A family history of vascular disease is an independent risk factor for both large-vessel atherosclerosis and small-vessel disease, especially in cases presenting before age 65 years. The estimated sample sizes for case-control studies illustrate how candidate gene studies for ischemic stroke might be made more effective by focusing on these specific phenotypes, in which the genetic component of the disease appears to be strongest.

Abstract-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 (nϭ554) aged 18 to 80 years (56% females) classified as current smokers (nϭ150), ex-smokers (nϭ136), and nonsmokers (nϭ268). Ex-smokers were categorized into Ͻ1 year, Ͼ1 and Ͻ10 years, and Ͼ10 years of smoking cessation. Key Words: smoking Ⅲ arterial stiffness Ⅲ pulse wave velocity Ⅲ augmentation index Ⅲ hypertension Ⅲ smoking cessation C igarette smoking is one of the most important avoidable causes of cardiovascular diseases worldwide, 1 and arterial stiffness may be one of the underlying pathophysiological mechanisms. Chronic cigarette smoking has been shown to be associated with increased arterial stiffness 2,3 and increases immediately after smoking 1 cigarette. 3 The standard measurement of arterial stiffness, aortic pulse wave velocity (PWV) in conjunction with augmentation index (AIx), an estimate of aortic wave reflection, provide a comprehensive assessment of arterial stiffness. 4 There is evidence that both PWV 5,6 and AIx 7 are independent predictors of cardiovascular events.Smoking cessation is an important lifestyle measure for the prevention of cardiovascular disease, and patients with myocardial infarction may experience as much as a 50% reduction in risk of reinfarction, sudden cardiac death, and total mortality if they quit smoking. 8 However, the speed and magnitude of risk reduction when a smoker quits is debatable, with studies quoting 3 to 20 years of smoking cessation associated with significant risk reductions in coronary artery disease. 8 Whether long-term smoking cessation is associated with a reduction in arterial stiffness compared with chronic smokers is not known. Therefore, we compared differences in arterial stiffness among nonsmokers, ex-smokers, and current smokers in a cross-sectional study. Methods SubjectsA total of 554 untreated subjects aged 18 to 80 years (47.8Ϯ0.6 years, meanϮSEM), 56% female, undergoing assessment for hypertension, were studied. None of the patients had secondary hypertension, coronary artery disease, valvular heart disorders, dysrhythmias, diabetes, heart failure, or renal impairment, and none were taking any vasoactive drugs. Current smokers were defined as those who had smoked Ͼ1 cigarette per day for Ն1 year, nonsmokers as those who had never smoked, and former or ex-smokers as those who had stopped smoking Ն1 month before examination. Ex-smokers were categorized into 3 subgroups according to smoking cessation duration: those who quit cigarette smoking for Ͻ1 year, between 1 and 10 years, and Ͼ10 years.Body weight, height, waist, and hip measurements were recorded in each patient. Body mass index (BMI) was calculated as body weight (kilograms) divided by height (meters squared), and the waist:hip ratio was calculated....

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 (nϭ3383), ICA-IMT, BIF-IMT, CCA-IMT, and vascular risk factors were evaluated at baseline and at 3-year follow-up. 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. Results-Mean

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; PϽ0.001, 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; Pϭ0.007) and cardioembolic disease (odds ratio, 0.54; 95% confidence interval, 0.37 to 0.80; Pϭ0.002). 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.

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-β-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 ≥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-β-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.

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.

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 (nϭ1000; 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; Pϭ0.014). Interactions were seen between genotype and alcohol consumption for both IL-6 levels and CCA-IMT. In individuals who drank Ͼ30 g/d of alcohol, the CC genotype was associated with higher IL-6 levels, elevated CCA-IMT (Pϭ0.001), and increased risk of carotid plaque (OR, 3.64; 95% CI, 1.15 to 11.54; Pϭ0.028). 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.

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.