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Completed

NCT Number: NCT03900832

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

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.

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Key information

Age range

21 year–85 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Early Phase 1

Primary location

Penn State Milton S. Hershey Medical Center

Hershey, Pennsylvania, 17033, United States

About this study

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.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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)

Treatment and study plan

Without Heating

Other

Subject will complete walking protocol without any heating procedure

Warm Bath

Other

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.

Neutral Bath

Other

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.

Heating Suit

Other

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.

Lower limb warm water immersion

Other

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.

Gardner walking protocol

Other

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.

Primary outcomes

  1. 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

  2. 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.

  3. 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

Secondary outcomes

  1. 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.

  2. 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).

Sponsors and collaborators

Lead sponsor

Milton S. Hershey Medical Center

Other

Registry information

Acronym: EPR

Important dates

Study start
2019
Primary completion
2025
Study completion
2025
First posted
Apr 3, 2019
Registry last updated
Sep 16, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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