Ryu Matsuo

Isolated Dissection of the Celiac Artery A Case Report

Isolated arterial dissection, which occurs with the absence of aortic dissection, has been reported in carotid and renal arteries but rarely in visceral arteries. A case of isolated celiac artery dissection is reported here. A healthy 58-year-old man experienced sudden upper abdominal pain, which continued for several days. A body computed tomogram (CT) showed a multiple low-density wedge-shaped area in the spleen, which was diagnosed as splenic infarction, and an aneurysm with thrombus in the celiac artery. A selective angiogram showed dilatation of the celiac artery with wall irregularity, and proximal occlusion of the hepatic artery. The distal hepatic artery was fed by collateral arteries from the superior mesenteric artery. Splenic infarction was probably due to the embolism from the thrombus in the dissected celiac artery. The absence of other vascular lesions and causes or risks for the arterial dissection would suggest the occurrence of spontaneous dissection. The dissection of visceral arteries should be considered in diag nosing acute abdominal pain.

Clinical significance of plasma VEGF value in ischemic stroke - research for biomarkers in ischemic stroke (REBIOS) study

BackgroundVascular endothelial growth factor (VEGF) is a well-known molecule mediating neuronal survival and angiogenesis. However, its clinical significance in ischemic stroke is still controversial. The goal of this study was to examine the temporal profile of plasma VEGF value and its clinical significance in ischemic stroke with taking its subtypes into consideration.MethodsWe prospectively enrolled 171 patients with ischemic stroke and age- and gender-matched healthy subjects. The stroke patients were divided into 4 subtypes: atherothrombotic infarction (ATBI, n = 34), lacunar infarction (LAC, n = 45), cardioembolic infarction (CE, n = 49) and other types (OT, n = 43). Plasma VEGF values were measured as a part of multiplex immunoassay (Human MAP v1.6) and we obtained clinical information at 5 time points (days 0, 3, 7, 14 and 90) after the stroke onset.ResultsPlasma VEGF values were significantly higher in all stroke subtypes but OT than those in the controls throughout 90 days after stroke onset. There was no significant difference in the average VEGF values among ATBI, LAC, and CE. VEGF values were positively associated with neurological severity in CE patients, while a negative association was found in ATBI patients. After adjustment for possible confounding factors, plasma VEGF value was an independent predictor of poor functional outcome in CE patients.ConclusionsAlthough plasma VEGF value increases immediately after the stroke onset equally in all stroke subtypes, its significance in functional outcome may be different among the stroke subtypes.

ABCD3 and ABCD3-I Scores Are Superior to ABCD2 Score in the Prediction of Short- and Long-Term Risks of Stroke After Transient Ischemic Attack

Background and Purpose— Several risk scores have been developed to predict the stroke risk after transient ischemic attack (TIA). However, the validation of these scores in different cohorts is still limited. The objective of this study was to elucidate whether these scores were able to predict short-term and long-term risks of stroke in patients with TIA. Methods— From the Fukuoka Stroke Registry, 693 patients with TIA were followed up for 3 years. Multivariable-adjusted Cox proportional hazards model was used to assess the hazard ratio of risk factors for stroke. The discriminatory ability of each risk score for incident stroke was estimated by using C-statistics and continuous net reclassification improvement. Results— The multivariable-adjusted Cox proportional hazards model revealed that dual TIA and carotid stenosis were both significant predictors for stroke after TIA, whereas abnormal diffusion-weighted image was not. ABCD3 (C-statistics 0.61) and ABCD3-I (C-statistics 0.66) scores improved the short-term predictive ability for stroke (at 7 days) compared with the ABCD2 score (C-statistics 0.54). Addition of intracranial arterial stenosis (at 3 years, continuous net reclassification improvement 30.5%; P<0.01) and exclusion of abnormal diffusion-weighted imaging (at 3 years, continuous net reclassification improvement 24.0%; P<0.05) further improved the predictive ability for stroke risk until 3 years after TIA. Conclusions— The present study demonstrates that ABCD3 and ABCD3-I scores are superior to the ABCD2 score for the prediction of subsequent stroke in patients with TIA. Addition of neuroimaging in the ABCD3 score may enable prediction of long-term stroke risk after TIA.

High Blood Pressure After Acute Ischemic Stroke Is Associated With Poor Clinical Outcomes Fukuoka Stroke Registry

The relationship between the poststroke blood pressure (BP) and functional outcomes in patients with acute ischemic stroke is still controversial. The aim of the present study was to elucidate the impact of the poststroke BP on the clinical outcomes of acute ischemic stroke. Among the patients in the Fukuoka Stroke Registry, 1874 patients with first-ever acute ischemic stroke (within 24 hours of onset) who had been functionally independent before onset were prospectively enrolled in the present study. The poststroke BP levels were defined as the average values during the 48 hours after onset. The study outcomes were a good neurological recovery, neurological deterioration, and a poor functional outcome. The higher poststroke BP levels were significantly associated with a lower probability of a good neurological recovery and elevated risks of neurological deterioration and a poor functional outcome after adjusting for potential confounding factors. The multivariate-adjusted odds ratios (95% confidence interval) in the highest quintile of systolic BP (versus the lowest quintile as a reference) were 0.51 (0.37–0.71) for a good neurological recovery, 1.92 (1.15–3.27) for neurological deterioration, and 2.51 (1.69–3.74) for a poor functional outcome. Similar associations were observed when we applied the poststroke diastolic BP or pulse pressure. No evidence of the J-curve phenomenon was observed for each association. These results suggest that a high poststroke BP was significantly associated with unfavorable clinical outcomes in patients with acute ischemic stroke. There was no evidence of the J-curve phenomenon between the poststroke BP levels and the clinical outcomes.

