Effects of Inorganic Nitrate and Intensity of Exercise on Cardiovascular Health in Post-Menopausal Females

Post-menopausal females experience elevated cardiovascular disease risk (CVD), compared to premenopausal females and age-matched males. Current exercise guidelines appear inadequate to ameliorate this increased risk and higher intensity exercise may be necessary. Oral inorganic nitrate supplementation enhances both exercise performance and CVD risk profile in several clinical conditions. However, the effects of this intervention in post-menopausal females is unexplored.

Study Overview

• Status: Completed
• Conditions: Arterial Stiffness; Vascular Dilation
• Intervention / Treatment: Drug: BEET IT - Concentrate Beet root juice; Drug: BEET IT - Concentrate Beet root juice (nitrate depleted)

Detailed Description

The purpose of this study is to determine whether acute inorganic nitrate supplementation and exercising at different exercise intensities (high vs moderate) improve vascular health in post-menopausal females.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Arthur Weltman, PhD; Phone Number: (434) 924-6191; Email: alw2v@virginia.edi
• Study Contact Backup: Name: Austin C Hogwood, MS; Phone Number: (804) 536-7036; Email: ach2jb@virginia.edu

Study Locations

• United States
  • Virginia
    • Charlottesville, Virginia, United States, 22902
      • Student Health and Wellness Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Post-menopausal female, defined as having not had a menstrual cycle for at least 1 year
• Greater than age 45 but less than age 75
• Sedentary (does not exercise regularly)
• No major changes in medication in the last 3 months

Exclusion Criteria:

