HypertensionNCT02034422
Understanding the Exercise-Hypertension Paradox
A study testing Oral Antioxidant and Exercise rehabilitation in people with Hypertension, run by VA Office of Research and Development at 1 site in United States.
Trial summary
Hypertension affects 37% of the Veteran population, making it the most common medical condition treated by the VA Health Care System. Physical activity is the first line of defense in the treatment and management of hypertension. Read more about this study
- Who is it for?
- Ages 40 to 60 yearsHealthy volunteers can take part
- Conditions the study is for
- Hypertension
- What is being tested?
- Oral Antioxidant and Exercise rehabilitation
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 75 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Feb 2014to 31 Dec 2021
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 to 60 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- A total of 72 middle-aged (40 - 60 years of age) healthy and hypertensive men and women will participate in these protocols after providing written informed consent.
- The investigators aim to include a 1 to 1 ratio of females and males in each group.
- Individuals diagnosed or presenting with stage 1 and stage 2 hypertension (range 140/90 to 179/109 mmHg, according to the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High BP) may be eligible for this study.
- Blood pressure status will be assessed in triplicate in the laboratory during the medical exam and during a 24 hour period using ambulatory blood pressure monitoring.
- Both methods must confer hypertension for study enrollment.
- Other than hypertension, all hypertensive patients will be otherwise healthy and free of overt disease as assessed by:
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- medical history;
- standard blood chemistries (chem. 7 panel),
- ECG at rest;
- limb vascular examination (ankle-brachial BP index > 0.9);
- resting BP > 140/90 mmHg; and
- skinfold % body fat assessment.
- Subjects will have a body mass index (BMI) between 19 and 30 and have plasma glucose concentrations < 7.0 mmol/L under fasting conditions and < 11.1 mmol/L at 120 minutes of an oral glucose tolerance test (OGTT), as defined by the American Diabetes Association.
- To reduce heterogeneity of the hypertensive subjects while maintaining a "real world" approach the following classes of drugs will be allowed;
- diuretics,
- angiotensin converting enzyme (ACE) inhibitors,
- and angiotensin II receptor blockers (ARB).
- Healthy normotensive subjects will be matched to their hypertensive counterparts and will be free from overt cardiovascular disease according to the criteria described above.
- Inclusion/Exclusion criteria with specific reference to the exaggerated exercise pressor reflex:
- Hypertensive subjects must exhibit a 10 mmHg or greater increase in MAP at 25% of their workrate maximum during knee extension exercise to be included in this study.
- Established criteria defining a cut off for an "exaggerated" exercise pressor reflex does not exist.
- Therefore, the investigators have set the operational definition at a 10 mmHg or greater increase in MAP during 25% of workrate maximum knee extensor exercise.
- This 10 mmHg increase in MAP was chosen as this value closely matches the investigators' preliminary data (Figure 1) and previous reports while concomitantly corresponding to an increase in BP that is at least 2 standard deviations greater than the normotensive response (i.e. 6 2 (SD) mmHg increase in MAP at 25% of their workrate maximum).
- The magnitude of the exercise-induced increase in MAP will be determined during preliminary testing.
- It should be noted that the magnitude of the pressor response is graded in relation to exercise intensity, therefore, by establishing an inclusion criterion of 10 mmHg at 25% of workrate maximum, the lowest intensity to be used in the proposed studies, the investigators have set a conservative standard for study enrollment.
Who cannot join
- Candidates demonstrating dyslipidemia based on the National Cholesterol Education Program Guidelines of plasma total cholesterol > 240 mg/dl with LDL-cholesterol > 160 mg/dl will be excluded from participation.
- Hypertensive patients receiving dual or monotherapy treatment for hypertension may be included.
- Less frequently prescribed classes of drugs for hypertension (beta blockers, aldosterone receptor blocker, centrally acting sympatholytics, calcium channel blocker, direct vasodilators, renin inhibitors, and alpha blockers) will be excluded.
