Echogenicity of medium-to-large carotid plaques predicts future vascular events.

BACKGROUND: Although the echolucent plaque in carotid stenosis is associated with future ischemic stroke, the predictive value of echogenicity in small and medium size carotid plaques on vascular events has not been thoroughly examined. Thus, we prospectively tested the hypothesis that plaque echogenicity of carotid atheroma can predict the future total cardiovascular events in patients with vascular risk factors. METHODS: Ultrasound assessment of carotid intima-media complex thickness (IMT) and plaque echogenicity using integrated backscatter (IBS) analysis was performed in 596 patients aged 40 or more, with any history of vascular events or with at least 1 risk factor, who were enrolled between 2001 and 2006 in the Osaka Follow-up Study for Carotid Atherosclerosis, part 2 (OSACA2). We followed the incidence of total cardiovascular events including cerebrovascular events, coronary heart disease (CHD), and peripheral artery disease (PAD) for 6.4 years. We divided the patients into two groups according to the IBS index above (echorich plaques) and under (echolucent plaque) the median value, and calculated the hazard ratios (HR) of the echolucent group compared with the echogenic group in the risk of cardiovascular events. RESULTS: Among 596 patients, carotid stenosis was found only in 87 patients. During the follow-up period, we observed 121 cardiovascular events including 63 cerebrovascular events, 45 CHD cases, and 13 PAD cases. The patients with incident cardiovascular events had larger plaque thickness and lower IBS index than those without incident vascular events. The relative risk of vascular events for echolucent versus echorich plaques was 1.45 (95% confidence interval [CI] 0.99-2.13, p = 0.058) after adjustment for risk factors and plaque thickness. In patients with plaque size above the median value (>2.1 mm), the relative risk of vascular events for echolucent plaques was 1.72 (95% CI 1.06-2.85, p = 0.029), but this association was not observed in patients with plaque size <2.0 mm. CONCLUSIONS: The association between echogenicity of carotid plaque and incident vascular events is dependent on the plaque size. Echolucent medium-to-large plaques, but not small plaques, are associated with the risk of future total cardiovascular events. This finding suggests that measurement of echolucency in medium-to-large carotid plaques may improve selection of patients at high risk for total vascular events.

Association of interleukin-6 with the progression of carotid atherosclerosis: a 9-year follow-up study.

BACKGROUND AND PURPOSE: Limited information is available on the long-term effects of interleukin-6 (IL-6) on systemic atherosclerosis. The purpose of the present study was to clarify the relationship between chronic elevation of IL-6 and the long-term progression of carotid atherosclerosis. METHODS: We prospectively evaluated 210 patients with ≥1 vascular risk factors for 9.0±1.0 years. Carotid mean-maximal intima-media thickness (mmIMT), the serum high-sensitivity C-reactive protein (hs-CRP) level, and the serum IL-6 level were measured at baseline and every 3 years. The associations between the progression of mmIMT and the long-term average levels of hs-CRP and IL-6 were analyzed. RESULTS: Carotid mmIMT increased throughout the study period (0.031±0.026 mm/y). Baseline mmIMT was significantly associated with baseline hs-CRP (P=0.002) and baseline IL-6 (P<0.001) levels. Progression of mmIMT was positively correlated with average hs-CRP (P=0.001) and average IL-6 (P<0.001) levels. When adjusted for age, sex, traditional risk factors, and baseline mmIMT, mmIMT progression remained significantly associated only with the average IL-6 level (standardized ß=0.17; P=0.02), but not with the average hs-CRP level (standardized ß=0.10; P=0.18). CONCLUSIONS: Chronic elevation of serum IL-6 was associated with the progression of atherosclerosis in patients with vascular risk factors. IL-6 could be used as a quantitative marker and a potential therapeutic target for accelerated atherosclerosis.

Chronic kidney disease is associated with dementia independent of cerebral small-vessel disease.