• Smokers within last 5 years
• Weight unstable (loss/gain of more than 3kg in the past 3 months)
• Any medical condition that prevents the subject from exercising safely
• Hormone replacement therapy (current or within last 3 months)
• Currently or recently on vasoactive medications (i.e., calcium channel blockers, statins, ACE or renin inhibitors, ARBs, nitrates, alpha- or beta-blockers, diuretics, proton pump inhibitors, etc.)
• Hysterectomy or oophorectomy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Acute High-Intensity Exercise; Subjects will exercise at an intensity of 75% of the difference between the lactate threshold and VO2peak until 200 kcal are expended. Pre- and post-testing measures of vascular health will be completed at baseline (0 min) and again 60, 90, 120, 150, 180 min post-baseline testing, with exercise taking place during time points 0-60 min.	Drug: BEET IT - Concentrate Beet root juice; Beet It Sport (James White Drinks, Ltd.) each containing 400mg of inorganic nitrate (~6.5 mmol) will be consumed twice daily (totalling ~13 mmol of inorganic nitrate per day) for at least 2 days prior to testing visits, as well as 2 hours prior to testing visits.; Other Names: Dietary Nitrate supplementation (nitrate rich); Drug: BEET IT - Concentrate Beet root juice (nitrate depleted); Beet It Sport (James White Drinks, Ltd.) each containing 0mg of inorganic nitrate (~0 mmol) will be consumed twice daily (totalling ~0 mmol of inorganic nitrate per day) for at least 2 days prior to testing visits, as well as 2 hours prior to testing visits. It is provided by the same company that produces the concentrated beet root juice shots (James White Drinks) but the placebo version is nitrate-depleted.; Other Names: Dietary Nitrate supplementation (nitrate depleted)
Active Comparator: Acute Moderate-Intensity Exercise; Subjects will exercise at an intensity at the lactate threshold until 200 kcal are expended. Pre- and post-testing measures of vascular health will be completed at baseline (0 min) and again 60, 90, 120, 150, 180 min post-baseline testing, with exercise taking place during time points 0-60 min.	Drug: BEET IT - Concentrate Beet root juice; Beet It Sport (James White Drinks, Ltd.) each containing 400mg of inorganic nitrate (~6.5 mmol) will be consumed twice daily (totalling ~13 mmol of inorganic nitrate per day) for at least 2 days prior to testing visits, as well as 2 hours prior to testing visits.; Other Names: Dietary Nitrate supplementation (nitrate rich); Drug: BEET IT - Concentrate Beet root juice (nitrate depleted); Beet It Sport (James White Drinks, Ltd.) each containing 0mg of inorganic nitrate (~0 mmol) will be consumed twice daily (totalling ~0 mmol of inorganic nitrate per day) for at least 2 days prior to testing visits, as well as 2 hours prior to testing visits. It is provided by the same company that produces the concentrated beet root juice shots (James White Drinks) but the placebo version is nitrate-depleted.; Other Names: Dietary Nitrate supplementation (nitrate depleted)
Placebo Comparator: Non-Exercise Control; Measures of vascular health will be completed at baseline (0 min) and again 60, 90, 120, 150, 180 min post-baseline testing, without exercise taking place during time points 0-60 min.	Drug: BEET IT - Concentrate Beet root juice; Beet It Sport (James White Drinks, Ltd.) each containing 400mg of inorganic nitrate (~6.5 mmol) will be consumed twice daily (totalling ~13 mmol of inorganic nitrate per day) for at least 2 days prior to testing visits, as well as 2 hours prior to testing visits.; Other Names: Dietary Nitrate supplementation (nitrate rich); Drug: BEET IT - Concentrate Beet root juice (nitrate depleted); Beet It Sport (James White Drinks, Ltd.) each containing 0mg of inorganic nitrate (~0 mmol) will be consumed twice daily (totalling ~0 mmol of inorganic nitrate per day) for at least 2 days prior to testing visits, as well as 2 hours prior to testing visits. It is provided by the same company that produces the concentrated beet root juice shots (James White Drinks) but the placebo version is nitrate-depleted.; Other Names: Dietary Nitrate supplementation (nitrate depleted)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline Flow-Mediated Dilation	Participants will be placed in a supine position with their left forearm slightly extended and supinated with legs straight. The brachial artery will be imaged using a high-resolution doppler ultrasound utilizing a 7.5MHz linear array transducer at rest, during 5 minutes of forearm occlusion via cuff inflation, and continuously for 2 minutes post-occlusion; an EKG trigger will be used to capture images during end-diastole of the cardiac cycle. Images will be analyzed offline using specialized software (Medical Imaging Applications, Inc.) to calculate the change in brachial artery diameter.	Baseline (minute 0).
Post-Exercise/Control Flow-Mediated Dilation (60 minutes)	Participants will be placed in a supine position with their left forearm slightly extended and supinated with legs straight. The brachial artery will be imaged using a high-resolution doppler ultrasound utilizing a 7.5MHz linear array transducer at rest, during 5 minutes of forearm occlusion via cuff inflation, and continuously for 2 minutes post-occlusion; an EKG trigger will be used to capture images during end-diastole of the cardiac cycle. Images will be analyzed offline using specialized software (Medical Imaging Applications, Inc.) to calculate the change in brachial artery diameter.	60 minutes post-baseline.
