Effects of Heating on Exercise Pressor Reflex in Peripheral Artery Disease: Exercise Ability

Study Overview
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Brief Summary
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The study objectives of this projects are to examine the hypothesis that the sympathetic and blood pressure responses to exercise will be attenuated during and after heat exposure in patients with peripheral artery disease, via altering the sensitivity of the muscle afferent receptors.

Detailed Description
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Peripheral arterial disease (PAD) affects 8-12 million Americans and its cardinal symptom is leg pain during exercise, termed intermittent claudication. The diagnosis of PAD involves measuring the ankle-brachial index (ABI, i.e. the systolic pressure in the ankle divided by the systolic pressure in the arm); values below 0.9 are indicative of large vessel obstruction. Intermittent claudication is the most common symptom of this disease and it regularly occurs during exercise/physical activity but is relieved promptly by rest. Previous studies suggest that as the exercise pressor reflex is activated in patients with PAD, BP and heart rate (HR) are exaggerated. The BP rises during walking in the PAD patients were significantly greater than that seen in healthy control subjects. A recent human study from our group further indicates that an early BP response occurred during plantar flexion exercise before claudication was noted by the subjects, which may suggest that the accentuated BP response was due to an augmented muscle mechanoreflex in PAD. Moreover, another recent study from our group also showed that PAD patients have augmented renal vasoconstriction during plantar flexion exercise. It has been shown that exercise has benefits for patients with PAD. However, exercise becomes limited due to the pain and fatigue associated with the disease. Moreover, the augmented pressor response to exercise in PAD may increase the risk for the end organ damage (e.g. brain and/or heart). Thus, finding alternate/complimentary interventions that modulate the cardiovascular system and autonomic nervous system, and can be tolerated by the patients, would be beneficial. One possible intervention is heat exposure, since acute bouts of exercise and acute heat exposure have similar acute effects on both the autonomic and cardiovascular systems. For example, both exercise and heat exposure increase body temperature, increase HR, increase cardiac output (CO), increase left ventricular ejection fraction (EF), and enhance myocardial function. In the peripheral circulation, both exercise and heat exposure increase limb blood flow , muscle blood flow, and skin blood flow. Moreover, recent studies suggest that whole body exposure improves the endothelium function in PAD patients (e.g. activates endothelial progenitor cells CD34+). However, the effect of heat treatment on the ability of walking of PAD patients has not been examined. Moreover, it is unknown if heating can normalize/decrease the accentuated the pressor responses to exercise in PAD patients.

Official Title
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Effects of Heating on Exercise Pressor Reflex in Peripheral Artery Disease: Exercise Ability

Conditions
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PAD

Intervention / Treatment
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* Other: Without Heating
* Other: Warm Bath
* Other: Neutral Bath
* Other: Heating Suit
* Other: Lower limb warm water immersion
* Other: Gardner walking protocol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All subjects Capable of giving informed consent Any race or ethnicity Men and women age 21- 85 years (inclusive) Fluent in written and spoken English Patients with peripheral arterial disease (PAD) Diagnosed with PAD (i.e., ankle-brachial index below 0.9) Fontaine stage II or less - no pain while resting Satisfactory history and physical exam Healthy subjects Satisfactory history and physical examination Free of acute medical conditions Exclusion Criteria: For patients with PAD and Healthy subjects Age < 21 years Pregnant or nursing women Decisional impairment Prisoners For patients with PAD History of CAD with symptoms of unstable angina or myocardial infarction (<6 months) History of epilepsy or seizure disorders For healthy subjects • Any other chronic diseases (heart, lung, neuromuscular disease or diabetes)