- Additionally, subjects reporting a history of myocardial infarction, unstable cardiac ischemia, recent cardiac catheterization, carotid artery disease, transient ischemic attack will be excluded.
- Participants must have no orthopedic limitations that would prohibit them from knee-extensor exercise or aerobic activity including cycle ergometry or treadmill exercise.
- Due to the age requirement of the subjects women may be either pre or post-menopausal.
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- All pre-menopausal women will be studied during days 1 - 7 of their menstrual cycle to standardize the influence of female hormones.
- Women taking hormone replacement therapy (HRT) currently or in the preceding year will be excluded from the proposed studies due to the direct vascular effects of HRT and the variety of regimes employed.
- Participants will be made up of primarily Veterans.
Trial locations and contacts
1 site in 1 country.
United States1 site
VA Salt Lake City Health Care System, Salt Lake City, UT
Salt Lake City, Utah, 84148
About this study
Official title: Understanding the Exercise-Hypertension Paradox: Implication for Rehabilitation
Hypertension affects 37% of the Veteran population, making it the most common medical condition treated by the VA Health Care System. Physical activity is the first line of defense in the treatment and management of hypertension. However, individuals with hypertension have impaired muscle blood flow and exhibit exaggerated increases in blood pressure during exercise (exercise pressor reflex or EPR) leading to exercise intolerance and increased risk of stroke and heart attack. The cause of these impairments is not known, but it is highly likely that free radical production and the subsequent increase in oxidative stress plays a significant role. Two aims are proposed; Aim 1 will identify the physiological consequences of elevated oxidative stress in hypertension, and Aim 2 will utilize an antioxidant treatment to ameliorate the effects of an exaggerated EPR allowing the safe performance of a clinical exercise rehabilitation program which will then, itself, attenuate the EPR and reduce hypertension.
Read the detailed description
Nearly 37% of all Veterans are clinically hypertensive, making hypertension the most common medical condition in the VA Health Care System. Importantly, of the 67 million Americans diagnosed with hypertension less than half are being effectively treated for their condition. Hypertension constitutes a major risk factor for cardiovascular disease and when left untreated leads to the development of heart failure, coronary heart disease, peripheral artery disease, stroke, and renal disease. Exercise and regular physical activity are considered the cornerstones of prevention and management of hypertension. However, individuals with hypertension exhibit exercise intolerance characterized by impaired skeletal muscle blood flow and heightened afferent fiber sensitivity leading to an exaggerated or greater than normal physiologic increase in blood pressure during exercise (i.e. exercise pressor reflex or EPR). This imbalance between the beneficial effects of exercise and exercise intolerance creates an interesting paradox, the causes and consequences of which are poorly understood. The etiology of hypertension is undoubtedly complex, however a common denominator in this condition, elevated oxidative stress, may contribute to impaired muscle blood flow and heightened skeletal muscle afferent feedback leading to the exaggerated EPR. Previous work from the investigators' laboratory and others suggests that elevated oxidative stress associated with aging impairs muscle blood flow. Additionally, free radicals, the initiators of oxidative stress, can directly stimulate skeletal muscle afferent fibers leading to the exaggerated EPR. Importantly, the role of oxidative stress in regulating muscle blood flow and afferent fiber function in human hypertension has not been determined. Preliminary studies support a significant role of oxidative stress in impairing muscle blood flow and contributing to the exaggerated EPR in hypertension. With this information as context two aims are proposed that will systematically identify the consequences of elevated oxidative stress in hypertension. Specific Aim 1 will determine the consequences of oxidative stress by examining how elevated free radicals contribute to heightened skeletal muscle afferent feedback and impaired muscle blood flow during exercise in hypertension leading to the exaggerated EPR. Additionally, vascular endothelial cells collected from an antecubital vein will provide novel insight regarding the endothelium as potential source of elevated oxidative stress in hypertension. Specific Aim 2 will determine the effectiveness of combined antioxidant therapy and exercise rehabilitation in the treatment of hypertension. The overall goal of this proposal is to provide novel information regarding the role of oxidative stress as a critical regulator of cardiovascular and hemodynamic responses to exercise in hypertension. By identifying potential causes and consequences of oxidative stress, important insight will be gained facilitating the development of novel approaches and therapeutic strategies for the treatment of hypertension. Importantly, the practical applications tested in these studies (i.e. antioxidant treatment and combined exercise rehabilitation) are designed to identify and document effective countermeasures to aid in the treatment and management of hypertension allowing for the safe performance of exercise in a large number of Veterans.
