Study Results
Results pending
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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Recruitment Status
NOT_YET_RECRUITING
Clinical Phase
NA
Total Enrollment
8 participants
Study Classification
INTERVENTIONAL
Study Start Date
2025-05-31
Study Completion Date
2026-06-30
Brief Summary
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The purpose of this study is to see if inorganic nitrate in the form of beetroot juice helps blood flow and physical fitness in women with ANOCA and CMD. The main questions it aims to answer are:
AIM 1: Test the hypothesis that fourteen days of nitrate rich beetroot juice will increase cardiac perfusion and improve quality of life compared to placebo.
AIM 2: Test the hypothesis that fourteen days of nitrate rich beetroot juice will increase physical fitness and reduce angina and dyspnea symptoms compared to placebo.
Exploratory AIM 3: Test the hypothesis that fourteen days of nitrate rich beetroot juice will improve vascular health and function.
Participants will:
* Take study beverage for 4 weeks total.
* Stress Cardiac magnetic resonance imaging and 12 lead electrocardiograms
* Complete questionnaires
* Cycling exercise test
* Non invasive vascular testing
* Blood draws
AIM 1: Test the hypothesis that fourteen days of nitrate rich beetroot juice will increase cardiac perfusion and improve quality of life compared to placebo.
AIM 2: Test the hypothesis that fourteen days of nitrate rich beetroot juice will increase physical fitness and reduce angina and dyspnea symptoms compared to placebo.
Exploratory AIM 3: Test the hypothesis that fourteen days of nitrate rich beetroot juice will improve vascular health and function.
Participants will:
* Take study beverage for 4 weeks total.
* Stress Cardiac magnetic resonance imaging and 12 lead electrocardiograms
* Complete questionnaires
* Cycling exercise test
* Non invasive vascular testing
* Blood draws
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Detailed Description
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Females with heart disease often present unique phenotypes but are underrepresented in clinical trials. In females with angina, 40-65% have non-obstructive coronary artery disease (ANOCA), often due to coronary microvascular dysfunction (CMD), which represents \~52% of ANOCA cases. CMD impairs myocardial perfusion (endothelial and/or non-endothelial dysfunction), often detected as reduced coronary flow reserve (CFR). CMD is underdiagnosed despite an elevated risk for major cardiac events and current treatments for it (e.g., beta-blockers, long-acting nitrates) may confer only marginal benefits.
A critical contributor to CMD is impaired nitric oxide (NO) production, essential for vascular function. Oral inorganic nitrate (NO3-) supplementation offers a promising strategy to enhance NO bioavailability through its conversion to nitrite (NO2-) by bacteria in the mouth. NO2- acts as a precursor to NO, releasing it under hypoxic or acidic conditions commonly seen in CMD. This non-enzymatic pathway bypasses the limitations of traditional nitrate therapies, such as systemic hypotension and nitrate tolerance. Moreover, despite established benefits of physical activity \~60% of ANOCA patients experience exercise-induced angina, reduced exercise tolerance, and diminished quality of life (QoL). Recent evidence suggests, however, that exercise can increase endothelial function, endogenous NO production, LVEF, and VO2peak in ANOCA patients. Thus, increased plasma NO2- via inorganic nitrate supplementation may enhance NO delivery, promote physical activity, improve fitness and QoL in this population, which in turn may increase vascular endothelial health.
In the WISE study, \>50% of women with angina had minimal or no obstructive CAD (ANOCA), yet experience worse outcomes than asymptomatic women. ANOCA involves diverse mechanisms, including coronary microvascular dysfunction (CMD), endothelial dysfunction, and vasospasm. These heterogeneities hinder responses to traditional treatments, with CMD being the most common and often linked to endothelial dysfunction.
Nitric oxide (NO) is crucial for coronary microvascular function, regulating vasodilation. In CMD, reduced NO bioavailability and endothelial nitric oxide synthase (eNOS) uncoupling impairs vasodilation and increases oxidative stress. Inflammation in CMD further exacerbates microvascular dysfunction.
Our group and others have utilized inorganic nitrate (NO3-) supplementation to increase NO bioavailability in conditions with vascular dysfunction. NO3- decreases blood pressure, arterial stiffness, oxidative stress and inflammation, while improving vascular and cardiac function. NO3- is reduced to NO under slight hypoxic or acidic conditions, common in CMD, bypassing the limitations of long-acting nitrates. ANOCA patients, a population with the high levels of initial dysfunction, may gain the most benefit from exogenous NO3-.