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: The investigators will examine (using a prospective observational design) if heating will affect walking ability, blood pressure and heart rate responses in PAD patients. Each subject will serve as their own control. Additionally, we will compare these responses between PAD patients and healthy controls subjects.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: PAD without heating<br>Subjects will walk on a treadmill using the Gardner protocol until the patient says they want to stop. BP, HR and NIRS will be continuously measured during Gardner protocol. Skin blood flow, skin temperature and BP will be measured in the supine position before and after the Gardner protocol. | Other: Without Heating<br>* Subject will complete walking protocol without any heating procedure<br>Other: Gardner walking protocol<br>* The Gardner protocol begins at 2 mph and 0% grade for 2 minutes. The grade increases by 2% every 2 minutes (the speed remains 2 mph) until the subject says they want to stop or 22 minutes maximum. BP and HR will also be measured throughout the protocol.<br>|
| Experimental: PAD warm bath<br>Subjects will take a warm bath. Then, subjects will walk on a treadmill using the Gardner protocol until the patient says they want to stop. BP, HR and NIRS will be continuously measured during Gardner protocol. Skin blood flow, skin temperature and BP will be measured in the supine position before and after the Gardner protocol. | Other: Warm Bath<br>* Subjects will sit in a warm bathtub with water up to their shoulders, while one arm will be out of water for BP and HR measurement. The water temperature and internal temperature (Tcore), BP and HR will be measured throughout the bath. The water temperature will be controlled between 38-41°C. Subjects will remain in the tub for ≤ 30 minutes. If the HR increases more than 15 -20 bpm, or a significant BP drop occurs (e.g. BP >20 mmHg), the subject will be removed from the bath even if the time is <30 min.<br>Other: Gardner walking protocol<br>* The Gardner protocol begins at 2 mph and 0% grade for 2 minutes. The grade increases by 2% every 2 minutes (the speed remains 2 mph) until the subject says they want to stop or 22 minutes maximum. BP and HR will also be measured throughout the protocol.<br>|
| Placebo Comparator: PAD neutral bath<br>Subjects will take a neutral bath. Then, subjects will walk on a treadmill using the Gardner protocol until the patient says they want to stop. BP, HR and NIRS will be continuously measured during Gardner protocol. Skin blood flow, skin temperature and BP will be measured in the supine position before and after the Gardner protocol. | Other: Neutral Bath<br>* Subjects will sit in a warm bathtub with water up to their shoulders, while one arm will be out of water for BP and HR measurement. The water temperature and internal temperature (Tcore), BP and HR will be measured throughout the bath. The water temperature will be controlled between 35 - 37°C. Subjects will remain in the tub for ≤ 30 minutes.<br>Other: Gardner walking protocol<br>* The Gardner protocol begins at 2 mph and 0% grade for 2 minutes. The grade increases by 2% every 2 minutes (the speed remains 2 mph) until the subject says they want to stop or 22 minutes maximum. BP and HR will also be measured throughout the protocol.<br>|
| Experimental: PAD heating suit<br>Whole body heating with the suit will be performed. Then, subjects will walk on a treadmill using the Gardner protocol until the patient says they want to stop. BP, HR and NIRS will be continuously measured during Gardner protocol. Skin blood flow, skin temperature and BP will be measured in the supine position before and after the Gardner protocol. | Other: Heating Suit<br>* The mean skin temperature Tsk will be controlled with a water-perfused suit worn by subjects. Whole-body heating will be accomplished by perfusing warm water (  45 - 50 °C) through the suit to elevate the Tsk to ≤ 38 °C (100 oF). Warm water is through plastic tubes, and subjects' skin will not directly touch warm water. The heating will be continued until the ∆Tcore reaches   0. 6 - 1.0 °C. This may take approximately 60 - 90 min.<br>Other: Gardner walking protocol<br>* The Gardner protocol begins at 2 mph and 0% grade for 2 minutes. The grade increases by 2% every 2 minutes (the speed remains 2 mph) until the subject says they want to stop or 22 minutes maximum. BP and HR will also be measured throughout the protocol.<br>|
| Experimental: PAD lower limb warm water immersion<br>Subjects will place their lower legs in warm water. Then, subjects will walk on a treadmill using the Gardner protocol until the patient says they want to stop. BP, HR and NIRS will be continuously measured during Gardner protocol. Skin blood flow, skin temperature and BP will be measured in the supine position before and after the Gardner protocol. | Other: Lower limb warm water immersion<br>* Subjects will sit on a chair and put their lower legs and feet in a bucket with warm water. The water level will be just below the knees (depth of approximately 40 cm). The water temperature will be monitored and controlled at  38 - 42 °C throughout the 30 minutes. BP, HR, Tcore, the skin temperature and skin blood flow (e.g. on a thigh and/or forearm) will be measured before, during and after the lower limbs warm water immersion.<br>Other: Gardner walking protocol<br>* The Gardner protocol begins at 2 mph and 0% grade for 2 minutes. The grade increases by 2% every 2 minutes (the speed remains 2 mph) until the subject says they want to stop or 22 minutes maximum. BP and HR will also be measured throughout the protocol.<br>|
| Placebo Comparator: Healthy subjects without heating<br>Subjects will walk on a treadmill using the Gardner protocol until the patient says they want to stop. BP, HR and NIRS will be continuously measured during Gardner protocol. Skin blood flow, skin temperature and BP will be measured in the supine position before and after the Gardner protocol. | Other: Without Heating<br>* Subject will complete walking protocol without any heating procedure<br>Other: Gardner walking protocol<br>* The Gardner protocol begins at 2 mph and 0% grade for 2 minutes. The grade increases by 2% every 2 minutes (the speed remains 2 mph) until the subject says they want to stop or 22 minutes maximum. BP and HR will also be measured throughout the protocol.<br>|
