Heat Therapy in Older Hypertensive Women
| Status: | Recruiting |
|---|---|
| Conditions: | High Blood Pressure (Hypertension) |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 65 - 85 |
| Updated: | 3/27/2019 |
| Start Date: | April 1, 2019 |
| End Date: | January 2024 |
| Contact: | Qi Fu, MD, PhD |
| Email: | QiFu@texashealth.org |
| Phone: | 214-345-8125 |
Chronic Lower Leg Heating for the Treatment of Hypertension in Older Women
The prevalence of hypertension is greater in older (≥65 years) women than in older men, while
the blood pressure (BP) control rate is lower in older women in the United States.
Uncontrolled hypertension is a major risk factor for cardiovascular morbidity and mortality.
Despite standard therapy and adherence to optimal drug regimens, over 50% of older
hypertensive women still have inadequate BP control (e.g. >140/90 mmHg), and the control rate
is further reduced with more aggressive BP targets recommended recently by the new 2017
ACC/AHA Hypertension Guidelines. Thus, the effectiveness of drug treatment alone in the
control of hypertension among older women is limited; hence, non-pharmacological approaches
are also needed to help reduce BP and cardiovascular morbidity and mortality in older
hypertensive women. One adjuvant, non-pharmacological approach that offers promise in
lowering BP is "heat therapy". Indeed, repeated (chronic) whole-body heat exposure has been
found to decrease BP in healthy humans. Whether this is also true after regional limb heating
in hypertensive patients is unknown. The global objectives of this research project are to
investigate the BP lowering effect of home-based lower leg heat therapy in older women with
hypertension, and to examine the impact of this therapeutic modality on neural-vascular
health in these patients. Specific Aim 1 will test the hypothesis that chronic lower leg heat
therapy combined with an antihypertensive drug is superior to drug treatment alone in
lowering BP in older hypertensive women. We will randomly assign older hypertensive women to
either an intervention group or a control group. Patients in the intervention group will
perform 8 weeks of home-based lower leg heat therapy via water immersion up to the knee in a
circulated bath (water temperature 42°C, 4 times per week, 45 min per session), whereas
patients in the control group will immerse their legs in a thermoneutral water bath (33°C) at
the same frequency and duration. All patients will also receive a fixed dose of
chlorthalidone (a diuretic, 25 mg orally once daily). We will compare ambulatory BP, the BP
control rate, and patient adherence and acceptability to treatment between the groups.
Specific Aim 2 will test the hypothesis that chronic lower leg heat therapy will improve
nitric oxide bioavailability which can decrease sympathetic vasoconstriction and improve
vascular function in older hypertensive women. We will use state-of-the-art techniques of
microneurography, Doppler ultrasound, applanation tonometry, and cutaneous microdialysis to
assess sympathetic neural control, indices of conduit and resistance vessel vasodilator
function, and interstitial metabolites (i.e. nitrate and nitrite) indicative of basal nitric
oxide bioavailability in all patients enrolled in Aim 1 before and after 8 weeks of heat
therapy. Information obtained from this research project will guide evidence-based clinical
practice. It is anticipated that our study may lead to revision of hypertension guidelines to
incorporate home-based heat therapy as adjuvant to antihypertensive drug(s) for older women,
as well as other patient populations.
the blood pressure (BP) control rate is lower in older women in the United States.
Uncontrolled hypertension is a major risk factor for cardiovascular morbidity and mortality.
Despite standard therapy and adherence to optimal drug regimens, over 50% of older
hypertensive women still have inadequate BP control (e.g. >140/90 mmHg), and the control rate
is further reduced with more aggressive BP targets recommended recently by the new 2017
ACC/AHA Hypertension Guidelines. Thus, the effectiveness of drug treatment alone in the
control of hypertension among older women is limited; hence, non-pharmacological approaches
are also needed to help reduce BP and cardiovascular morbidity and mortality in older
hypertensive women. One adjuvant, non-pharmacological approach that offers promise in
lowering BP is "heat therapy". Indeed, repeated (chronic) whole-body heat exposure has been
found to decrease BP in healthy humans. Whether this is also true after regional limb heating
in hypertensive patients is unknown. The global objectives of this research project are to
investigate the BP lowering effect of home-based lower leg heat therapy in older women with
hypertension, and to examine the impact of this therapeutic modality on neural-vascular
health in these patients. Specific Aim 1 will test the hypothesis that chronic lower leg heat
therapy combined with an antihypertensive drug is superior to drug treatment alone in
lowering BP in older hypertensive women. We will randomly assign older hypertensive women to
either an intervention group or a control group. Patients in the intervention group will
perform 8 weeks of home-based lower leg heat therapy via water immersion up to the knee in a
circulated bath (water temperature 42°C, 4 times per week, 45 min per session), whereas
patients in the control group will immerse their legs in a thermoneutral water bath (33°C) at
the same frequency and duration. All patients will also receive a fixed dose of
chlorthalidone (a diuretic, 25 mg orally once daily). We will compare ambulatory BP, the BP
control rate, and patient adherence and acceptability to treatment between the groups.