Dr. Allen's lab has shown that acute NO3- supplementation increases NO metabolites and augments post-exercise vascular function. Our preliminary data in postmenopausal females (PMF) also suggest a link between NO3- supplementation and reduced ET-1 and IL-6 levels compared to PL. Supplementation with NO3- may increase the "delivery pool" of NO and improve ET-1 and Il-6 dysregulation, thus augmenting vascular function, leading to improved physical function and quality of life in females with CMD.
Approach:
This will be a single-site, double-blind, randomized crossover pilot study to investigate the effects of twice daily 70 mL of beetroot juice (BTR) (\~13 mmol total NO3-/day) versus PL (NO3- -depleted) in eight females. Participants with clinically stable CMD (diagnosis \<2 by CMR) will be enrolled. Participants will have angina or equivalent symptoms, and no evidence of obstructive epicardial CAD (stenosis \<50%) by invasive catheterization or coronary computer tomography angiography (CCTA) or FFR/CT-FFR \> 0.8 within the previous 2 years.
STUDY PROCEDURES:
Participants will undergo eligibility screening and informed consent by the study coordinators. Following baseline testing, subjects will be randomized to receive consume either ∼13 mmol of NO3- (BTR) or NO3- depleted placebo (PL) daily via two (morning and night) 70-mL bottles of juice (Beet It, James White Drinks Ltd., Ipswich, UK) for 14 days. Following a 7 day washout period, participants will consume the alternate treatment (BTR or PL) for an additional 14 days.
Baseline and testing at the end of each treatment allocation will include resting vitals, fasting venous blood draw (for plasma NO3-, NO2-, ET-1, IL-6), vascular function (brachial artery flow-mediated dilation, pulse wave velocity and reflection), exercise economy testing at 2 submaximal cycle workloads, QofL questionnaires (EQ-5D-3L, Duke Activity Status Inventory, Modified Morisky Medicine Scale, Rose Dyspnea Score, and Seattle Angina Q), and stress cardiac MRI (to evaluate myocardial perfusion using dynamic first-pass imaging).
A critical contributor to CMD is impaired nitric oxide (NO) production, essential for vascular function. Oral inorganic nitrate (NO3-) supplementation offers a promising strategy to enhance NO bioavailability through its conversion to nitrite (NO2-) by bacteria in the mouth. NO2- acts as a precursor to NO, releasing it under hypoxic or acidic conditions commonly seen in CMD. This non-enzymatic pathway bypasses the limitations of traditional nitrate therapies, such as systemic hypotension and nitrate tolerance. Moreover, despite established benefits of physical activity \~60% of ANOCA patients experience exercise-induced angina, reduced exercise tolerance, and diminished quality of life (QoL). Recent evidence suggests, however, that exercise can increase endothelial function, endogenous NO production, LVEF, and VO2peak in ANOCA patients. Thus, increased plasma NO2- via inorganic nitrate supplementation may enhance NO delivery, promote physical activity, improve fitness and QoL in this population, which in turn may increase vascular endothelial health.
In the WISE study, \>50% of women with angina had minimal or no obstructive CAD (ANOCA), yet experience worse outcomes than asymptomatic women. ANOCA involves diverse mechanisms, including coronary microvascular dysfunction (CMD), endothelial dysfunction, and vasospasm. These heterogeneities hinder responses to traditional treatments, with CMD being the most common and often linked to endothelial dysfunction.
Nitric oxide (NO) is crucial for coronary microvascular function, regulating vasodilation. In CMD, reduced NO bioavailability and endothelial nitric oxide synthase (eNOS) uncoupling impairs vasodilation and increases oxidative stress. Inflammation in CMD further exacerbates microvascular dysfunction.
Our group and others have utilized inorganic nitrate (NO3-) supplementation to increase NO bioavailability in conditions with vascular dysfunction. NO3- decreases blood pressure, arterial stiffness, oxidative stress and inflammation, while improving vascular and cardiac function. NO3- is reduced to NO under slight hypoxic or acidic conditions, common in CMD, bypassing the limitations of long-acting nitrates. ANOCA patients, a population with the high levels of initial dysfunction, may gain the most benefit from exogenous NO3-.
