Xanthine Oxidase Inhibition and Heart Failure

Abstract

See related article, pages 271–279 Myocardial dysfunction and heart failure perturb cardiovascular homeostatic signaling pathways as well as initiate a program of molecular, biochemical, and structural modifications to remodel the failing ventricle. Accumulating evidence suggests that the cardiovascular redox state plays an integral role in these processes. In fact, in the failing heart, elevated levels of reactive oxygen species (ROS) and cardiomyocyte oxidant stress are associated with maladaptive ventricular remodeling and a progressive decline in cardiovascular function. The association between ROS and heart failure has been established. Increased indices of oxidant stress have been measured in patients with congestive heart failure. In clinical studies, patients with heart failure were found to have evidence of lipid peroxidation and elevated 8-iso-prostaglandin F2α levels1–4 whereas in experimental models of heart failure, investigators have been able to directly measure increased ROS production from cardiomyocytes.5,6 These findings have been corroborated in studies that measured ROS levels in explanted human hearts at the time of transplant.7 Furthermore, a number of neurohormonal and mechanical stressors that are associated with the heart failure phenotype augment ROS generation.8,9 Prolonged exposure to ROS, in turn, results in cardiomyocyte dysfunction.10 At a cellular level, elevated levels of ROS impair cardiomyocyte function by damaging ion channels as well as inhibiting contractility. ROS disrupt the structural integrity of ion channels via membrane lipid peroxidation.2,11 ROS also decrease expression and activity of the sarcoplasmic reticulum Ca2+ ATPase SERCA2,12 which is critical for effective cardiac calcium handling. Interestingly, ROS have also been shown to decrease myofilament calcium …