Differences in stroke subtypes between black and white patients with stroke: the South London Ethnicity and Stroke Study.

BACKGROUND: Determining whether the distribution of stroke subtypes differs between ethnic groups is important in understanding the mechanisms of the increased stroke incidence in black patients. METHODS AND RESULTS: In this study, 600 black and 600 white patients with stroke were prospectively and consecutively recruited to determine differences in stroke subtypes. The pathophysiological Trial of Org 10172 (TOAST) classification was used and compared with a clinical (Oxfordshire Community Stroke Project) subtype classification. Stroke subtypes were determined by one investigator by review of original imaging. Black patients with stroke were significantly younger and had higher prevalences of hypertension, diabetes, and obesity. They were less likely to be smokers and had lower prevalences of myocardial infarction and atrial fibrillation. In the black patients, 33% of stroke was due to cerebral small vessel disease compared with 14% in the white stroke cohort (odds ratio, 2.94; 95% confidence interval, 1.97 to 4.39; P<0.001, controlling for age, gender, cardiovascular risk factors, and social class). The black stroke cohort had less large vessel atherosclerosis (odds ratio, 0.49; 95% confidence interval, 0.29 to 0.82; P=0.007) and cardioembolic disease (odds ratio, 0.54; 95% confidence interval, 0.37 to 0.80; P=0.002). Using a classification based on clinical syndrome alone gave a higher estimate of the frequency of small vessel disease stroke, particularly in white patients. CONCLUSIONS: A relative excess of small vessel disease was observed in black patients with stroke compared with an excess of extracranial atherosclerosis and cardioembolic stroke in white patients with stroke that was independent of conventional risk factors and social class. Whether these excesses are due to differences in genetic susceptibility or as-yet undetermined differences in environmental risk remains to be determined.

Ambulatory arterial stiffness index, pulse wave velocity and augmentation index--interchangeable or mutually exclusive measures?

BACKGROUND: The ambulatory arterial stiffness index (AASI) has been proposed as a novel measure of arterial stiffness and has been prospectively shown to predict stroke and cardiovascular death, but not cardiac death. This index has prompted considerable controversy as to whether it is a true measure of arterial stiffness. OBJECTIVE AND METHODS: The present study aimed to examine three different measures of arterial stiffness - pulse wave velocity (PWV; Complior), wave reflection [augmentation index (AIx)] and AASI - in a large hypertensive population, comparing their determinants and intercorrelations, both unadjusted and adjusted for confounders, and using Bland-Altman analysis to determine 95% confidence intervals for the ability of the AASI to predict PWV, the proposed gold standard of arterial stiffness. RESULTS: The AASI correlated univariately with both PWV and the AIx in individuals overall (r = 0.28 for PWV and r = 0.24 for AIx; both P < 0.001) and in those with untreated or treated hypertension. Adjustment for age in the current study negated entirely the positive correlation between the AASI, PWV and AIx. Additional adjustment for confounders did not significantly alter these nonsignificant relationships. Furthermore, the 95% prediction limits for the AASI to predict PWV were +/- 4.18 m/s and for the AASI to predict AIx were +/- 25.4%, suggesting that the methods would not be interchangeable in a clinical setting. Direct comparative studies would be required to establish the relative predictive strength of each measure and whether combining measures can provide additional risk prediction. Until such data become available, we propose that the measures should not be considered interchangeable.

Circadian blood pressure variation: relationship between dipper status and measures of arterial stiffness.

BACKGROUND: Compared with dippers, hypertensive individuals with a nondipping nocturnal blood pressure (BP) profile have more target organ damage and a worse cardiovascular prognosis, potentially mediated through arterial stiffness. OBJECTIVE: To examine arterial stiffness and dipping in a population of 314 untreated hypertensive individuals, mean age 48 +/- 8 years, 55% men. METHODS: Dipping was defined as a 10-20% fall in nocturnal BP; extreme dipping as greater than 20%, nondipping as less than 10%, and reverse-dipping as 0% at most fall in nocturnal BP. Aortic pulse wave velocity (PWV) (Complior) and augmentation index (Sphygmocor) were measured. RESULTS: Groups did not differ by age, gender, 24-h or daytime mean BP, body mass index, smoking, cholesterol, glucose, renin or aldosterone. The relationship between PWV and dipper-status was J-shaped, with extreme-dippers and reverse-dippers having the highest PWV. Nondippers and reverse-dippers had significantly higher age and sex-adjusted PWV compared with dippers. Following multivariate adjustment for age, gender, mean arterial pressure, heart rate and smoking, reverse-dippers had significantly higher PWV than either dippers or nondippers (P = 0.005 and P = 0.006, respectively). Dipper status was not associated with augmentation index. CONCLUSIONS: A reverse-dipper pattern, corresponding to the 95% percentile of the night: day BP ratio on ambulatory BP monitoring, identifies a population group with increased PWV. This difference could not be explained by the measured risk factors. Reverse-dippers had significantly less day: night variability in heart rate and wider pulse pressures at night than any of the other groups, suggesting altered sympathetic tone at night as a potential mechanism.