Specific Aim 2 will test the hypothesis that chronic lower leg heat therapy will improve
nitric oxide bioavailability which can decrease sympathetic vasoconstriction and improve
vascular function in older hypertensive women. We will use state-of-the-art techniques of
microneurography, Doppler ultrasound, applanation tonometry, and cutaneous microdialysis to
assess sympathetic neural control, indices of conduit and resistance vessel vasodilator
function, and interstitial metabolites (i.e. nitrate and nitrite) indicative of basal nitric
oxide bioavailability in all patients enrolled in Aim 1 before and after 8 weeks of heat
therapy. Information obtained from this research project will guide evidence-based clinical
practice. It is anticipated that our study may lead to revision of hypertension guidelines to
incorporate home-based heat therapy as adjuvant to antihypertensive drug(s) for older women,
as well as other patient populations.
We expect that over a period of 6 years, 500 older hypertensive women will be screened, 200
of them will be enrolled, and 100 will complete the entire project.
Aim 1: To test the hypothesis that chronic heat therapy combined with an antihypertensive
drug is superior to drug treatment alone in lowering BP in older hypertensive women. We will
randomly assign older hypertensive women to either an intervention group or a control group.
Patients in the intervention group will be required to perform 8 weeks of home-based lower
leg heat therapy via water immersion up to the knee in a circulated bath (water temperature
42°C, 4 times per week, 45 min per session), whereas patients in the control group will
immerse their legs in a thermoneutral water bath (33°C) at the same frequency and duration.
All patients will also receive a fixed dose of chlorthalidone (a diuretic, 25 mg orally once
daily). We will compare 24-hour ambulatory BP, the BP control rate, and patient adherence and
acceptability to treatment between the groups.
Aim 2: To test the hypothesis that chronic heat therapy will improve nitric oxide
bioavailability which can decrease sympathetic vasoconstriction and improve vascular function
in older hypertensive women. We will use state-of-the-art techniques of microneurography,
Doppler ultrasound and applanation tonometry to assess sympathetic neural control and
cardiac-vascular function in all patients enrolled in Aim 1 before and after 8 weeks of heat
therapy.
Study Procedures:
Screening: Potential participants will be invited into the laboratory where a research nurse
and investigators will have the patient read the institutionally approved consent form and
explain the study. Informed consent will be obtained prior to screening. After that, we will
perform a physical exam, a review of medical history and medication, and a further evaluation
of inclusion and exclusion criteria in potential patients.
Wash-out: Patients who are currently treated with antihypertensive agents will gradually stop
taking their own medications. At least one week after all antihypertensive medications are
stopped, 24-hour ambulatory BP monitoring (SunTech) will be performed. Patients with awake BP
<140/90 or ≥180/110 mmHg will be excluded.
Run-in: All patients will have a 2-week run-in prior to pre-testing and they will be treated
with a fixed dose of chlorthalidone (a diuretic, 25 mg orally once daily) during this period
to avoid excessive increases in BP (for safety reasons). This is a first-line
antihypertensive agent commonly prescribed. Previous studies showed that chlorthalidone does
not reduce oxidative stress, nor does it alter nitric oxide bioavailability and endothelial
function.
