Mechanisms That Produce the Leg Dysfunction of Claudication (Leg Pain and Limping During Walking) and Treatment Strategies for the Care of Patients With Claudication

Claudication, defined as walking-induced leg discomfort and gait dysfunction relieved by
rest, affects 5% of Americans over 55 years of age. Claudicating patients adopt sedentary
lifestyles and cluster at the extreme low end of the physical activity spectrum, escalating
risk for adverse health effects. The primary therapeutic goals for claudicating patients are
restoration of leg function and prevention of disease progression. Current, rehabilitative
interventions focus on inadequate blood flow as the only cause of claudication. Operative
revascularization and/or exercise therapy are the principal conventional therapeutic
modalities, providing only modest rehabilitative benefit. Applying biomechanical analysis to
gait of claudicating patients, the investigators team has developed preliminary data
indicating that blood flow is not the only mechanism producing the limb dysfunction of
claudication. Several laboratories including the investigators own have demonstrated a
myopathy, characterized by mitochondrial dysfunction, oxidative damage and inflammation, in
leg skeletal muscle of claudicating patients. These conditions have not been quantified,
comprehensively, in relation to claudication, and their association with severity of
claudication is not known. The investigators hypothesis is that blood flow restriction is not
a good predictor of limb dysfunction in claudication, whereas muscle mitochondrial
dysfunction, oxidative damage and inflammation are strong predictors of limb dysfunction both
at baseline and after conventional therapy with revascularization or supervised exercise.
Under Aim #1, the investigators will acquire precise measurements of gastrocnemius
mitochondrial function, oxidative damage and inflammation in claudicating patients, at the
time of their initial presentation, and evaluate these measurements as predictors of
objective measures of limb function and subjective measures of quality of life. Under Aims #2
and #3, the investigators will evaluate the effects of revascularization (Aim#2) and
supervised exercise therapy (Aim#3) on mitochondrial dysfunction, oxidative damage and
inflammation in claudicating gastrocnemius and on objective measures of limb function and
subjective measures of quality of life. If the investigators hypothesis is correct, the work
in Aim #2 will for the first time definitively demonstrate that blood flow restriction due to
blockages in the arterial tree is not the only cause of claudication. The work under Aims #2
and #3 will determine whether revascularization or exercise therapy has a beneficial effect
on the myopathy of claudicating muscle with associated improvement in limb function and
quality of life. Finally, the proposed studies under Aims #1, #2 and #3 will provide
quantitative modeling of a panel of mechanistic (bioenergetics, oxidative stress and
inflammation) parameters as predictors of objective measurements of claudicating limb
function and subjective measures of quality of life commonly used for clinical assessment.
Measurements of gastrocnemius mitochondrial function, oxidative damage and inflammation may
be useful tools that permit staging of disease for optimum intervention and evaluation of
therapeutic interventions that specifically target these conditions, improving rehabilitative
outcomes.

Inclusion Criteria:

- a positive history of chronic claudication

- exercise-limiting claudication established by history and direct observation during a
screening walking test administered by the evaluating vascular surgeon

- an ankle/brachial index < 0.90 at rest

Exclusion Criteria:

- absence of Peripheral Arterial Disease (PAD)

- acute lower extremity ischemic event secondary to thromboembolic disease or acute
trauma

- exercise capacity limited by conditions other than claudication including leg
(joint/musculoskeletal, neurologic) and systemic (heart, lung disease) pathology