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

• ClinicalTrials.gov Identifier: NCT01970332
• Recruitment Status: Completed
• First Posted: October 28, 2013
• Last Update Posted: September 26, 2017
• Sponsor: University of Nebraska
• Collaborators: National Institute on Aging (NIA); National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Iraklis I Pipinos, MD, University of Nebraska

Study Description

Brief Summary:

Intermittent claudication afflicts 5% of the US population older than 55 years of age and develops along with hardening of the arteries of the legs. Claudicating patients limp and can only walk very short distances because their legs hurt. This protocol evaluates the mechanisms that may produce the leg dysfunction of claudication and its successful completion can ultimately produce significant new diagnostic and treatment strategies for the care of claudicating patients.

Condition or disease	Intervention/treatment	Phase
Peripheral Arterial Disease	Procedure: Revascularization Surgery; Other: Supervised exercise therapy	Not Applicable

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 220 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Health Services Research
• Official Title: Mitochondrial Dysfunction, Oxidative Damage and Inflammation in Claudication
• Study Start Date: September 2010
• Actual Primary Completion Date: May 30, 2016
• Actual Study Completion Date: May 30, 2016

Arms and Interventions

Arm	Intervention/treatment
No Intervention: No Exercise Therapy or Revascularization operation; The patient is evaluated but no intervention
Experimental: Revascularization Surgery; The patient undergoes surgery to revascularize the ischemic, symptomatic limb(s)	Other: Supervised exercise therapy
Experimental: Exercise Therapy; The patient undergoes supervised exercise therapy for 6 months	Procedure: Revascularization Surgery

Outcome Measures

Primary Outcome Measures :

1. Walking distances [ Time Frame: six months ]
   Initial Claudication Distance, Absolute Claudication Distance, 6-Minute Walking Distance
2. Quality of life [ Time Frame: six months ]
   Walking Impairment Questionnaire and the Medical Outcomes Study Short Form 36 Healthy Survey
3. Leg biomechanics [ Time Frame: six months ]
   Propulsion Impulse, Ankle plantarflexor torque, Ankle plantarflexor power and maximum isometric plantarflexion force
4. Leg hemodynamics [ Time Frame: 6 months ]
   Ankle Brachial Index

Secondary Outcome Measures :

1. Myofiber Mitochondrial Function [ Time Frame: 6 months ]
   Mitochondrial Respiration measured via polarography
2. Myofiber Oxidative Damage [ Time Frame: 6 months ]
   Myofiber content of HNE adducts and protein carbonyls. Muscle Manganese Superoxide Dismutase activity
3. Muscle inflammation [ Time Frame: 6 months ]
   Expression of pro- and anti-inflammatory cytokines and monocyte/macrophage cell counts.
4. Myofiber Morphology [ Time Frame: 6 months ]
   Cross-sectional area of the myofibers

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Nebraska

Omaha VA Medical Center

Omaha, Nebraska, United States, 68105

Sponsors and Collaborators

University of Nebraska

National Institute on Aging (NIA)

National Heart, Lung, and Blood Institute (NHLBI)

More Information

• Responsible Party: Iraklis I Pipinos, MD, Principal Investigator, University of Nebraska
• ClinicalTrials.gov Identifier: NCT01970332
• Other Study ID Numbers: 510-10; 5R01AG034995 ( U.S. NIH Grant/Contract )
• First Posted: October 28, 2013
• Last Update Posted: September 26, 2017
• Last Verified: September 2017

Keywords provided by Iraklis I Pipinos, MD, University of Nebraska:

Peripheral Arterial Disease; Peripheral Vascular Disease; Claudication; Myopathy; Oxidative stress; Mitochondrial dysfunction; Biomechanics; Inflammation

Additional relevant MeSH terms:

Peripheral Arterial Disease; Peripheral Vascular Diseases; Intermittent Claudication; Atherosclerosis; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases