history of stroke (n = 77; 38 male and 39 female, 70.7 ± 9.5 years) were consecutively enrolled in this study. White matter lesions were assessed via the fluid-attenuated inversion recovery image of magnetic resonance images using the Fazekas classification. The serum alpha2-macroglobulin levels were measured by nephelometry. The serum alpha2-macroglobulin levels at admission in patients with acute ischemic stroke were higher than those in the control patients (230.2 ± 73.7 vs. 205.0 ± 55.8 mg/dl, p = 0.009). The serum alpha2-macroglobulin levels were positively correlated with age and the severity of the white matter lesions (R (2) = 0.048, p < 0.001 and R (2) = 0.058, p < 0.001, respectively), although there was no significant association between serum alpha2-macroglobulin levels and IL-6 levels. In addition, multivariate analysis showed that increased serum alpha2-macroglobulin levels were independently associated with the severity of white matter lesions [standardized partial regression coefficient (ß) 0.102, p = 0.026]. Increased serum alpha2-macroglobulin levels might be involved in the pathophysiology of acute ischemic stroke. Furthermore, serum alpha2-macroglobulin levels, which were associated with high-grade white matter lesions, may reflect the chronic pathophysiological condition of cerebral small vessel disease.

Association of serum anti-periodontal pathogen antibody with ischemic stroke.

BACKGROUND: Periodontitis increases the risk of atherosclerotic cardiovascular disease and ischemic stroke. In this study, we evaluated whether serum antibody levels against individual periodontal pathogens are significantly associated with ischemic stroke subtypes and their risk factors. METHODS: Patients with acute ischemic stroke (n = 132; 74 male and 58 female, 71.3 ± 10.7 years) and patients with no previous stroke (n = 77; 38 male and 39 female, 70.7 ± 9.5 years) were consecutively enrolled in this study. Stroke subtype was evaluated based on the Trial of Org 10172 in Acute Stroke Treatment classification. Serum was obtained from each patient after obtaining their consent to participate in the study. The levels of serum antibodies against Aggregatibacter actinomycetemcomitans (Aa), Porphyromonas gingivalis (Pg) and Prevotella intermedia (Pi) were evaluated by ELISA. Serum high-sensitivity C-reactive protein (hs-CRP) levels were measured by nephelometry. RESULTS: Serum hs-CRP levels were significantly associated with acute ischemic stroke even after controlling for acute ischemic stroke, hypertension, diabetes mellitus and bulb/ internal carotid artery (ICA) atherosclerosis which were statistically selected (coefficient 0.245, 95% CI 0.142-0.347, p < 0.0001). The serum-antibody level of Pi was significantly higher in atherothrombotic-stroke patients than in patients with no previous stroke (p = 0.0035). Detectable serum anti-Pg antibody was significantly associated with atrial fibrillation (overall χ(2) = 35.5, R(2) = 0.18, n = 209, p < 0.0001; anti-Pg antibody: OR 4.36, 95% CI 1.71-12.10, p = 0.0017), and detectable serum anti-Pi antibody was significantly associated with bulb/ICA atherosclerosis after controlling for the statistically selected associated factors (overall χ(2) = 46.1, R(2) = 0.18, n = 209, p < 0.0001; anti-Pg antibody: OR 16.58, 95% CI 3.96-78.93, p < 0.0001). The levels of serum anti-Pi antibody were significantly associated with atherothrombotic stroke with the statistically selected associated factors excluding bulb/ICA atherosclerosis (overall χ(2) = 77.0, R(2) = 0.44, n = 129, p < 0.0001; anti-Pi antibody: OR 23.6, 95% CI 2.65-298.2, p = 0.008). However, when we included bulb/ICA atherosclerosis in this model, the levels of serum anti-Pi antibody were no longer significantly associated with atherothrombotic stroke (overall χ(2) = 98.0, R(2) = 0.56, n = 129, p < 0.0001; anti-Pi antibody: p = 0.107). CONCLUSIONS: Our results suggest that anti-Pg antibody is associated with atrial fibrillation and that anti-Pi antibody is associated with carotid artery atherosclerosis. In addition, anti-Pi antibody may be associated with atherothrombotic stroke through its association with carotid artery atherosclerosis. Thus, periodontitis may lead to serious systemic diseases.

Relation of postischemic delayed hypoperfusion and cerebral edema after transient forebrain ischemia.

