Infectious burden and carotid plaque thickness: the northern Manhattan study.

BACKGROUND AND PURPOSE: The overall burden of prior infections may contribute to atherosclerosis and stroke risk. We hypothesized that serological evidence of common infections would be associated with carotid plaque thickness in a multiethnic cohort. METHODS: Antibody titers to 5 common infectious microorganisms (ie, Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, and herpesvirus 1 and 2) were measured among stroke-free community participants and a weighted index of infectious burden was calculated based on Cox models previously derived for the association of each infection with stroke risk. High-resolution carotid duplex Doppler studies were used to assess maximum carotid plaque thickness. Weighted least squares regression was used to measure the association between infectious burden and maximum carotid plaque thickness after adjusting for other risk factors. RESULTS: Serological results for all 5 infectious organisms were available in 861 participants with maximum carotid plaque thickness measurements available (mean age, 67.2+/-9.6 years). Each individual infection was associated with stroke risk after adjusting for other risk factors. The infectious burden index (n=861) had a mean of 1.00+/-0.35 SD and a median of 1.08. Plaque was present in 52% of participants (mean, 0.90+/-1.04 mm). Infectious burden was associated with maximum carotid plaque thickness (adjusted increase in maximum carotid plaque thickness 0.09 mm; 95% CI, 0.03 to 0.15 mm per SD increase of infectious burden). CONCLUSIONS: A quantitative weighted index of infectious burden, derived from the magnitude of association of individual infections with stroke, was associated with carotid plaque thickness in this multiethnic cohort. These results lend support to the notion that past or chronic exposure to common infections, perhaps by exacerbating inflammation, contributes to atherosclerosis. Future studies are needed to confirm this hypothesis and to define optimal measures of infectious burden as a vascular risk factor.

Sleep and Stroke: New Updates on Epidemiology, Pathophysiology, Assessment, and Treatment.

PURPOSE OF REVIEW: This review aims to discuss the most recent data on sleep disorders and stroke, highlighting relevant findings for the practicing neurologist or health providers who encounter patients with sleep disorders and stroke. RECENT FINDINGS: Sleep apnea and abnormal sleep duration have the strongest association with stroke risk. Possible mechanisms include non-dipping of blood pressure during sleep, hypoxemia or reoxygenation leading to sympathetic activation, hypertension, atrial fibrillation and impaired cerebral hemodynamics. Treatment studies suggest that continuous positive airway pressure (CPAP) for sleep apnea could improve primary prevention of stroke, but data is equivocal for secondary prevention. However, CPAP could improve functional outcomes after stroke. SUMMARY: Sleep disorders present an opportunity to improve stroke risk and functional outcomes. However, new strategies are needed to determine the patients at high-risk who would most likely benefit from targeted care. Novel methods for phenotyping sleep disorders could provide personalized stroke care to improve clinical outcomes and public health strategies.

Metabolic syndrome and ischemic stroke risk: Northern Manhattan Study.

BACKGROUND AND PURPOSE: More than 47 million individuals in the United States meet the criteria for the metabolic syndrome. The relation between the metabolic syndrome and stroke risk in multiethnic populations has not been well characterized. METHODS: As part of the Northern Manhattan Study, 3298 stroke-free community residents were prospectively followed up for a mean of 6.4 years. The metabolic syndrome was defined according to guidelines established by the National Cholesterol Education Program Adult Treatment Panel III. Cox proportional-hazards models were used to calculate hazard ratios (HRs) and 95% CIs for ischemic stroke and vascular events (ischemic stroke, myocardial infarction, or vascular death). The etiologic fraction estimates the proportion of events attributable to the metabolic syndrome. RESULTS: More than 44% of the cohort had the metabolic syndrome (48% of women vs 38% of men, P<0.0001), which was more prevalent among Hispanics (50%) than whites (39%) or blacks (37%). The metabolic syndrome was associated with increased risk of stroke (HR=1.5; 95% CI, 1.1 to 2.2) and vascular events (HR=1.6; 95% CI, 1.3 to 2.0) after adjustment for sociodemographic and risk factors. The effect of the metabolic syndrome on stroke risk was greater among women (HR=2.0; 95% CI, 1.3 to 3.1) than men (HR=1.1; 95% CI, 0.6 to 1.9) and among Hispanics (HR=2.0; 95% CI, 1.2 to 3.4) compared with blacks and whites. The etiologic fraction estimates suggest that elimination of the metabolic syndrome would result in a 19% reduction in overall stroke, a 30% reduction of stroke in women; and a 35% reduction of stroke among Hispanics. CONCLUSIONS: The metabolic syndrome is an important risk factor for ischemic stroke, with differential effects by sex and race/ethnicity.

