|
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.
| 