Manabu Sakaguchi

Higher Levels of Interleukin-6 Are Associated With Lower Echogenicity of Carotid Artery Plaques

Background and Purpose— Echo-lucent carotid plaques can be fragile and vulnerable to rupture, representing a risk factor for ischemic stroke. Given the studies showing that elevated levels of circulating inflammatory markers are predictive of cardiovascular events, we sought to determine whether higher levels of serum interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP) are associated with lower echogenicity of carotid plaques. Methods— The study comprised 246 patients who had carotid atherosclerotic plaques as evidenced by ultrasound. Using acoustic densitometry, we quantified the echogenicity of the largest plaque in each patient by integrated backscatter analysis. Serum IL-6 and hsCRP levels were determined in all patients. Results— Both log-transformed IL-6 and hsCRP concentrations were negatively correlated with carotid plaque echogenicity (r =−0.28, P <0.001, and r =−0.14, P <0.05, respectively). When traditional atherosclerotic risk factors, plaque thickness, and medication use were controlled for, IL-6 levels were inversely associated with plaque echogenicity (&bgr;=−0.21, P <0.01), whereas such an association was of borderline significance for hsCRP (&bgr;=−0.12, P =0.06). Conclusions— Higher IL-6 levels, in addition to hsCRP levels, appear to be associated with lower echogenicity of carotid plaques, suggesting a link between inflammation and potential risk of plaques.

Carotid Intima-Media Thickness and Risk of Cardiovascular Events in High-Risk Patients

Background and Purpose: There is epidemiological evidence that increased carotid intima-media thickness (IMT) is a predictor of cardiovascular disease (CVD) events. However, the significance of carotid IMT in high-risk patients in whom risk factors are managed clinically has not been adequately investigated. The purpose of this study was to determine the usefulness of carotid IMT measurement in such patients. Methods: The study comprised 900 outpatients with cardiovascular risk factors or established atherosclerosis. Carotid IMT was calculated as the mean bilateral IMT of the common carotid artery, bifurcation, and internal carotid artery. Baseline vascular risk factors, medications, and history of CVD were recorded at the time of enrollment. The incidence of CVD events was determined prospectively. Results: During a mean follow-up period of 2.6 years, there were 64 CVD events. The relative risk (RR) of a CVD event increased with increased IMT. Association between CVD events and carotid IMT was significant after adjustment for risk factors and history of CVD, showing an increased risk per IMT tertile from the middle tertile (RR, 2.5; 95% confidence interval [CI]: 1.0–6.3) to the highest (RR, 3.6; 95% CI: 1.4–9.0). When patients with a history of CVD were excluded (n = 574), the predictive value of IMT was significant even after adjustment for risk factors (hazard ratio per 1 SD IMT increase was 1.57 [95% CI: 1.11–2.20]). Conclusions: Carotid IMT is an independent predictor of vascular events in high-risk patients in whom risk factors are managed clinically.

Significance of Earlier Carotid Atherosclerosis for Stroke Subtypes

Background and Purpose— In addition to advanced stenosis, earlier stages of carotid atherosclerosis are associated with the risk for stroke. However, the significance has not been established for specific stroke subtypes. This study examines the association of earlier carotid atherosclerosis with stroke subtypes. Methods— The subjects comprised 1059 patients (mean±SD age, 62±11 years) with <60% carotid stenosis. With the use of ultrasound, carotid atherosclerosis was evaluated by the plaque score, as defined by the sum of all plaque heights in bilateral carotid arteries. On the basis of neurological signs and symptoms, medical history, and brain MRI, we diagnosed stroke and its subtypes as follows: no stroke (n=738), atherothrombotic infarction (AI) (n=56), lacunar infarction (LI) (n=117), cardioembolic infarction (n=65), cerebral hemorrhage (n=26), and other or unclassified stroke (n=57). Results— The plaque score was higher in AI (10.5±5.9) and LI (6.0±5.1) groups than in the no-stroke group (4.3±4.9) (both P <0.05), although it was similar between other stroke groups and the no-stroke group. Each 1 SD greater plaque score was associated with 2.5-fold (95% CI, 2.0 to 3.2) higher risk for AI and 1.4-fold (95% CI, 1.2 to 1.7) higher risk for LI compared with the no-stroke group. When we adjusted for cardiovascular risk factors, plaque score remained significantly associated with AI but not with LI. By receiver operating characteristic curve analyses, the receiver operating characteristic area for AI (0.81 to 0.86) was greater than that for LI (0.62 to 0.67) when we used plaque score either alone or in combination with cardiovascular risk factors. Conclusions— Although evaluation of carotid atherosclerosis may aid in the risk assessment for AI and LI, the benefit appears to be greater for AI.