Metabolic syndrome, endothelial dysfunction, and risk of cardiovascular events: the Northern Manhattan Study (NOMAS).

BACKGROUND: Metabolic syndrome (MetS) predisposes to cardiovascular disease. Endothelial dysfunction is thought to be an important factor in the pathogenesis of atherosclerosis. We tested the hypothesis that both MetS and endothelial dysfunction are vascular risk factors and provide additive prognostic values in predicting cardiovascular events in a multiethnic community sample. METHODS: The study population consisted of 819 subjects (467 female, mean age 66.5 +/- 8.8 years, 66% Hispanic) enrolled in the NOMAS. Metabolic syndrome was defined using the revised Adult Treatment Panel III criteria. Brachial artery flow-mediated dilation (FMD) was measured using high-resolution ultrasound. Endothelial dysfunction was defined as FMD <8.44% (lower 3 quartiles). Cox proportional hazards models were used to assess the effect of MetS and endothelial dysfunction on risk of cardiovascular events. RESULTS: During 81 +/- 21 months of follow-up, events occurred in 84 subjects. Metabolic syndrome was independently associated with cardiovascular events in a multivariate model, including cardiovascular risk factors (adjusted hazard ratio 2.08, 95% CI 1.27-3.40). Subjects with both MetS and endothelial dysfunction were at higher risk for cardiovascular events than those with either one of them alone (adjusted hazard ratio 2.60, 95% CI 1.14-5.92). CONCLUSIONS: Metabolic syndrome is associated with incident cardiovascular events. Combined use of MetS and FMD identifies those who are at higher risk of cardiovascular events. Metabolic syndrome and noninvasive FMD testing can be used concurrently for cardiovascular risk prediction.

Multiple genetic determinants of plasma lipid levels in Caribbean Hispanics.

OBJECTIVES: To identify candidate genes in relation to plasma lipid levels in Caribbean Hispanics. DESIGN AND METHODS: A total of 114 single nucleotide polymorphisms (SNPs) at 17 lipid-related genes were genotyped in 477 Caribbean Hispanics from the Northern Manhattan Study (NOMAS). Analyses for each SNP and haplotype were performed to evaluate the associations with four lipid traits: high- and low-density lipoprotein cholesterol (HDL-C, LDL-C), triglyceride (TG) and total cholesterol (TC). RESULTS: We identified 19 SNPs at 10 genes that were significantly related to lipids (p<0.01), including nine involved in the reverse cholesterol transport pathway, and one involved in bile acid synthesis. Three genes, namely the apolipoprotein A5, apolipoprotein B and cytochrome p450 polypeptide 7A1 genes, accounted for the largest proportion of variation in HDL-C/TG, TC and LDL-C respectively. CONCLUSIONS: The cumulative effects of multiple genetic variants led to a substantially better prediction of inter-individual variations in lipid levels.

Transient ischemic attack before nonlacunar ischemic stroke in the elderly.

BACKGROUND: Several studies suggest transient ischemic attack (TIA) may be neuroprotective against ischemic stroke analogous to preinfarction angina's protection against acute myocardial infarction. However, this protective ischemic preconditioning-like effect may not be present in all ages, especially among the elderly. The purpose of this study was to determine the neuroprotective effect of TIAs (clinical equivalent of cerebral ischemic preconditioning) to neurologic damage after cerebral ischemic injury in patients over 65 years of age. METHODS: We reviewed the medical charts of patients with ischemic stroke for presence of TIAs within 72 hours before stroke onset. Stroke severity was evaluated by the National Institutes of Health Stroke Scale and disability by a modified Rankin scale. RESULTS: We evaluated 203 patients (>or=65 years) with diagnosis of acute ischemic stroke and categorized them according to the presence (n = 42, 21%) or absence (n = 161, 79%) of TIAs within 72 hours of stroke onset. Patients were monitored until discharged from the hospital (length of hospital stay 14.5 +/- 4.8 days). No significant differences in the National Institutes of Health Stroke Scale and modified Rankin scale scores were observed between those patients with TIAs and those without TIAs present before stroke onset at admission or discharge. CONCLUSION: These results suggest that the neuroprotective mechanism of cerebral ischemic preconditioning may not be present or functional in the elderly.

