REACTIVE OXYGEN SPECIES IN HUMAN HEART FAILURE

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。心力衰竭的病理生理学仍然被完全误解。最近的证据表明，氧化应激在心力衰竭中增加，可能有助于左心室功能障碍的发病机制。体外和体内动物研究表明，活性氧可以发挥直接的肌毒性作用，包括收缩性损伤和细胞死亡。在心力衰竭动物模型中，心肌氧化应激增加，抗氧化酶活性降低；抗氧化剂的使用已被证明可以防止心力衰竭的发展。这一建议的总体假设是，氧化应激增加有助于人类心力衰竭的发病机制。本研究的目的是验证收缩期心力衰竭患者的系统性氧化应激增加，并与更快的疾病进展相关的假设。在100例左室收缩功能障碍患者中，我们将在基线和3年内每年测量血液中的8-异前列腺素作为全身氧化应激的标志物。我们将通过磁共振成像将9-异前列腺素与心肌肌钙蛋白I （cTnI）和左室舒张末期容积（LVEDV）联系起来，后者是衡量持续心肌损伤的指标，后者是衡量结构重塑的指标。此外，我们将检验锰超氧化物歧化酶（MnSOD）多态性的假设，MnSOD是心肌中的主要SOD，导致心力衰竭患者氧化应激增加和疾病进展更快。在Aim 1研究的患者中，我们将确定MnSOD的-9Ala/Val多态性的存在，该多态性与酶活性降低有关。这种多态性的存在可能与来自Aim 1的8-异前列腺素和重塑标记有关。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The pathophysiology of heart failure remains completely misunderstood. Recent evidence suggests that oxidative stress is increased in heart failure and may contribute to the pathogenesis of left ventricular (LV) dysfunction. In vitro and in vivo animal studies indicate that reactive oxygen species can exert direct myotoxic effects including impairment of contractility and cell death. In animal models of heart failure, there is increased myocardial oxidative stress and decreased antioxidant enzyme activity; and administration of antioxidants has been shown to prevent the development of heart failure. The overall hypothesis of this proposal is that increased oxidative stress contributes to the pathogenesis of human heart failure. The purpose of this study is to 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 LV systolic dysfunction, 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 9-isoprostanes with cardiac troponin I (cTnI), a measure of ongoing myocardial damage, and LV end-diastolic volume (LVEDV) by magnetic resonance imaging, a measure of structural remodeling. In addition, we will test the hypothesis that polymorphisms of manganese superoxide disumtase (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 1 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 1.