Postischemic delayed hypoperfusion (PDH) is based on the imbalance between local vasodilators and vasoconstrictors. We evaluated the time course of cerebral blood flow and cerebral specific gravity representing cerebral edema after transient forebrain ischemia induced by bilateral occlusion of the common carotid arteries in anesthetized gerbils to determine whether PDH is a significant factor in development of cerebral edema. PDH appeared 45 minutes after reperfusion followed by the increase of cerebral edema. Thereafter, the local cerebral blood flow recovered from PDH 24 hours after reperfusion in spite of the stable cerebral specific gravity. Furthermore, cerebral specific gravity established a linear correlation with the local cerebral blood flow 120 minutes after reperfusion in the 3 different durations of cerebral ischemia (30, 60, and 90 minutes). It is suggested that cerebral edema is not the cause in PDH development, but PDH may cause cerebral edema.

Smoking, fasting serum insulin, and obesity are the predictors of carotid atherosclerosis in relatively young subjects.

The purpose of this study was to identify predictors of atherosclerosis in a healthy young cohort comprised of 241 subjects who underwent a regular employee medical check-up at Ohshima National Sanatorium over a 9-month period. All subjects underwent carotid ultrasound examinations to determine maximal common carotid artery intima media thickness. In addition, serum total cholesterol, triglycerides, high-density lipoprotein cholesterol, blood urea nitrogen, creatinine, glucose, and insulin were evaluated. The subjects were relatively young (mean age, 44 years; range, 18 to 62 years), with 130 females (54%) and 111 males (46%). Maximal common carotid artery intima media thickness was predicted by smoking habit, body mass index, fasting blood sugar, fasting serum insulin, and systolic blood pressure (F(5,235) = 52.8, P < 10(-5)). There was clear separation in common carotid artery intima media thickness values based on body mass index, smoking, and fasting serum insulin, and somewhat more overlap with systolic blood pressure and fasting blood sugar. These findings suggest that smoking and high values of body mass index, fasting serum insulin, systolic blood pressure, and fasting blood sugar are warning factors for early atherosclerosis development, and could conceivably serve as the basis of diagnostic screening. Smoking is particularly deleterious, as smokers with high body mass index, high fasting serum insulin, or high systolic blood pressure tend to have larger common carotid artery intima media thickness values than would have been predicted by consideration solely of the individual risk factors.

Plasma adrenomedullin and carotid atherosclerosis in atherothrombotic ischemic stroke.

OBJECTIVE: Adrenomedullin is known to exert anti-atherosclerotic actions by inhibiting proliferation and migration of smooth muscle cells in vitro. Here we examine the relationship between the plasma concentration of adrenomedullin and ultrasonographic characteristics of carotid arteries both in ischemic stroke and in the absence of cerebrovascular disease. METHODS: We studied 61 patients with atherothrombotic ischemic stroke in the chronic phase and 50 patients without any cerebrovascular disease. Intima-media thickness and vascular lumen diameters were evaluated by carotid ultrasonography. Plasma mature-adrenomedullin was determined by radioimmunoassay. RESULTS: Plasma mature-adrenomedullin in the patients with atherothrombotic ischemic stroke in the chronic phase (2.01 +/- 0.58 fmol/ml) was significantly higher than that in the patients without any cerebrovascular disease (1.24 +/- 0.18 fmol/ml, P < 0.001). With multiple regression analysis, plasma mature-adrenomedullin was found to be predicted by: stroke status (atherothrombotic ischemic stroke versus no cerebrovascular disease), diabetes status (yes/no), left ventricular ejection fraction, internal carotid artery intima-media thickness, and common carotid artery pressure strain elastic modulus (R = 0.79; F5,105 = 85.39, P < 0.0001). CONCLUSION: Plasma mature-adrenomedullin showed significantly positive associations with carotid atherosclerosis and atherothrombotic ischemic stroke, independent of systolic blood pressure.

Comparison of magnetic resonance imaging and transesophageal echocardiography in detection of thrombus in the left atrial appendage.