Risk of myocardial infarction or vascular death after first ischemic stroke: the Northern Manhattan Study.

BACKGROUND AND PURPOSE: In national guidelines, absolute long-term risk of myocardial infarction (MI) or coronary death determines target low-density lipoprotein levels, but stroke patients are not explicitly addressed. We determined the absolute 5-year risk of cardiovascular outcomes and their predictors after first ischemic stroke in a multiethnic cohort. METHODS: A population-based cohort of first ischemic stroke patients > or =40 years old was prospectively followed annually for recurrent stroke, MI and cause-specific mortality. Kaplan-Meier 5-year risks for MI or vascular death (primary outcome), and other cardiovascular events, were calculated. Univariate and multivariate Cox proportional hazards models were used to calculate hazard ratios and 95% CI for predictors of cardiovascular outcomes. RESULTS: Mean age (n=655) was 69.7+/-12.7 years; 55.4% of participants were women, and 51.3% Hispanic. The 5-year risk of MI or vascular death was 17.4% (95% CI, 14.2% to 20.6%). Independent historical predictors of MI or vascular death were age >70 years (hazard ratio 1.62, 1.07 to 2.44), history of coronary artery disease (hazard ratio 1.76, 1.13 to 2.74), and atrial fibrillation (hazard ratio 1.76, 1.05 to 2.94). In the lowest risk group, those < or =70 years old without coronary artery disease, 5-year risk of MI or vascular death was 9.7%. CONCLUSIONS: The absolute risk of MI or vascular death after ischemic stroke, even in those without high-risk features, approximates levels used by national organizations to designate groups of patients at high risk of vascular events. The comparability of levels of absolute risk among stroke and cardiac patients may have treatment implications.

Design of a family study among high-risk Caribbean Hispanics: the Northern Manhattan Family Study.

Stroke continues to kill disproportionately more Blacks and Hispanics than Whites in the United States. Racial/ethnic variations in the incidence of stroke and prevalence of stroke risk factors are probably explained by both genetic and environmental influences. Family studies can help identify genetic predisposition to stroke and potential stroke precursors. Few studies have evaluated the heritability of these stroke risk factors among non-White populations, and none have focused on Caribbean Hispanic populations. The aim of the Northern Manhattan Family Study (NOMAFS) is to investigate the gene-environment interaction of stroke risk factors among Caribbean Hispanics. The unique recruitment and methodologic approaches used in this study are relevant to the design and conduct of genetic aggregation studies to investigate complex genetic disorders in non-White populations. The aim of this paper is to describe the NOMAFS and report enrollment and characteristics of the participants. The NOMAFS will provide a data resource for the exploration of the genetic determinants of highly heritable stroke precursor phenotypes that are less complex than the stroke phenotype. Understanding the gene environment interaction is the critical next step toward the development of new and unique approaches to disease prevention and interventions.

Ischemic stroke subtype incidence among whites, blacks, and Hispanics: the Northern Manhattan Study.