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.

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.

Cerebral microbleeds predict impending intracranial hemorrhage in infective endocarditis.

Background: Cerebral microbleeds (CMBs) detected by T2*-weighted MRI are a potential indicator of hypertension, microvascular disease and hemorrhagic stroke. An association between infective endocarditis (IE) and CMBs has been reported recently, but the clinical significance remains unclear. We hypothesized that CMBs in patients with IE are associated with vascular vulnerabilities such as mycotic aneurysm or pyogenic vasculitis. Methods: We retrospectively reviewed 26 consecutive patients with definite IE who underwent T2*-weighted MRI and were admitted to 2 medical centers in Osaka, Japan, between January 2006 and June 2010. We examined the incidence of symptomatic intracranial hemorrhage (ICH) occurring after initial MRI examination and investigated the association between ICH, CMBs and other clinical characteristics. Results: CMBs were identified in 14 patients (54%), and 72% of CMBs were found in the lobar region. Symptomatic ICH was observed in 8 patients (31%) during the 3-month follow-up period after initial MRI examination. In multiple logistic regression analyses, the presence of preceding ICH [odds ratio (OR) 40.0, 95% confidence interval (CI) 2.5–2,870] and the presence of CMBs (OR 34.0, 95% CI 1.3–17,300) were independent predictors of the development of ICH. Using cutoff values for CMBs of ≧2 and ≧3, the adjusted ORs for ICH increased (OR 42.1, 95% CI 1.9–24,300, and OR 70.1, 95% CI 2.5–105,000, respectively). Conclusions: In addition to prior ICH, the presence of CMBs was a strong predictor of impending ICH in patients with IE. CMBs might represent vascular vulnerability related to IE.

Multiple or mixed cerebral microbleeds and dementia in patients with vascular risk factors

Objective: To investigate whether cerebral microbleeds (CMBs) are independently associated with incident dementia in patients with vascular risk factors. Methods: Using data from a Japanese cohort of participants with vascular risk factors in an observational study from 2001, we evaluated the association between CMBs at baseline and incident dementia. Baseline brain MRI was used to determine small-vessel disease (CMBs, lacunar infarcts, and white matter hyperintensities) and brain 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 524 subjects (mean age 68 ± 8.3 years, 57.6% male, 12.8 ± 2.6 years of schooling, 21.6% CMBs), 44 patients with incident dementia (20 Alzheimer disease, 18 vascular dementia, 3 mixed-type, and 3 other) were diagnosed during the median 7.5-year follow-up. In multivariate analysis, the presence of overall CMBs was not associated with an increased risk of incident all-cause dementia (p = 0.15). However, multiple CMBs (≥2) or mixed (lobar and deep) CMBs were associated with the increased risk of all-cause dementia, whereas strictly lobar CMBs showed no association with any dementia. Conclusions: Multiple CMBs or mixed CMBs independently showed higher risk of all-cause dementia. Our results reinforce the hypothesis that CMBs exert deleterious effects on dementia incidence, suggesting that this association may be mediated by vascular burden.

