The overall goal of this project is to determine the functional significance of myocardial nitric oxide (NO) and oxidative stress in humans with heart failure (CHF). Recent evidence suggests that NO is increased in failing human myocardium and may contribute to the pathophysiology of CHF. In addition, increased myocardial oxidative stress has been demonstrated in heart failure. In vitro studies indicate that reactive oxygen species (ROS) can exert direct toxic effects on the myocardium associated with impaired contractility, fetal gene expression and cell death. Moreover, antioxidants have been shown to attenuate the negative inotropic effects of ROS and prevent the development of heart failure in animal models. In left ventricular (LV) failure, the heart rate- mediated increase in contractility (force-frequency relationship) is attenuated, flat or even inverted. While the failure to increase contractility with tachycardia likely contributes to the reduced cardiac output response and exercise intolerance observed in patients with CHF, the underlying mechanisms are poorly understood.
In Specific Aim 1, we will test the hypothesis that increased myocardial NO synthase (NOS) activity attenuates the force- frequency relationship in humans with LV failure by measuring the changes in the peak rate of rise of LV pressure (+dP/dt) that occur with increasing heart rates before and during intracoronary infusion of NG-monomethyl-L-arginine, an inhibitor of NOS.
In Specific Aim 2, we will test the hypothesis that increased myocardial oxidative stress attenuates the force-frequency relationship in humans with LV failure by determining the force- frequency relationship before and during intracoronary infusion of the antioxidant ascorbic acid.
Aims 1 and 2 are invasive protocols that will assess the acute functional significance of myocardial NO and oxidative stress in heart failure.
In Specific Aim 3, we will test the ability of a novel, non-invasive system to detect acute changes in contractile state by measuring LV end-systolic elastance during atrial pacing tachycardia and intracoronary dobutamine infusion in patients with dilated cardiomyopathy. If we show that this new technology is able to measure changes in contractility in the catheterization laboratory, we will assess its ability to detect chronic changes in LV performance by measuring end-systolic elastance before and after therapy with antioxidants and/or anti- inflammatory agents in patients with systolic heart failure.
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