Patient monitoring during run-in: Patients will be required to measure/record their BP daily
at home using an automated device we provide (Life-Source). Patients will visit our lab
weekly for a BP check, pill counting, and monitoring of safety and tolerability of the study
drug (e.g. low levels of potassium and sodium, high levels of uric acid and calcium,
symptomatic hypotension, etc). Patients will be excluded if they cannot tolerate the study
drug. In addition, patients will be asked to resume their own antihypertensive medication(s)
and will thereafter be excluded from the study if their systolic BP is ≥160 mmHg and/or
diastolic BP is ≥100 mmHg after 2 weeks of run-in or if the patient has clinical symptoms
associated with elevated BP (i.e. headache, dizziness, or nausea). We believe this approach
will not impose excessive risks to the patients and will allow for better experimental
control. Twenty-four-hour ambulatory BP will be repeated immediately after the run-in period,
and patients with awake BP <130/80 mmHg will be excluded from the study based on the new
hypertension guidelines.8, 9 This run-in approach has been successfully implemented in the
PI's laboratory.
Laboratory assessments: Sympathetic neural control and vascular function will be assessed
immediately after the run-in period (see Day 1 and Day 2 testing below for detail). These
neural-vascular assessments will be repeated after 8 weeks of intervention or control
treatments within 48 hours of last heat therapy session.
Day 1: Assessment of sympathetic neural control. These assessments will take place at the
Institute for Exercise and Environmental Medicine. Patients will be relaxed in the supine
position, and an intravenous catheter will be inserted into the antecubital vein on the
non-dominant arm. Arm-cuff BP will be measured by electrosphygmomanometry (SunTech).
Beat-by-beat finger BP will be measured by photoplethysmography (Nexfin). The beat-by-beat BP
recordings will be validated using the SunTech measures as Nexfin is accurate for changes in
BP but not absolute values. Heart rate will be measured from lead II of the
electrocardiogram. Respiratory movements will be monitored with a nasal cannula. Muscle
sympathetic nerve activity (MSNA) will be recorded from the peroneal nerve
(microneurography). Brain blood flow (middle cerebral artery) will be measured using
Transcranial Doppler. Femoral blood flow will be obtained using duplex ultrasound.
At least 30 min after the instrumentation, blood samples will be taken through the
intravenous catheter for measurements of plasma catecholamine concentration, plasma renin
activity, aldosterone, vasopressin, electrolytes, hemoglobin and hematocrit. Cardiac output
will be measured intermittently using the acetylene rebreathing technique. Left ventricular
function will be assessed by echocardiography.
At least 10 min after an acceptable nerve signal has been obtained, baseline data will be
collected during spontaneous breathing and controlled breathing (0.2 Hz, 12 breaths per
minute) for 10 min each. After that, a Valsalva maneuver at 40 mmHg expired pressure will be
performed for assessment of baroreflex function and the straining period will last for 20
sec. Next, a cold pressor test will be performed to evaluate the integrity of central
vasomotor processes and their efferent pathways. Baseline measurements will be made for 5
min, and then the patient's dominant hand will be placed into an ice water bath (50% ice and
50% water, ~4°C) up to the wrist for 2 min. After a sufficient recovery period (i.e. ≥15
min), patients will then perform static handgrip using the dominant hand at 40% of maximal
voluntary contraction until fatigue, followed by 2 min of post-exercise circulatory occlusion
with an upper arm cuff inflated to 250 mmHg. The handgrip test will assess cardiovascular
reactivity to isometric exercise and post-exercise circulatory occlusion provides a means to
isolate the activation of the skeletal muscle metaboreflex independent of mechanoreflex
activation, and central command. After another sufficient recovery period (i.e. ≥15 min),
baseline measurements will be made for 10 min, a graded upright tilt (30⁰ for 5 min and 60⁰
for 20 min or until presyncope) will be performed to assess autonomic circulatory control
during orthostatic stress. BP, heart rate, respiration, MSNA, and brain blood flow will be
continuously recorded, while cardiac output, femoral artery diameter and blood velocity will
be measured at the end of 30° tilting and every 5 min during 60° tilt. Blood sample will be
taken after 5 and 20 min of 60⁰ tilting. Then, the patient will be returned to the supine
position for recovery and the microneurographic electrodes will be removed.
After a sufficient recovery period (i.e. ≥30 min), blood volume will be measured using a
modified carbon monoxide rebreathing method in the sitting position.
Day 2: Assessment of vascular function. These assessments will take place at the University
of North Texas Health Science Center. Arterial tonometry with simultaneous electrocardiogram
will be obtained from the radial, femoral, and carotid arteries using a pencil-sized probe
(SphygmoCor)) over the maximal pulsation of the artery. Transit distances will be measured by
body-surface measurements from the suprasternal notch to each pulse-recording site. Tonometry
data obtained will be used to assess pulse wave velocity and augmentation pressure or index.