Nox4 Is a Major Source of Superoxide Production in Human Brain Pericytes

Background: Pericytes are multifunctional cells surrounding capillaries and postcapillary venules. In brain microvasculature, pericytes play a pivotal role under physiological and pathological conditions by producing reactive oxygen species (ROS). The aims of this study were to elucidate the source of ROS and its regulation in human brain pericytes. Methods: The expression of Nox enzymes in the cells was evaluated using RT-PCR and western blot. Superoxide production was determined by superoxide dismutase-inhibitable chemiluminescence. Silencing of Nox4 was performed using RNAi, and cell proliferation was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Results: Nox4 was predominant among the Nox family in human brain pericytes. Membrane fractions of cells produced superoxide in the presence of NAD(P)H. Superoxide production was almost abolished with diphenileneiodonium, a Nox inhibitor; however, inhibitors of other possible superoxide-producing enzymes had no effect on NAD(P)H-dependent superoxide production. Pericytes expressed angiotensin II (Ang II) receptors, and Ang II upregulated Nox4 expression. Hypoxic conditions also increased the Nox4 expression. Silencing of Nox4 significantly reduced ROS production and attenuated cell proliferation. Conclusion: Our study showed that Nox4 is a major superoxide-producing enzyme and that its expression is regulated by Ang II and hypoxic stress in human brain pericytes. In addition, Nox4 may promote cell growth.

Role of NHE1 in calcium signaling and cell proliferation in human CNS pericytes

The central nervous system (CNS) pericytes play an important role in brain microcirculation. Na(+)/H(+) exchanger isoform 1 (NHE1) has been suggested to regulate the proliferation of nonvascular cells through the regulation of intracellular pH, Na(+), and cell volume; however, the relationship between NHE1 and intracellular Ca(2+), an essential signal of cell growth, is still not known. The aim of the present study was to elucidate the role of NHE1 in Ca(2+) signaling and the proliferation of human CNS pericytes. The intracellular Ca(2+) concentration was measured by fura 2 in cultured human CNS pericytes. The cells showed spontaneous Ca(2+) oscillation under quasi-physiological ionic conditions. A decrease in extracellular pH or Na(+) evoked a transient Ca(2+) rise followed by Ca(2+) oscillation, whereas an increase in pH or Na(+) did not induce the Ca(2+) responses. The Ca(2+) oscillation was inhibited by an inhibitor of NHE in a dose-dependent manner and by knockdown of NHE1 by using RNA interference. The Ca(2+) oscillation was completely abolished by thapsigargin. The proliferation of pericytes was attenuated by inhibition of NHE1. These results demonstrate that NHE1 regulates Ca(2+) signaling via the modulation of Ca(2+) release from the endoplasmic reticulum, thus contributing to the regulation of proliferation in CNS pericytes.

Involvement of platelet-derived growth factor receptor β in fibrosis through extracellular matrix protein production after ischemic stroke.

Fibrosis is concomitant with repair processes following injuries in the central nervous system (CNS). Pericytes are considered as an origin of fibrosis-forming cells in the CNS. Here, we examined whether platelet-derived growth factor receptor β (PDGFRβ), a well-known indispensable molecule for migration, proliferation, and survival of pericytes, was involved in the production of extracellular matrix proteins, fibronectin and collagen type I, which is crucial for fibrosis after ischemic stroke. Immunohistochemistry demonstrated induction of PDGFRβ expression in vascular cells of peri-infarct areas at 3-7days in a mouse stroke model. The PDGFRβ-expressing cells extended from peri-infarct areas toward the ischemic core after day 7 while expressing fibronectin and collagen type I in the infarct areas. In contrast, desmin and α-smooth muscle actin, markers of pericytes, were only expressed in vascular cells. In PDGFRβ heterozygous knockout mice, the expression of fibronectin and collagen type I was attenuated at both mRNA and protein levels with an enlargement of the infarct volume after ischemic stroke compared with that in wild-type littermates. In cultured brain pericytes, the expression of PDGF-B, PDGFRβ, fibronectin, and collagen type I, but not desmin, was significantly increased by serum depletion (SD). The SD-induced upregulation of fibronectin and collagen type I was suppressed by SU11652, an inhibitor of PDGFRβ, while PDGF-B further increased the SD-induced upregulation. In conclusion, the expression level of PDGFRβ may be a crucial determinant of fibrosis after ischemic stroke. Moreover, PDGFRβ signaling participates in the production of fibronectin and collagen type I after ischemic stroke.