Early carotid atherosclerosis and family history of vascular disease: specific effects on arterial sites have implications for genetic studies.

OBJECTIVE: Carotid artery intima-media thickness (IMT) is an intermediate phenotype for atherosclerosis. In a community population (n=5400), we determined whether a parental history of myocardial infarction (MI) or stroke is associated with increased IMT and whether associations differ at specific sites in the carotid arterial tree. METHODS AND RESULTS: Using regression modeling, the proportion of IMT that remains unexplained after controlling for vascular risk factors was determined. A parental history of stroke was associated with both increased common carotid artery (CCA) and increased internal carotid artery (ICA)-IMT, but in young individuals (

Evaluating the genetic component of ischemic stroke subtypes: a family history study.

BACKGROUND AND PURPOSE: Twin and family history studies support a role for genetic factors in stroke risk. Because the etiology of ischemic stroke is heterogeneous, genetic factors may vary by etiologic subtype. We determined the familial aggregation of stroke risk in different stroke phenotypes and used the results to model estimated sample size requirements for case-control studies. METHODS: One thousand consecutive white subjects with ischemic stroke and 800 white controls matched for age and sex were recruited. A first-degree family history of stroke and myocardial infarction was obtained by structured interview. Stroke subtype was determined with the use of modified Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. RESULTS: A family history of stroke at < or =65 years was a significant risk factor for large-vessel disease (odds ratio [OR], 2.24; 95% CI, 1.49 to 3.36; P<0.001) and for small-vessel disease (OR, 1.93; 95% CI, 1.25 to 2.97; P=0.003). When only cases aged

Promoter polymorphism in the endotoxin receptor (CD14) is associated with increased carotid atherosclerosis only in smokers: the Carotid Atherosclerosis Progression Study (CAPS).

BACKGROUND AND PURPOSE: The risk of atherosclerosis from endotoxemia is increased in smokers. Endotoxin is a potent mediator of inflammation, and smokers have elevated plasma levels of endotoxin. The endotoxin receptor CD14 can enhance the endotoxin-neutralization capacity of plasma. A functional polymorphism in the promoter region of the CD14 gene (CD14 -159C/T) was studied to determine its impact on common carotid artery (CCA) intima-media thickness (IMT) and any interactions with environmental inflammatory stimuli. METHODS: A community population (n=992; aged 50 to 65 years) underwent genotypic examination for the CD14 -159 polymorphism by restriction fragment length polymorphism analysis. RESULTS: The CC genotype was associated with increased CCA IMT. The age- and sex-adjusted odds ratio for IMT above the 75th percentile was 1.63 (95% CI, 1.19 to 2.24; P=0.002) and 1.70 (95% CI, 1.18 to 2.44; P=0.004) after additional adjustment for conventional risk factors. This gene effect was found only in current smokers and ex-smokers. Multivariate analysis in this group (n=503) increased the odds ratio to 2.02 (95% CI, 1.23 to 3.34; P=0.006). No significant interactions were found in nonsmokers or with alcohol consumption. CONCLUSIONS: The CD14 -159 polymorphism is associated with increased CCA IMT in smokers from a general population. CD14 may modulate the inflammatory effects of smoking in atherogenesis.

Inflammatory gene load is associated with enhanced inflammation and early carotid atherosclerosis in smokers.

BACKGROUND AND PURPOSE: Smoking acts as a pro-inflammatory stimulus. Inflammation may provide a key mechanism by which smoking causes atherosclerosis. If so, then the degree to which an individual mounts an inflammatory response is likely to influence atherosclerosis severity. This study examined the impact of inflammatory gene polymorphisms and gene-smoking interactions on common carotid artery intima-media thickness (IMT), a measure of early atherosclerosis. METHODS: In a community population (n=1000), mean IMT was determined using ultrasound. This population was genotyped for 6 polymorphisms in 4 inflammatory genes: IL-6-174, IL-6-572, and IL-6-597; IL-1-beta-31; IL-1 receptor antagonist VNTR and CD14-159. Serum IL-6 levels were measured in the first 500 subjects. Genotypes/haplotypes associated with higher IL-6 levels were designated "inflammatory haplotypes." A gene load score was calculated, in which 2 represented individuals homozygous for > or =2 inflammatory genotypes/haplotypes and 0 was homozygous for none. RESULTS: Increasing gene load of inflammatory genotypes was associated with a linear increase in serum IL-6 levels (P=0.018) and increased carotid artery IMT (P=0.003). There was a significant interaction between gene load and smoking status on carotid IMT (P for interaction=0.002). Specifically, in smokers, carriers of inflammatory haplotypes had significantly increased age- and sex-adjusted IMT (IL-6-174C/IL-6-572G/IL-6-597A, P=0.005; IL-1-beta-31T/IL-1RN*2,P=0.04; CD14-159CC, P=0.028). CONCLUSIONS: These findings support the hypothesis that inflammation and cytokine responses provide a key mechanism by which smoking causes atherogenesis. Secondly, they highlight the importance of gene-environment, and gene-gene-environment interactions in the pathogenesis of atherosclerosis.