OBJECTIVE: To determine whether chronic kidney disease (CKD) is associated with incident dementia independent of cerebral small-vessel disease (SVD) in patients with vascular risk factors. METHODS: Using data from a Japanese cohort of participants with vascular risk factors in an ongoing observational study from 2001, we evaluated the association between CKD at baseline and incident dementia. Baseline brain MRI was used to determine SVD (lacunar infarction, white matter hyperintensities), medial-temporal atrophy, and subcortical atrophy. Cox proportional hazards analyses were performed for predictors of dementia adjusting for age, sex, APOE ε4 allele, educational level, baseline Mini-Mental State Examination score, cerebrovascular events, vascular risk factors, and MRI findings. RESULTS: Of the 600 subjects (mean age 68 ± 8.3 years, 57% male, 12.8 ± 2.6 years of education; CKD: 29%), 50 patients with incident dementia (Alzheimer disease: 24; vascular dementia: 18; mixed-type dementia: 5; other types: 3) were diagnosed during the median 7.5-year follow-up. CKD at baseline was associated with an increased risk of all-cause dementia in models adjusted for age, sex, educational level, and APOE ε4 allele. The associations of CKD at baseline remained significant even after additional adjusting for MRI findings and confounding variables (hazard ratio: 1.96 [1.08-3.58], p = 0.026). CONCLUSIONS: CKD is independently related to the risk of all-cause dementia in patients with vascular risk factors. Our results reinforce the hypothesis that CKD exerts deleterious effects on dementia incidence.

Ischemic stroke in patients with solid gynecologic tract tumors and coagulopathy.

AIM: Patients with gynecological neoplasms often suffer ischemic stroke. This study aimed to clarify the underlying mechanisms of ischemic stroke in patients with gynecological tract tumors. METHODS: We retrospectively reviewed 6 patients with gynecologic tumors and hypercoagulability who were being treated for acute ischemic stroke between 2006 and 2012. Diffusion-weighted magnetic resonance imaging (DW-MRI), cardiovascular risk factors including plasma D-dimer levels, and histologic examination of the patients' solid tumors were performed. All 6 patients underwent transesophageal echocardiography (TEE) for nonbacterial thrombotic endocarditis (NBTE) and paradoxical embolism. RESULTS: All 6 patients showed elevated plasma D-dimer levels. In 1 patient, paradoxical embolism was diagnosed. In the remaining 5 patients, DW-MRI scans showed numerous lesions in multiple vascular territories, and in 4 of these 5 patients, TEE demonstrated vegetations on the mitral valve, leading to the diagnosis of NBTE. Interestingly, 2 of these 4 patients had benign uterine tumors, whereas the other 2 had ovarian cancer. CONCLUSIONS: NBTE was the main etiology for ischemic stroke in patients with gynecologic tract tumors and coagulopathy. Both malignant and benign tumors of the gynecologic tract can cause NBTE.

Basilar artery diameter is an independent predictor of incident cardiovascular events.

OBJECTIVE: Basilar arterial (BA) dolichoectasia is associated with cerebral small-vessel disease and stroke. However, the association between moderate dilation of the BA and cerebral small-vessel disease or subsequent cardiovascular events remains unclear. This study aims to clarify the factors related to BA diameter and to clarify whether the BA diameter is an independent predictor of cardiovascular events. APPROACH AND RESULTS: The study subjects comprised 493 outpatients with atherosclerotic risk factors. BA diameter, lacunar infarct, severity of deep white matter hyperintensities, and intracranial steno-occlusive lesions were assessed with MRI and magnetic resonance angiography. Then, we prospectively evaluated the association between BA diameter and cardiovascular events. The BA diameter ranged from 1.1 to 5.2 mm, and only 0.8% of the patients had dolichoectasia. Male sex, the presence of lacunar infarcts, the severity of deep white matter hyperintensities, the fetal-type variation of the circle of Willis, and intracranial steno-occlusive lesions were independently associated with BA diameter. In the mean follow-up of 6.0 years, 91 patients developed cardiovascular events. BA diameter was independently associated with total cardiovascular events after adjusting for age, sex, and conventional risk factors (hazard ratio, 1.55 per 1 mm increase in BA diameter; P=0.009). CONCLUSIONS: Increased BA diameter within the normal range is related to both large-vessel disease and cerebral small-vessel disease, and it could be a new predictor of cardiovascular events.

Relationship between plasma (D)-dimer level and cerebral infarction volume in patients with nonvalvular atrial fibrillation.

