Understanding the Exercise-Hypertension Paradox

NCT02034422 | Completed Results DMC

• 2 other identifiers: O1215-W1IK2RX001215
• Study Type: interventional
• Target: 75
• Locations: 1 country
• Sites: 1

Brief 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. 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.

Conditions

Hypertension

Keywords

Exercise

Outcome Measures

Primary Outcomes (1)

• 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

  Immediate to 8 weeks

Study Arms (2)

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.

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.

Dietary Supplement: Oral Antioxidant; Other: Exercise rehabilitation

Interventions

Oral Antioxidant DIETARY_SUPPLEMENT

Consisting of vitamins C, E and alpha lipoic acid.

Specific Aim #1; Specific Aim #2

Exercise rehabilitation OTHER

8 weeks of exercise rehabilitation

Specific Aim #2

Eligibility Criteria

• Age: 40 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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:
• 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,

You may not qualify if:

• 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.
• 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.
• 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.

Sponsors & Collaborators

• VA Office of Research and Development: lead

Study Sites (1)

VA Salt Lake City Health Care System, Salt Lake City, UT

Salt Lake City, Utah, 84148, United States

Location

MeSH Terms

Conditions

Hypertension; Motor Activity

Interventions

Antioxidants; Exercise Therapy

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases; Behavior

Intervention Hierarchy (Ancestors)

Biological Factors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Protective Agents; Physiological Effects of Drugs; Specialty Uses of Chemicals; Rehabilitation; Aftercare; Continuity of Patient Care; Patient Care; Therapeutics; Physical Therapy Modalities

Results Point of Contact

• Title: Joel Trinity, PhD
• Organization: Salt Lake City VAMC

joel.trinity@va.gov

801-582-1565

Study Officials

• Joel Douglas Trinity, PhD

  VA Salt Lake City Health Care System, Salt Lake City, UT

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 9, 2014
• First Posted: January 13, 2014
• Study Start: February 1, 2014
• Primary Completion: December 31, 2021
• Study Completion: December 31, 2021
• Last Updated: April 12, 2024
• Results First Posted: April 12, 2024

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)