CAROTID INTIMA-MEDIA THICKNESS (C-IMT) : BIOMARKER, SURROGATE END POINT OR BOTH?

Intima-media thickness of extracranial carotid arteries (C-IMT) is a non-invasive marker of early arterial wall alteration, which is easily assessed by high resolution B-mode ultrasonography, and more and more widely used in clinical research. Measurement of C-IMT has been extensively validated using different approaches, in order to reduce intra- and inter-observer variability. A number of cross sectional studies indicate that C-IMT correlates with conventional or certain emerging cardiovascular risk factors, as lipoproteins, psychosocial status and hyperhomocysteinemia. In addition, C-IMT is associated with the incidence of coronary artery disease, detected by angiography, ECG or clinically. Thus, C-IMT satisfies the criteria for biomarker definition. Moreover, on the basis of the results of cross sectional studies C-IMT has been chosen as a "surrogate end point" to evaluate the effects of pharmacological intervention aimed at reducing atherosclerosis risk factors. A variety of cardiovascular drugs, with different mechanisms of action, have been shown to influence C-IMT. In addition, pharmacologically induced changes in C-IMT have been associated with concomitant reduction of cardiovascular events, which further supports the C-IMT as a surrogate index of atherosclerotic disease. The translation of the concept of C-IMT from biomarker to that of surrogate end point, however, requires additional evidence showing that C-IMT progression is an effective predictor of new vascular events. Studies, however, evaluating the relationship between C-IMT progression and cardiovascular events, are still limited. To fill this gap, we have designed the IMPROVE study. The IMPROVE is a multicentre, longitudinal (three years), observational study, funded by EU, aimed at defining the predictive properties of IMT progression of future cardiovascular events in a population of high risk patients. The study involves seven clinical centres, which have the responsibility of patient enrolment and of ultrasonic studies, and two not recruiting centres for the assessment of the prevalence of polymorphisms of candidate genes. Primary objectives are: a) the association between 15 month C-IMT progression of carotid artery and the rate of vascular events (from the 15th to the 36th month of follow up) in 3600 subjects with at least three vascular risk factors b) the association between cross-sectional carotid arteries C-IMT and the rate of vascular events. Secondary objectives are the evaluation of the effects of gene polymorphisms, lipid peroxidation, socio-economic and psychological variables on C-IMT progression. Positive results emerging from this study will clearly hold major implications for the management of patients, and for further therapeutic advances in the prevention of cardiovascular diseases.