Brachial blood pressure will be measured using electrophygmomanometry (SunTech). The
diameter, pulse waveform, and the intima-media thickness of the right common carotid artery
will be measured (ultrasound Doppler). The common carotid artery stiffness index will be
calculated from pulsatile changes of arterial diameter and systemic blood pressure of the
carotid artery.
The venoarteriolar response will be assessed during leg dependency in the supine position.
Briefly, measurement of femoral artery diameter and velocity will be made using ultrasound
Doppler on one leg while in the horizontal position. Then, that leg will be lowered at the
hip ~40 cm below the contralateral (i.e., supine) ankle. Following a 60-sec stabilization
period, the aforementioned ultrasound Doppler measurements will be repeated, along with
continuously measures of heart rate and blood pressure. The leg will be in the dependent
position for 5 minutes. After that, the lowered leg will be returned to horizontal.
Endothelium-dependent flow-mediated dilation of the brachial and superficial femoral arteries
will be measured using the high-resolution Doppler ultrasound machine. A BP cuff will be
placed on the subject's right forearm or right thigh. The arteries will be scanned
longitudinally for 1 minute, and the end-diastolic diameter and blood velocity will be
measured. After that, the blood pressure cuff will be inflated to a pressure of 250 mmHg for
5 min and will then be deflated rapidly. Images will be recorded for 1.5 minutes before cuff
deflation and continuously for 3 minutes post-cuff deflation.
Endothelium-independent dilation of the brachial artery will be measured using a high
resolution Doppler ultrasound machine. The brachial artery will be scanned longitudinally
during 1 minute baseline period and for 10 min after sublingual administration of
nitroglycerin (400 μg metered spray).
Cutaneous microvascular function will be assessed in the arm and/or leg using the
microdialysis technique. This approach allows for the assessment of microvascular function
and the modulation of this response by nitric oxide and the quantification of microvascular
remodeling by assessing maximal vasodilation. Using aseptic technique, 2 microdialysis probes
will be inserted in the dermal layer of the skin in the lower leg using a 24 G needle.
Subsequently, Ringers solution or 0.9% saline (control) or the arginine analog
Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME, 20 mM), an inhibitor of nitric oxide
synthase will be infused through the microdialysis probes. A laser Doppler flowmeter housed
within a local heating device will be placed directly over each microdialysis probe and will
be used to measure basal cutaneous blood flow and the vasodilator response to local heating
of the skin (39°C). The vasodilatory response to this local heating stimulus is largely
nitric oxide-dependent. Thus, we can determine the effect chronic heat therapy on nitric
oxide-dependent microvascular function by comparing cutaneous vasodilation between control
and L-NAME sites. Finally, the skin be will be heated to 43°C and sodium nitroprusside (56
mM) will be infused in all probes in order to assess maximal microcirculatory dilator
function.
Circulating markers of vascular injury and vasoactive substances will be assessed in serum
and/or plasma. An intravenous catheter will be inserted into an antecubital vein.
Approximately 40 ml of venous blood will be drawn and distributed into separate tubes
containing appropriate preservatives and reagents. Tubes will then be centrifuged, the plasma
or serum extracted and stored in a freezer for subsequent analysis. If subjects agree, their
de-identified data and blood samples (collected from this research study) may be kept
indefinitely and securely for future research on cardiovascular health.
Lower leg heat therapy: Patients in the intervention group will be required to perform lower
leg heating via water immersion up to the knee in a circulated water bath (FootSmart® Foot
and Leg Bath Massager) 4 times per week with each session lasting 45 min. The provided leg
spa can finely and uniformly control water temperature at 42°C. Patients will be provided
with a therapy log in which they are required to track the dates and times of each therapy
session. Skin temperature from an immersed leg as well as water temperature will be recorded
and logged electronically via a low-cost battery-operated data logging thermometer (Omega
NOMAD) that will be provided to each subject. BP will be measured prior to and immediately
after each heating session, and heart rate will be recorded using a Polar heart rate monitor.
Heat therapy will last for 8 weeks. This heat regimen (e.g. frequency and duration) is
proposed based on prior work utilizing regional and whole-body heat therapy.
Patients in the control group will immerse their legs in a thermoneutral water bath (33°C) at
the same frequency and duration.
