The stratification of cardiovascular risk is associated with a multimarker score of global oxidative statusSpecific role of oxidized low-density lipoprotein

Résumé

Cardiovascular disease (CVD) is the leading cause of death and disability worldwide. Attempts to reduce CVD burden include the estimation of cardiovascular risk (CVR) which is the risk of suffering a CVD in a defined time frame. CVR estimation usually neglects populations with low CVR in the short-term such as young adults and women, as well as populations considered at especially high CVR such as older populations and subjects with history of CVD. CVR is estimated on the basis of CVR factors, which are associated with oxidative stress. Additionally, oxidative stress induces vascular damage that further increase CVR. We hypothesized that oxidative stress is associated with CVR in neglected populations independently of traditional CVR factors. Since there is not a gold-standard parameter to determine oxidative stress, we developed a multimarker approach to globally determine oxidative damage (OxyScore), including biomarkers of oxidative damage to proteins (protein carbonyls), lipids (oxidized low-density lipoprotein, oxLDL), DNA (8-hydroxy-2'-deoxyguanosine, 8-OHdG), and the enzymatic pro-oxidant capacity of xanthine oxidase (XOD); and antioxidant defense (AntioxyScore), including the enzymatic antioxidant capacity of catalase, and superoxide dismutase (SOD), and the total antioxidant capacity (TAC) of low molecular weight antioxidants. We found significant positive associations between CVR and oxLDL, 8-OHdG, catalase activity and TAC in a young population. Moreover, OxyScore was associated with long-term CVR independently of traditional CVR factors. The strong association between oxLDL and CVR, and the independency of total and LDL cholesterol led to the hypothesis that oxLDL may induce atherosclerotic-independent CVD. Therefore, we studied the in vitro acute effect of oxLDL on Ca2+ handling in adult rat ventricular cardiomyocytes. oxLDL indeed induced anomalies in cardiomyocyte function and increased arrhythmic events. Subsequently, we assessed whether the oxidative stress profile is maintained in an older population, finding an imbalance in protein carbonyls, 8-OHdG, and catalase activity. This suggested that the underlying mechanisms leading to CVD in the young and the older are different. Finally, the levels of oxidative stress in subjects with history of CVD were similar to those with low CVR in both young and older populations, suggesting that intensive therapy reduces the burden of oxidative stress. The results presented in this Doctoral Dissertation indicate that oxidative stress is associated with the risk of suffering a CVD throughout life, although the interactions with CVR factors and underlying mechanisms vary between young, old and stable CVD populations. Moreover, oxLDL induces cardiac dysfunction independently of atherosclerotic CVD