BACKGROUND: Stroke incidence is greater in blacks than in whites; data on Hispanics are limited. Comparing subtype-specific ischemic stroke incidence rates may help to explain race-ethnic differences in stroke risk. The aim of this population-based study was to determine ischemic stroke subtype incidence rates for whites, blacks, and Hispanics living in one community. METHODS AND RESULTS: A comprehensive stroke surveillance system incorporating multiple overlapping strategies was used to identify all cases of first ischemic stroke occurring between July 1, 1993, and June 30, 1997, in northern Manhattan. Ischemic stroke subtypes were determined according to a modified NINDS scheme, and age-adjusted, race-specific incidence rates calculated. The annual age-adjusted incidence of first ischemic stroke per 100,000 was 88 (95% CI, 75 to 101) in whites, 149 (95% CI, 132 to 165) in Hispanics, and 191 (95% CI, 160 to 221) in blacks. Among blacks compared with whites, the relative rate of intracranial atherosclerotic stroke was 5.85 (95% CI, 1.82 to 18.73); extracranial atherosclerotic stroke, 3.18 (95% CI, 1.42 to 7.13); lacunar stroke, 3.09 (95% CI, 1.86 to 5.11); and cardioembolic stroke, 1.58 (95% CI, 0.99 to 2.52). Among Hispanics compared with whites, the relative rate of intracranial atherosclerotic stroke was 5.00 (95% CI, 1.69 to 14.76); extracranial atherosclerotic stroke, 1.71 (95% CI, 0.80 to 3.63); lacunar stroke, 2.32 (95% CI, 1.48 to 3.63); and cardioembolic stroke, 1.42 (95% CI, 0.97 to 2.09). CONCLUSIONS: The high ischemic stroke incidence among blacks and Hispanics compared with whites is due to higher rates of all ischemic stroke subtypes.

Moderate alcohol consumption reduces risk of ischemic stroke: the Northern Manhattan Study.

BACKGROUND AND PURPOSE: Moderate alcohol consumption is protective against coronary disease, but its relationship to ischemic stroke (IS) is controversial. METHODS: Stroke-free participants > or =40 years of age identified by random-digit dialing were enrolled in a prospective cohort study between 1993 and 2001. Alcohol consumption was assessed through in-person interview and categorized as none in the past year, > or =1 drink in past month to < or =2 per day (moderate drinkers), and >2 drinks daily. Lifetime drinking was also assessed. Cox proportional hazard regression modeling was used to assess hazard ratios and their 95% CIs for the association of drinking with risk of stroke and vascular events. RESULTS: Mean age among participants (n=3176) was 69.1+/-10.3 years; 62.8% were women, 20.8% were non-Hispanic white, 24.5% non-Hispanic black, and 52.4% were Hispanic. No alcohol in the previous year was present in 62.3%, and 32.5% drank moderately. After adjusting for other risk factors compared with those who did not drink in the past year, moderate drinkers had a reduced risk of IS (0.67; 95% CI, 0.46 to 0.99) and IS, myocardial infarction, or vascular death (0.74; 95% CI, 0.59 to 0.94). Results were similar when never-drinkers were used as referent group. Reduction in risk was seen for nonatherosclerotic IS subtypes, and results stratified by age, sex, and race-ethnicity were similar. CONCLUSIONS: Moderate alcohol consumption is associated with decreased risk of IS in a multiethnic population. This effect is independent of other risk factors and holds for nonatherosclerotic stroke subtypes.

Left ventricular systolic dysfunction and the risk of ischemic stroke in a multiethnic population.

BACKGROUND AND PURPOSE: Left ventricular dysfunction (LVD) is associated with cardiovascular mortality. Its association with ischemic stroke has been mainly documented after myocardial infarction. The stroke risk associated with LVD, especially of mild degree, in the general population is unclear. The purpose of this study was to evaluate the relationship between LVD and ischemic stroke in a multiethnic cohort. METHODS: LV systolic function was assessed by transthoracic 2-dimensional echocardiography in a subset of subjects from the Northern Manhattan Study (NOMAS), 270 patients with first ischemic stroke and 288 age-, gender- and race-matched community controls. LV ejection fraction was measured by a simplified cylinder-hemiellipsoid formula, and categorized as normal (>50%), mildly (41% to 50%), moderately (31% to 40%) or severely (< or =30%) decreased. The association between impaired ejection fraction and ischemic stroke was evaluated by logistic regression analysis after adjustment for established stroke risk factors. RESULTS: LVD of any degree was more frequent in stroke patients (24.1%) than in controls (4.9%; P<0.0001), as was moderate/severe LVD (13.3% versus 2.4%; P<0.001). A decreased ejection fraction was associated with ischemic stroke even after adjusting for other stroke risk factors. The adjusted odds ratio for any degree of LVD was 3.92 (95% CI, 1.93 to 7.97). The adjusted odds ratio for mild LVD was 3.96 (95% CI, 1.56 to 10.01) and for moderate/severe LVD 3.88 (95% CI, 1.45 to 10.39). The association between LVD of any degree and stroke was present in all age, gender and race-ethnicity subgroups. CONCLUSIONS: LVD, even of mild degree, is independently associated with an increased risk of ischemic stroke. The assessment of LV function should be considered in the assessment of the stroke risk.