Antihypertensive drug treatment and safety evaluation: All patients will continue to take
chlorthalidone (25 mg once daily) during 8 weeks of intervention. Patients will be required
to measure BP daily at home and visit our lab every two weeks. Safety and tolerability of the
study drug will be evaluated during each visit, and patients will be asked to resume their
own medication(s) and will thereafter be excluded if BP ≥160/100 mmHg (for safety reasons).
Patient adherence to the study drug will be assessed by pill counting during office visit
every 2 weeks and blood test after 8 weeks of treatment.
of them will be enrolled, and 100 will complete the entire project.
Aim 1: To test the hypothesis that chronic heat therapy combined with an antihypertensive
drug is superior to drug treatment alone in lowering BP in older hypertensive women. We will
randomly assign older hypertensive women to either an intervention group or a control group.
Patients in the intervention group will be required to perform 8 weeks of home-based lower
leg heat therapy via water immersion up to the knee in a circulated bath (water temperature
42°C, 4 times per week, 45 min per session), whereas patients in the control group will
immerse their legs in a thermoneutral water bath (33°C) at the same frequency and duration.
All patients will also receive a fixed dose of chlorthalidone (a diuretic, 25 mg orally once
daily). We will compare 24-hour ambulatory BP, the BP control rate, and patient adherence and
acceptability to treatment between the groups.
Aim 2: To test the hypothesis that chronic heat therapy will improve nitric oxide
bioavailability which can decrease sympathetic vasoconstriction and improve vascular function
in older hypertensive women. We will use state-of-the-art techniques of microneurography,
Doppler ultrasound and applanation tonometry to assess sympathetic neural control and
cardiac-vascular function in all patients enrolled in Aim 1 before and after 8 weeks of heat
therapy.
Study Procedures:
Screening: Potential participants will be invited into the laboratory where a research nurse
and investigators will have the patient read the institutionally approved consent form and
explain the study. Informed consent will be obtained prior to screening. After that, we will
perform a physical exam, a review of medical history and medication, and a further evaluation
of inclusion and exclusion criteria in potential patients.
Wash-out: Patients who are currently treated with antihypertensive agents will gradually stop
taking their own medications. At least one week after all antihypertensive medications are
stopped, 24-hour ambulatory BP monitoring (SunTech) will be performed. Patients with awake BP
<140/90 or ≥180/110 mmHg will be excluded.
Run-in: All patients will have a 2-week run-in prior to pre-testing and they will be treated
with a fixed dose of chlorthalidone (a diuretic, 25 mg orally once daily) during this period
to avoid excessive increases in BP (for safety reasons). This is a first-line
antihypertensive agent commonly prescribed. Previous studies showed that chlorthalidone does
not reduce oxidative stress, nor does it alter nitric oxide bioavailability and endothelial
function.
Patient monitoring during run-in: Patients will be required to measure/record their BP daily
at home using an automated device we provide (Life-Source). Patients will visit our lab
weekly for a BP check, pill counting, and monitoring of safety and tolerability of the study
drug (e.g. low levels of potassium and sodium, high levels of uric acid and calcium,
symptomatic hypotension, etc). Patients will be excluded if they cannot tolerate the study
drug. In addition, patients will be asked to resume their own antihypertensive medication(s)
and will thereafter be excluded from the study if their systolic BP is ≥160 mmHg and/or
diastolic BP is ≥100 mmHg after 2 weeks of run-in or if the patient has clinical symptoms
associated with elevated BP (i.e. headache, dizziness, or nausea). We believe this approach
will not impose excessive risks to the patients and will allow for better experimental
control. Twenty-four-hour ambulatory BP will be repeated immediately after the run-in period,
and patients with awake BP <130/80 mmHg will be excluded from the study based on the new
hypertension guidelines.8, 9 This run-in approach has been successfully implemented in the
PI's laboratory.
Laboratory assessments: Sympathetic neural control and vascular function will be assessed
immediately after the run-in period (see Day 1 and Day 2 testing below for detail). These
neural-vascular assessments will be repeated after 8 weeks of intervention or control
treatments within 48 hours of last heat therapy session.
Day 1: Assessment of sympathetic neural control. These assessments will take place at the
Institute for Exercise and Environmental Medicine. Patients will be relaxed in the supine
position, and an intravenous catheter will be inserted into the antecubital vein on the
non-dominant arm. Arm-cuff BP will be measured by electrosphygmomanometry (SunTech).
