Xanthine Oxidase and Uric Acid in Atrial Fibrillation

URIC ACID METABOLISM AND ATRIAL REMODELING Potential sources and factors implicated in AF-related oxidative stress include NADPH oxidase activation, calcium overloading and mitochondrial damage, angiotensin system activation, NO synthase uncoupling, XO activation, altered expression of redoxrelated genes, other genetic factors, aging, obesity, and other associated cardiovascular conditions (Korantzopoulos et al., 2007). The presence and localization of XO in the human heart has been debated. Earlier studies found no evidence of XO activity (Grum et al., 1989) while latter studies confirmed the presence of XO activity in human hearts (MacGowan et al., 1995) and besides its localization in capillary endothelial cells additional localization in vascular smooth muscle cells, macrophages, and mast cells was demonstrated (HellstenWesting, 1993). In a porcine atrial tachypacing model of AF left atrial XO activity was 4.4 times greater in the paced than in the control group. Superoxide production was reduced by 85% after administration of oxypurinol (a XO inhibitor; (Dudley et al., 2005). In this model, XO in the atria was less abundant than NADPH oxidase. It is worth noting that in another study no significant effect of oxypurinol on superoxide production was found in human atrial specimens, thus failing to support a role of XO in oxidative stress associated with human AF (Kim et al., 2005). A potential explanation for this evident discrepancy could be the existence of regional differences since in the porcine model the increased XO activity was apparent in the left atrial appendage (Dudley et al., 2005), whereas in the human study only tissue specimens from right atrial appendage were examined (Kim et al., 2005). Of note, in a similar porcine model, forming the toxic molecule peroxynitrite. Collectively, ROS such as hydroxyl radicals and peroxynitrite trigger cellular responses ranging from subtle changes of cell functioning to severe oxidative damage of the affected macromolecules leading to necrosis or apoptosis (Glantzounis et al., 2005). The highest activity of XO is detected in endothelium, intestine, and liver. Endothelial XO plays a crucial role in the vascular oxidative stress. Remarkably, angiotensin II-induced NADPH oxidase activation increases XO activity indicating that there is a redox sensitive activation of endothelial XO (Landmesser et al., 2007). It has also been suggested that endothelialderived ROS have direct effects on myocardial functional performance (Doehner and Landmesser, 2011). UA has emerged as a simple and independent marker of morbidity and mortality in a variety of cardiovascular disease states including coronary artery disease and heart failure (Dawson and Walters, 2006; George and Struthers, 2008; Ndrepepa et al., 2012). Regardless of the debate whether it is a predictor or a causative factor, UA has been clearly associated with oxidative stress and inflammation in several pathological conditions (Glantzounis et al., 2005; Doehner and Landmesser, 2011). It has also been proposed that UA reflects the presence of other diseases and cardiovascular risk factors that increase oxidative stress. In pathophysiological terms, UA reflects upregulated XO activity. Apart from this well-known pathway, UA may have additional effects. Specifically, it appears to be a low potency antioxidant outside the cell (Glantzounis et al., 2005). On the other hand, inside the cell it enhances oxidative stress by activating NADPH oxidase while it activates the renin-angiotensin system (Kelkar et al., 2011). Moreover, UA may represent an endogenous signal of cell injury activating the cellular immune response (Shi et al., 2003). In fact, UA has been associated with a pro-inflammatory BACKGROUND The pathophysiology of atrial remodeling is very complex and the molecular pathways implicated in the initiation and perpetuation of atrial fibrillation (AF) show a high diversity and variability across different underlying substrates (Schotten et al., 2011; Wakili et al., 2011). During the past few years the role of pathophysiologic pathways that involve inflammatory and oxidative processes is under meticulous investigation (Korantzopoulos et al., 2007; Van Wagoner, 2008; Negi et al., 2010). Given that most of the published data on this subject regards the study of inflammatory and oxidative stress markers, the cause-effect relationship with atrial remodeling is not very clear. Possibly, both procedures are operative in this setting. Bearing in mind that most of the associated cardiovascular conditions are associated with oxidative stress and inflammation, the study of oxidative, and inflammatory aspects of atrial remodeling becomes more complicated.