Traditional Risk Factors are Causally Related to Carotid Intima-Media Thickness Progression : Inferences from Observational Cohort Studies and Interventional Trials

In the present review, associations between traditional vascular risk factors (VRFs) and carotid intima-medial thickness progression (C-IMTp) as well as the effects of therapies for VRFs control on C-IMTp were appraised to infer causality between each VRF and C-IMTp. Cohort studies indicate that smoking, binge drinking, fatness, diabetes, hypertension and hypercholesterolemia are associated with accelerated C-IMTp. An exception is physical activity, with mixed data. Interventions for the control of obesity, diabetes, hypertension and hypercholesterolemia decelerate C-IMTp. Conversely, scarce information is available regarding the effect of smoking cessation, stop of excessive alcohol intake and management of the metabolic syndrome. Altogether, these data support a causative role of several traditional VRFs on C-IMTp. Shortcomings in study design and/or ultrasonographic protocols may account for most negative studies, which underlines the importance of a careful consideration of methodological aspects in investigations using C-IMTp as the outcome

A priori-defined Mediterranean-like dietary pattern predicts cardiovascular events better in north Europe than in Mediterranean countries

The Mediterranean Diet (MD) is a model of healthy eating contributing to a favorable health status, but its clinical usefulness is still debated. The aim of this study was to relate the adherence to MD with the incidence of cardio/cerebro-vascular events (VEs) in north and south European participants of the IMPROVE study

Association of lifelong occupation and educational level with subclinical atherosclerosis in different European regions. Results from the IMPROVE study

Background and aims We aimed to examine the association between socioeconomic status (SES) and subclinical atherosclerosis, as assessed by carotid intima-media-thickness (C-IMT) and to investigate whether the effect of social inequality on C-IMT is mediated by cardiovascular (CV) risk factors and whether it is dissimilar in men and women, and in different European countries. Methods We assessed the association of lifelong occupation and educational level with C-IMT in the IMPROVE study cohort including 3703 subjects (median age 64.4 years; 48% men) from Southern (Italy), Western (France and the Netherlands) and Northern Europe (Finland and Sweden). Three summary measures of C-IMT (IMTmean, IMTmax, IMTmean-max), obtained from four segments of both carotids, were considered. Results After adjusting for conventional CV risk factors, current employment status and diet, C-IMT was higher in manual workers than in white collars (+7.7%, +5.3%, +4.6% for IMTmax, IMTmean-max and IMTmean, respectively; all p<.0001). Similar results were obtained by stratification for educational level. The effect of occupation on C-IMT was comparable in men and women and in different age groups, and was only partially mediated by differences in CV risk factors. Of note, the association of C-IMT with occupation was significant in Western and Northern Europe but not in Italy, with a significant statistical interaction (p = .0005). Conclusions Low SES was associated with subclinical atherosclerosis in subjects with at least three CV risk factors. Such association was stronger in Northern and Western Europe than in Italy. This difference was not completely explained by inequalities in CV risk factors and behavioural variables

Light or regular cigarette smoking: effect on brachial artery flow mediated dilation

AIM: Many smokers use light cigarettes in the belief that this may reduce the risk for health. In this study we investigated whether the effect of cigarette smoking on brachial artery flow mediated dilation (FMD%) is related to the cigarettes\u2019 content of tar, nicotine or carbon-monoxide. METHODS: 206 subjects (59% men, age 52\ub113 yr) participated in the study. FMD% was measured by B-mode ultrasound. Smoking habits were recorded on the basis of a face-to-face interview. Cigarettes\u2019 were defined as \u201clight\u201d or \u201cregular\u201d on the basis of a content of tar, nicotine and carbon monoxide above or below their respective medians. The chronic effect was assessed in 53 consumers of light cigarettes, 85 consumers of regular cigarettes and 68 never smokers. The acute effect was assessed in 51 and 29 smokers, who smoked a single light or regular cigarette smokers, respectively. In these subjects, FMD% was measured before and 10 min after smoking. RESULTS: FMD% of both light (5.66\ub13.18%) and regular cigarettes (6.15\ub13.33%) consumers were lower than that of never smokers (8.86\ub13.41%, p0.05). Both types of cigarettes induced an acute reduction of FMD% (Both p0.05). CONCLUSIONS: Consumption of light cigarettes does not reduce the detrimental effect of smoking on FMD% observed in consumers of regular cigarettes

