Trial Studies Exercise Role in Relieving Peripheral Arterial Disease
DURHAM, N.C. – While physicians often recommend exercise to help
relieve the symptoms of peripheral arterial obstructive disease (PAOD)
-- a potentially debilitating disorder that afflicts one in eight
Americans -- they have done so without fully understanding why it seems
to help. However, a new clinical trial led by Duke University Medical
Centers aims to supply the scientific basis for this clinical practice.
is characterized by atherosclerotic plaques in the arteries of the leg
that can slowly starve muscle of needed nutrients and oxygen. In mild
cases, known as intermittent claudication, patients feel muscle pain
upon exertion that is only relieved by rest. More severe cases, known
as critical limb ischemia, can lead to gangrene or tissue death, often
necessitating amputation of the effected limb.
long appreciated that exercise in general can stimulate formation of
new blood vessels in skeletal muscle, a process known as angiogenesis.
The Duke researchers, collaborating with colleagues at the University
of Colorado Health Sciences Center, Denver, believe that this
angiogenic response to exercise underlies the improvements in walking
endurance and symptom relief of PAOD patients.
The Duke team is
now enrolling patients in a clinical trial to test this hypothesis. The
trial is supported by the five-year, $3.9 million grant from the
National Heart Lung Blood Institute.
"Almost every physician will
recommend exercise for their patients with peripheral arterial
obstructive disease, but the reality is that we don't really know why
it works," said Duke cardiologist Brian Annex, M.D., principal
investigator for the trial.
"If we can understand why exercise
works, it would be much easier to make our treatments more effective,"
Annex continued. "The main reason for intermittent claudication is a
blockage in the arteries, which then leads to inadequate skeletal
muscle perfusion during physical activity. However, the mechanisms by
which exercise can improve walking times for patients with intermittent
claudication are not completely understood."
It is estimated that
between 8 and 12 million Americans suffer from PAOD, an incidence that
is slightly less than coronary artery disease. While many patients with
PAOD also have coronary artery disease, Annex said that almost half of
them have no heart disease. As is the case for coronary artery disease,
people who smoke, have diabetes, high blood pressure or elevated
cholesterol levels are higher risk of PAOD. Drugs and invasive
procedures are used to treat the disorder, but none are particularly
effective, the researchers said.
While up to three-quarters of
patients do not report symptoms, there is a simple test to screen for
PAOD. The ankle-brachial index (ABI), which is the ratio of the blood
pressure recorded at the ankle and the arm, can often detect the
presence of PAOD. The American Diabetes Association recommends that all
diabetics receive annual ABI testing after the age of 50 to screen for
"Many people feel that leg pain is just a normal part of
aging, but that is not necessarily true," Annex said. "The pain of PAOD
is felt in the muscles, and not the joints."
For the trial, which
is recruiting patients at Duke and the University of Colorado,
researchers plan to enroll 160 participants, equally divided among men
and women. These patients will be randomized to either an
individualized exercise program conducted at home or to a supervised
exercise program on campus. An additional 66 age-matched participants
will be recruited to serve as controls by not exercising.
important goal of this trial is to document the gender differences in
the disease and the responses to exercise," Annex said. "In the past,
women have been horribly under-represented in PAOD studies, even though
the incidence of the disease in women is similar to men. The results of
our trial should help to establish whether current exercise
prescriptions are adequate for both men and women with PAOD, or whether
different therapeutic strategies are needed."
Because of this
focus on gender, the National Institutes of Health's Office of Research
on Women's Health is a co-sponsor of the trial, which has been named
Angiogenesis and Mechanisms of Exercise Training in PAOD (AMNESTI).
the three-month trial, researchers will make detailed measurements at
regular intervals -- using ABI, magnetic resonance imaging and muscle
biopsies to determine if exercise is indeed stimulating the growth of
new vessels, and furthermore if these changes correlate with
improvement of symptoms.
The researchers will follow such markers
as the growth of new capillaries in leg muscles, the occurrence of
programmed cell death (apoptosis) within leg muscle, and blood levels
of vascular progenitor cells, which are produced in the bone marrow and
are responsible for blood vessel repair.
Patients who are
interested in enrolling in the PAOD trial should contact Leslie Kelly,
recruitment coordinator, at (919) 660-6739 or Kelly045@mc.duke.edu.