Ultrasound assessment of subclinical cardiovascular disease in a community-based multiethnic population and comparison to the Framingham score.

The presence of subclinical cardiovascular disease has been documented to indicate high coronary risk. This study investigated the impact of subclinical cardiovascular disease derived from echocardiography and carotid ultrasonography on traditional coronary risk stratification using the Framingham risk score (FRS) in a community-based, multiethnic population. Echocardiography and carotid ultrasonography were performed in 1,445 subjects (aged >39 years; 40% men; 53% Hispanic, 20% white, 24% black) from the Northern Manhattan Study. Subclinical cardiovascular disease was defined as the presence of left ventricular hypertrophy and/or carotid plaque greater than the gender-specific 75th percentile of the left ventricular mass index and maximal carotid plaque thickness distribution. The prevalence of subclinical cardiovascular disease was examined in each FRS category (low, intermediate, and high risk). In subjects with low or intermediate FRSs, 35% had subclinical cardiovascular disease (low FRS 29%, intermediate FRS 42%). In the intermediate FRS category, subclinical cardiovascular disease was significantly more prevalent in women than in men (53% vs 32%, p <0.0001) and in black and white subjects than in Hispanics (59% and 46% vs 33%, p <0.0001 and p = 0.040, respectively). In conclusion, the ultrasound assessment of subclinical cardiovascular disease may help reclassify 1/3 of subjects with low or intermediate FRSs into higher risk groups. In the intermediate FRS category, FRS appears to underestimate the coronary risk more in women than in men and more in whites and especially in blacks than in Hispanics.

Heritability of carotid artery distensibility in Hispanics: the Northern Manhattan Family Study.

BACKGROUND AND PURPOSE: Reduced arterial distensibility has been introduced as a novel risk factor for atherosclerosis. The importance of the genetic contribution to variation in distensibility is largely unknown. The purpose of this study was to estimate heritability of carotid distensibility. METHODS: The ongoing Northern Manhattan Family Study recruits high-risk Caribbean Hispanic families to study genetic effects on stroke/cardiovascular risk factors. The distensibility metrics (strain, stiffness, distensibility, and elastic modulus) were measured from the right common carotid artery, and the heritability for each was estimated. Variance component methods were used to estimate age- and sex-adjusted heritability. Correlations were calculated to evaluate the relationship between distensibility phenotypes and intimamedia thickness (IMT) at each carotid segment. RESULTS: The current data included 88 probands and 605 relatives from 88 families. Age- and sex-adjusted heritability was 25% for strain, 17% for distensibility, 20% for stiffness, and 20% for elastic modulus. Without adjustment for covariates, strong correlations were found between distensibility metrics and IMT: the absolute values of correlation coefficients were between 0.2 and 0.5, and all P values were <0.001. However, the correlation coefficients were reduced substantially after adjusting for age and sex. CONCLUSIONS: These results suggested that genetic factors explained a moderate proportion of the variability of carotid distensibility. The correlations between distensibility and IMT were mainly attributable to age and sex effects. The regulation of carotid distensibility and IMT may reflect different underlying genetic and environmental mechanisms.

Interleukin-2 levels are associated with carotid artery intima-media thickness.

OBJECTIVE: To show that serum interleukin levels are associated with carotid intima-media thickness (IMT). BACKGROUND: Inflammation is hypothesized to play a central role in atherogenesis, and serum markers of inflammation are predictive of cardiovascular disease. Interleukin-2, a pro-inflammatory cytokine produced largely by naive CD4 T cells and Th1 (pro-inflammatory) T cells, has been found in a high proportion of carotid plaques. METHODS: High-resolution ultrasound of the carotid arteries and serum cytokine levels were measured in stroke-free participants. The mean of the maximum IMT in bilateral bifurcation, common and internal carotid artery segments was measured. Serum levels of interleukin (IL)-1beta, IL-2, IL-6, C-reactive protein, tumor necrosis factor (TNF) alpha and TNF receptors were measured using enzyme-linked immunosorbent assay. RESULTS: IL-2 levels were significantly correlated with IMT (r=0.33, P<0.0001), but other cytokines were not. Each unit increase in IL-2 was significantly associated with a mean increase in IMT of 0.18 mm (P=0.0001). After adjusting for other atherosclerotic risk factors, the association was unchanged (mean increase in IMT per unit increase IL-2=0.18 mm, P<0.0001). Each standard deviation increase in the level of IL-2 was associated with an increased risk (adjusted odds ratio 1.80, 95% CI 1.12-2.89) for an IMT> or =1.0mm (75th percentile for IMT). CONCLUSION: Serum levels of IL-2, a pro-inflammatory cytokine, are associated with carotid artery IMT, a predictor of stroke and vascular disease. Serum inflammatory markers may provide a novel marker of atherosclerotic risk, and inflammation may provide a new therapeutic target for stroke prevention.

