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.
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