Impacts of Mitochondrial-targeted Antioxidant on Peripheral Artery Disease Patients
| Status: | Recruiting |
|---|---|
| Conditions: | Peripheral Vascular Disease |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 50 - 85 |
| Updated: | 2/22/2019 |
| Start Date: | September 5, 2018 |
| End Date: | February 1, 2020 |
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.
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.
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.
Inclusion Criteria:
1. be able to give written, informed consent
2. demonstrate positive history of chronic claudication
3. have a history of exercise limiting claudication
4. have an ankle/brachial index < 0.90 at rest
5. have a stable blood pressure regimen, stable lipid regimen, stable diabetes regimen
and risk factor control for 6 weeks.
6. be between 50-85 years old
Exclusion Criteria:
1. rest pain or tissue loss due to PAD (Fontaine stage III and IV)
2. acute lower extremity ischemic event secondary to thromboembolic disease or acute
trauma
3. walking capacity limited by conditions other than claudication including leg
(joint/musculoskeletal, neurologic) and systemic (heart, lung disease) pathology
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