Impacts of Mitochondrial-targeted Antioxidant on Peripheral Artery Disease Patients

Impacts of Mitochondrial-targeted Antioxidant on Leg Function, Leg Blood Flow and Skeletal Muscle Mitochondrial Function in Peripheral Artery Disease Patients

Title: Impacts of mitochondrial-targeted antioxidant on leg blood flow and skeletal muscle mitochondrial function in peripheral artery disease patients. 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 patients 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.

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. We have recently demonstrated that patients with PAD have higher levels of systemic and local skeletal muscle inflammation due to impaired oxygen transfer capacity of leg blood vessels, which causes hypoxic conditions, meaning lack of oxygen, in the leg skeletal muscle. Skeletal muscle mitochondrial dysfunction and elevated reactive oxygen species (ROS) represent key pathological processes linked to atherosclerosis-mediated hypoxic and metabolic stress in PAD patients. One potential defensive mechanism to these negative consequences of impaired oxygen transfer capacity-induced hypoxic stress may be having higher levels of antioxidant capacity. 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 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. This research project may help us to understand the beneficial effects of higher mitochondrial specific antioxidant capacity on oxygen transfer capacity of leg blood vessels, mitochondria function, leg performance and leg pain in patients with PAD.

Subjects will be tested on two different days, first day will be baseline and MitoQ and second day will be Placebo. Testing will take place forty-minutes after MitoQ/placebo intake. There will be a 2-week washout between testing days.

Subjects will be tested on two different days, first day will be baseline and Placebo and second day will be MitoQ. Testing will take place forty-minutes after placebo/MitoQ intake. There will be a 2-week washout between testing days.

A mitochondrial-targeting antioxidant "MitoQ" or a placebo will be given to each subject in a crossover, double-blinded design and measures of leg function and leg blood flow will be measured.

Flow-mediated dilation will be used to measure vasodilation in the brachial artery, and blood flow in the femoral and popliteal arteries. This is measured in percents. Scale range is approximately 8-12% for healthy populations. A higher value represents a better outcome.

Subject will walk on a treadmill starting at a speed of 2.0 mph for two minutes with 0% incline. Every two minutes the treadmill incline will increase by 2% up to a maximum of 14%. The subject will be asked to walk until they feel pain in there legs, at which point the test will stop. This is measured in meters (distance) and seconds (time). Scale range is ~800 meters and 840 for healthy populations. A higher value represents a better outcome.

Blood draws will be taken to measure oxidative stress markers in the blood. This is measured in units per liter (U/L). Measures of oxidative stress are approximately 70-80 U/L in healthy populations. A lower value represents a better outcome.

Near-infrared spectroscopy will be used to measure leg muscle oxygenation. Measures of oxygenation are measured in percents. Scale range is ~70-90% in healthy populations. A higher value represents a better outcome.

Nitroglycerin-mediated dilation will be used to measure vascular smooth muscle function. This is measured in percents. Scale range is ~22-26% in healthy populations. A higher value represents a better outcome.

Inclusion Criteria: be able to give written, informed consent demonstrate positive history of chronic claudication have a history of exercise limiting claudication have an ankle/brachial index < 0.90 at rest have a stable blood pressure regimen, stable lipid regimen, stable diabetes regimen and risk factor control for 6 weeks. be between 50-85 years old Exclusion Criteria: rest pain or tissue loss due to 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