Assessment and relevance of carotid intima-media thickness (C-IMT) in primary and secondary cardiovascular prevention

Interventions aimed to prevent cardiovascular diseases (CVD) are more effective if administered to subjects carefully selected according to their CVD risk. Usually, this risk is evaluated on the basis of the presence and severity of conventional vascular risk factors (VRFs); however, atherosclerosis, the main pathologic substrate of CVD, is not directly revealed by VRFs. The measurement of the arterial wall, using imaging techniques, has increased the early identification of individuals prone to develop atherosclerosis and to quantify its changes over time. B-mode ultrasound is a technique which allows a non-invasive assessment of the arterial wall of peripheral arteries (e.g. extracranial carotid arteries), and provides measures of the intima-media thickness complex (C-IMT) and additional data on the occurrence, localization and morphology of plaques. Being an independent predictor of vascular events, C-IMT has been considered as a tool to optimize the estimation of CVD risk but this application is still a matter of debate. Though the technique is innocuous, relatively inexpensive and repeatable, its use in the clinical practice is limited by the lack of standardized protocols and clear guidelines. This review outlines the rationale for the potential use of C-IMT in the stratification of cardio- and cerebro-vascular risk and discusses several topics related to the measurement of this variable, which are still controversial among experts of the field

L-arginine does not improve endothelial function in patients with metabolic syndrome

AIM: Metabolic syndrome (MS) is associated with impaired endothelial function. In this study we investigated whether L-Arginine improves endothelial dysfunction in patients with MS. METHODS: In a randomized double blind study, 38 subjects with MS received either 6.64 g/die of L-Arginine (n=19, group A) or placebo (n=19, group B) for 6 weeks. Flow mediated dilatation (FMD), systolic and diastolic blood pressure, visceral obesity, lipids, blood glucose, insuline, L-arginine, total NOx and symmetric and asymmetric dimethylarginine (SDMA and ADMA) were measured at baseline (T0) and at the end of the study (T6). RESULTS: At baseline, groups A and B differed just for waist circumference (100\ub17 vs. 107\ub112 cm; p<0.05). After treatment, beside the expected increases in both L-arginine (from 83\ub117 to 97\ub126 \ub5M; p=0.002) and of L-arginine/ADMA ratio (from 215\ub140 to 243\ub153; p=0.002) no change was detected in L-arginine treated group. An increase of total cholesterol (from 173\ub147 to 184\ub144 mg/dL, p=0.027), LDL (from 95\ub126 to 109\ub134 mg/dL, p=0.012), HDL (from 44\ub17 to 46\ub18 mg/dL, p=0.003) and ADMA (from 0.39\ub10.07 to 0.42\ub10.09 \ub5M, p=0.005) was observed in the placebo group. After data adjustment for possible confounders (age, pack-years and change in ADMA, arginine, blood glucose and pharmacological treatments) FMD significantly increased in the L-arginine treated group but not in the placebo group. Group A difference in FMD, however, lost its statistical significance after adjustment of the analysis for Brachial artery diameter measured at rest. CONCLUSIONS: The oral supply of L-Arginine does not influence the endothelial function in patients with MS

Familial aggregation of carotid artery intima media thickness: a three-generation study

