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Effect of Inorganic Nitrates (Beetroot Juice) on Arterial Hemodynamics and Exercise Capacity

Primary Purpose

Heart Failure With Normal Ejection Fraction

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Nitrate rich beetroot juice
Nitrate depleted beetroot juice
Sponsored by
Corporal Michael J. Crescenz VA Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Heart Failure With Normal Ejection Fraction focused on measuring Heart Failure, Arterial hemodynamics, Exercise capacity, Mitochondrial oxidative capacity

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

The investigators will enroll 20 subjects >18 years of age who have a diagnosis of heart failure with preserved ejection fraction (>50%) by 2d echocardiography, with current New York Heart Association Class II-IV symptoms.

In addition, subjects with heart failure must meet the following inclusion criteria:

  1. Chronic treatment with a loop diuretic for control of HF symptoms.
  2. If EF is normal, subjects must demonstrate elevated filling pressures as evidenced by at least one of the following: a) left atrial enlargement (LAVI > 32 mL/m2); b) at least stage II diastolic dysfunction; c) Documentation of elevated NT-pro BNP levels or other natriuretic peptide marker (BNP, ANP) according to the laboratory and assay upper limit of normal in the previous year.
  3. Stable medical therapy as defined by: (I) No addition or removal of ACE, ARB, beta-blockers, or calcium channel blockers (CCBs) for 30 days. (II) No change in dosage of ACE, ARBs, beta-blockers or CCBs of more than 100% for 30 days. (III) No change in diuretic dose for 10 days.

Exclusion Criteria:

  1. Rhythm other than sinus rhythm (i.e., atrial fibrillation).
  2. Neuromuscular, orthopedic or other non-cardiac condition that prevents patient from exercising.
  3. Valve disease (> mild aortic or mitral stenosis; > moderate aortic or mitral regurgitation).
  4. Hypertrophic cardiomyopathy.
  5. Known infiltrative or inflammatory myocardial disease (amyloid, sarcoid).
  6. Pericardial disease.
  7. Primary pulmonary arteriopathy.
  8. Have experienced a myocardial infarction or unstable angina, or have undergone percutaneous transluminal coronary angiography (PTCA) or coronary artery bypass grafting (CABG) within 60 days prior to consent, or requires either PTCA or CABG at the time of consent.
  9. Other clinically important causes of dyspnea such as morbid obesity or significant lung disease defined by clinical judgment or use of steroids or oxygen for lung disease within the past 6 months.
  10. Systolic blood pressure < 110 mmHg or > 180 mm Hg.
  11. Diastolic blood pressure < 40 mmHg or > 100 mmHg.
  12. Resting heart rate (HR) > 100 bpm.
  13. Hemoglobin <10 g/dL.
  14. Patients with known severe liver disease (AST > 3x normal, alkaline phosphatase or bilirubin > 2x normal).
  15. Patients with a clinically indicated stress test demonstrating significant ischemia within a year of enrollment which was not followed by percutaneous or surgical revascularization.
  16. Current therapy with phosphodiesterase inhibitors, such as sildenafil, vardanafil or tadalafil.
  17. Known allergies to beetroot or lemon juice.
  18. Current use of organic nitrates or phosphodiesterase inhibitors.
  19. Pregnancy. Although beetroot juice has not knows teratogenic effects, we feel that not enough data exist in this regard. Therefore, all females patients of reproductive age will be required to undergo a pregnancy test prior to enrollment.

Sites / Locations

  • Philadelphia Veterans Affairs Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Nitrate rich beetroot juice

Nitrate depleted beetroot juice

Arm Description

Subjects with heart failure with preserved ejection fraction will receive 140 mL of Nitrate-rich concentrated beetroot juice (containing 12 mmol of NO-3). This will be a cross-over study. Therefore all subjects will receive both interventions, but the order of the interventions will be randomized.

