by Joseph A. Vita, M.D. John F. Keaney, Jr., MD Boston University School of Medicine

Physicians generally accept the idea that exercise promotes cardiovascular health, a concept that enjoys considerable support from epidemiological evidence. In both men and women, there is an inverse relation between the level of physical activity and the incidence of cardiovascular disease, and this relation persists after control for other risk factors for cardiovascular disease.

Among patients with established cardiovascular disease, mortality is lower among those who participate in an exercise program than among those who do not. These and other data have prompted the inclusion of an exercise program in recommendations for the primary and secondary prevention of cardiovascular disease.

Despite the clear association between exercise and a reduced risk of cardiovascular disease, the precise mechanisms responsible for this association remain unclear. Exercise training has a favorable effect on the severity of traditional cardiovascular risk factors such as hypertension, diabetes, hypercholesterolemia, and obesity.

However, such influences probably do not account for the overall effect of exercise on cardiovascular disease, since the effect of exercise is independent of the traditional risk factors. Exercise training also improves myocardial perfusion but has only a limited effect on the extent of atherosclerotic lesions.

In addition to the presence of atherosclerotic lesions, cardiovascular disease is characterized by important abnormalities in vascular function. In particular, endothelial control of vascular tone, thrombosis, and platelet activity is impaired in patients with coronary artery disease.

The mechanisms responsible for these effects have been elucidated in animal models and in cell-culture systems. Physical exercise increases coronary blood flow, resulting in increased shear stress on the surface of the endothelium. Endothelial cells respond to short-term increases in shear stress by producing vasodilator compounds such as prostacyclin and nitric oxide.

Sustained increases in shear stress elicit an adaptive response in endothelial cells that is manifested, in part, by increased expression of the enzyme that catalyzes nitric oxide production. Predictably, endothelial function in animals that perform regular exercise is improved as a result of increased endothelial nitric oxide production and is better than that in animals that do not exercise.Such adaptive responses of the endothelium also apply to the coronary circulation in humans, even in those with coronary artery disease.

There is growing recognition that abnormal endothelial function is central to the development of atherosclerosis and symptoms of coronary artery disease. Normally, the endothelium performs several homeostatic functions: for instance, it maintains vasodilatation and prevents platelets and inflammatory cells from adhering to the vascular surface.

Restoration of these normal properties would be expected to have a number of important consequences. For example, the progression of atherosclerosis is dependent on the recruitment of inflammatory cells into the vascular wall, a process that is normally limited by endothelium-derived nitric oxide. Consequently, improving the production of endothelium-derived nitric oxide by means of exercise training should limit the progression of atherosclerosis.

Restoration of nitric oxide-dependent vasodilatation in conduit vessels and microvessels should improve myocardial perfusion and limit angina pectoris. Similarly, enhanced endothelial nitric oxide production should limit platelet activation and the risk of thrombus formation, which is an important event in the development of myocardial infarction. Thus, the overall effect of exercise training in restoring normal endothelial function would be expected to limit the clinical manifestations of coronary artery disease.

If improved endothelial function does translate into a lower risk of cardiovascular disease, other interventions that improve endothelial function might also be expected to have demonstrable effects on the risk of cardiovascular events. Available evidence supports this hypothesis. In patients with established coronary artery disease, cholesterol-lowering therapy and angiotensin-converting-enzyme inhibitors improve endothelial function, and in randomized trials these interventions also decreased the rate of cardiovascular events.

Other factors associated with a lower risk of cardiovascular events, including smoking cessation and premenopausal status, are also associated with improved endothelial function.

In summary, the well-established beneficial effects of regular exercise on cardiovascular disease may be a consequence of a number of factors, including improvement of coronary-artery endothelial function, as demonstrated by Hambrecht and colleagues.

These findings are consistent with the growing understanding that changes in vascular-wall function have important implications for the clinical manifestations of cardiovascular disease.

Clearly, elucidating specific mechanisms and developing strategies to reverse abnormal vascular function in patients with atherosclerosis will provide new insights into the treatment of cardiovascular disease. In addition, examination of endothelial function has potential as a way to assess the risk of cardiovascular disease and to guide risk-modification strategies.

http://www.nejm.org/content/2000/0342/0007/0503.asp

The New England Journal of Medicine February 17, 2000;342:454-460, 503-504.