Significance of plasma adiponectin for diagnosis, neurological severity and functional outcome in ischemic stroke — Research for Biomarkers in Ischemic Stroke (REBIOS)

OBJECTIVE Although adiponectin is a major adipocytokine that affects the pathogenesis of various cardiovascular diseases, its clinical significance in stroke remains controversial. We investigated the clinical significance of plasma adiponectin for the diagnosis, neurological severity and functional outcomes of patients with ischemic stroke. METHODS We prospectively enrolled 171 patients with ischemic stroke and 171 age- and sex-matched healthy controls. Blood samples and clinical information were obtained at day 0, 3, 7, 14 and 90 after stroke onset. RESULTS Average adiponectin values at day 0 did not significantly differ between the controls and the patients, but were significantly lower and higher in patients with atherothrombotic brain (ATBI) (p=0.047) and cardioembolic (CE) (p=0.008) infarction, respectively, than in the controls. Multivariate logistic regression analyses showed that the adiponectin value at day 0 could predict ATBI (odds ratio, 0.75; 95% confidence interval, 0.58 to 0.91, p=0.009, per 1-μg/mL increase). Adiponectin values at day 0 were positively associated with neurological severity as evaluated by the National Institute of Health Stroke Scale upon admission (r=0.420, p=0.003) and were higher in the groups with poor outcomes (modified Rankin Scale (mRS) ≥ 3 on day 90) than in those with good ones (mRS ≤ 2) in all stroke subtypes, with statistical significance in ATBI (p=0.015). CONCLUSIONS Plasma adiponectin values may help to classify stroke subtypes and predict neurological severity and functional outcome in ischemic stroke patients.

Sex Differences in Short-Term Outcomes After Acute Ischemic Stroke The Fukuoka Stroke Registry

Background and Purpose— Variable sex differences in clinical outcomes after stroke have been reported worldwide. This study aimed to elucidate whether sex is an independent risk factor of poor functional outcome after acute ischemic stroke. Methods— Using the database of patients with acute stroke registered in the Fukuoka Stroke Registry in Japan from 1999 to 2013, 6236 previously independent patients with first-ever ischemic stroke who were admitted within 24 hours of onset were included in this study. Baseline characteristics were assessed on admission. Study outcomes included neurological improvement, neurological deterioration, and poor functional outcome (modified Rankin Scale score, 3–6 at discharge). Logistic regression analyses were performed to evaluate the association between sex and clinical outcomes. Results— Overall, 2398 patients (38.5%) were women. Severe stroke (National Institutes of Health Stroke Scale score, ≥8) on admission was more prevalent in women than in men. The frequency of neurological improvement or deterioration during hospitalization was not different between the sexes. After adjusting for possible confounders, including age, stroke subtype and severity, risk factors, and poststroke treatments, it was found that female sex was independently associated with poor functional outcome at discharge (odds ratio, 1.30; 95% confidence interval, 1.08–1.57). There was heterogeneity of the association between sex and poor outcome according to age: women had higher risk of poor outcome than men among patients aged ≥70 years, but no clear sex difference was found in patients aged <70 years. Conclusions— Female sex was associated with the risk of poor functional outcome at discharge after acute ischemic stroke.

Intensity of Anticoagulation and Clinical Outcomes in Acute Cardioembolic Stroke The Fukuoka Stroke Registry

Background and Purpose— The relationship between the intensity of anticoagulation at the onset of acute cardioembolic stroke and clinical outcome after stroke is unclear. Here, we elucidated the relationship between prothrombin time–international normalized ratio (PT-INR) values on admission and clinical outcomes in patients with acute cardioembolic stroke. Methods— A total of 602 patients from the Fukuoka Stroke Registry in Japan who had been treated with warfarin but developed cardioembolic stroke were enrolled. The patients were classified into 3 groups according to their PT-INR values on admission: PT-INR <1.50, 411 patients; PT-INR 1.50 to 1.99, 146 patients; and PT-INR ≥2.00, 45 patients. The associations between PT-INR categories and severe neurological deficits (National Institutes of Health Stroke Scale ≥10) on admission and poor functional outcome (modified Rankin scale 4–6) at discharge were investigated using a logistic regression analysis. Results— Neurological deficits on admission were less severe, and functional outcome at discharge was more favorable as the PT-INR level on admission increased. The multivariate analysis revealed that severe neurological deficits were inversely associated with PT-INR on admission (PT-INR 1.50–1.99: odds ratio, 0.66; 95% confidence interval, 0.43–1.00; PT-INR ≥2.00: odds ratio, 0.41; 95% confidence interval, 0.20–0.83; compared with a reference group of PT-INR <1.50). Poor functional outcome was less likely in patients with PT-INR ≥2.00 (odds ratio, 0.20; 95% confidence interval, 0.06–0.55) after adjustment for confounders. Conclusions— Prestroke PT-INR ≥2.0 is associated with favorable clinical outcomes after acute cardioembolic stroke.