Post-Exercise/Control Flow-Mediated Dilation (90 minutes)	Participants will be placed in a supine position with their left forearm slightly extended and supinated with legs straight. The brachial artery will be imaged using a high-resolution doppler ultrasound utilizing a 7.5MHz linear array transducer at rest, during 5 minutes of forearm occlusion via cuff inflation, and continuously for 2 minutes post-occlusion; an EKG trigger will be used to capture images during end-diastole of the cardiac cycle. Images will be analyzed offline using specialized software (Medical Imaging Applications, Inc.) to calculate the change in brachial artery diameter.	90 minutes post-baseline.
Post-Exercise/Control Flow-Mediated Dilation (120 minutes)	Participants will be placed in a supine position with their left forearm slightly extended and supinated with legs straight. The brachial artery will be imaged using a high-resolution doppler ultrasound utilizing a 7.5MHz linear array transducer at rest, during 5 minutes of forearm occlusion via cuff inflation, and continuously for 2 minutes post-occlusion; an EKG trigger will be used to capture images during end-diastole of the cardiac cycle. Images will be analyzed offline using specialized software (Medical Imaging Applications, Inc.) to calculate the change in brachial artery diameter.	120 minutes post-baseline.
Post-Exercise/Control Flow-Mediated Dilation (150 min)	Participants will be placed in a supine position with their left forearm slightly extended and supinated with legs straight. The brachial artery will be imaged using a high-resolution doppler ultrasound utilizing a 7.5MHz linear array transducer at rest, during 5 minutes of forearm occlusion via cuff inflation, and continuously for 2 minutes post-occlusion; an EKG trigger will be used to capture images during end-diastole of the cardiac cycle. Images will be analyzed offline using specialized software (Medical Imaging Applications, Inc.) to calculate the change in brachial artery diameter.	150 minutes post-baseline.
Post-Exercise/Control Flow-Mediated Dilation (180 min)	Participants will be placed in a supine position with their left forearm slightly extended and supinated with legs straight. The brachial artery will be imaged using a high-resolution doppler ultrasound utilizing a 7.5MHz linear array transducer at rest, during 5 minutes of forearm occlusion via cuff inflation, and continuously for 2 minutes post-occlusion; an EKG trigger will be used to capture images during end-diastole of the cardiac cycle. Images will be analyzed offline using specialized software (Medical Imaging Applications, Inc.) to calculate the change in brachial artery diameter.	180 minutes post-baseline.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline Pulse Wave Velocity	Supine measures of carotid to femoral pulse wave velocity will be measured using a SphygmoCor Xcel device.	Baseline (minute 0).
Post-Exercise/Control Pulse Wave Velocity (60 min)	Supine measures of carotid to femoral pulse wave velocity will be measured using a SphygmoCor Xcel device.	60 minutes post-baseline.
Post-Exercise/Control Pulse Wave Velocity (90 min)	Supine measures of carotid to femoral pulse wave velocity will be measured using a SphygmoCor Xcel device.	90 minutes post-baseline.
Post-Exercise/Control Pulse Wave Velocity (120 min)	Supine measures of carotid to femoral pulse wave velocity will be measured using a SphygmoCor Xcel device.	120 minutes post-baseline.
Post-Exercise/Control Pulse Wave Velocity (150 min)	Supine measures of carotid to femoral pulse wave velocity will be measured using a SphygmoCor Xcel device.	150 minutes post-baseline.
Post-Exercise/Control Pulse Wave Velocity (180 min)	Supine measures of carotid to femoral pulse wave velocity will be measured using a SphygmoCor Xcel device.	180 minutes post-baseline.

Collaborators and Investigators

• Sponsor: University of Virginia
• Investigators: Principal Investigator: Arthur Weltman, PhD, Professor of Kinesiology

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2021
• Primary Completion (Actual): April 1, 2023
• Study Completion (Actual): April 1, 2023

Study Registration Dates

• First Submitted: October 14, 2021
• First Submitted That Met QC Criteria: January 21, 2022
• First Posted (Actual): February 3, 2022

Study Record Updates

• Last Update Posted (Actual): November 30, 2023
• Last Update Submitted That Met QC Criteria: November 27, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Vascular function; Pulse wave velocity; Flow-mediated dilation; Exercise intensity
• Additional Relevant MeSH Terms: Pathological Conditions, Anatomical; Dilatation, Pathologic
• Other Study ID Numbers: HSR210326

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Microsoft excel sheets, Graphpad Prism files, Informed Consent, and Study Protocol forms will be available upon reasonable request. All identifiable data de-identified on 24 participants will be available.
• IPD Sharing Time Frame: De-identified data will be shared upon reasonable request for 3 years after study completion
• IPD Sharing Access Criteria: Email Austin Hogwood at ach2jb@virginia.edu for any requests.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No