Kyoko Nishi

Oxidized LDL in Carotid Plaques and Plasma Associates With Plaque Instability

Objective—Oxidation of LDL plays a significant pathogenic role in atherosclerosis. In this study, we attempted to clarify the correlation between the morphology of human atherosclerotic plaques and the oxidized LDL (OxLDL) levels in plasma and carotid plaques. Methods and Results—OxLDL levels (ng/&mgr;g apolipoprotein B) in plasma and carotid plaques from 44 patients undergoing carotid endarterectomy and OxLDL levels in 17 control plasma and 9 normal intima samples were determined by a sandwich ELISA by using specific antibodies against OxLDL (DLH3) and apolipoprotein B. The plaques were immunohistochemically classified as macrophage (M&phgr;)-rich and M&phgr;-poor. In paired samples from individual patients, plaque OxLDL was nearly 70 times higher than plasma OxLDL (mean±SEM, 11.9±1.7 vs 0.18±0.01 ng/&mgr;g apoB, P <0.0001). The OxLDL level was significantly higher in M&phgr;-rich- than M&phgr;-poor plaques (19.6±2.8 vs 5.50±0.77ng/&mgr;g apoB, P <0.0001) and corresponded with DLH3 antigen positivity of the plaques. In patients with M&phgr;-rich plaques, plasma OxLDL was significantly higher than in the controls (0.20±0.02 vs 0.13±0.01ng/&mgr;g apoB, P =0.02). Conclusions—Our results suggest that LDL undergoes further oxidation in plaques, and that high plasma and plaque levels of OxLDL are correlated with the vulnerability to rupture of atherosclerotic lesions.

Raised plasma oxidised LDL in acute cerebral infarction.

Background: The association between oxidised low density lipoprotein (OxLDL) and cerebral infarction is suspected but not established. Objectives: To determine whether plasma OxLDL is a useful marker for monitoring oxidative stress in stroke patients. Methods: Plasma OxLDL concentrations were determined in 56 stroke patients with cerebral infarction (n = 45) or cerebral haemorrhage (n = 11), and in 19 age matched controls, using a novel sandwich enzyme linked immunosorbent assay. Results: Compared with the controls (0.130 (0.007) ng/μg LDL, mean (SEM)), OxLDL was significantly raised in patients with cerebral infarction (0.245 (0.022); p < 0.0001) but not in those with haemorrhage (0.179 (0.023)). Patients with cortical ischaemic infarcts (n = 22) had higher OxLDL levels than either the controls (p < 0.0001) or the patients with non-cortical ischaemic infarcts (n = 23) (p < 0.001). Increased OxLDL concentrations in patients with cortical infarcts persisted until the third day after stroke onset. The National Institutes of Health stroke scales in patients with cortical infarction were higher than in those with non-cortical infarction (p < 0.01). Conclusions: There is a significant association between raised plasma OxLDL and acute cerebral infarction, especially cortical infarction. Plasma OxLDL may reflect oxidative stress in stroke patients.

Significance of the Hemorrhagic Site for Recurrent Bleeding: Prespecified Analysis in the Japan Adult Moyamoya Trial

Background and Purpose— The primary results of the Japan Adult Moyamoya Trial revealed the statistically marginal superiority of bypass surgery over medical treatment alone in preventing rebleeding in moyamoya disease. The purpose of this analysis is to test the prespecified subgroup hypothesis that the natural course and surgical effects vary depending on the hemorrhagic site at onset. Methods— The hemorrhagic site, classified as either anterior or posterior, was the only stratifying variable for randomization. Statistical analyses were focused on the assessment of effect modification according to the hemorrhagic site and were based on tests of interaction. Results— Of 42 surgically treated patients, 24 were classified as anterior hemorrhage and 18 as posterior hemorrhage; of 38 medically treated patients, 21 were classified as anterior and 17 as posterior. The hazard ratio of the primary end points (all adverse events) for the surgical group relative to the nonsurgical group was 0.07 (95% confidence interval, 0.01–0.55) for the posterior group, as compared with 1.62 (95% confidence interval, 0.39–6.79) for the anterior group (P=0.013 for interaction). Analysis within the nonsurgical group revealed that the incidence of the primary end point was significantly higher in the posterior group than in the anterior group (17.1% per year versus 3.0% per year; hazard ratio, 5.83; 95% confidence interval, 1.60–21.27). Conclusions— Careful interpretation of the results suggests that patients with posterior hemorrhage are at higher risk of rebleeding and accrue greater benefit from surgery, subject to verification in further studies. Clinical Trial Registration— URL: http://www.umin.ac.jp/ctr/index.htm. Unique identifier: C000000166.

