PhD defence B.G. (Belinda) Spoto

In this thesis, epidemiologic and genetic data analyses in high-risk populations for cardiovascular disease (CVD) and excess mortality show that insulin resistance, inflammation and oxidative stress are crucial pathophysiological pathways mediating the increased susceptibility to adverse cardiovascular (CV) outcomes and mortality. Specifically, findings from the cross-sectional study in severely obese subjects point to a prevailing role of the abdominal subcutaneous adipose tissue (SAT) on visceral adipose tissue (VAT) with respect to inflammatory gene expression, generating the hypothesis that topography of fat accumulation is relevant for the risk of inflammation and, consequently, of CV complications. Furthermore, a polymorphism in the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene, a genetic marker of insulin resistance associated with myocardial hypertrophy and LV concentric remodeling in dialysis patients, modifies the relationship between a myocardial pro-fibrotic cytokine, the tissue inhibitors of metalloproteinase 1 (TIMP-1), and left ventricular (LV) geometry and function. The crucial role of fat mass in the increased risk of adverse and/or fatal clinical events has also been prospectively investigated in both chronic kidney disease (CKD) and end-stage kidney failure (ESKF). In relation to the endocrine function of the adipose tissue, a study in a cohort of patients with kidney failure shows a mutual relationship between resistin and adiponectin (ADPN) in determining death and CV events. Indeed, the risk for all-cause and CV mortality portended by a fixed increase in plasma resistin depends on plasma ADPN concentration, being evident in patients with low levels of ADPN but absent in those with high levels of this adipokine. In line with this evidence, the variability of the fat mass and obesity-associated (FTO) gene, a genetic biomarker of diabetes and hypertension, contributed to mortality in three cohorts of patients with CKD. In the context of inflammation as a trigger of CV complications, prospective follow up of patients with CKD revealed a strong and significant association between interleukin-6 (IL-6) and fatal and non-fatal CV events. Since serum IL-6 levels are genetically regulated, it was obvious to use a Mendelian randomization method that exploited a functional polymorphism in the IL-6 gene as instrumental variable: my findings strongly support that the link between serum IL-6 levels and CV complications is causal in nature. Finally, the role of oxidative stress on CV risk and mortality has been investigated in a cohort of healthy elderly since aging is, par excellence, the result of unbalanced pro-oxidant processes. In the participants of the Invecchiare in Chianti study, gamma-glutamyltransferase (GGT), a multifaceted biomarker of oxidative stress, emerged as a risk factor for all-cause and cardiovascular (CV) mortality independently of liver disease and alcohol intake. In addition, circulating oxidized low-density lipoproteins (oxLDL) amplified the effect of GGT on the adverse health outcomes. This supports the notion that GGT may underlie a mechanism which enhances the toxic effects of oxLDL on the vascular system or, vice versa, oxLDL enhances atherogenic properties of GGT.

The public defence will take place at the Senatehall, 1st floor of the Erasmus Building, Campus Woudestein. The ceremony will begin exactly at 11.30 hrs. In light of the solemn nature of the ceremony, we recommend that you do not take children under the age of 6 to the first part of the ceremony.