Biomarcatori ecografici di funzione e struttura vascolare nell'uomo Imaging biomarkers of vascular function and structure in humans

Cardiovascular (CV) disease is the first cause of mortality and morbidity in the world. Prevention of this condition, which is responsible of more than 2200 deaths per day only in United States, is a public health priority. Thus in the last decades great efforts have been made in the search of non-invasive biomarkers, able to identify the individual at risk for CV events in the asymptomatic, subclinical stage. Some biomarkers are currently recommended in order to improve stratification of CV risk, whereas other are considered useful only for research purposes. In particular, increased intima-media thickness of the common carotid artery (C-IMT), representing a marker of early atherosclerosis significantly correlated with coronary or cerebrovascular disease, has been considered as an intermediate stage in the continuum of vascular disease and as a predictor of CV risk. Current guidelines also introduced other vascular parameters evaluating mechanical and functional arterial properties of peripheral and central arteries. Increased aortic stiffness has been shown to predict future CV events and it has been recognized as a marker of subclinical target organ damage in hypertensive patients. Earlier vascular abnormalities, such as endothelial dysfunction in the peripheral arteries, have been also mentioned for their possible use in future. However, several questions in this field are still open, limiting the wide use of these tools in the clinical practice. The open issues concern methodological as well as pathophysiological and prognostic aspects, and in this thesis we will discuss only a small part of these ones. First, C-IMT and arterial stiffness represent two sides of vascular aging, atherosclerosis and arteriosclerosis respectively, and are generally considered structural alterations. The identification of a “functional” component in these alterations would be of interest, since it will suggest a possibility of reversibility of vascular aging. Second, vascular aging is a process involving the whole organism, while different techniques explore different districts. The quantification of the impact of different CV risk factors on different vascular districts might indicate the most adequate biomarker to use for future studies and suggest specific mechanisms of disease in different conditions. Third, vascular aging is often accompanied by cardiac and renal damage, but the relationship between organ damage in different districts is still largely unexplored. Fourth, while hypertension and diabetes have become the main cause of end-stage renal disease, and chronic kidney disease has been recognized as a main cause of CV events, to date early markers of renal vascular damage have not been developed. For this PhD thesis I examined cross-sectionally a cohort of healthy subjects and patients with traditional CV risk factors in order to elucidate some of the abovementioned aspects. My original contribution to the knowledge in this field consists in: - the demonstration of a “functional” component in aortic stiffness, that is present only in diabetic patients and relies on endothelium-mediated mechanisms; - the demonstration of a differential impact of different CV risk factors on carotid and aortic stiffness; - the demonstration, in hypertensive patients, of an additive role of carotid and aortic stiffness in determining cardiac organ damage; - the identification of a new marker of renal vascular damage. In the second part of the PhD thesis, I sought to demonstrate the usefulness of imaging biomarkers of vascular function and structure not only for risk stratification in patients with traditional CV risk factors, but also to explore CV consequences of non primarily CV diseases and conditions. We hypothesized that a comprehensive, multiparametric approach would be the best strategy to detect early vascular damage in one or more districts, possibly in a subclinical, reversible stage. This approach could allow identifying the “CV footprint” characterizing each condition, with a double aim: to elucidate the pathophysiology of CV complications in non-CV diseases and to propose the most useful test to be used in the clinical practice for screening and follow-up. During my PhD thesis I applied this strategy to some primarily non-CV conditions that might qualify as emerging CV risk factors, such as exposure to environmental and iatrogenic radiation doses, obstructive sleep apnea syndrome (OSAS) in the absence of traditional CV risk factors, and chronic exposure to hypobaric hypoxia at high altitude. My original contribution to the knowledge in this field consisted in: - the demonstration of a selective reduction of circulating endothelial progenitor cells, in the presence of preserved vascular function and structure, in young adults exposed during childhood to environmental radiation doses after the Chernobyl disaster and to therapeutic radioiodine treatment after thyroid cancer; - the demonstration that conduit artery endothelial dysfunction and impaired renal vasodilating capacity are part of the vascular phenotype of OSAS per se, since they are present even in the absence of traditional CV risk factors, while structural alterations such as arterial stiffness and increased C-IMT characterized only obese and/or hypertensive OSAS patients; - the demonstration that Himalayan high altitude dwellers, chronically living above 2500 meters of altitude, present a mainly microcirculatory endothelial dysfunction and a maladaptive carotid remodeling even in the absence of traditional CV risk factors.