NO AND OXIDATIVE STRESS IN HUMAN MYOCARDIAL FAILURE

该项目的总体目标是确定心肌一氧化氮（NO）和氧化应激在心力衰竭（CHF）患者中的功能意义。最近的证据表明，NO在衰竭的人心肌中增加，并可能参与CHF的病理生理。此外，心肌氧化应激增加已在心力衰竭中得到证实。体外研究表明，活性氧（ROS）可对心肌产生直接毒性作用，与收缩性受损、胎儿基因表达和细胞死亡相关。此外，抗氧化剂已被证明可以减轻ROS的负性肌力效应，并在动物模型中预防心力衰竭的发生。在左心室（LV）衰竭时，心率介导的收缩力增加（力-频率关系）减弱、平缓甚至反转。虽然不能增加收缩性并伴有心动过速可能导致心力衰竭患者心输出量反应降低和运动不耐受，但其潜在机制尚不清楚。在特异性目的1中，我们将通过测量在冠状动脉内灌注一氧化氮抑制剂ng -单甲基- l-精氨酸之前和期间随着心率增加而出现的左室压上升峰值速率（+dP/dt）的变化，来检验心肌一氧化氮合成酶（NOS）活性增加减弱左室衰竭患者力频关系的假设。我们将通过测定抗氧化剂抗坏血酸在冠状动脉内灌注之前和期间的力-频率关系来验证心肌氧化应激增加减弱左室衰竭患者力-频率关系的假设。目的1和2是侵入性方案，将评估心肌NO和氧化应激在心力衰竭中的急性功能意义。在Specific Aim 3中，我们将通过测量扩张型心肌病患者心房起搏心动过速和冠状动脉内多巴酚丁胺输注期间左室收缩末期弹性来测试一种新型无创系统检测收缩状态急性变化的能力。如果我们证明这项新技术能够在导管实验室中测量收缩力的变化，我们将通过测量收缩期心力衰竭患者在抗氧化剂和/或抗炎药治疗前后的收缩末期弹性来评估其检测左室表现慢性变化的能力。

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.