Lipoprotein Utilization and Oxidation in CHF

CHF 中脂蛋白的利用和氧化

• 批准号: 7317833
• 负责人: ULRICH P JORDE
• 金额: $ 40.25万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7317833
• 关键词: 3-nitrotyrosine; Acute; Angiotensin II; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Attenuated; Blood Plasma Volume; Blood Vessels; Cardiomyopathies; Cholesterol; Clinical; Data; Development; Double-Blind Method; Down-Regulation; Drug Controls; Exercise; Exercise stress test; Exhibits; Future; Glucose; Hand; Heart Diseases; Infusion Technique; Insulin; Laboratories; Lead; Lectin; Lipids; Lipoproteins; Longevity; Low Density Lipoprotein oxidation; Low-Density Lipoproteins; Measurement; Measures; Mediating; Medical; Metabolism; Methods; Myocardial Ischemia; Nonesterified Fatty Acids; Norepinephrine; Obstruction; Outcome; Oxidants; Oxidative Stress; Pathologic Processes; Patients; Peroxidase; Pharmacotherapy; Placebos; Plasma; Predictive Value; Process; Production; Public Health; Randomized; Receptor, Angiotensin, Type 1; Renin; Rest; Role; Source; Strenuous Exercise; Sympathetic Nervous System; System; Testing; Vasoconstrictor Agents; Vasodilation; Very low density lipoprotein; attenuation; brachial artery; improved; isoprostaglandin F2alpha type-III; low density lipoprotein inhibitor; mortality; outcome forecast; oxidation; oxidized low density lipoprotein; preference; prognostic; promoter; receptor; receptor downregulation; response; stable isotope

DESCRIPTION (provided by applicant): Oxidative stress, altered metabolism and oxidation of lipoproteins, increased renin-angiotensin as well as sympathetic nervous system (SNS) activity are interrelated pathological processes that may cause and promote the progression of CHF. Statin therapy may impact these processes favorably. Our preliminary data indicate: 1) Low density lipoprotein (LDL) and its oxidized form (oxLDL) acutely increase during exercise in CHF, but not in normal subjects, 2) the LDL increase is positively correlated with SNS activation during exercise in CHF 3) the increase in oxLDL is independently associated with adverse clinical outcomes 4) Statin therapy is associated with reduced levels of oxLDL and LDL, but does not alter the oxLDLADL ratio not the exercise induced rise in oxLDL and 5) Statin therapy is associated with an attenuated vasoconstrictor response to angiotensin II. We propose to comprehensively assess lipoprotein oxidation and SNS activity during exercise in 144 subjects with CHF and 33 healthy controls. Subjects with CHF will be followed for two years to determine the predictive value of exercise induced oxLDL increase for CHF exacerbations. Laboratory measurements will include oxLDL, myeloperoxidase, 8- isoprostane, nitrotyrosine, and norepinephrine. Substudies will be performed to control for drug-induced alterations in lipoprotein metabolism and to identify mechanisms underlying exercise induced increases in LDL. In addition, a randomized, double- blind trial will be conducted in 66 subjects with CHF due to non-ischemic heart disease to investigate a possible pleiotropic effect of statin therapy in CHF: Angiotensin II type-1 receptor downregulation. CHF is major public health issue. Our study will significantly enhance and may alter the current understanding of the role of cholesterol in advanced heart disease. If our hypotheses can be proven, they may lead to developments of new therapies to improve exercise capacity and longevity in patients afflicted with CHF.

描述（由申请人提供）：氧化应激、脂蛋白代谢和氧化改变、肾素-血管紧张素增加以及交感神经系统（SNS）活性是可能导致和促进CHF进展的相互关联的病理过程。他汀类药物治疗可能会对这些过程产生有利的影响。我们的初步数据表明：1) 低密度脂蛋白 (LDL) 及其氧化形式 (oxLDL) 在 CHF 运动期间急剧增加，但在正常受试者中则不然；2) LDL 增加与 CHF 运动期间 SNS 激活呈正相关；3) oxLDL 增加与不良临床结果独立相关；4) 他汀类药物治疗与 oxLDL 和 LDL 水平降低相关，但 不会改变 oxLDLADL 比率，也不会改变运动引起的 oxLDL 升高，并且 5) 他汀类药物治疗与血管紧张素 II 的血管收缩反应减弱有关。我们建议对 144 名 CHF 受试者和 33 名健康对照者运动期间的脂蛋白氧化和 SNS 活性进行全面评估。患有 CHF 的受试者将被跟踪两年，以确定运动引起的 oxLDL 增加对 CHF 恶化的预测价值。实验室测量包括 oxLDL、髓过氧化物酶、8-异前列腺素、硝基酪氨酸和去甲肾上腺素。将进行亚组研究以控制药物引起的脂蛋白代谢改变，并确定运动引起的低密度脂蛋白增加的潜在机制。此外，还将在 66 名因非缺血性心脏病而患有 CHF 的受试者中进行一项随机、双盲试验，以研究他汀类药物治疗 CHF​​ 可能的多效性：血管紧张素 II 1 型受体下调。瑞士法郎是主要的公共卫生问题。我们的研究将显着增强并可能改变目前对胆固醇在晚期心脏病中作用的认识。如果我们的假设得到证实，它们可能会导致新疗法的开发，以提高患有慢性心力衰竭的患者的运动能力和寿命。