BACKGROUND: Family history of premature cardiovascular events (FHPCE) is an independent risk factor for atherosclerosis and for vascular events, partially explainable by genetic or environmental atherosclerosis risk factors. Carotid intima media thickness (IMT) is a widely accepted subclinical marker of carotid and coronary atherosclerosis. On this basis, some authors have tried to confirm the nature of FHPCE as a risk factor for atherosclerosis by evaluating the amount of \u201coffspring-carotid IMT variability\u201d explained by parent\u2019s IMT. These studies, however, reported contrasting results with an amount of offspring IMT variability explained by parent\u2019s IMT ranging from 20 to 92%.(Moskau S et al., Stroke 2005;36;5-8) We hypothesized that these discrepancies might be related to the age of generational pairs (parent \u2013 offspring) studied. The contribution of parent\u2019s-IMT to offspring-IMT variability in relatively young generational pairs (for example when parent-age is lower than 60) might, in fact, be different from the one evaluated in generational pairs relatively older (for example parent-age>75) in which environmental factors might have had the time to act as confounders. METHODS: Sixty-seven grandchildren (33 men and 34 women), one of their parents (37 men and 30 women) and one of their grandparents (18 men and 49 women), were recruited. Each of them had their CC-IMTmean, Bif-IMTmean, ICA-IMTmean and IMTmean measured by B-Mode ultrasound. Simple linear regression analysis was used to investigate correlations between carotid IMT in the young generational pairs (grandchildren vs parents) as well as in the old generational pairs (parents vs grandparents). For each generational pairs, the squared correlation coefficient (r2) was used to evaluate the extent of offspring\u2019s carotid IMT variability explained by the carotid IMT of their respective parents. RESULTS: The mean age (\ub1SD) of grandparents, parents and children was 70\ub18.3, 44\ub19.1 and 14\ub18.7, respectively. The corresponding figures for IMTmean was 1.17\ub10.19 mm, 1.11\ub10.35 mm and 1.06\ub10.28 mm, respectively. Mean carotid IMT variables of progenitors correlated with carotid IMT of their offspring in the young generational pairs (IMTmean: r2 =0.34 p<0.0001; IMTmax: r2 =0.21, p=0.001) but not in the old generational pairs. CONCLUSIONS: Familial aggregation of carotid IMT is better appreciable in the young generational pairs. This may be due to the higher prevalence of potential confounding environmental factors in the older generational pairs

Is the enlargement of brachial artery diameter a novel marker of atherosclerotic risk?

Background. During the atherogenic process, the arterial diameter measured in plaques free areas tends to enlarge. This enlargement does not reflect the process defined "vascular remodeling", which occurs primarily as a local response to the rheological changes induced by the presence of atherosclerotic plaques, but rather it occurs as simple compensatory response of arteries to the presence of atherosclerosis risk factors. Several studies suggested this arterial enlargement as a further surrogate marker of atherosclerosis. In a recent study (1), we have shown that the addition of the inter-adventitia common carotid artery diameter (ICCAD) measured in plaque-free areas to algorithms for the assessment of global cardiovascular risk improves the patient's risk stratification. However, carotid arteries are rarely free of atherosclerotic lesions, especially in adult or elderly subjects, and even if the measures are taken in plaque free areas, it cannot be excluded the presence of plaques in the surroundings which might alter the vessel rheology, thus being the indirect responsible of the enlargement observed. Some studies have recently evaluated the diameter of other arterial districts known to be less prone to the development of atherosclerosis lesions. Most of these studies, focused on the brachial artery diameter (BAD), indicate that the arterial enlargement is a generalized phenomenon, and suggest that, as carotid diameter, also the enlargement of this arterial district may be useful to further improve the prediction of vascular events. All these studies, however, have been carried out in relatively small samples. In addition, limited information is available regarding the determinants of the enlargements evaluated simultaneously in different vascular districts. Aim of the Study. To validate, in a large sample, the role of BAD as an independent marker of atherosclerosis and to investigate whether the addition of BAD measurements to ICCAD measurements may actually offer additional information for the definition of patients' cardiovascular risk profile. Methods. 4641 patients (44.6% women and 55.4% men; age (mean\ub1SD) 58\ub113 and 55\ub113, respectively) have their BAD, ICCAD and carotid Intima media thickness (C-IMT) measured by B-Mode ultrasound. Measurements have been taken during the first visit at the Centro Dislipidemie E. Grossi Paoletti, (Ospedale Ca' Granda di Niguarda) or at the Centro Cardiologico Monzino, IRCCS. Both BAD and ICCAD were measured in plaque free areas. A total of 4271 subjects were asymptomatic, whereas 335 (64 women and 27I men) experienced a myocardial infarction and 35 (11 women and 24 men) a stroke. Results. BAD was associated with the prevalence of vascular events in both women and men. After adjustment for age, traditional risk factors, C-IMT and ICCAD, this associations persisted in women (O.R and CI: 2.2 [1.1-4.4]; p<0.05) but not in men (O.R and CI: 1.1 [0.8-1.7]; p=NS). When the analysis was performed considering myocardial infarction and stroke separately, it becomes clear that the observed significant association was mainly due to association with myocardial infarction (O.R and CI: 2.6 [1.2-5.6]; p<0.05). BAD was closely associated with ICCAD (Beta of about 0.30\ub10.03; P<0.0001, in both sexes). Despite this, determinants of the enlargement of the two vascular districts were very different. (For example, the relationship between BAD and the Framingham risk score was two times lower than that observed with ICCAD). Conclusions. The BAD is an independent marker of myocardial infarction, which, at least in women, may provide information which is complementary to that coming from vascular risk factors and ICCAD. Reference: 1. Baldassarre. J Am Coll Cardiol. 2012:60:1489-99