Subjects with heart failure with preserved ejection fraction will receive 140 mL of nitrate-depleted beetroot juice (containing <0.01 mmol of NO-3).This will be a cross-over study. Therefore all subjects will receive both interventions, but the order of the interventions will be randomized.

Outcomes

Primary Outcome Measures

Change in Peak exercise efficiency during maximal effort supine-bicycle exercise and peak oxygen consumption (VO2) during a maximal effort supine-bicycle exercise test
We will assess the relationship between total power output and total O2 consumption (VO2, assessed via expired gas analysis) during a maximal-effort supine bicycle exercise test.

Secondary Outcome Measures

Change in Arterial wave reflection magnitude
Reflection wave magnitude will be assessed using arterial tonometry to arrive at the augmentation index. The data will also be processed using custom designed software for wave separation analysis to quantify the magnitude and timing of the reflected waves.
Change in Peripheral vascular resistance, total arterial compliance and reflection magnitude during supine bicycle peak exercise
Change in lower extremity exercise vasodilator reserve (change in femoral vascular resistance between rest and maximal effort supine-bicycle exercise)
Change in lower extremity blood flow reserve (change in femoral artery blood flow between rest and maximal effort supine-bicycle exercise)
Change in submaximal exercise efficiency (O2 consumption per power output during submaximal exercise and standardized handgrip exercise)
Change in Skeletal Muscle Mitochondrial Oxidative Capacity
The investigators will assess the oxygen consumption recovery kinetics after moderate forearm exercise, using repeated cuff brachial artery occlusions and near-infrared spectroscopy.
Change in post-ischemic vasodilatory response
The investigators will assess the post-ischemic vasodilatory response in the forearm using brachial artery pulsed wave Doppler interrogations before and after inflation of a brachial cuff at 200 mmHg for 5 minutes. The investigators will also assess forearm microvascular skeletal muscle flow with near-infrared spectroscopy and forearm skin microvascular flow using laser Doppler.

Full Information

First Posted
July 22, 2013
Last Updated
April 27, 2015
Sponsor
Corporal Michael J. Crescenz VA Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT01919177
Brief Title
Effect of Inorganic Nitrates (Beetroot Juice) on Arterial Hemodynamics and Exercise Capacity
Official Title
Effect of Inorganic Nitrates on Arterial Hemodynamics and Exercise Capacity
Study Type
Interventional

2. Study Status

Record Verification Date
April 2015
Overall Recruitment Status
Completed
Study Start Date
January 2013 (undefined)
Primary Completion Date
September 2014 (Actual)
Study Completion Date
November 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Corporal Michael J. Crescenz VA Medical Center

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The main objective is to test the hypothesis that inorganic nitrate supplementation will: (1) Improve exercise efficiency and performance; (2) Enhance the systemic vasodilator reserve during exercise and specifically, the vasodilator response in exercising muscle; (3) Reduce arterial wave reflections and arterial load; (4) Improve skeletal muscle mitochondrial function in subjects with heart failure with preserved ejection fraction.
Detailed Description
This represents a series of double-blind, controlled pilot randomized studies in which the effects of nitrate-rich beetroot juice and nitrate-depleted beetroot juice will be assessed in patients with heart failure and preserved ejection fraction (n=20). A total of 20 subjects will be enrolled over a 1.5 year period and randomized in a cross-over design to a single dose of nitrate-rich beetroot juice and nitrate-depleted beetroot juice. The order of the interventions will be randomized; thus, all subjects will receive the nitrate-rich and nitrate-depleted juice, with a 4-7 day washout period in-between studies.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heart Failure With Normal Ejection Fraction
Keywords
Heart Failure, Arterial hemodynamics, Exercise capacity, Mitochondrial oxidative capacity