Clinicopathological significance of lipid peroxidation in carotid plaques

Several reports have suggested an association between lipid peroxidation and human carotid atherosclerosis, but few reports have demonstrated a link between lipid peroxidation and carotid plaques in humans. In this study, we investigated the relationship between clinical features, histopathological characteristics and lipid peroxidation in patients undergoing carotid endarterectomy (CEA). Forty-one carotid plaques were obtained. A portion of the most severe lesions was subjected to histopathologic examination, and the remainder of the plaques examined for lipid peroxidation. Thiobarbituric acid-reactive substances (TBARS) values were determined as a marker for lipid peroxidation. The lipid-rich core (LC) and macrophage infiltration (Mphi) component as a percentage of total plaque area were measured morphometrically. Based on the results, all plaques were classified into four groups. Group I (GI): LC <10%; Group IIa (GIIa): LC 10-30%, Mphi <5%; Group IIb (GIIb): LC 10-30%, Mphi < or = 5%, and Group III (GIII): LC < or =30%. The plaque TBARS values of GIII were significantly higher than those of GI, GIIa, and GIIb. The TBARS values of GIIb were one-and-a-half times higher than those of GIIa. Our results show that lipid peroxidation in carotid plaques is significantly associated with carotid atherosclerosis, especially plaque instability. These findings provide direct evidence of an association between lipid peroxidation and human atherosclerosis.

Carotid endarterectomy with external shunt: a new device and indication for use: technical note.

OBJECTIVE We designed a new external shunt system and evaluated its indications and efficacy in patients undergoing carotid endarterectomy (CEA). METHODS In 8 of 332 CEA procedures, external shunts were placed between the common carotid artery and the internal carotid artery (ICA). This procedure was implemented for one of two indications: 1) a change in electroencephalographic and/or somatosensory evoked potential readings immediately after ICA occlusion, or 2) elongation of the ICA made safe insertion of an internal shunt impossible. In addition, a shunt was placed between the common carotid artery and the external carotid artery to establish collateral circulation from the external carotid artery to the intracranial circulation, which is essential during ICA occlusion. RESULTS All external shunts were functional, and electroencephalography and somatosensory evoked potentials demonstrated no significant abnormalities during the CEAs. All patients awoke from surgery without manifestation of new neurological deficits. CONCLUSION Our new external shunt device proved safe and efficacious in cases that did not permit the placement of an internal shunt.

Hemodynamic cerebral ischemia during carotid endarterectomy evaluated by intraoperative monitoring and post-operative diffusion-weighted imaging

Abstract Objective: We used the result of monitoring to evaluate patients with post-operative neurological deficits attributable to hemodynamic cerebral ischemia owing to cross-clamping of the carotid artery. Methods: We evaluated 131 carotid endarterectomy (CEA) procedures performed on 118 patients, 96 men and 22 women ranging in age from 38 to 82 years (mean: 67.1 years). For monitoring, we used a combination of somatosensory evoked potential (SEP), functional dynamic electroencephalography (EEG), near-infrared spectroscopy (NIRS) and transcranial Doppler (TCD). Patients who awoke with neurological deficits after CEA immediately underwent diffusion-weighted imaging (DWI) and magnetic resonance angiography (MRA). Results: In 30 of the 131 procedures (22.9%), intraoperative monitoring disclosed abnormalities after cross-clamping of the internal carotid artery (ICA). In two of these 30 patients, shunt was not introduced, because of full recovery of monitoring after blood pressure increasing, however, one patient demonstrated transient ischemic attack (TIA). In six of remaining 28 patients who need shunt, transient hemodynamic cerebral ischemia occurred, however, all patients recovered gradually within 18 hours after CEA. No new lesions were detected on post-operative DWI of the seven patients and MRA demonstrated good patency of the carotid artery. The other 101 patients whose intraoperative monitoring after cross-clamping of the ICA did not disclose abnormalities demonstrated no hemodynamic TIA. Conclusion: Hemodynamic ischemia owing to cross-clamping of the ICA is rare in patients treated by CEA. However, in patients manifesting neurological deficits upon awakening from CEA, DWI and MRA should be performed immediately to facilitate their prompt treatment.

