Endothelial function as an end-point in interventional trials: concepts, methods and current data.

Abstract

SURROGATE END-POINTS: Pharmacotherapy of cardiovascular disease has been increasingly validated in large interventional trials to assess its efficacy, safety and costs. As endpoints, morbidity and mortality are evaluated. More recently, surrogate end-points have been included in interventional trials, both to increase our understanding of pathogenic mechanisms and for their potential use as markers of risk in patients. ENDOTHELIAL FUNCTION: The endothelium lies in a strategic anatomical position between the circulating blood and vascular smooth muscle and hence is a major local mediator of cardiovascular function. Also, endothelial cells are a target for mechanical forces and cardiovascular risk factors in the circulation. Thus, it is not surprising that their function becomes impaired at an early stage in the disease process. The cells are able to produce numerous proteins and mediators. This review focuses on nitric oxide and endothelin-1, which are endothelium-derived relaxing and constrictor factors, respectively. Nitric oxide also prevents platelet adhesion and aggregation and the adhesion of monocytes. Both substances also affect vascular structure in that nitric oxide inhibits while endothelin stimulates vascular smooth muscle proliferation and migration. MEASUREMENTS OF ENDOTHELIAL FUNCTION: Endothelial function and the effects of nitric oxide and endothelin in particular can be evaluated in the coronary circulation by quantitative coronary angiography and Doppler flow wire, and in the peripheral circulation with plethysmography and new ultrasound/Doppler devices. In these experimental set-ups, lipid-lowering drugs and angiotensin converting enzyme (ACE) inhibitors have been evaluated. Lipid-lowering drugs improve endothelium-dependent vasodilation in the coronary and forearm circulation of patients with hyperlipidemia and atherosclerosis. Similarly, ACE inhibitors improve coronary vasomotion in patients with coronary artery disease and normal lipid levels. In hypertension, ACE inhibitors have failed to improve endothelium-dependent vasodilation, while studies with other drugs are planned. CONCLUSIONS: Endothelial function can now be assessed precisely in patients in vivo, in both the coronary and the peripheral circulation. Tests can detect early dysfunction in patients with a risk of cardiovascular disease and the possible effects of drugs on endothelial function. Large interventional trials are needed to establish how far endothelial dysfunction can or cannot predict clinical outcome.