Health care resource use after acute stroke in the Glycine Antagonist in Neuroprotection (GAIN) Americas trial.

BACKGROUND AND PURPOSE: To compare 3-month stroke outcomes and stroke-related health care resource use between the US and Canada in the Glycine Antagonist in Neuroprotection (GAIN) Americas study. Delivery of medical care for stroke patients, often driven by efforts to curb costs, varies substantially between countries. Data on the potential impact of these variations on clinical outcomes are sparse. METHODS: The analysis of health care resource included total length of stay (LOS) in hospital, intensive care unit (ICU), and acute-care ward or rehabilitation unit, or both; number of outpatient rehabilitation sessions and visits to a physician; place of residence after discharge; and employment status. Cox proportional hazards models and logistic regression were used to calculate survival hazards and predictors of favorable functional outcome (Barthel Index of 95 to 100). RESULTS: One thousand six hundred four patients who were independent before stroke (mean age: 69.9+/-12.7 years, 53% men, 85% ischemic stroke, 69% in the US) were included. Three-month survival and functional outcome did not differ between the US and Canada. Survival rate was 80% in both countries. Favorable functional outcome was achieved in 43% of Canadian and 47% of US patients. Fewer Canadian patients received treatment in ICU (19% versus 63% in the US), and Canadians had longer stays in hospital or rehabilitation facility (median: 33 days versus 16 days in the US). CONCLUSIONS: Despite similar 3-month survival and functional outcome, patterns of health care resource varied substantially between the US and Canada. US patients had more intensive early care; Canadian patients had longer hospitalizations and rehabilitation care. Further research is required to determine the most cost-effective treatment and rehabilitation plan for people who have a stroke.

Tumor necrosis factor receptor levels are associated with carotid atherosclerosis.

BACKGROUND AND PURPOSE: Recent evidence suggests that atherosclerosis is an inflammatory condition. Serum levels of inflammatory markers may serve as measures of the severity of atherosclerosis and risk of stroke. We sought to determine whether tumor necrosis factor-alpha (TNF-alpha) and TNF receptor levels are associated with carotid plaque thickness. METHODS: The Northern Manhattan Stroke Study is a community-based study of stroke risk factors. For this cross-sectional analysis, inflammatory marker levels, including TNF-alpha and TNF receptors 1 and 2, were measured by immunoassay in stroke-free community subjects undergoing carotid duplex Doppler ultrasound. Maximal carotid plaque thickness (MCPT) was measured for each subject. Analyses were stratified by age < 70 and > or =70 years. Simple and multiple linear regression analyses were used to calculate the association between marker levels and MCPT. Multiple logistic regression was used to calculate odds ratios and 95% CIs for the association of inflammatory markers with MCPT > or =1.5 mm (>75th percentile), after adjustment for demographic and potential medical confounding factors. RESULTS: The mean age of the 279 subjects was 67.6+/-8.5 years; 49% were men; 63% were Hispanic, 17% black, and 17% white. Mean values for TNF-alpha and its receptors were as follows: TNF-alpha, 1.88+/-3.97 ng/mL; TNF receptor 1, 2.21+/-0.99 ng/mL; and TNF receptor 2, 4.85+/-2.23 ng/mL. Mean MCPT was elevated in those in the highest quartiles compared with lowest quartiles of TNF receptor 1 and 2 (1.24 versus 0.79 mm and 1.23 versus 0.80 mm, respectively). Among those aged < 70 years, TNF receptor 1 and 2 were associated with an increase in MCPT (mean difference=0.36 mm, P=0.01 for TNF receptor 1 and mean difference=0.10 mm, P=0.04 for TNF receptor 2). After adjustment for sex, race-ethnicity, hypertension, diabetes mellitus, LDL cholesterol, smoking, and body mass index, associations remained (mean difference=0.36 mm, P=0.001 for TNF receptor 1 and mean difference=0.09 mm, P=0.051 for TNF receptor 2). There was no association for TNF receptors in those aged > or = 70 years old and no association for TNF-alpha in either age group. Among those aged < 70 years, each unit increase in TNF receptor level increased the odds of the participant's having MCPT > or =1.5 mm (adjusted odds ratio=4.7; 95% CI, 1.7 to 15.4 for TNF receptor 1; odds ratio=1.9; 95% CI, 1.3 to 2.9 for TNF receptor 2). CONCLUSIONS: Relative elevation in TNF receptor levels, but not TNF-alpha, is associated with carotid atherosclerosis among individuals aged < 70 years in this multiethnic, urban population. Chronic subclinical infection or inflammation may account for this association, and modification of these inflammatory pathways may provide a novel approach to stroke prevention.