Improvement of Plasma Biomarkers after Switching Stroke Patients from Other Angiotensin II Type I Receptor Blockers to Olmesartan

BACKGROUND Managing hypertension is crucial for preventing stroke recurrence. Some stroke patients experience resistant hypertension. In our experimental stroke model, olmesartan increased the expression of angiotensin (Ang) II converting enzyme-2. We hypothesized that switching to olmesartan affects biomarkers and the blood pressure (BP) in stroke patients whose BP is insufficiently controlled by standard doses of Ang II type I receptor blockers (ARBs) other than olmesartan. METHODS We recruited 25 patients to study our hypothesis. All had a history of stroke or silent cerebral infarction. We switched them to olmesartan (10-40 mg per day) for 12 weeks and determined their plasma level of Ang-(1-7), peroxiredoxin, oxidized low-density lipoprotein (oxLDL)/β-2-glycoprotein I (β2GPI) complex, adiponectin, high mobility group box 1 (HMGB1), and tumor necrosis factor-α (TNFα) and recorded their BP before and after olmesartan treatment. RESULTS After switching the patients to olmesartan, their plasma level of Ang-(1-7) as a vasoprotective indicator and adiponectin regulating metabolic syndrome was increased, and peroxiredoxin and the oxLDL/β2GPI complex indicating its antioxidative stress and its proatherogenicity were lower than their baseline. This suggests that olmesartan may be more effective than other ARBs to improve these conditions. Neither HMGB1 nor TNFα reflecting an inflammatory response was affected, suggesting that the anti-inflammatory effects of olmesartan are similar to those of other ARBs. The recommended BP (<140/90) was obtained in 10 of the 25 patients after switching to olmesartan. No adverse events occurred. CONCLUSIONS Switching from other ARBs to olmesartan may be a promising therapeutic option in patients with resistant hypertension.

Elevation of plasma oxidized LDL in acute stroke patients is associated with ischemic lesion depicted by DWI and predictive of infarct enlargement

Oxidized low-density lipoprotein (OxLDL) plays a major role in atherosclerosis. In our previous study, we used specific antibody against oxidized phosphatidylcholine (FOH1a/ DLH3) by which OxLDL is recognized, and first demonstrated the significant association between raised plasma OxLDL and acute cerebral infarction, especially cortical infarction. We undertook the present study to clarify the relationship between plasma OxLDL and the ischemic volume. We used ELISA to determine plasma OxLDL levels and performed diffusion- and perfusion-weighted MRI (DWI, PWI) to measure the ischemic volume in 44 ischemic stroke patients. Based on the location of the ischemic lesion, they were divided into 3 groups: Group I (GI, n=21) had cortical lesions, Group II (GII, n=17) had lesions in the basal ganglia or brain stem, and Group III (GIII, n=6) had massive lesions that involved one entire hemisphere. In GI, but not GII and GIII, plasma OxLDL was significantly higher than in 19 age-matched controls (p<0.01) and was significantly correlated with the initial ischemic volume visualized on DWI (p=0.01), PWI (p<0.01), and the DWI-PWI mismatch (p<0.05)(Figure 1a–c). A persistent increase in plasma OxLDL was associated with enlargement of the ischemic lesion in the early phase after the insult. These findings suggest that elevated plasma OxLDL levels are associated with moderate ischemic damage in patients with cortical lesions (GI) but not those with massive hemispheric lesions (GIII) which may be irreversible. In addition, elevated plasma OxLDL may represent a predictor of enlargement of the ischemic lesion.