Clinical trial NCT03506633: Impacts of Mitochondrial-targeted Antioxidant on Peripheral Artery Disease Patients
Official title: Impacts of Mitochondrial-targeted Antioxidant on Leg Function, Leg Blood Flow and Skeletal Muscle Mitochondrial Function in Peripheral Artery Disease Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Peripheral Arterial Disease
Peripheral Artery Disease
Lead sponsor: University of Nebraska
Sponsor class: OTHER
First posted: 2018-04-24
Enrollment: 14
Sex: ALL
Minimum age (years): 50
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: 1:1 Randomized, cross-over, double-blinded design
Primary purpose: TREATMENT

Brief summary: Peripheral artery disease (PAD) is a common cardiovascular disease, in which narrowed arteries reduce blood flow to the limbs, causing pain, immobility and in some cases amputation or death. PAD patients have shown higher levels of systemic and skeletal muscle inflammation due to the impaired oxygen transfer capacity of these blood vessels. This attenuated oxygen transfer capacity causes hypoxic conditions in the skeletal muscle and results in mitochondrial dysfunction and elevated reactive oxygen species (ROS). These harmful byproducts of cell metabolism are the major cause of intermittent claudication, defined as pain in the legs that results in significant functional limitations. One potential defensive mechanism to these negative consequences may be having higher antioxidant capacity, which would improve blood vessel vasodilatory function, enabling more blood to transfer to the skeletal muscles. Therefore, the purpose of this project is to examine the impact of mitochondrial targeted antioxidant (MitoQ) intake on oxygen transfer capacity of blood vessels, skeletal muscle mitochondrial function, leg function, and claudication in participants with PAD. Blood vessel oxygen transfer capacity in the leg will be assessed in the femoral and popliteal arteries. Skeletal muscle mitochondrial function and ROS levels will be analyzed in human skeletal muscle via near infrared spectroscopy and through blood samples. Leg function will be assessed by walking on a force platform embedded treadmill and claudication times will be assessed with the Gardner maximal walking distance treadmill test.

Detailed description: Peripheral artery disease (PAD) is a common cardiovascular disease, in which narrowed arteries reduce blood flow to the limbs, causing pain, immobility and in some cases amputation or death. Previous studies reported that atherosclerotic lesions are distributed non-uniformly in the leg arteries, and the resulting impaired blood flow, and concomitant reduced oxygen delivery to skeletal muscle results in the pathophysiology of PAD. PAD patients have shown higher levels of systemic and skeletal muscle inflammation due to the impaired oxygen transfer capacity of these blood vessels. This attenuated oxygen transfer capacity causes hypoxic conditions in the skeletal muscle and results in mitochondrial dysfunction and elevated reactive oxygen species (ROS). These harmful byproducts of cell metabolism are the major cause of intermittent claudication, defined as pain in the legs that results in significant functional limitations.

One potential defensive mechanism to these negative consequences may be having higher antioxidant capacity, which would improve blood vessel vasodilatory function, enabling more blood to transfer to the skeletal muscles. MitoQ, a derivative of CoQ10, is a commercial antioxidant that counteracts this oxidative stress within the mitochondria. High ROS levels have been positively correlated with reduced Nitric oxide (NO) bioavailability, which limits the ability of the blood vessels to dilate, thereby increasing the occlusion that leads to claudication in PAD patients. MitoQ should reduce these ROS levels and increase vasodilatory function. However, the influence of MitoQ intake on leg blood flow, ROS production, claudication and leg function has not yet been investigated in this disease population.

Therefore, the purpose of this project is to examine the impact of mitochondrial targeted antioxidant (MitoQ) intake on oxygen transfer capacity of blood vessels, skeletal muscle mitochondrial function, leg function, and claudication in participants with PAD. Blood vessel oxygen transfer capacity in the leg will be assessed in the femoral and popliteal arteries. Skeletal muscle mitochondrial function and ROS levels will be analyzed in human skeletal muscle via near infrared spectroscopy and through blood samples. Leg function will be assessed by walking on a force platform embedded treadmill and claudication times will be assessed with the Gardner maximal walking distance treadmill test.

Eligibility criteria: Inclusion Criteria:

* Able to give written, informed consent
* Demonstrated positive history of chronic claudication
* History of exercise limiting claudication
* Ankle/brachial index \< 0.90 at rest
* Stable blood pressure regimen, stable lipid regimen, stable diabetes regimen and risk factor control for 6 weeks prior to study entry
* 50-85 years old

Exclusion Criteria:

* Resting pain or tissue loss due to Peripheral artery disease (PAD), Fontaine stage III and IV
* Acute lower extremity ischemic event secondary to thromboembolic disease or acute trauma
* Walking capacity limited by conditions other than claudication including leg (joint/musculoskeletal, neurologic) and systemic (heart, lung disease) pathology

Primary outcomes:
measure: Endothelial Function
timeFrame: 2 days
Secondary outcomes:
measure: Walking Function
timeFrame: 2 days (1 day for MitoQ and 1 day for Placebo)
measure: Oxidative Stress
timeFrame: 2 days
measure: Skeletal Muscle Oxygenation
timeFrame: 2 days
measure: Autonomic Nervous System Activity
timeFrame: 2 days
measure: Microvascular Function
timeFrame: 2 days
Other outcomes:
Locations:
city: Omaha
country: United States
facility: University of Nebraska - Omaha
state: Nebraska
Study officials:
affiliation: University of Nebraska
name: Song-Young Park, PhD
role: PRINCIPAL_INVESTIGATOR
References: