Lipoprotein Utilization and Oxidation in CHF

描述（由申请方提供）：氧化应激、脂蛋白代谢和氧化改变、肾素-血管紧张素以及交感神经系统（SNS）活性增加是可能导致和促进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，但在正常受试者中不增加，2）LDL增加与CHF运动期间SNS激活正相关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，但不改变oxLDLADL比率，不改变运动诱导的oxLDL升高，和5）他汀类药物治疗与对血管紧张素II的血管收缩反应减弱有关。我们建议全面评估144名CHF患者和33名健康对照者在运动过程中的脂蛋白氧化和SNS活性。将对CHF受试者随访2年，以确定运动诱导的oxLDL升高对CHF急性加重的预测价值。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。将进行子研究，以控制药物诱导的脂蛋白代谢变化，并确定运动诱导LDL升高的潜在机制。此外，将在66例非缺血性心脏病所致CHF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的可能多效性：血管紧张素II 1型受体下调。CHF是主要的公共卫生问题。我们的研究将显著增强并可能改变目前对胆固醇在晚期心脏病中作用的理解。如果我们的假设能够得到证实，它们可能会导致新疗法的发展，以改善CHF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.