Beat-by-beat finger BP will be measured by photoplethysmography (Nexfin). The beat-by-beat BP
recordings will be validated using the SunTech measures as Nexfin is accurate for changes in
BP but not absolute values. Heart rate will be measured from lead II of the
electrocardiogram. Respiratory movements will be monitored with a nasal cannula. Muscle
sympathetic nerve activity (MSNA) will be recorded from the peroneal nerve
(microneurography). Brain blood flow (middle cerebral artery) will be measured using
Transcranial Doppler. Femoral blood flow will be obtained using duplex ultrasound.
At least 30 min after the instrumentation, blood samples will be taken through the
intravenous catheter for measurements of plasma catecholamine concentration, plasma renin
activity, aldosterone, vasopressin, electrolytes, hemoglobin and hematocrit. Cardiac output
will be measured intermittently using the acetylene rebreathing technique. Left ventricular
function will be assessed by echocardiography.
At least 10 min after an acceptable nerve signal has been obtained, baseline data will be
collected during spontaneous breathing and controlled breathing (0.2 Hz, 12 breaths per
minute) for 10 min each. After that, a Valsalva maneuver at 40 mmHg expired pressure will be
performed for assessment of baroreflex function and the straining period will last for 20
sec. Next, a cold pressor test will be performed to evaluate the integrity of central
vasomotor processes and their efferent pathways. Baseline measurements will be made for 5
min, and then the patient's dominant hand will be placed into an ice water bath (50% ice and
50% water, ~4°C) up to the wrist for 2 min. After a sufficient recovery period (i.e. ≥15
min), patients will then perform static handgrip using the dominant hand at 40% of maximal
voluntary contraction until fatigue, followed by 2 min of post-exercise circulatory occlusion
with an upper arm cuff inflated to 250 mmHg. The handgrip test will assess cardiovascular
reactivity to isometric exercise and post-exercise circulatory occlusion provides a means to
isolate the activation of the skeletal muscle metaboreflex independent of mechanoreflex
activation, and central command. After another sufficient recovery period (i.e. ≥15 min),
baseline measurements will be made for 10 min, a graded upright tilt (30⁰ for 5 min and 60⁰
for 20 min or until presyncope) will be performed to assess autonomic circulatory control
during orthostatic stress. BP, heart rate, respiration, MSNA, and brain blood flow will be
continuously recorded, while cardiac output, femoral artery diameter and blood velocity will
be measured at the end of 30° tilting and every 5 min during 60° tilt. Blood sample will be
taken after 5 and 20 min of 60⁰ tilting. Then, the patient will be returned to the supine
position for recovery and the microneurographic electrodes will be removed.
After a sufficient recovery period (i.e. ≥30 min), blood volume will be measured using a
modified carbon monoxide rebreathing method in the sitting position.
Day 2: Assessment of vascular function. These assessments will take place at the University
of North Texas Health Science Center. Arterial tonometry with simultaneous electrocardiogram
will be obtained from the radial, femoral, and carotid arteries using a pencil-sized probe
(SphygmoCor)) over the maximal pulsation of the artery. Transit distances will be measured by
body-surface measurements from the suprasternal notch to each pulse-recording site. Tonometry
data obtained will be used to assess pulse wave velocity and augmentation pressure or index.
Brachial blood pressure will be measured using electrophygmomanometry (SunTech). The
diameter, pulse waveform, and the intima-media thickness of the right common carotid artery
will be measured (ultrasound Doppler). The common carotid artery stiffness index will be
calculated from pulsatile changes of arterial diameter and systemic blood pressure of the
carotid artery.
The venoarteriolar response will be assessed during leg dependency in the supine position.
Briefly, measurement of femoral artery diameter and velocity will be made using ultrasound
Doppler on one leg while in the horizontal position. Then, that leg will be lowered at the
hip ~40 cm below the contralateral (i.e., supine) ankle. Following a 60-sec stabilization
period, the aforementioned ultrasound Doppler measurements will be repeated, along with
continuously measures of heart rate and blood pressure. The leg will be in the dependent
position for 5 minutes. After that, the lowered leg will be returned to horizontal.
Endothelium-dependent flow-mediated dilation of the brachial and superficial femoral arteries
will be measured using the high-resolution Doppler ultrasound machine. A BP cuff will be
placed on the subject's right forearm or right thigh. The arteries will be scanned
longitudinally for 1 minute, and the end-diastolic diameter and blood velocity will be
measured. After that, the blood pressure cuff will be inflated to a pressure of 250 mmHg for
5 min and will then be deflated rapidly. Images will be recorded for 1.5 minutes before cuff
deflation and continuously for 3 minutes post-cuff deflation.