- Conditions
- Hypertension
- Being tested
- Oral Antioxidant, Exercise rehabilitation
- Keywords
- Exercise
- Medical subject headings
- Hypertension, Motor Activity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Oral AntioxidantDietary supplement
Consisting of vitamins C, E and alpha lipoic acid.
Exercise rehabilitationOther
8 weeks of exercise rehabilitation
| Study group | Role | What they receive |
|---|---|---|
| Specific Aim #1 | Experimental | Specific Aim 1: Determine the consequences of oxidative stress on skeletal muscle afferent feedback and muscle blood flow during exercise in hypertension. Hypothesis: Afferent feedback sensitivity, determined by passive leg movement (isolation of mechanoreceptor sensitivity) and post exercise circulatory occlusion (isolation of metaboreceptor sensitivity) will be greater in hypertension leading to the exaggerated EPR. Muscle blood flow, assessed by Doppler ultrasound during multiple exercise intensities, will be impaired in hypertension leading to exercise intolerance. Reductions in oxidative stress, achieved by an oral antioxidant treatment (Vitamins C, E and alpha lipoic acid), will reduce afferent fiber sensitivity and improve muscle blood flow in hypertension. Additionally, venous endothelial cells will express elevated markers of oxidative stress providing novel evidence that the vascular endothelium contributes to the greater oxidative stress in hypertension. Receives: Dietary Supplement: Oral Antioxidant |
| Specific Aim #2 | Experimental | Specific Aim 2: Determine the remediable effect of combined antioxidant treatment and exercise rehabilitation in the treatment of hypertension. Hypothesis: Acute antioxidant treatment administered prior to exercise in hypertensive patients will ameliorate the exaggerated EPR resulting in a normal and safe blood pressure response to exercise-based rehabilitation. This two-pronged approach (antioxidants and exercise training) will result in a safely achieved reduction in skeletal muscle afferent feedback facilitating improved exercise tolerance, improved muscle blood flow and ultimately reduced cardiovascular risk in this population. Receives: Dietary Supplement: Oral Antioxidant; Other: Exercise rehabilitation |
What is being measured
The primary outcome is the main question the study is designed to answer.
Blood Pressure
Blood pressure with be assessed prior to the study intervention and during exercise (Aim #1). Additionally, blood pressure will be assessed following 8 weeks of exercise rehabilitation
Measured: Immediate to 8 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Jan 2014 (estimated)
- Study start1 Feb 2014
- Primary completion31 Dec 2021
- Study completion31 Dec 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for HypertensionStudies of the same condition, open and under way.
