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Biological mechanisms for the clinical success of lipid-lowering in coronary artery disease and the use of surrogate end-points
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机译：Biological mechanisms for the clinical success of lipid-lowering in coronary artery disease and the use of surrogate end-points
The small changes in luminal narrowing observed with lowering total cholesterol are unlikely to be the principal mechanism by which lipid-lowering achieves a reduction in clinical events and revascularization rates. Endothelium dependent vasomotor function, and the cellular characteristics of plaques that seem to be intimately related to rupture and thrombosis, are factors that may explain the clinical success from correcting the dyslipidemias. Dyslipidemias cause endothelial dysfunction that predisposes to vasoconstriction of the epicardial coronary arteries and the resistance vessels relative to metabolic demand. Dysfunctional endothelium also promotes the recruitment of inflammatory cells into the vessel wall which contributes to the activation of vascular smooth muscle cells and sets up an environment within the plaque that predisposes to rupture and a prothrombotic state. Aggressive lowering of total cholesterol, and especially LDL and oxidized LDL, improves coronary endothelial function both of the epicardial and resistance vessels, and leads to a reduction in myocardial ischemia. Lipid-lowering may promote plaque stability in part by reducing the recruitment of inflammatory cells, and possibly by changing the size or consistency of the lipid-rich core of plaques. A thicker fibrous cap and stiffer plaque that is less likely to rupture may result, and in the event that rupture does occur, cholesterol lowering may reduce the formation of overlying thrombus. Testing coronary or peripheral artery endothelial vasomotor dysfunction may be a surrogate measure for assessing the effectiveness of interventions to prevent coronary heart disease. These tests are likely to be used increasingly to identify interventions that deserve greater attention in larger clinical trials, as well as providing mechanisms for any observed clinical benefits.
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