- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03900832
Effects of Heating on Exercise Pressor Reflex in Peripheral Artery Disease: Exercise Ability (EPR)
Study Overview
Status
Conditions
Detailed Description
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.
Study Type
Enrollment (Estimated)
Phase
- Early Phase 1
Contacts and Locations
Study Contact
- Name: Jian Cui, PhD
- Phone Number: 7175311799
- Email: jcui@pennstatehealth.psu.edu
Study Contact Backup
- Name: Kris Gray, MS
- Phone Number: 7175314589
- Email: kgray1@pennstatehealth.psu.edu
Study Locations
-
-
Pennsylvania
-
Hershey, Pennsylvania, United States, 17033
- Recruiting
- Penn State Milton S. Hershey Medical Center
-
Contact:
- Kristen Gray
- Phone Number: 717-531-4589
- Email: kgray1@pennstatehealth.psu.edu
-
Contact:
- Jian Cui
- Phone Number: 717-531-1799
- Email: jcui@pennstatehealth.psu.edu
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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)
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: Single
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Placebo Comparator: PAD without heating
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.
|
Subject will complete walking protocol without any heating procedure
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.
|
Experimental: PAD warm bath
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.
|
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.
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. |
Placebo Comparator: PAD neutral bath
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.
|
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.
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. |
Experimental: PAD heating suit
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.
|
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.
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.
|
Experimental: PAD lower limb warm water immersion
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.
|
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.
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.
|
Placebo Comparator: Healthy subjects without heating
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.
|
Subject will complete walking protocol without any heating procedure
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.
|
Experimental: Healthy subjects warm bath
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.
|
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.
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. |
Placebo Comparator: Healthy subjects neutral bath
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.
|
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.
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. |
Experimental: Healthy subjects heat suit
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.
|
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.
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.
|
Experimental: Healthy subjects lower limb immersion
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.
|
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.
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.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Walking time in minutes
Time Frame: Recording walking time to fatigue (up to 22 minutes maximum) during of every 3-4 hour study visit.
|
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
Time Frame: Recorded continuously during the 3-4 hour study visit
|
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
Time Frame: Recorded continuously during the 3-4 hour study visit
|
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
Time Frame: Recorded continuously during the 3-4 hour study visit
|
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
Time Frame: Recorded continuously during the 3-4 hour study visit
|
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
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Jian Cui, Penn State College of Medicine
Publications and helpful links
General Publications
- Cui J, Blaha C, Sinoway LI. Whole body heat stress attenuates the pressure response to muscle metaboreceptor stimulation in humans. J Appl Physiol (1985). 2016 Nov 1;121(5):1178-1186. doi: 10.1152/japplphysiol.00212.2016. Epub 2016 Oct 7.
- Cui J, Blaha C, Moradkhan R, Gray KS, Sinoway LI. Muscle sympathetic nerve activity responses to dynamic passive muscle stretch in humans. J Physiol. 2006 Oct 15;576(Pt 2):625-34. doi: 10.1113/jphysiol.2006.116640. Epub 2006 Jul 27.
- Cui J, Boehmer J, Blaha C, Sinoway LI. Muscle sympathetic nerve activity response to heat stress is attenuated in chronic heart failure patients. Am J Physiol Regul Integr Comp Physiol. 2017 Jun 1;312(6):R873-R882. doi: 10.1152/ajpregu.00355.2016. Epub 2017 Mar 22.
- Cui J, Muller MD, Blaha C, Kunselman AR, Sinoway LI. Seasonal variation in muscle sympathetic nerve activity. Physiol Rep. 2015 Aug;3(8):e12492. doi: 10.14814/phy2.12492.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- STUDY00005798
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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