OXIDATIVE STRESS/ANTIOXIDANT ENZYMES IN HEART FAILURE

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The pathophysiology of heart failure remains incompletely understood. Recent evidence suggests that oxidative stress is increased in clinical heart failure (HF) and may contribute to the pathogenesis of left ventricular (LV) dysfunction. In vitro and in vivo animal studies indicate that reactive oxygen species (ROS) can exert direct myotoxic effects including impairment of contractility and cell death. In animal models of hemodynamic overload leading to heart failure, there is decreased antioxidant enzyme activity, and exogenous antioxidants have been shown to prevent the development of heart failure. The overall goal of this proposal is to determine the extent to which ROS in animal models contribute to the pathogenesis of human heart failure. In Specific Aim 1, we will test the hypothesis that oxidative stress is increased in the myocardium from patients with severe heart failure. Myocardial tissue samples will be obtained at the time of transplantation from patients with severe heart failure. Oxidative stress in the myocardium will be determined by measuring 8-isoprostane and the ratio of reduced/oxidized glutathione. In Specific Aim 2, we will test the hypothesis that there is decreased activity of antioxidant enzymes in the myocardium of patients with severe heart failure. In the myocardial tissue samples obtained for Aim 1, we will measure the activity and expression of superoxide dismutase, glutathione peroxidase and catalase. We will examine the extent to which changes in enzyme activity are due to changes in gene expression vs. post-translational modifications known to inhibit enzyme activity. In Specific Aim 3, we will test the hypothesis that systemic oxidative stress is increased in patients with systolic heart failure, and is associated with more rapid disease progression. In 100 patients with systolic LV dysfunction, followed in the Cardiomyopathy clinics at Boston Medical Center, we will measure 8-isoprostanes in the blood as a marker of systemic oxidative stress at baseline and annually for 3 years. We will correlate 8-isoprostanes with cardiac troponin I (cTn-I), a measure of ongoing myocardial damage and LV end-diastolic diameter by echocardiography (LVEDD), a measure of structural remodeling. In Specific Aim 4, we will test the hypothesis that polymorphisms of MnSOD, the major SOD in the myocardium, lead to increased oxidative stress and more rapid disease progression in patients with heart failure. In patients studied in Aim 3 we will determine the presence of the -9Ala/Val polymorphism of MnSOD that has been associated with reduced enzyme activity. The presence of this polymorphism will be correlated to 8- isoprostanes and remodeling markers from Aim 3.