BACKGROUND: Plasma D-dimer level may reflect the activity of thrombus formation in the left atrium of patients with nonvalvular atrial fibrillation (NVAF). Proper anticoagulation with warfarin dramatically decreases the rate of cerebral embolism, reduces stroke severity and subsequent risk of death, as well as the level of D-dimer in NVAF patients. However, the predictive value of D-dimer level on cerebral embolism severity has not been examined. Thus, the purpose of this study was to investigate the association between plasma D-dimer level at admission and infarct size in NVAF patients. METHODS: We identified 124 patients with consecutive ischemic stroke and NVAF who were admitted within 48 h of symptom onset. We measured infarction volume from CT taken after 3 ± 1 days from the onset. Plasma D-dimer levels were measured at the time of admission. Relationships were analyzed between infarction volume and plasma D-dimer levels, cardiovascular risk factors, preadmission medications and admission conditions. We also assessed the influence of D-dimer level on functional outcome in patients with preadmission modified Rankin Scale (mRS) score of 0-1 and patients by tertile of D-dimer level (≤0.83, 0.83-2.16 and ≥2.16 µg/ml). RESULTS: Infarction volume significantly correlated with D-dimer level (r = 0.309, p < 0.001), systolic blood pressure (r = 0.201, p = 0.026), diastolic blood pressure (r = 0.283, p = 0.002), National Institutes of Health Stroke Scale (NIHSS) score on admission (r = 0.546, p < 0.001) and mRS score at discharge (r = 0.557, p < 0.001). Multivariate regression analyses showed that the D-dimer level was significantly associated with infarction volume after adjusting for age, sex, current smoker or not, prothrombin time-international normalized ratio ≥1.6, diastolic blood pressure, CHADS(2) score and NIHSS score on admission. In patients with a preadmission mRS score of 0-1 (n = 108), D-dimer level was significantly associated with NIHSS score at admission (r = 0.318, p < 0.001) and mRS score at discharge (r = 0.310, p = 0.001). Patients in the highest D-dimer tertile group showed worse outcome than those in the middle (p = 0.041) and lowest (p < 0.001) tertiles. CONCLUSIONS: Plasma D-dimer level on admission is significantly related to infarction volume and functional outcome, following cardioembolic stroke in NVAF patients.

Association between interleukin-6 levels and first-ever cerebrovascular events in patients with vascular risk factors.

OBJECTIVE: The objective of this study was to examine the association of inflammatory markers with risk of first-ever cerebrovascular events (CVEs), while simultaneously evaluating subclinical vascular disease. METHODS AND RESULTS: We enrolled 464 outpatients who had vascular risk factors without any preexisting cardiovascular disease. We examined the presence of silent lacunar infarction (SLI) by magnetic resonance imaging; carotid intima-media thickness by ultrasound; and measured high-sensitivity C-reactive protein, interleukin (IL)-6, and IL-18 at baseline, and assessed their associations with CVEs using Cox proportional hazards models of 4.8±2.6 years follow-up. We further calculated measures of reclassification and discrimination. In age- and sex-adjusted analysis, IL-6, but neither high-sensitivity C-reactive protein nor IL-18, was associated with CVEs. The association remained significant after adjustment for conventional risk factors, intima-media thickness, and SLI (hazard ratios: 1.80, per 1-SD increase in log IL-6, P=0.03). Compared with the patients with below median IL-6 without SLI, those with above median IL-6 and SLI had a higher risk of CVEs (hazard ratios: 4.14, P=0.0014). The combination of IL-6 and SLI resulted in the net reclassification improvement of 14.3% (P=0.04), and the integrated discrimination improvement gain of 2.1% (P=0.05). CONCLUSIONS: IL-6 levels were independently associated with CVEs and could improve reclassification in those with SLI.

The relation between carotid plaque echogenicity and oxidative stress marker 8-iso-prostaglandin F2α.