BACKGROUND AND PURPOSE: A noninvasive technique of visualizing the left atrial appendage (LAA) and its thrombus in patients with atrial fibrillation would be of great interest. This study examined the utility of MRI for the assessment of thrombus in the LAA. METHODS: We evaluated 50 subjects with nonrheumatic continuous atrial fibrillation and a history of cardioembolic stroke. Each patient received an MRI and a transesophageal echocardiography (TEE) on the same day for thrombus detection in the LAA. Both double- and triple-inversion recovery sequences were used for the MRI evaluations. RESULTS: In all subjects, the LAA was readily visualized with MRI. High-intensity masses in the LAA were clearly distinguishable from the LAA wall in the triple-inversion recovery sequences. Concordance between detection of high-intensity mass with MRI and thrombus with TEE was high: no mass (MRI), no thrombus (TEE), 31 patients; mass (MRI), thrombus (TEE), 16 patients; and mass (MRI), no thrombus (TEE), 3 patients (overall kappa=0.876, SE=0.068). CONCLUSIONS: MRI is a noninvasive and reproducible modality for thrombus detection in the LAA of patients with nonrheumatic continuous atrial fibrillation and previous cardioembolic stroke.

Carotid turbulent flow observed by convergent color Doppler flowmetry in silent cerebral infarction.

AIM: A newly developed convergent color Doppler (CCD) was used for evaluating the possible relationship of the flow dynamics of the internal carotid artery to silent cerebral infarction (SCI). METHODS: In 108 patients (65+/-8 years) with stroke risk factors, the CCD simultaneously images information, on both flow direction and Doppler signal energy. The relation between turbulent flow and the incidence of brain lesions of SCI as identified by magnetic resonance imaging was investigated in 212 vessels, excluding four occluded vessels. Percent area stenosis was measured as (vessel area - lumen area)/(vessel area) on cross-sectional echo image of stenotic site. RESULTS: Incidence of turbulent flow in SCI patients with 50-70% or 70-90% stenosis was higher (76.5 or 59.1%) than that in non-SCI patients (17.4 or 33.3%, both p < 0.0001). CONCLUSION: Non-invasive assessment of flow dynamics by CCD imaging can be useful for proposing the early stages of brain damage even in patients free from neurological deficits.

Vascular proliferation and transforming growth factor-beta expression in pre- and early stage of diabetes mellitus in Otsuka Long-Evans Tokushima fatty rats.

The roles of transforming growth factor (TGF)-beta 1 in vascular proliferation, atherosclerosis, and plaque still remain controversial. TGF-beta 1 has been previously reported to inhibit the proliferation and migration of vascular smooth muscle cells and endothelial cells, in vitro. On the other hand, administration or transgenic overexpression of TGF-beta 1 enhances extracellular matrix synthesis and cellular hyperplasia of the intima and media in the normal artery and injured artery in vivo. We evaluated the correlation of arterial proliferation with plasma levels of TGF-beta 1 and TGF-beta receptor type II, respectively, in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a new strain of spontaneous non-insulin-dependent diabetes mellitus (NIDDM) models. OLETF rats (n=30) were divided into three groups aged 5,15, and 30 weeks. Long-Evans Tokushima Otsuka (LETO) rats (n=30) were used as age-matched non-diabetic controls. Plasma TGF-beta1 and insulin were determined by enzyme-linked immunosorbent assay. Immunoreactive TGF-beta receptor type II antigen was detected by immunohistochemistry on the thoracic artery. Arterial media area was measured microscopically. Oral glucose tolerance test was performed to examine the stage of diabetes mellitus. The thoracic aorta wall section area increased significantly from the age of 15 weeks in OLETF rats, versus LETO rats. In both OLETF and LETO rats, plasma TGF-beta 1 increased significantly from the age of 15 weeks. In OLETF rats, plasma TGF-beta 1 increased significantly over that in LETO rats (P<0.001). Furthermore, TGF-beta receptor type II was detected on aortic wall as strong signals in OLETF rats, but only weakly in LETO rats. OLETF rats showed hyperinsulinemia and insulin resistance from the age of 15 weeks. With oral glucose tolerance test, from the age of 15 weeks, the high glucose level in OLETF rats was prolonged to 2 h after loading, and the insulin levels at both fasting and after loading were significantly higher than those of LETO rats (P<0.001). There are significant linear relations between plasma TGF-beta 1 antigen and aorta wall section area, and plasma TGF-beta 1 antigen and fasting insulin level (P<0.001, respectively). We found that plasma TGF-beta 1 and vascular TGF-beta type II receptors existed to a greater extent in pre- and early stages of diabetes mellitus (DM) in OLETF rats compared with LETO rats. The greater extent of each in OLETF rats was associated with hyperinsulinemia and/or vascular thickening.