Dottorato in MALATTIE INFETTIVE, MICROBIOLOGIA E SANITA' PUBBLICA

Titolo della tesi: Extracellular volume quantification in Cardiac CT: a new marker of cardiovascular risk in HIV positive individuals?

Inflammation in response to infection and injury is a critical survival mechanism used by all higher vertebrates. Chronic inflammatory conditions are associated with the prolonged release of inflammatory mediators and the activation of harmful signal transduction pathways, all of which contribute disease development and phenotypes. Extracellular Volume Fraction (ECV) may be able to detect subtle abnormalities such as diffuse inflammation acute or chronic due to infection and/or fibrosis. The validity of this technique was preliminarily evaluated in a study with 20 patients suspected to have diffuse inflammation in the myocardial tissue. Using HU (Hounsfield Unit) values before and after administration of an Extracellular Contrast Agent (ECA) allows the additional calculation of the ECV, well established in CT. In fact, the ratio of the change in blood and tissue attenuation (delta-HU) represents the contrast agent partition coefficient. People living with HIV (PLWH) have an increase vulnerability to sub-clinical and clinical cardiovascular (CV) diseases. Purpose: PLWH are prone to develop sub-clinical Cardiovascular (sCV) disease, despite the effectiveness of combined AntiRetroviral Therapy (cART). Algorithms developed to predict CV risk in the general population could be inaccurate when applied to PLWH. Myocardial Extra-Cellular Matrix (ECM) expansion, measured by computed tomography, has been associated with an increased CV vulnerability in HIV-negative population. Measurement of Myocardial ECV by computed tomography or magnetic resonance, is considered a useful surrogate for clinical evaluation of ECM expansion. In the present study, we aimed to determine the extent of cardiovascular involvement in asymptomatic HIV-infected patients with the use of a comprehensive cardiac computed tomography (CCT) approach. In this study, ECV in low atherosclerotic CV risk PLWH was compared with ECV of age and gender matched HIV- individuals. 53 asymptomatic HIV+ individuals (45 males, median age 48 (IQR:42.5-48) years) on effective cART (CD4+ cell count: 450 cells/μL (IQR: 328-750); plasma HIV RNA: <37 copies/ml in all subjects) and 18 age and gender matched controls (14 males, median age 55 (IQR:44.5-56) years) were retrospectively enrolled. All participants underwent CCT protocol to obtain native and postcontrast Hounsfield unit values of blood and myocardium, ECM was calculated accordingly. The ECV was significantly higher in HIV+ patients than in the control group (ECV: 31% (IQR: 28%-31%) vs 27.4% (IQR: 25%-28%), p<0.001). The duration of cART (standardized beta =0.56 (0.33-0.95), p=0.014) and the years of exposure to HIV infection [standardized beta =0.53 (0.4-0.92), p<0.001], were positively and strongly associated with ECV values. Differences in ECV (p<0.001) were also observed regarding the duration of exposure to cART (<5 years, 5-10 years and >10 years). Moreover, ECV was independently associated with age of participants [standardized  = 0.42 (0.33-0.89), p=0.084]. We hypothesized that quantitative assessment of tissue ECV would be clinically useful for detecting both focal and diffuse tissue abnormalities in a variety of acute and chronic infectious conditions. ECV imaging can quantitatively characterize tissue inflammation, atypical diffuse fibrosis, and subtle tissue abnormalities not clinically apparent on different method images. Therefore, ECV not only can detect tissue inflammation and/or fibrosis but also might quantify response to treatment during follow-up. HIV infection and exposure to antiretrovirals play a detrimental role on ECV expansion. An increase in ECV indicates ECM expansion, which has been associated to a higher CV risk in the general population. The non-invasive evaluation of ECM trough ECV could represent an important tool to further understand the relationship between HIV infection, cardiac pathophysiology and the increased CV risk observed in PLWH.