- More trials run by VA Office of Research and DevelopmentThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 75 participants (actual)
Sponsor and investigators
- Lead sponsor
- VA Office of Research and Development
- Sponsor type
- US federal agency
- Responsible party
- Sponsor
- Investigators
- Joel Douglas Trinity, PhD, Principal investigator, VA Salt Lake City Health Care System, Salt Lake City, UT
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02034422
- Sponsor's protocol ID
- O1215-W
- Other IDs
- 1IK2RX001215
- Status last verified
- Oct 2023
- First submitted
- 9 Jan 2014
- Last updated
- 12 Apr 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 12 Apr 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Understanding the Exercise-Hypertension Paradox: Implication for Rehabilitation
- ClinicalTrials.gov ID
- NCT02034422
- Acronym / sponsor ID
- O1215-W
- Conditions
- Hypertension
- Keywords
- Exercise
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 75 participants (actual)
- Lead sponsor
- VA Office of Research and DevelopmentUS federal agency
- Study start
- 1 Feb 2014 (actual)
- Primary completion
- 31 Dec 2021 (actual)
- Study completion
- 31 Dec 2021 (actual)
- First posted
- 13 Jan 2014 (estimated)
- Results
- Posted 12 Apr 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Hypertension affects 37% of the Veteran population, making it the most common medical condition treated by the VA Health Care System. Physical activity is the first line of defense in the treatment and management of hypertension. However, individuals with hypertension have impaired muscle blood flow and exhibit exaggerated increases in blood pressure during exercise (exercise pressor reflex or EPR) leading to exercise intolerance and increased risk of stroke and heart attack. The cause of these impairments is not known, but it is highly likely that free radical production and the subsequent increase in oxidative stress plays a significant role. Two aims are proposed; Aim 1 will identify the physiological consequences of elevated oxidative stress in hypertension, and Aim 2 will utilize an antioxidant treatment to ameliorate the effects of an exaggerated EPR allowing the safe performance of a clinical exercise rehabilitation program which will then, itself, attenuate the EPR and reduce hypertension.
Detailed description
Nearly 37% of all Veterans are clinically hypertensive, making hypertension the most common medical condition in the VA Health Care System. Importantly, of the 67 million Americans diagnosed with hypertension less than half are being effectively treated for their condition. Hypertension constitutes a major risk factor for cardiovascular disease and when left untreated leads to the development of heart failure, coronary heart disease, peripheral artery disease, stroke, and renal disease. Exercise and regular physical activity are considered the cornerstones of prevention and management of hypertension. However, individuals with hypertension exhibit exercise intolerance characterized by impaired skeletal muscle blood flow and heightened afferent fiber sensitivity leading to an exaggerated or greater than normal physiologic increase in blood pressure during exercise (i.e. exercise pressor reflex or EPR). This imbalance between the beneficial effects of exercise and exercise intolerance creates an interesting paradox, the causes and consequences of which are poorly understood. The etiology of hypertension is undoubtedly complex, however a common denominator in this condition, elevated oxidative stress, may contribute to impaired muscle blood flow and heightened skeletal muscle afferent feedback leading to the exaggerated EPR. Previous work from the investigators' laboratory and others suggests that elevated oxidative stress associated with aging impairs muscle blood flow. Additionally, free radicals, the initiators of oxidative stress, can directly stimulate skeletal muscle afferent fibers leading to the exaggerated EPR. Importantly, the role of oxidative stress in regulating muscle blood flow and afferent fiber function in human hypertension has not been determined. Preliminary studies support a significant role of oxidative stress in impairing muscle blood flow and contributing to the exaggerated EPR in hypertension. With this information as context two aims are proposed that will systematically identify the consequences of elevated oxidative stress in hypertension. Specific Aim 1 will determine the consequences of oxidative stress by examining how elevated free radicals contribute to heightened skeletal muscle afferent feedback and impaired muscle blood flow during exercise in hypertension leading to the exaggerated EPR. Additionally, vascular endothelial cells collected from an antecubital vein will provide novel insight regarding the endothelium as potential source of elevated oxidative stress in hypertension. Specific Aim 2 will determine the effectiveness of combined antioxidant therapy and exercise rehabilitation in the treatment of hypertension. The overall goal of this proposal is to provide novel information regarding the role of oxidative stress as a critical regulator of cardiovascular and hemodynamic responses to exercise in hypertension. By identifying potential causes and consequences of oxidative stress, important insight will be gained facilitating the development of novel approaches and therapeutic strategies for the treatment of hypertension. Importantly, the practical applications tested in these studies (i.e. antioxidant treatment and combined exercise rehabilitation) are designed to identify and document effective countermeasures to aid in the treatment and management of hypertension allowing for the safe performance of exercise in a large number of Veterans.