THE EFFECT OF HMG COA REDUCTASE INHIBITORS ON CBF

点击翻译按钮获取中文摘要

DESCRIPTION: (Verbatim from the Applicant's Abstract) 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) increase basal cerebral blood flow (CBF) in mice through upregulation end endothelial nitric oxide synthase (eNOS). The increase in blood flow provides cerebral protection from ischemia. This mechanism may be responsible for the reduction in the risk of ischemic stroke observed in clinical trials of statins in patietns with atherosclerotic risk factors. The primary objectives of this translational study are to test the hypotheses that (1) statin therapy will increase CBF in patients with atherosclerotic coronary disease (Specific Aim 1), in whom the stroke risk reduction has been reported, and (2) that statins will not increase CBF in patients with atherosclerotic cerebrovascular disease and pre-existing auto regulatory vasodilatation (Specific Aim 2). Patients with either atherosclerotic coronary artery disease (n=30) or unilateral carotid artery occlusion (n=40) will be entered in a randomized, controlled , double-blinded study of simvastatin therapy (40 mg per day) versus placebo for 30 days. Quantitative regional measurements of CBF will be made with positron emission tomography at baseline and at 30 days. Secondary objectives are to determine: (1) if statin therapy will increase CBF in the hemisphere contralateral to the occluded carotid artery; (2) the magnitude of the effect of simvastatin on peripheral nitric oxide mediated vasodilatory responses; and (3) if treatment results in an increase in serum levels of nitric oxide metabolites. The proposed studies will determine whether statins can increase CBF in humans at risk for stroke and will provide insight into the mechanism by which these drugs provide stroke protection in patients with coronary artery disease. If no effect on DBF is found other mechanism such as antithrombotic or antiatherosclerotic effects of statins, may be more important and further drug development can be tailored appropriately. In addition, the data from these studies will determine if statins can increase CBF in humans with atherosclerotic cerebrovascular disease, with and without reduced perfusion pressure. Positive results from these experiments would support further investigation of a potentially important mechanism of stroke protection applicable to all patients with atherosclerotic coronary and cerebrovascular disease.