Rates and determinants of site-specific progression of carotid artery intima-media thickness: the carotid atherosclerosis progression study.

BACKGROUND AND PURPOSE: Carotid intima-media thickness (IMT) progression rates are increasingly used as an intermediate outcome for vascular risk. The carotid bifurcation (BIF) and internal carotid artery (ICA) are predilection sites for atherosclerosis. IMT measures from these sites may be a better estimate of atherosclerosis than common carotid artery (CCA) IMT. The study aim was to evaluate site-specific IMT progression rates and their relationships to vascular risk factors compared with baseline IMT measurements. METHODS: In a community population (n=3383), ICA-IMT, BIF-IMT, CCA-IMT, and vascular risk factors were evaluated at baseline and at 3-year follow-up. RESULTS: Mean (SD) IMT progression was significantly greater at the ICA (0.032 [0.109] mm/year) compared with the BIF (0.023 [0.108] mm/year) and the CCA (0.001 [0.040] mm/year) (P<0.001). Only ICA-IMT progression significantly correlated with baseline vascular risk factors (age, male gender, hypertension, diabetes, and smoking). Change in risk factor profile over follow-up, estimated using the Framingham risk score, was a predictor of IMT progression only. For all arterial sites, correlations were stronger, by a factor of 2 to 3, for associations with baseline IMT compared with IMT progression. CONCLUSIONS: Progression rates at the ICA rather than the CCA yield greater absolute changes in IMT and better correlations with vascular risk factors. Vascular risk factors correlate more strongly with baseline IMT than with IMT progression. Prospective data on IMT progression and incident vascular events are required to establish the true value of progression data as a surrogate measure of vascular risk.

Interleukin-6 promoter polymorphism modulates the effects of heavy alcohol consumption on early carotid artery atherosclerosis: the Carotid Atherosclerosis Progression Study (CAPS).

BACKGROUND AND PURPOSE: A J-shaped relationship has been demonstrated between alcohol and both clinical cardiovascular events and carotid atherosclerosis. A similar J-shaped relationship has been found between alcohol intake and inflammatory markers. If inflammation were on the intermediate causal pathway between alcohol intake and atherosclerosis, then genetic determinants of enhanced inflammation would be expected to modify this relationship. METHODS: In a large community population (n=1000; age, 50 to 65 years), we studied the effects of the interleukin-6 (IL-6)-174 polymorphism and gene-alcohol interactions on common carotid artery intima-media thickness (CCA-IMT) and carotid plaque. RESULTS: The CC genotype was associated with significantly higher IL-6 levels; the odds ratio (OR) for IL-6 in the top quartile was 2.07 (95% CI, 1.16 to 3.72; P=0.014). Interactions were seen between genotype and alcohol consumption for both IL-6 levels and CCA-IMT. In individuals who drank >30 g/d of alcohol, the CC genotype was associated with higher IL-6 levels, elevated CCA-IMT (P=0.001), and increased risk of carotid plaque (OR, 3.64; 95% CI, 1.15 to 11.54; P=0.028). The J-shaped relationship between alcohol intake and IMT was seen only for the CC genotype. CONCLUSIONS: These data suggest that the IL-6-174 promotor polymorphism may modulate the effects of alcohol on carotid atherosclerosis. These data support the hypothesis that inflammation forms part of the intermediate causal pathway between alcohol intake and atherosclerosis.

Ethnic differences in markers of thrombophilia: implications for the investigation of ischemic stroke in multiethnic populations: the South London Ethnicity and Stroke Study.