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
17 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Nitrate rich beetroot juice
Arm Type
Active Comparator
Arm Description
Subjects with heart failure with preserved ejection fraction will receive 140 mL of Nitrate-rich concentrated beetroot juice (containing 12 mmol of NO-3). This will be a cross-over study. Therefore all subjects will receive both interventions, but the order of the interventions will be randomized.
Arm Title
Nitrate depleted beetroot juice
Arm Type
Placebo Comparator
Arm Description
Subjects with heart failure with preserved ejection fraction will receive 140 mL of nitrate-depleted beetroot juice (containing <0.01 mmol of NO-3).This will be a cross-over study. Therefore all subjects will receive both interventions, but the order of the interventions will be randomized.
Intervention Type
Dietary Supplement
Intervention Name(s)
Nitrate rich beetroot juice
Other Intervention Name(s)
Beet It Stamina Sports shots
Intervention Description
Subjects will receive 140 mL of Nitrate-rich concentrated beetroot juice.
Intervention Type
Dietary Supplement
Intervention Name(s)
Nitrate depleted beetroot juice
Other Intervention Name(s)
Beet It nitrate extracted (depleted) placebo shots
Intervention Description
Subjects will receive 140 mL of nitrate-depleted beetroot juice.
Primary Outcome Measure Information:
Title
Change in Peak exercise efficiency during maximal effort supine-bicycle exercise and peak oxygen consumption (VO2) during a maximal effort supine-bicycle exercise test
Description
We will assess the relationship between total power output and total O2 consumption (VO2, assessed via expired gas analysis) during a maximal-effort supine bicycle exercise test.
Time Frame
Baseline study, repeat study 4-7 days later
Secondary Outcome Measure Information:
Title
Change in Arterial wave reflection magnitude
Description
Reflection wave magnitude will be assessed using arterial tonometry to arrive at the augmentation index. The data will also be processed using custom designed software for wave separation analysis to quantify the magnitude and timing of the reflected waves.
Time Frame
Baseline study, repeat study 4-7 days later
Title
Change in Peripheral vascular resistance, total arterial compliance and reflection magnitude during supine bicycle peak exercise
Time Frame
Baseline study, repeat study 4-7 days later
Title
Change in lower extremity exercise vasodilator reserve (change in femoral vascular resistance between rest and maximal effort supine-bicycle exercise)
Time Frame
Baseline study, repeat study 4-7 days later
Title
Change in lower extremity blood flow reserve (change in femoral artery blood flow between rest and maximal effort supine-bicycle exercise)
Time Frame
Baseline study, repeat study 4-7 days later
Title
Change in submaximal exercise efficiency (O2 consumption per power output during submaximal exercise and standardized handgrip exercise)
Time Frame
Baseline study, repeat study 4-7 days later
Title
Change in Skeletal Muscle Mitochondrial Oxidative Capacity
Description
The investigators will assess the oxygen consumption recovery kinetics after moderate forearm exercise, using repeated cuff brachial artery occlusions and near-infrared spectroscopy.
Time Frame
Baseline study, repeat study 4-7 days later
Title
Change in post-ischemic vasodilatory response
Description
The investigators will assess the post-ischemic vasodilatory response in the forearm using brachial artery pulsed wave Doppler interrogations before and after inflation of a brachial cuff at 200 mmHg for 5 minutes. The investigators will also assess forearm microvascular skeletal muscle flow with near-infrared spectroscopy and forearm skin microvascular flow using laser Doppler.
Time Frame
Baseline study, repeat study 4-7 days later

