Peripheral Arterial Disease, Peripheral Artery Disease
Conditions
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.
Interventions
DIETARY_SUPPLEMENTMitoQ
A mitochondrial-targeting antioxidant MitoQ or a placebo will be given to each participant in a crossover, double-blinded design and measures of leg function and leg blood flow will be measured.
Sponsors
University of Nebraska
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention model description
1:1 Randomized, cross-over, double-blinded design
Eligibility
Sex/Gender
ALL
Age
50 Years to 85 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Endothelial Function | 2 days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Walking Function | 2 days (1 day for MitoQ and 1 day for Placebo) | 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. This assessment occurred on two separate days (one for each intervention). |
| Oxidative Stress | 2 days | Blood draws will be taken to measure oxidative stress markers in the blood. This is measured in units per milliliter (U/mL). Measures of oxidative stress are approximately 70-80 U/mL in healthy populations. A lower value represents a better outcome. |
| Skeletal Muscle Oxygenation | 2 days | 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. |
| Autonomic Nervous System Activity | 2 days | Autonomic nervous system function will be measured non-invasively using heart rate variability via the head-up tilt test. Raw R-R interval data will be converted to time frequency domain with the wavelet transform across the frequency intervals 0.04-0.15 Hz (low-frequency, (LF)) and 0.15-0.4 Hz (high-frequency, HF). Units for both will be expressed as ms\^2. Final outcome measure will be the ratio of LF/HF, which is a unitless ratio to indicate sympathetic-to-parasympathetic nervous system function. |
| Microvascular Function | 2 days | Microvascular function will be assessed using near-infrared spectroscopy. NIRS measurements were taken continuously throughout the entire protocol at a sampling rate of 10 Hz. Hemoglobin and myoglobin possess indistinguishable spectral characteristics in the NIRS signal; therefore, the signal is considered to be primarily derived from Hb. The signals were analyzed according to a modified Beer- Lambert's law, and a constant differential path length factor was not used due to the assumption that constant optical scattering of the photons has been demonstrated to affect alterations in NIRS signals. Data were expressed as relative changes with respect to baseline as a percentage (TOI). Tissue reoxygenation was estimated by calculating the initial slope of TOI recovery, which has been used as an index of microvascular function. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MitoQ-Placebo 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.
MitoQ: 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. | 7 |
| Placebo-MitoQ 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.
MitoQ: 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. | 6 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Washout (14 Days) | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo-MitoQ | Total | MitoQ-Placebo |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 9 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 4 Participants | 2 Participants |
| Age, Continuous | 71.5 years STANDARD_DEVIATION 8.4 | 71.5 years STANDARD_DEVIATION 8.4 | 71.5 years STANDARD_DEVIATION 8.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 12 Participants | 6 Participants |
| Region of Enrollment United States | 6 participants | 13 participants | 7 participants |
| Sex: Female, Male Female | 3 Participants | 7 Participants | 4 Participants |
| Sex: Female, Male Male | 3 Participants | 6 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 13 |
| other Total, other adverse events | 0 / 13 | 0 / 13 |
| serious Total, serious adverse events | 0 / 13 | 0 / 13 |
Outcome results
Primary
Endothelial Function
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.
Time frame: 2 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MitoQ | Endothelial Function | 6.13 % dilation | Standard Deviation 2.1 |
| Placebo | Endothelial Function | 3.78 % dilation | Standard Deviation 1.13 |
Secondary
Autonomic Nervous System Activity
Autonomic nervous system function will be measured non-invasively using heart rate variability via the head-up tilt test. Raw R-R interval data will be converted to time frequency domain with the wavelet transform across the frequency intervals 0.04-0.15 Hz (low-frequency, (LF)) and 0.15-0.4 Hz (high-frequency, HF). Units for both will be expressed as ms\^2. Final outcome measure will be the ratio of LF/HF, which is a unitless ratio to indicate sympathetic-to-parasympathetic nervous system function.
Time frame: 2 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MitoQ | Autonomic Nervous System Activity | 3.6 ratio | Standard Deviation 2.3 |
| Placebo | Autonomic Nervous System Activity | 2.7 ratio | Standard Deviation 1.8 |
Secondary
Microvascular Function
Microvascular function will be assessed using near-infrared spectroscopy. NIRS measurements were taken continuously throughout the entire protocol at a sampling rate of 10 Hz. Hemoglobin and myoglobin possess indistinguishable spectral characteristics in the NIRS signal; therefore, the signal is considered to be primarily derived from Hb. The signals were analyzed according to a modified Beer- Lambert's law, and a constant differential path length factor was not used due to the assumption that constant optical scattering of the photons has been demonstrated to affect alterations in NIRS signals. Data were expressed as relative changes with respect to baseline as a percentage (TOI). Tissue reoxygenation was estimated by calculating the initial slope of TOI recovery, which has been used as an index of microvascular function.
Time frame: 2 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MitoQ | Microvascular Function | 48.1 % reoxygenation rate | Standard Deviation 18.8 |
| Placebo | Microvascular Function | 32.3 % reoxygenation rate | Standard Deviation 17.9 |
Secondary
Oxidative Stress
Blood draws will be taken to measure oxidative stress markers in the blood. This is measured in units per milliliter (U/mL). Measures of oxidative stress are approximately 70-80 U/mL in healthy populations. A lower value represents a better outcome.
Time frame: 2 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MitoQ | Oxidative Stress | 29.55 U/mL | Standard Error 1.62 |
| Placebo | Oxidative Stress | 34.14 U/mL | Standard Error 0.98 |
Secondary
Skeletal Muscle Oxygenation
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.
Time frame: 2 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MitoQ | Skeletal Muscle Oxygenation | 48.1 percentage of oxygenation | Standard Deviation 19.3 |
| Placebo | Skeletal Muscle Oxygenation | 30.7 percentage of oxygenation | Standard Deviation 18.2 |
Secondary
Walking Function
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. This assessment occurred on two separate days (one for each intervention).
Time frame: 2 days (1 day for MitoQ and 1 day for Placebo)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MitoQ | Walking Function | 451.07 meters | Standard Deviation 217.14 |
| Placebo | Walking Function | 404.49 meters | Standard Deviation 218.09 |