Echolucent plaques are associated with high risk of ischemic cerebrovascular events. Oxidative stress has been implicated in the process of atherosclerotic plaque development from initiation to progression. We assessed the relation between carotid plaque echogenicity and urinary 8-iso-prostaglandin F2α, as an index of oxidative stress. This cross-sectional study was conducted prospectively on 290 consecutive outpatients. Each patient was evaluated for carotid plaque echogenicity using the gray-scale median at the maximal thickness plaque and urinary 8-iso-prostaglandin F2α using enzyme linked immunosorbent assay. By Pearson correlation analysis, we found significant negative linear relation between gray-scale median values and the urinary 8-iso-prostaglandin F2α levels (r = -0.133, p = 0.023). This correlation remained significant after adjustment for atherosclerotic risk factors, thickness of the maximal plaque and medication use (ß = -0.137, p = 0.031). We herein show that higher levels of urinary 8-iso-prostaglandin F2α is associated with lower plaque echogenicity.

Chronic kidney disease and carotid atherosclerosis.

Chronic kidney disease is an independent risk factor for cardiovascular disease. The association between carotid intima-media thickness (IMT) and chronic kidney disease is controversial, however. In addition, whether renal dysfunction promotes vascular calcification in patients with chronic kidney disease is not clear. The study subjects were 1003 patients aged ≥50 years who underwent carotid ultrasonography in our hospital. Kidney function was evaluated based on the estimated glomerular filtration rate (eGFR) and the presence of proteinuria. Patients with end-stage renal failure were excluded. We measured the mean max-IMT (which indicates mean maximal wall thickness) at 12 carotid segments, and examined the characteristics of the maximal plaques by carotid ultrasonography. We evaluated the association between mean max-IMT and eGFR, and also evaluated the clinical factors associated with mean max-IMT and calcification of the maximal plaques. We found that eGFR was significantly correlated with mean max-IMT. Reduced eGFR, proteinuria, age, male sex, cardiovascular disease, hypertension, diabetes, and smoking were independently associated with mean max-IMT in multiple regression analysis. Kidney function was not associated with calcified plaque. Kidney dysfunction was associated with carotid atherosclerosis in patients with mild or moderate chronic kidney disease.

Preadmission therapeutic anticoagulation reduces cerebral infarct volume in patients with nonvalvular atrial fibrillation.

AIM: We investigated the influence of preadmission anticoagulation on infarct volume in patients with nonvalvular atrial fibrillation (NVAF). METHODS: Data were collected on consecutive ischemic stroke patients with NVAF admitted to Osaka University Hospital between 2004 and 2011. Patients were divided into 3 groups: the no-anticoagulation group, the subtherapeutic anticoagulation group [admission prothrombin time international normalized ratio (PT-INR) <1.6], and the therapeutic anticoagulation group (PT-INR ≥1.6). In analyses of neurological outcome, we excluded patients with a modified Rankin Scale (mRS) score of >1 before onset. RESULTS: Of the 68 patients, 45 were classified into the no-anticoagulation group, 9 into the subtherapeutic group, and 14 into the therapeutic group. The median value of infarct volume was 60 (interquartile range 9-176), 142 (64-184), and 8 (3-46) ml in each group, respectively. Infarct volume in the therapeutic group was significantly smaller than in the subtherapeutic group (p = 0.010), and tended to be smaller than in the no-anticoagulation group (p = 0.086). National Institute of Health Stroke Scale score at admission, and mRS score at discharge were significantly reduced in the therapeutic group compared with those in the other groups (p = 0.028 and p = 0.017, respectively). CONCLUSION: Therapeutic anticoagulation reduces infarct volume and improves neurological outcome after ischemic stroke in patients with NVAF.

Relations of blood inflammatory marker levels with cerebral microbleeds.

BACKGROUND AND PURPOSE: Cerebral microbleeds (CMB) are observed in the elderly and have been regarded as one of the manifestations of small vessel disease. Although inflammatory processes have attracted much attention not only in large-artery disease, but also in small vessel disease, their involvement in CMB remains to be determined. The purpose of this study is to clarify relations between inflammatory marker levels and CMB. METHODS: Four hundred thirty-one patients without histories of cerebrovascular diseases were prospectively enrolled. The presence and number of CMB were assessed on gradient-echo magnetic resonance imaging. As common inflammatory markers, serum levels of high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and interleukin-18 (IL-18) were evaluated. RESULTS: CMB were found in 65 patients (15%). In 35 patients, at least one CMB was found in deep locations, but 30 patients had strictly lobar CMB. Levels of hsCRP, IL-6, and IL-18 were higher in patients with CMB than in those without. Logistic regression analyses showed that each 1SD increase in each inflammatory marker level was significantly associated with the presence of CMB after adjustment for age and sex, and after additional adjustment for cardiovascular risk factors, silent lacunar infarction, and white matter hyperintensity. The OR (95% CI) of hsCRP, IL-6, and IL-18 was 1.81 (1.35-2.46), 1.73 (1.18-2.61), and 2.41 (1.44-4.52), respectively. Furthermore, the inflammatory marker levels were associated with both deep and lobar CMB. CONCLUSIONS: Higher levels of hsCRP, IL-6, and IL-18 are associated with CMB, in both deep and lobar locations, suggesting the involvement of inflammation in CMB.