Endothelium-independent dilation of the brachial artery will be measured using a high
resolution Doppler ultrasound machine. The brachial artery will be scanned longitudinally
during 1 minute baseline period and for 10 min after sublingual administration of
nitroglycerin (400 μg metered spray).
Cutaneous microvascular function will be assessed in the arm and/or leg using the
microdialysis technique. This approach allows for the assessment of microvascular function
and the modulation of this response by nitric oxide and the quantification of microvascular
remodeling by assessing maximal vasodilation. Using aseptic technique, 2 microdialysis probes
will be inserted in the dermal layer of the skin in the lower leg using a 24 G needle.
Subsequently, Ringers solution or 0.9% saline (control) or the arginine analog
Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME, 20 mM), an inhibitor of nitric oxide
synthase will be infused through the microdialysis probes. A laser Doppler flowmeter housed
within a local heating device will be placed directly over each microdialysis probe and will
be used to measure basal cutaneous blood flow and the vasodilator response to local heating
of the skin (39°C). The vasodilatory response to this local heating stimulus is largely
nitric oxide-dependent. Thus, we can determine the effect chronic heat therapy on nitric
oxide-dependent microvascular function by comparing cutaneous vasodilation between control
and L-NAME sites. Finally, the skin be will be heated to 43°C and sodium nitroprusside (56
mM) will be infused in all probes in order to assess maximal microcirculatory dilator
function.
Circulating markers of vascular injury and vasoactive substances will be assessed in serum
and/or plasma. An intravenous catheter will be inserted into an antecubital vein.
Approximately 40 ml of venous blood will be drawn and distributed into separate tubes
containing appropriate preservatives and reagents. Tubes will then be centrifuged, the plasma
or serum extracted and stored in a freezer for subsequent analysis. If subjects agree, their
de-identified data and blood samples (collected from this research study) may be kept
indefinitely and securely for future research on cardiovascular health.
Lower leg heat therapy: Patients in the intervention group will be required to perform lower
leg heating via water immersion up to the knee in a circulated water bath (FootSmart® Foot
and Leg Bath Massager) 4 times per week with each session lasting 45 min. The provided leg
spa can finely and uniformly control water temperature at 42°C. Patients will be provided
with a therapy log in which they are required to track the dates and times of each therapy
session. Skin temperature from an immersed leg as well as water temperature will be recorded
and logged electronically via a low-cost battery-operated data logging thermometer (Omega
NOMAD) that will be provided to each subject. BP will be measured prior to and immediately
after each heating session, and heart rate will be recorded using a Polar heart rate monitor.
Heat therapy will last for 8 weeks. This heat regimen (e.g. frequency and duration) is
proposed based on prior work utilizing regional and whole-body heat therapy.
Patients in the control group will immerse their legs in a thermoneutral water bath (33°C) at
the same frequency and duration.
Antihypertensive drug treatment and safety evaluation: All patients will continue to take
chlorthalidone (25 mg once daily) during 8 weeks of intervention. Patients will be required
to measure BP daily at home and visit our lab every two weeks. Safety and tolerability of the
study drug will be evaluated during each visit, and patients will be asked to resume their
own medication(s) and will thereafter be excluded if BP ≥160/100 mmHg (for safety reasons).
Patient adherence to the study drug will be assessed by pill counting during office visit
every 2 weeks and blood test after 8 weeks of treatment.
Inclusion Criteria:
- Women between the ages of 65-85 years with essential hypertension (systolic BP 140-179
and/or diastolic BP 90-109 mmHg)
- Must be able to understand and speak English
Exclusion Criteria:
- Illness or disabilities that preclude home-based heat therapy
- Any evidence of cardiopulmonary disease
- Severe hypertension (BP ≥180/110 mmHg; for safety reasons)
- Secondary hypertension
- Being on ≥3 antihypertensive agents
- Chronic kidney disease
- Diabetes mellitus or other systemic illness
- Any history of substance abuse (other than tobacco)
- Current cigarette smokers
- History of gouty arthritis
- Taking hormonal replacement therapy
- Being obese (body mass index ≥30 kg/m2)
- Endurance trained athletes
- Impaired cognitive function or diagnosed dementia
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