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind (participant)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Specific Aim #1 | Experimental | Dietary Supplement: Oral AntioxidantSpecific Aim 1: Determine the consequences of oxidative stress on skeletal muscle afferent feedback and muscle blood flow during exercise in hypertension. Hypothesis: Afferent feedback sensitivity, determined by passive leg movement (isolation of mechanoreceptor sensitivity) and post exercise circulatory occlusion (isolation of metaboreceptor sensitivity) will be greater in hypertension leading to the exaggerated EPR. Muscle blood flow, assessed by Doppler ultrasound during multiple exercise intensities, will be impaired in hypertension leading to exercise intolerance. Reductions in oxidative stress, achieved by an oral antioxidant treatment (Vitamins C, E and alpha lipoic acid), will reduce afferent fiber sensitivity and improve muscle blood flow in hypertension. Additionally, venous endothelial cells will express elevated markers of oxidative stress providing novel evidence that the vascular endothelium contributes to the greater oxidative stress in hypertension. |
| Specific Aim #2 | Experimental | Dietary Supplement: Oral Antioxidant, Other: Exercise rehabilitationSpecific Aim 2: Determine the remediable effect of combined antioxidant treatment and exercise rehabilitation in the treatment of hypertension. Hypothesis: Acute antioxidant treatment administered prior to exercise in hypertensive patients will ameliorate the exaggerated EPR resulting in a normal and safe blood pressure response to exercise-based rehabilitation. This two-pronged approach (antioxidants and exercise training) will result in a safely achieved reduction in skeletal muscle afferent feedback facilitating improved exercise tolerance, improved muscle blood flow and ultimately reduced cardiovascular risk in this population. |
Who may qualify
- Ages
- 40 to 60 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (25 listed)
- A total of 72 middle-aged (40 - 60 years of age) healthy and hypertensive men and women will participate in these protocols after providing written informed consent.
- The investigators aim to include a 1 to 1 ratio of females and males in each group.
- Individuals diagnosed or presenting with stage 1 and stage 2 hypertension (range 140/90 to 179/109 mmHg, according to the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High BP) may be eligible for this study.
- Blood pressure status will be assessed in triplicate in the laboratory during the medical exam and during a 24 hour period using ambulatory blood pressure monitoring.
- Other than hypertension, all hypertensive patients will be otherwise healthy and free of overt disease as assessed by:
Key exclusion criteria (9 listed)
- Candidates demonstrating dyslipidemia based on the National Cholesterol Education Program Guidelines of plasma total cholesterol > 240 mg/dl with LDL-cholesterol > 160 mg/dl will be excluded from participation.
- Hypertensive patients receiving dual or monotherapy treatment for hypertension may be included.
- Less frequently prescribed classes of drugs for hypertension (beta blockers, aldosterone receptor blocker, centrally acting sympatholytics, calcium channel blocker, direct vasodilators, renin inhibitors, and alpha blockers) will be excluded.
- Additionally, subjects reporting a history of myocardial infarction, unstable cardiac ischemia, recent cardiac catheterization, carotid artery disease, transient ischemic attack will be excluded.
- Participants must have no orthopedic limitations that would prohibit them from knee-extensor exercise or aerobic activity including cycle ergometry or treadmill exercise.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Oral AntioxidantConsisting of vitamins C, E and alpha lipoic acid. | Dietary supplement | Specific Aim #1, Specific Aim #2 |
| Exercise rehabilitation8 weeks of exercise rehabilitation | Other | Specific Aim #2 |
Primary outcome
Blood Pressure
Time frame: Immediate to 8 weeks
Blood pressure with be assessed prior to the study intervention and during exercise (Aim #1). Additionally, blood pressure will be assessed following 8 weeks of exercise rehabilitation
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Apr 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Joel Douglas Trinity, PhD principal investigator
VA Salt Lake City Health Care System, Salt Lake City, UT
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Oral Antioxidant and Exercise rehabilitation in people with Hypertension, run by VA Office of Research and Development at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 25 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 12 Apr 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 12 Apr 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Blood Pressure (time frame: Immediate to 8 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Apr 2024.