Long-term effects of pioglitazone on carotid atherosclerosis in Japanese patients with type 2 diabetes without a recent history of macrovascular morbidity.

AIM: No previous studies have evaluated the long-term anti-atherosclerotic effects of pioglitazone in Asian patients with type 2 diabetes. Therefore, the present study investigated the protective effects of pioglitazone on the progression of carotid intima-media thickness (IMT), an established surrogate marker of cardiovascular events in Japanese type 2 diabetic patients without a recent history of cardiovascular morbidity. METHODS: This 2.5-4-year, randomized, open-label, blinded endpoint study was conducted in 6 centers across Japan. Patients received pioglitazone with or without other oral glucose-lowering drugs (excluding another thiazolidinedione) (n=89) or oral glucose-lowering drugs, excluding thiazolidinediones (n=97). Treatment was adjusted to achieve HbA(1c) <6.5%. The primary endpoints of the study were the absolute changes from the baseline to final visit in max- and mean-IMT in the average of bilateral common carotid arteries. RESULTS: Pioglitazone induced carotid IMT regression compared to baseline measurements (from 1.060 ± 0.2368 to 0.992 ± 0.1921 mm; p=0.0042 in max-IMT and from 0.839 ± 0.1873 to 0.780 ± 0.1571 mm; p=0.0019 in mean-IMT). Although the between-group difference did not reach statistical significance, the regression of carotid IMT values was greater in the pioglitazone-treatment group than in the non-pioglitazone group, (max-IMT: -0.069 ± 0.2199 mm vs -0.031 ± 0.2327 mm, respectively; p=NS, mean-IMT: -0.058 ± 0.1718 mm vs -0.043 ± 0.1644 mm, respectively; p=NS). CONCLUSIONS: Pioglitazone induced and maintained the long-term regression of carotid IMT in Japanese type 2 diabetic patients. This suggests that pioglitazone may inhibit the progression of atherosclerosis in this patient group. Further studies are required to verify these findings.

Associations of local release of inflammatory biomarkers during carotid artery stenting with plaque echogenicity and calcification.

BACKGROUND AND PURPOSE: The purpose of this study is to evaluate whether release of inflammatory markers locally from an atherosclerotic plaque after carotid artery stenting (CAS) is associated with plaque echogenicity and calcification. METHODS: The study consisted of 36 patients with 42 severely stenotic carotid arteries who underwent CAS with the distal balloon occlusion. Before CAS, the plaque echogenicity was evaluated by acoustic densitometry and the distribution of calcification was investigated. Systemic blood samples were obtained from the aorta before CAS and local blood samples under distal balloon occlusion just after CAS. RESULTS: The interleukin (IL)-6 and osteopontin (OPN) levels markedly increased at the plaque site in comparison to the systemic values (p < 0.001). Moreover, the local IL-18 level slightly increased compared to the systemic values. In contrast, the local high-sensitive C-reactive protein level slightly decreased. The local matrix metalloproteinase (MMP)-2, tissue inhibitor of MMP-1 and soluble intercellular adhesion molecule 1 levels were not changed. The levels of local IL-6 release were associated with lower echogenicity and less calcification (p < 0.05), while those of local OPN release were independent of plaque characteristics. CONCLUSIONS: Our observations show that IL-6 and OPN were released from carotid stenotic lesions after CAS. The association between high levels of IL-6 release and lower plaque echogenicity and less plaque calcification suggests that IL-6 is prone to be released from vulnerable carotid plaques after CAS.