Monitoring of cerebral vasodilatory capacity with transcranial Doppler carbon dioxide inhalation in patients with severe carotid artery disease.

BACKGROUND AND PURPOSE: Cerebral vasodilatory capacity (CVC) testing with transcranial Doppler has been shown to be useful in the assessment of stroke risk in patients with symptomatic and asymptomatic internal carotid artery (ICA) stenosis and occlusion, but whether hemodynamic status improves, deteriorates, or remains the same over time is uncertain. METHODS: Thirty-five patients with >or=80% carotid artery stenosis or complete occlusion underwent CVC testing at baseline and 6 months later. CVC was assessed by measuring the increase in ipsilateral middle cerebral artery mean flow velocity in response to 5% inhaled CO2. Continuous tracings of left and right middle cerebral artery flow velocity, heart rate, respiratory rate, and Pco2 were recorded and then analyzed offline. One-way analysis of variance was used to compare baseline CVC in symptomatic and asymptomatic patients with control subjects. A paired t test was used to compare CVC before and after revascularization. Also, chi2 analysis was used to compare rates of cerebrovascular events in patients with low compared with normal CVC over the 6-month period and in 14 patients whose ICAs were revascularized. RESULTS: Patients with high-grade stenosis or occlusion of the ICA who had ICA disease had an average CVC of 2.4+/-1.9%/mm Hg Pco2; control subjects averaged 4.2+/-1.1%/mm Hg Pco2. (P=0.01). In the revascularization group, CVC increased from an average of 1.4+/-1.7%/mm Hg Pco2 at baseline to an average of 2.8+/-1.0%/mm Hg Pco2 after revascularization, significantly different from the spontaneous change in the natural history group over 6 months (P=0.003). Over the 6-month follow-up period, in the natural history group and in the treatment group after revascularization, 4 ischemic events occurred, all in patients with abnormal CVCs; abnormal CVC was associated with ischemic events (Fisher's exact test, P=0.03). CONCLUSIONS: In a timeframe pertinent to clinical decision making and clinical trial outcomes, cerebral hemodynamic status may not be constant. A higher ischemic risk may be present in patients with severe carotid artery disease whose CVC is poor at baseline, becomes poor over 6 months, or fails to normalize after revascularization.

Genetic and environmental contributions to carotid intima-media thickness and obesity phenotypes in the Northern Manhattan Family Study.