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: The investigators will enroll 20 subjects >18 years of age who have a diagnosis of heart failure with preserved ejection fraction (>50%) by 2d echocardiography, with current New York Heart Association Class II-IV symptoms. In addition, subjects with heart failure must meet the following inclusion criteria: Chronic treatment with a loop diuretic for control of HF symptoms. If EF is normal, subjects must demonstrate elevated filling pressures as evidenced by at least one of the following: a) left atrial enlargement (LAVI > 32 mL/m2); b) at least stage II diastolic dysfunction; c) Documentation of elevated NT-pro BNP levels or other natriuretic peptide marker (BNP, ANP) according to the laboratory and assay upper limit of normal in the previous year. Stable medical therapy as defined by: (I) No addition or removal of ACE, ARB, beta-blockers, or calcium channel blockers (CCBs) for 30 days. (II) No change in dosage of ACE, ARBs, beta-blockers or CCBs of more than 100% for 30 days. (III) No change in diuretic dose for 10 days. Exclusion Criteria: Rhythm other than sinus rhythm (i.e., atrial fibrillation). Neuromuscular, orthopedic or other non-cardiac condition that prevents patient from exercising. Valve disease (> mild aortic or mitral stenosis; > moderate aortic or mitral regurgitation). Hypertrophic cardiomyopathy. Known infiltrative or inflammatory myocardial disease (amyloid, sarcoid). Pericardial disease. Primary pulmonary arteriopathy. Have experienced a myocardial infarction or unstable angina, or have undergone percutaneous transluminal coronary angiography (PTCA) or coronary artery bypass grafting (CABG) within 60 days prior to consent, or requires either PTCA or CABG at the time of consent. Other clinically important causes of dyspnea such as morbid obesity or significant lung disease defined by clinical judgment or use of steroids or oxygen for lung disease within the past 6 months. Systolic blood pressure < 110 mmHg or > 180 mm Hg. Diastolic blood pressure < 40 mmHg or > 100 mmHg. Resting heart rate (HR) > 100 bpm. Hemoglobin <10 g/dL. Patients with known severe liver disease (AST > 3x normal, alkaline phosphatase or bilirubin > 2x normal). Patients with a clinically indicated stress test demonstrating significant ischemia within a year of enrollment which was not followed by percutaneous or surgical revascularization. Current therapy with phosphodiesterase inhibitors, such as sildenafil, vardanafil or tadalafil. Known allergies to beetroot or lemon juice. Current use of organic nitrates or phosphodiesterase inhibitors. Pregnancy. Although beetroot juice has not knows teratogenic effects, we feel that not enough data exist in this regard. Therefore, all females patients of reproductive age will be required to undergo a pregnancy test prior to enrollment.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Julio A Chirinos, MD, PhD
Organizational Affiliation
Philadelphia VA Medical Center & University of Pennsylvania
Official's Role
Principal Investigator
Facility Information:
Facility Name
Philadelphia Veterans Affairs Medical Center
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
12524257
Citation
American Thoracic Society; American College of Chest Physicians. ATS/ACCP Statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med. 2003 Jan 15;167(2):211-77. doi: 10.1164/rccm.167.2.211. No abstract available. Erratum In: Am J Respir Crit Care Med. 2003 May 15;1451-2.
Results Reference
background
PubMed Identifier
21982360
Citation
Manetos C, Dimopoulos S, Tzanis G, Vakrou S, Tasoulis A, Kapelios C, Agapitou V, Ntalianis A, Terrovitis J, Nanas S. Skeletal muscle microcirculatory abnormalities are associated with exercise intolerance, ventilatory inefficiency, and impaired autonomic control in heart failure. J Heart Lung Transplant. 2011 Dec;30(12):1403-8. doi: 10.1016/j.healun.2011.08.020. Epub 2011 Oct 7.
Results Reference
background
PubMed Identifier
25533966
Citation
Zamani P, Rawat D, Shiva-Kumar P, Geraci S, Bhuva R, Konda P, Doulias PT, Ischiropoulos H, Townsend RR, Margulies KB, Cappola TP, Poole DC, Chirinos JA. Effect of inorganic nitrate on exercise capacity in heart failure with preserved ejection fraction. Circulation. 2015 Jan 27;131(4):371-80; discussion 380. doi: 10.1161/CIRCULATIONAHA.114.012957. Epub 2014 Dec 22.
Results Reference
result

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Effect of Inorganic Nitrates (Beetroot Juice) on Arterial Hemodynamics and Exercise Capacity

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