Association of inflammatory markers and carotid intima-media thickness with the risk of cardiovascular events in high-risk patients.

OBJECTIVE: Both inflammatory markers and carotid intima-media thickness (IMT) are associated with future cardiovascular disease (CVD). We investigated whether inflammatory markers can be predictors for incident CVD independent of carotid IMT in atherosclerotic high-risk patients and evaluated the joint effect of inflammatory markers and IMT in CVD prediction. METHODS: We performed a prospective cohort study of 770 patients who had one or more atherosclerotic risk factors. Serum high-sensitive C-reactive protein (hsCRP), interleukin (IL)-6, IL-18, and carotid IMT were assessed at baseline and the incidence of CVD was determined. RESULTS: During 4.3 years of mean follow-up, CVD occurred in 104 patients (14%). In univariate analyses, higher levels of hsCRP, IL-6, and IL-18 were significantly related to an increased risk of CVD. However, only IL-6, but not hsCRP or IL-18, was associated with incident CVD after adjustment for conventional risk factors and carotid IMT (hazard ratio of upper half to lower half, 1.87; 95% confidence interval, 1.20-2.93). Measuring IL-6 level in combination with carotid IMT improves the prediction of incident CVD. CONCLUSIONS: Elevated IL-6 is associated with the risk of CVD independently of carotid IMT in atherosclerotic high-risk patients.

Silent cerebral infarction is associated with incident stroke and TIA independent of carotid intima-media thickness.

BACKGROUND: Both silent cerebral infarction (SCI) and carotid intima-media thickness (IMT) are associated with future stroke. We evaluated whether SCI could be a predictor for incident stroke independent of carotid IMT in high-risk patients. METHODS: We performed a prospective cohort study among 282 outpatients who had one or more atherosclerotic risk factors but without a history of cardiovascular disease. We conducted cranial MRI and measured carotid IMT at baseline, and then evaluated the risks of incident stroke and transient ischemic attacks (TIA) using Cox proportional hazards models. RESULTS: SCI was present in 67 patients (23.7%) at baseline. During 4.1 years of follow-up, stroke and TIA occurred in 8 patients (2.8%). The incidence of stroke/TIA was 22.3 per 1,000 person-years in those with SCI compared with 2.2 per 1,000 person-years in those without SCI. Both SCI and carotid IMT at baseline were associated with incident stroke/TIA events after adjustment for age, sex, and traditional vascular risk factors. The predictive value of SCI remained significant even after adjustment for carotid IMT (HR 8.56; 1.72-42.55). CONCLUSION: SCI, similar to carotid IMT, is an independent predictor of stroke and TIA in high-risk patients.

Interleukin-6 release after carotid artery stenting and periprocedural new ischemic lesions.

Carotid artery stenting (CAS) is currently a standard procedure to treat severe carotid artery stenosis. This procedure causes mechanical plaque rupture, potentially releasing soluble factors into the circulating blood. The purpose of this study is to clarify whether inflammation factors are released from an atherosclerotic plaque after CAS and whether local release of inflammation factors is associated with periprocedural new ischemic lesions. The study consisted of 35 patients with 40 severely stenotic carotid arteries who underwent CAS. Blood samples were obtained from the aorta before the procedure and from the carotid plaque site just after the procedure. Blood levels of interleukin-6 (IL-6), interleukin-18, matrix metalloproteinase (MMP)-2, and tissue inhibitor of MMP-1 were determined. Diffusion-weighted magnetic resonance imaging was performed before and after the procedure. Among inflammatory markers, IL-6 levels markedly increased at the plaque site in comparison to those at the aorta (P<0.001). The IL-6 levels in the local samples were significantly higher in symptomatic lesions than those in asymptomatic lesions. More importantly, higher local IL-6 levels were associated with the appearance of new ischemic lesions (P=0.003). The association remained significant (P=0.030) after controlling for potential risk factors for CAS. Association of local IL-6 levels and periprocedural new ischemic lesions suggests that massive release from the plaque and entry into the cerebral circulation of IL-6 might be one of important factors on periprocedural complications related to CAS.

Cyclo-oxygenase-2 -765G > C promoter variants are associated with lower carotid plaque echogenicity in Japanese.