BACKGROUND AND PURPOSE: Both carotid intima-media thickness (IMT) and obesity are independent determinants of stroke and cardiovascular disease. The prevalence of obesity is higher in Hispanics. The genetic basis of IMT and obesity has not been well-characterized in Caribbean Hispanics. The purpose of this study was to examine the genetic and environmental contributions to IMT and obesity in this population. METHODS: The data included 440 subjects from 77 Caribbean Hispanic families. Mean IMT and maximum IMT were measured in the internal carotid artery, common carotid artery, and carotid bifurcation. The total IMT was calculated as the mean value of IMT at all segments. Obesity phenotypes included body mass index (BMI), waist circumference, waist-to-hip ratio (WHR), and skin-fold thickness. Variance component methods were used to estimate age-adjusted and sex-adjusted heritability. Bivariate analyses were conducted to test for genetic and environmental correlations between IMT and obesity. RESULTS: Heritabilities for IMT ranged from 9% to 40%, with the highest for total maximum IMT and lowest for internal carotid artery maximum IMT. Heritabilities for BMI, waist circumference, WHR, and skin-fold thickness were 44%, 47%, 5%, and 36%, respectively. There were significant genetic, but not environmental, correlations between IMT and BMI, waist circumference, and skin-fold thickness. There were no genetic or environmental correlations between IMT and WHR. CONCLUSIONS: We found a substantial genetic contribution to IMT, BMI, waist circumference, and skin-fold thickness. Obesity and IMT may share common genetic factors. Future gene mapping studies are warranted to identify genes predisposing to IMT and obesity in this population.

Carotid intima-media thickness is associated with allelic variants of stromelysin-1, interleukin-6, and hepatic lipase genes: the Northern Manhattan Prospective Cohort Study.

BACKGROUND AND PURPOSE: Atherosclerosis is a complex disorder with hereditary and environmental causes. Carotid artery intima-media wall thickness (IMT) is a useful measure of atherosclerosis. The objective of this study was to determine the association between carotid IMT and functional promoter variants of stromelysin-1 (MMP3: -1612 5A>6A), interleukin-6 (IL6: -174G>C), and hepatic lipase (HL: -480C>T) genes. METHODS: B-mode carotid ultrasound was performed among 87 subjects (mean age, 70+/-12 years; 55% women; 60% Caribbean-Hispanic, 25% black, and 13% white) from the Northern Manhattan Prospective Cohort Study. Carotid IMT was calculated as a composite measure (mean of the maximum IMT in the bifurcation, the common carotid artery, and the internal carotid artery). RESULTS: For all polymorphisms, genotype distribution was not significantly different from Hardy-Weinberg equilibrium. The frequencies of the rare alleles were as follows: MMP3 -1612 5A>6A, 0.31 (95% CI, 0.25 to 0.39); IL6 -174 G>C, 0.20 (95% CI, 0.13 to 0.25); and HL -480 C>T, 0.45 (95% CI, 0.35 to 0.50). Carotid IMT in the sample was 0.78+/-0.18 mm. Subjects with the MMP3 genotype 6A6A had 8% greater mean carotid IMT than the other MMP3 genotypes combined (0.95+/-0.17 versus 0.87+/-0.15 mm; P=0.04). Subjects with the IL6 genotype GG had 11% greater IMT (0.85+/-0.17 versus 0.76+/-0.16 mm; P=0.03), and those with the HL genotype CC had 13% greater IMT (0.87+/-20 versus 0.76+/-0.18 mm; P=0.02) than the other genotypes combined. Adjustment for other risk factors did not change these associations. CONCLUSIONS: Carotid IMT is higher among subjects homozygous for functional variants in genes related to matrix deposition (MMP3 -16126A), inflammation (IL6 -174G), and lipid metabolism (HL -480C). These associations were independent of race-ethnicity and some environmental exposures. Further studies are needed to confirm these genotype-phenotype associations.

Leukocyte lysosomal enzymes in Alzheimer's disease and Down's syndrome.

Previous studies suggested the possibility of accelerated lysosomal degradation of brain gangliosides in Alzheimer's disease (AD). As AD pathology affects both neural and nonneural tissues, the aim of this study was to determine possible changes of glycosphingolipid metabolism in available peripheral cells in AD and Down's syndrome (DS). The activities of several lysosomal enzymes involved in catabolism of gangliosides and sulfatides were measured in leukocytes from subjects with dementia of the Alzheimer type, DS, and age-matched controls, by fluorimetry and spectrophotometry using specific substrates. The results showed a statistically significant increase of beta-galactosidase activity in both dementia of the Alzheimer type and DS leukocytes when compared with age-matched controls (p <.01 and p <.05, respectively; Student's t test). Not significantly increased activities of beta-galactosidase, beta-hexosaminidase, beta-hexosaminidase A, and slightly decreased activity of arylsulfatase A were observed in control leukocytes with aging. Our results indicate that a metabolic dysfunction and the acceleration of at least some lysosomal catabolic pathways are present in AD and DS nonneural cells.