Lipoprotein Utilization and Oxidation in 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进展的相关病理过程。他汀类药物治疗可能有利于这些过程。我们的初步数据表明：1)低密度脂蛋白（LDL）及其氧化形态（oxLDL）在CHF运动期间急剧升高，但在正常受试者中无明显升高；2)LDL升高与CHF运动期间SNS激活呈正相关；3)oxLDL升高与不良临床结局独立相关；4)他汀类药物治疗与降低oxLDL和LDL水平相关。但不改变氧化低密度脂蛋白的比例，而不是运动引起的氧化低密度脂蛋白升高，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。我们拟综合评估144名CHF患者和33名健康对照者运动时的脂蛋白氧化和SNS活性。对CHF患者进行为期两年的随访，以确定运动诱导的oxLDL升高对CHF加重的预测价值。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，以控制药物引起的脂蛋白代谢改变，并确定运动引起LDL增加的机制。此外，一项随机双盲试验将在66例非缺血性心脏病引起的CHF患者中进行，以研究他汀类药物治疗在CHF中的可能的多效作用：血管紧张素II型1受体下调。CHF是一个重大的公共卫生问题。我们的研究将显著加强并可能改变目前对胆固醇在晚期心脏病中的作用的理解。如果我们的假设可以被证明，它们可能会导致新疗法的发展，以提高运动能力和延长心力衰竭患者的寿命。

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.