BACKGROUND AND PURPOSE: Recent studies revealed that inflammation contributes to plaque instability. Cyclo-oxygenase (COX)-2 is one of the key enzymes in plaque inflammation. We examined the relation between a polymorphism in the COX-2 gene and carotid plaque echogenicity in patients with high risk of cerebrovascular disease to evaluate the involvement of COX-2 in plaque instability. METHODS: The study comprised 469 individuals with carotid atherosclerotic plaques. We quantified the echogenicity of the largest plaque in each participant by integrated backscatter analysis. The -765G > C variant of the COX-2 gene was genotyped by restriction enzyme fragment length polymorphism analysis. Urinary 6-keto prostaglandin F(1)(alpha) levels and flow-mediated dilation were measured in 25 participants from the -765GC genotype group and 25 matched participants from the -765GG genotype group. RESULTS: The carotid plaque echogenicity in the variant genotype group (n = 44) was lower than that in the -765GG genotype group (n = 425, p = 0.017). The association remained significant when we controlled for atherosclerotic risk factors, plaque thickness and serum levels of interleukin-6 (p = 0.027). The level of urinary 6-keto prostaglandin F(1)(alpha) and flow-mediated dilation in the variant genotype group was significantly lower than that in the -765GG genotype group. CONCLUSIONS: The -765G > C variant of COX-2 was associated with reduced carotid plaque echogenicity in Japanese. Diminished COX-2 activity in the endothelium may contribute to plaque instability.

Statin therapy increases carotid plaque echogenicity in hypercholesterolemic patients.

Stabilization of carotid artery plaques by pharmacologic intervention is a promising strategy for the prevention of ischemic stroke. In this study, we examined the effect of 12 months of statin therapy on carotid plaque echogenicity. This study included 81 hypercholesterolemic patients with carotid atherosclerotic plaques. Echogenicity of the largest plaque in each patient was evaluated by ultrasound with integrated backscatter analysis. All patients underwent dietary modification. Forty patients were treated with simvastatin (10 mg/day, n = 24) or atorvastatin (5 mg/day, n = 16) according to the choice by each attending physician. Carotid plaques were monitored by measuring plaque thickness and echogenicity during a 12-month follow-up period. Levels of serum high-sensitivity CRP (hs-CRP), interleukin (IL)-6 and IL-18 were determined in all patients. Total cholesterol, triglyceride, hs-CRP and IL-18 were significantly decreased after 12 months of statin therapy. The change in IL-6 level was not significant. Significant increases in echogenicity of carotid plaques and decreases in plaque thickness were noted after statin therapy. In the 41 patients without statin therapy, carotid plaque echogenicity, plaque thickness and serum levels of inflammatory markers were not significantly altered. Our results suggest that statin therapy in hypercholesterolemic patients for 12 months increases carotid plaque echogenicity and decreases plaque thickness, in addition to lowering serum levels of lipids and inflammatory markers.

Relation between interleukin-6 level and subclinical intracranial large-artery atherosclerosis.

BACKGROUND: The levels of systemic inflammatory markers have been shown to predict future cardiovascular events, but whether they are associated with intracranial large-artery atherosclerosis is uncertain. We investigated the relation between the level of inflammatory markers interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP) and subclinical intracranial large-artery atherosclerosis in patients with risk factors for atherosclerosis. METHODS: Magnetic resonance angiography (MRA) was performed in 226 Japanese patients age range, 45-87 years without a history of cerebrovascular disease. Serum IL-6 and hsCRP and conventional risk factors for atherosclerosis were assessed. RESULTS: Forty-six patients (20.4%) were found by MRA to have one or more intracranial steno-occlusive lesions. Mean IL-6 levels were higher in patients with intracranial large-artery atherosclerosis than in those without. In addition, patients in the highest IL-6 tertile had higher unadjusted odds ratio (OR) for intracranial large-artery atherosclerosis than that of those in the lowest tertile (OR 3.25, 95% CI; 1.42-7.39). These associations were only slightly attenuated upon adjustment for conventional atherosclerotic risk factors and carotid intima-media thickness. CONCLUSIONS: Increased levels of IL-6 appear to be associated with intracranial large-artery disease, suggesting a role for the inflammatory process in atherosclerosis of intracranial large arteries.