BACKGROUND AND PURPOSE: The role of hypercoagulable states in the pathogenesis of ischemic stroke in black subjects is not known, and data on normal reference ranges in black populations are lacking. This study estimated ethnic-specific reference ranges in a community population to determine the prevalence of thrombophilic states in a multiethnic stroke population. METHODS: Free protein S, protein C, antithrombin III, activated protein C resistance, IgG anticardiolipin antibodies, and lupus anticoagulant were determined in 130 consecutive ischemic stroke cases < or =65 years of age (50 black Caribbeans, 30 black Africans, 50 whites) and 130 community controls. RESULTS: Black African controls had significantly lower protein S (P<0.001) and protein C (P=0.049) and a trend toward lower antithrombin III (P=0.056) levels compared with white controls. Black Caribbean and African controls had higher diluted Russell's viper venom time ratios compared with whites (P=0.001, P<0.001). Using ethnic-specific reference ranges, 8 controls (6.3%) and 11 cases (8.5%) had thrombophilia abnormalities (odds ratio [OR], 1.39; 95% confidence interval [CI], 0.54 to 3.57; P=0.50). ORs were 0.96 (95% CI, 0.18 to 4.99; P=0.96) for whites, 1.57 (95% CI, 0.41 to 5.94; P=0.51) for black Caribbeans, and 2.07 (95% CI, 0.18 to 24.2; P=0.95) for black Africans. CONCLUSIONS: Failure to account for ethnic differences in the normal reference ranges for thrombophilia markers may lead to inappropriate diagnosis and investigation of hypercoagulable states in black individuals. Protein S and protein C deficiencies and lupus anticoagulant may contribute to stroke risk in a minority of black cases, but they are unlikely to be major contributors to the excess stroke risk seen in young individuals of African and African-Caribbean descent.

Impact of smoking and smoking cessation on arterial stiffness and aortic wave reflection in hypertension.

Cigarette smoking is an important modifiable cardiovascular risk factor and pathophysiological mechanisms may include a stiff vascular tree. Although smokers have stiffer arteries, whether smoking cessation is associated with reduced arterial stiffness is not known. We compared never-treated patients with essential hypertension (n=554) aged 18 to 80 years (56% females) classified as current smokers (n=150), ex-smokers (n=136), and nonsmokers (n=268). Ex-smokers were categorized into <1 year, >1 and <10 years, and >10 years of smoking cessation. Measurements included aortic stiffness, assessed as pulse wave velocity (Complior), wave reflection (augmentation index [AIx]), and transit time (T(R)) (Sphygmocor). Current and ex-smokers had significantly higher pulse wave velocity and AIx compared with nonsmokers (pulse wave velocity for current smokers: 10.7+/-0.2; ex-smokers: 10.6+/-0.2; nonsmokers: 9.9+/-0.1 m/s; P<0.001; AIx for current smokers: 31+/-1; ex-smokers: 30+/-1; nonsmokers: 27+/-0.8%; P<0.05), whereas T(R) was lower in current and ex-smokers compared with nonsmokers (T(R) for current smokers: 131+/-1.0; ex-smokers: 135+/-1; nonsmokers: 137+/-0.8 m/s; P<0.0001). There was a significant linear relationship between smoking status and pulse wave velocity (P<0.001), AIx (P<0.001), and T(R) (P<0.001), even after adjusting for age, sex, mean arterial pressure, heart rate, and body mass index. In ex-smokers, duration of smoking cessation had a significant linear relationship with improvement in pulse wave velocity (P<0.001), AIx (P<0.001), and T(R) (P<0.001), with arterial stiffness parameters returning to nonsignificant levels after a decade of smoking cessation.

Characteristics and treatment of asylum seekers reviewed by psychiatrists in an Irish inner city area.

OBJECTIVES: To assess social and educational status, trauma experienced, diagnosis and treatment of asylum seekers, who presented to psychiatrists in St James's hospital Dublin over a two-year period. METHOD: All files of asylum seekers assessed by psychiatrists in St James's hospital over a two-year period were scrutinised. Using a pro-forma, data was obtained about social and educational status, language skills, trauma suffered, diagnosis, treatment and follow-up. Demographic data was obtained from the Department of Justice, the Irish refugee centre and various social welfare offices. RESULTS: Over a two-year period 31 asylum seekers were in contact with this service. Most originated from Africa. Overall subjects were well educated but socially isolated with poor language skills. Many had been imprisoned or tortured, or had relatives or friends tortured or killed prior to migration. Almost one third met criteria for PTSD and greater than a third met criteria for major depression. The majority of subjects received pharmacological treatment, but few were offered psychological treatments. Most had no prior psychiatric diagnosis and dropped out of treatment at an early stage. CONCLUSIONS: Large numbers of asylum seekers are currently residing in Dublin and may need specialised psychological support and treatment. They have been exposed to significant levels of pre-migratory trauma, often have poor language skills and drop out of treatment quickly which may indicate dissatisfaction with existing treatment approaches. There is an urgent need for increased funding for the psychological needs of this vulnerable group, for the provision of trained interpreters, specialised psychotherapy and assessment of their needs.