Familial aggregation of carotid intima media thickness is better appreciable in young generational pairs

AIM: Carotid intima media thickness (C-IMT) aggregates at family level. It has been reported that the amount of offspring C-IMT variability explained by parents' C-IMT ranges from 20 to 92%. To assess whether this wide range of association is related to the age of generational pairs studied, we compared the amount of offspring C-IMT variability explained by parents\u2019 C-IMT detected in \u201cyoung generational pairs\u201d (offspring in paediatric age) with that of \u201cold generational pairs\u201d (parent in geriatric age). METHODS: We studied 201 individuals from 67 families, each consisting of a grandchildren, a parent and a grandparent. Each of them had C-IMTmean and C-IMTmax measured. The amount of offspring C-IMT variability explained by C-IMT of parents was expressed in terms of squared correlation coefficients (r2). The r2 of young and old generational pairs were then compared. RESULTS: The mean age (\ub1SD) of grandparents, parents and children was 70\ub18.3, 44\ub19.1 and 14\ub18.7, respectively. The corresponding figures for C-IMTmean was 1.17\ub10.19 mm, 1.11\ub10.35 mm and 1.06\ub10.28 mm, respectively. C-IMT variables of parents correlated with C-IMT of their offspring just in the young generational pairs (C-IMTmean: r2=0.34 p<0.0001; C-IMTmax: r2=0.21, p=0.001) but not in the old generational pairs. Analogous results were obtained when the analyses were repeated in groups homogeneous for gender (father Vs. son, mother Vs. daughter, etc). CONCLUSIONS: Familial aggregation of C-IMT is appreciable only in young generational pairs. This might be due to the fact that in older generational pairs, familial aggregation is masked by a higher prevalence of environmental confounders

The effects of tobacco smoke and of the social class on carotid intima media thickness (c-IMT) and on c-IMT progression are stronger in women than in men

Background: The harmful effect of smoking on atherosclerosis and cardiovascular health is well established. Educational campaigns have been successful in reducing the number of smokers in men but not in women, where the number of smokers (initially lower than men) is even increasing. Aim of the study: To investigate the gender differences in the association of tobacco smoke with subclinical atherosclerosis and atherosclerosis progression also taking into account the effects of other variables strongly associated with tobacco smoke: C reactive protein (CRP) and number of white blood cells (WBC) as inflammation markers, and education as an index of social class. Methods: The IMPROVE Study cohort includes 1694 men and 1893 women (age 54-79 yr) at high risk of cardiovascular disease of five European countries. Baseline mean and maximum IMT of the left and right common carotids, bifurcations and internal carotid arteries and the fastest IMT-progression (15 months of follow up) detected in the whole carotid tree regardless of its location were computed. Associations were assessed by multivariable analysis adjusting for conventional cardiovascular risk factors and recruiting centre. Results: Pack-years, a lifelong index of tobacco exposure, significantly associated with baseline C-IMT in both genders. However, the estimated C-IMT increase for each pack-year was more than double in women than in men (3.7\ub10.7 vs. 1.5\ub10.5 \ub5m) with a significant gender 7 dose interaction (P=0.01). Moreover, the estimated increase in the fastest C-IMT progression associated with a unit of cigarettes/day, an index of daily dose of tobacco exposure, was more than five-fold in women than in men (5.5\ub11.3 vs. 1.0\ub11.3 \ub5m/yr), (P-int =0.008). Also the relationships between C-IMT and CRP (P-int =0.015), WBC (P-int =0.011) and education (P-int =0.014) were different in men and women. Gender differences were also observed considering the relationships between current smoking and CRP (P-int =0.045) and WBC (P-int =0.049). Finally, a significant gender difference was also found in the relationship between education and smoking exposure (P-int =0.0003). Conclusions. The effects of tobacco smoking on cross-sectional subclinical atherosclerotic burden, and on carotid atherosclerosis progression appear to be more harmful in women than in men, prompting studies on gender specific mechanisms and development of preventive actions expressly oriented to women. Inflammation and social class seems to be implicated in the complex interrelation between tobacco smoke, gender and subclinical atherosclerosis