Mechanisms That Produce the Leg Dysfunction of Claudication & Treatment Strategies

Mitochondrial Dysfunction, Oxidative Damage and Inflammation in Claudication

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.

Study Overview

• Status: Completed
• Conditions: Peripheral Arterial Disease
• Intervention / Treatment: Other: Supervised exercise therapy; Procedure: Revascularization Surgery

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 Type: Interventional
• Enrollment (Actual): 220
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Nebraska
    • Omaha, Nebraska, United States, 68105
      • Veterans Affairs Medical Center, Omaha

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Health Services Research
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Walking distances	Initial Claudication Distance, Absolute Claudication Distance, 6-Minute Walking Distance	six months
Leg biomechanics	Propulsion Impulse, Ankle plantarflexor torque, Ankle plantarflexor power and maximum isometric plantarflexion force	six months
Leg hemodynamics	Ankle Brachial Index	6 months
Quality of life Questionnaires	Walking Impairment Questionnaire and the Medical Outcomes Study Short Form 36 Healthy Survey	six months

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: University of Nebraska
• Collaborators: National Institute on Aging (NIA); American Heart Association
• Investigators: Principal Investigator: Iraklis I Pipinos, MD, PhD, University of Nebraska

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2010
• Primary Completion (Actual): May 30, 2016
• Study Completion (Actual): May 30, 2016

Study Registration Dates

• First Submitted: September 4, 2013
• First Submitted That Met QC Criteria: October 22, 2013
• First Posted (Estimated): October 28, 2013

Study Record Updates

• Last Update Posted (Actual): September 7, 2023
• Last Update Submitted That Met QC Criteria: September 1, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Oxidative stress; Inflammation; Claudication; Peripheral Vascular Disease; Biomechanics; Mitochondrial dysfunction; Peripheral Arterial Disease; Myopathy
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis; Peripheral Arterial Disease; Peripheral Vascular Diseases; Intermittent Claudication
• Other Study ID Numbers: 0510-10-ET; 5R01AG034995 (U.S. NIH Grant/Contract); 15POST25520004 (Other Grant/Funding Number: American Heart Association)