Lipoprotein Utilization and Oxidation in CHF

描述(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)活动是可能导致和促进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影响。我们的初步数据显示：1)低密度脂蛋白(LDL)及其氧化形式(OxLDL)在CHF运动中显著升高，但在正常人中不明显；2)低密度脂蛋白(LDL)升高与CHF运动中SNS激活呈正相关；3)oxLDL升高与不良临床结局独立相关；4)他汀类药物治疗与oxLDL和LDL水平降低有关，但不改变oxLDLADL比率；5)他汀类药物治疗与血管收缩反应减弱有关。我们建议对144例CHF患者和33名健康对照组的运动中脂蛋白氧化和SNS活性进行全面评估。将对CHF受试者进行为期两年的跟踪，以确定运动诱导的oxLDL升高对CHF恶化的预测价值。实验室测量将包括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。将进行亚研究，以控制药物诱导的脂蛋白代谢变化，并确定运动诱导的低密度脂蛋白增加的潜在机制。此外，一项随机双盲试验将在66名非缺血性心脏病引起的CHF患者中进行，以调查他汀类药物在CHF中可能的多效性作用：血管紧张素II 1型受体下调。充血性心力衰竭是主要的公共卫生问题。我们的研究将显著提高，并可能改变目前对胆固醇在晚期心脏病中的作用的理解。如果我们的假设能够得到证实，它们可能会导致新疗法的开发，以提高充血性心力衰竭患者的运动能力和寿命。

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.