DETERMINANTI DI ATEROSCLEROSI CAROTIDEA IN UNA POPOLAZIONE EUROPEA AD ALTO RISCHIO CARDIOVASCOLARE: ANALISI DEI DATI BASALI DELLO STUDIO IMPROVE

Background. Since many cardiovascular events occur in asymptomatic individuals and coronary heart disease is often fatal to its debut, the recognition and early treatment of patients at high risk of atherosclerosis represent the first step in reducing the incidence of atherothrombotic events. However, the capability to predict vascular events by using mathematical algorithms able to take into account of more than one risk factor for atherosclerosis is rather limited. Therefore, identification of markers of subclinical atherosclerosis is fundamental. Intima–media thickness or IMT of extracranial carotid arteries, measured by high-resolution B-Mode ultrasound, is the most widely accepted non-invasive marker of subclinical atherosclerosis, which has been used in clinical and epidemiological studies as a surrogate marker of prevalent and incident of coronary heart disease. Since the classical risk factors show poor correlation with carotid IMT (C-IMT), more important determinants of the development and progression of atherosclerosis apparently exist. For example, the lifestyle has a significant importance. Therefore, the identification of the major determinants of atherosclerosis and the study of their effect on the disease itself are extremely important. Aims. To achieve this aim was designed the “IMPROVE study”, a prospective, multicentre, longitudinal and observational study. The primary objective of the IMPROVE study was to investigate whether cross-sectional C-IMT and overall IMT progression are predictors of new vascular events in European individuals at high risk of cardiovascular disease for the presence of at least three conventional vascular risk factors (VRFs). Among the secondary end-points, there was the assessment of the determinants of C-IMT. This PhD thesis reports the results of the baseline analyses of the IMPROVE study to identify the major determinants of increased C-IMT. Methods. A total of 3711 subjects (1935 females and 1776 males, age range 54–79 years) with at least three VRFs were recruited in seven centres in Finland, France, Italy, the Netherlands and Sweden. Collected variables included clinical, biochemical, genetic, socioeconomic, psychological, nutritional and educational data, personal and family history of diseases, drug intake and physical activity. Results. By analysis of covariance, for anthropometric, clinical and lipid variables taken into account, both IMTmean and IMTmax were increased in men than in women and increased progressively with age, blood pressure and quintiles of leukocytes (all p<0.0001). C-IMT decreased progressively with HDL cholesterol (p<0.0001) and increased with LDL cholesterol (p<0.05). Regarding the variables related to nutrition taken into account, both IMTmean and IMTmax were positively associated with consumption of coffee and inversely associated with consumption of wine (all p<0.05). As the variables related to lifestyle concerned, only cigarette smoking (pack-years, years of smoking, number of cigarette smoking per day and years elapsed since smoking cessation) was associated with IMT (all p<0.001). The differences were statistically significant both before and after adjusting the analyses for possible confounding variables and similar results were obtained for all ultrasound variables considered. By multiple linear regression analysis, C-IMT was positively associated with latitude, age, gender, pulse pressure, pack-years and hypertension, and inversely with educational level (all p<0.0001 for IMTmean–max). Latitude was the strongest independent determinant of C-IMT (partial r2 for IMTmean–max =0.109, p<0.0001) and alone accounted for nearly half of the variation explained by the regression model (partial r2 for IMTmean–max =0.243, p<0.0001). The geographical gradient for C-IMT paralleled the well-known north-to-south cardiovascular mortality gradient (r2 for IMTmean =0.96). Conclusion. In a European population of subjects at high cardiovascular risk, among several anthropometric, clinical and lipid variables taken into account, only gender, age, blood pressure, leukocytes, HDL and LDL cholesterol appear to be strong independent determinants of subclinical atherosclerosis. Regarding the variables related to lifestyle and nutrition, only cigarette smoking, type of occupation and, in a less powerful, the consumption of wine and coffee seem to be independent determinants of C-IMT. This study reports an independent association between latitude and C-IMT in a large sample of European individuals presenting with at least three VRFs. The study not only shows that latitude explains a large proportion of the variation in C-IMT but also that the observed geographical gradient is independent of established and novel VRFs. This suggests that unknown mechanisms underlie this geographical gradient, candidates being heritable factors predisposing to (in the North) or protecting from (in the South) atherosclerosis. This study also shows that a large part of the risk for development of atherosclerosis is not explained by traditional risk factors. This finding underscores the importance of continuing the search for novel risk factors. The most likely place to find those risk factors are in genetics and/or environmental factors with a north to south gradient in Europe.