Mechanical compression of the extracranial vertebral artery during neck rotation

Using duplex ultrasonography (US), the authors showed compression of the extracranial vertebral artery (ECVA) during neck rotation in 5.0% of 1,108 patients. Age (per 10-year increase, OR 0.80, 95% CI 0.67 to 0.96), vessel diameters (per 0.5-mm diameter increase, OR 0.63, 95% CI 0.51 to 0.79), and symptoms upon neck rotation (OR 4.01, 95% CI 1.35 to 11.9) were associated with vessel compression. In one case, SPECT revealed decreased cerebral perfusion of the hindbrain during rotation. ECVA US is useful in identifying vessel compression, especially in patients with symptoms on neck rotation.

Relationship between cerebral blood flow and later cognitive decline in hypertensive patients with cerebral small vessel disease

Vascular risk factors are thought to be important for dementia. However, there is little evidence for a prospective association between cerebral blood flow and the risk of cognitive decline. Twenty-seven cognitively intact hypertensive patients aged 55 years and older with lacunar infarction or white matter lesions in magnetic resonance imaging (MRI) underwent positron emission tomography (PET) to measure cerebral blood flow (CBF) and cerebral vascular reactivity (CVR). Cognitive function was assessed at baseline and 3 years later with the mini-mental state examination (MMSE). Patients whose MMSE score fell by more than three points were classified as having cognitive decline. Six patients showed cognitive decline. Baseline CBF in these patients was significantly lower than that of the 21 patients without cognitive decline (31.2±2.4 vs. 42.6±5.9 ml per 100 g min−1, respectively; P<0.001). A moderate linear association was found between CBF and change in MMSE score over a 3–year period (r=0.59, P=0.001), not between CBF and baseline MMSE score. In contrast, no association between CVR and later cognitive decline was found. This study suggests that cerebral hypoperfusion is associated with later cognitive decline.

Effects of daily alcohol intake on the blood pressure differ depending on an individual's sensitivity to alcohol : oriental flushing as a sign to stop drinking for health reasons

Objective To determine whether flushing of the facial skin in response to alcohol consumption (alcohol flushing) is a warning sign of hypertension. We also sought the relationship between alcohol flushing and other risk factors that may contribute to the development of hypertension. Methods We first investigated the relationship of the aldehyde dehydrogenase 2 (ALDH2) genotype to alcohol flushing for 53 normal volunteers. We evaluated the relationships among hypertension, alcohol consumption, and facial flushing for 1011 middle-aged Japanese men (aged 40–68 years; mean 51.6 ± 5.5 years), on the basis of their responses to questionnaires and health records. Results The first examination of 53 normal volunteers showed that there were differences in the degree of alcohol flushing between the ALDH2 genotypes (P < 0.01). Hypertension was observed in 27.4% of the study population (277 of 1011), and was correlated positively to alcohol consumption (P < 0.01). The prevalence of hypertension differed significantly among these four groups: there was a 22.4% prevalence (70 of 312) among subjects with no flushing, a 33.8% prevalence (113 of 334) among those with slight flushing, a 27% prevalence (84 of 311) among those with visible flushing, and an 18.5% prevalence (10 of 54) among subjects who were almost completely intolerant to alcohol (P < 0.05). In particular, heavy drinkers who consumed ≥ 1.5 Go (a traditional Japanese unit equivalent to 27 g ethanol) a day had a high prevalence of hypertension with slight and visible skin flushing [42% (63 of 150) and 40.7% (24 of 59), respectively]. That a family history of hypertension, greater age, heavy alcohol consumption, obesity, and symptoms of intoxication including flushing were correlated significantly to the prevalence of hypertension for all groups was demonstrated by multiple logistic regression analysis (P < 0.05). Conclusions A repeated heavy alcohol intake could increase the risk of hypertension for Japanese subjects who exhibit skin flushing in response to alcohol consumption. Chronic alcohol intake by subjects with alcohol flushing might bring about a significant increase in blood acetaldehyde levels and cause an additional rise in the blood pressure.