| Experimental: Healthy subjects warm bath<br>Subjects will take a warm bath. Then, subjects will walk on a treadmill using the Gardner protocol until the patient says they want to stop. BP, HR and NIRS will be continuously measured during Gardner protocol. Skin blood flow, skin temperature and BP will be measured in the supine position before and after the Gardner protocol. | Other: Warm Bath<br>* Subjects will sit in a warm bathtub with water up to their shoulders, while one arm will be out of water for BP and HR measurement. The water temperature and internal temperature (Tcore), BP and HR will be measured throughout the bath. The water temperature will be controlled between 38-41°C. Subjects will remain in the tub for ≤ 30 minutes. If the HR increases more than 15 -20 bpm, or a significant BP drop occurs (e.g. BP >20 mmHg), the subject will be removed from the bath even if the time is <30 min.<br>Other: Gardner walking protocol<br>* The Gardner protocol begins at 2 mph and 0% grade for 2 minutes. The grade increases by 2% every 2 minutes (the speed remains 2 mph) until the subject says they want to stop or 22 minutes maximum. BP and HR will also be measured throughout the protocol.<br>|
| Placebo Comparator: Healthy subjects neutral bath<br>Subjects will take a neutral bath. Then, subjects will walk on a treadmill using the Gardner protocol until the patient says they want to stop. BP, HR and NIRS will be continuously measured during Gardner protocol. Skin blood flow, skin temperature and BP will be measured in the supine position before and after the Gardner protocol. | Other: Neutral Bath<br>* Subjects will sit in a warm bathtub with water up to their shoulders, while one arm will be out of water for BP and HR measurement. The water temperature and internal temperature (Tcore), BP and HR will be measured throughout the bath. The water temperature will be controlled between 35 - 37°C. Subjects will remain in the tub for ≤ 30 minutes.<br>Other: Gardner walking protocol<br>* The Gardner protocol begins at 2 mph and 0% grade for 2 minutes. The grade increases by 2% every 2 minutes (the speed remains 2 mph) until the subject says they want to stop or 22 minutes maximum. BP and HR will also be measured throughout the protocol.<br>|
| Experimental: Healthy subjects heat suit<br>Whole body heating with the suit will be performed. Then, subjects will walk on a treadmill using the Gardner protocol until the patient says they want to stop. BP, HR and NIRS will be continuously measured during Gardner protocol. Skin blood flow, skin temperature and BP will be measured in the supine position before and after the Gardner protocol. | Other: Heating Suit<br>* The mean skin temperature Tsk will be controlled with a water-perfused suit worn by subjects. Whole-body heating will be accomplished by perfusing warm water (  45 - 50 °C) through the suit to elevate the Tsk to ≤ 38 °C (100 oF). Warm water is through plastic tubes, and subjects' skin will not directly touch warm water. The heating will be continued until the ∆Tcore reaches   0. 6 - 1.0 °C. This may take approximately 60 - 90 min.<br>Other: Gardner walking protocol<br>* The Gardner protocol begins at 2 mph and 0% grade for 2 minutes. The grade increases by 2% every 2 minutes (the speed remains 2 mph) until the subject says they want to stop or 22 minutes maximum. BP and HR will also be measured throughout the protocol.<br>|
| Experimental: Healthy subjects lower limb immersion<br>Subjects will place their lower legs in warm water. Then, subjects will walk on a treadmill using the Gardner protocol until the patient says they want to stop. BP, HR and NIRS will be continuously measured during Gardner protocol. Skin blood flow, skin temperature and BP will be measured in the supine position before and after the Gardner protocol. | Other: Lower limb warm water immersion<br>* Subjects will sit on a chair and put their lower legs and feet in a bucket with warm water. The water level will be just below the knees (depth of approximately 40 cm). The water temperature will be monitored and controlled at  38 - 42 °C throughout the 30 minutes. BP, HR, Tcore, the skin temperature and skin blood flow (e.g. on a thigh and/or forearm) will be measured before, during and after the lower limbs warm water immersion.<br>Other: Gardner walking protocol<br>* The Gardner protocol begins at 2 mph and 0% grade for 2 minutes. The grade increases by 2% every 2 minutes (the speed remains 2 mph) until the subject says they want to stop or 22 minutes maximum. BP and HR will also be measured throughout the protocol.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Walking time in minutes | Walking time on treadmill using Gardner protocol | Recording walking time to fatigue (up to 22 minutes maximum) during of every 3-4 hour study visit. | 
| Blood pressure in mmHg | Cuffs placed on a finger and arm will monitor blood pressure. | Recorded continuously during the 3-4 hour study visit | 
| Heart Rate in beats per minute | Electrocardiogram (ECG) patches attached to a Cardiocap will monitor heart rat | Recorded continuously during the 3-4 hour study visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Internal Temperature in degrees C | The internal temperature (Tcore) will be measured from the stomach/intestines via a telemetry pill swallowed by subjects. | Recorded continuously during the 3-4 hour study visit | 
| Near infrared spectroscopy (NIRS) in arbitrary units | This system is designed specifically for non-invasive measurements of muscle tissue. The system measures the tissue saturation of the investigated muscle, called the 'tissue saturation index' (TSI). | Recorded continuously during the 3-4 hour study visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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exercise, blood pressure response, heating