Dr. Allen's lab has shown that acute NO3- supplementation increases NO metabolites and augments post-exercise vascular function. Our preliminary data in postmenopausal females (PMF) also suggest a link between NO3- supplementation and reduced ET-1 and IL-6 levels compared to PL. Supplementation with NO3- may increase the "delivery pool" of NO and improve ET-1 and Il-6 dysregulation, thus augmenting vascular function, leading to improved physical function and quality of life in females with CMD.
Approach:
This will be a single-site, double-blind, randomized crossover pilot study to investigate the effects of twice daily 70 mL of beetroot juice (BTR) (\~13 mmol total NO3-/day) versus PL (NO3- -depleted) in eight females. Participants with clinically stable CMD (diagnosis \<2 by CMR) will be enrolled. Participants will have angina or equivalent symptoms, and no evidence of obstructive epicardial CAD (stenosis \<50%) by invasive catheterization or coronary computer tomography angiography (CCTA) or FFR/CT-FFR \> 0.8 within the previous 2 years.
STUDY PROCEDURES:
Participants will undergo eligibility screening and informed consent by the study coordinators. Following baseline testing, subjects will be randomized to receive consume either ∼13 mmol of NO3- (BTR) or NO3- depleted placebo (PL) daily via two (morning and night) 70-mL bottles of juice (Beet It, James White Drinks Ltd., Ipswich, UK) for 14 days. Following a 7 day washout period, participants will consume the alternate treatment (BTR or PL) for an additional 14 days.
Baseline and testing at the end of each treatment allocation will include resting vitals, fasting venous blood draw (for plasma NO3-, NO2-, ET-1, IL-6), vascular function (brachial artery flow-mediated dilation, pulse wave velocity and reflection), exercise economy testing at 2 submaximal cycle workloads, QofL questionnaires (EQ-5D-3L, Duke Activity Status Inventory, Modified Morisky Medicine Scale, Rose Dyspnea Score, and Seattle Angina Q), and stress cardiac MRI (to evaluate myocardial perfusion using dynamic first-pass imaging).
Conditions
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Coronary Microvascular Dysfunction (CMD)
Angina Patients With Non-obstructive Coronary Artery Disease
Study Design
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Allocation Method
RANDOMIZED
Intervention Model
CROSSOVER
single-site, double-blind, randomized crossover pilot study
Primary Study Purpose
HEALTH_SERVICES_RESEARCH
Blinding Strategy
QUADRUPLE
Participants
Caregivers
Investigators
Outcome Assessors
Study Groups
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Beetroot juice followed by placebo
70mL Nitrate Rich Beetroot Juice for 14 days followed by placebo (70mL nitrate depleted beetroot juice) for 14 days
Group Type
OTHER
70mL Nitrate Rich Beetroot Juice followed by placebo (Nitrate depleted beetroot juice)
Intervention Type
DIETARY_SUPPLEMENT
70mL Nitrate Rich Beetroot Juice for 14 days followed by placebo (Nitrate depleted beetroot juice) for 14 days
Placebo followed by Beetroot juice
Placebo (70 mL nitrate depleted beetroot juice) for 14 days followed by Nitrate rich Beetroot juice for 14 days
Group Type
OTHER
Placebo (70 mL Nitrate depleted beetroot juice) followed by 70mL Nitrate Rich Beetroot Juice
Intervention Type
DIETARY_SUPPLEMENT
Placebo (70 mL Nitrate depleted beetroot juice) for 14 days followed by 70mL Nitrate Rich Beetroot Juice for 14 days
Interventions
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70mL Nitrate Rich Beetroot Juice followed by placebo (Nitrate depleted beetroot juice)
70mL Nitrate Rich Beetroot Juice for 14 days followed by placebo (Nitrate depleted beetroot juice) for 14 days
Intervention Type
DIETARY_SUPPLEMENT
Placebo (70 mL Nitrate depleted beetroot juice) followed by 70mL Nitrate Rich Beetroot Juice
Placebo (70 mL Nitrate depleted beetroot juice) for 14 days followed by 70mL Nitrate Rich Beetroot Juice for 14 days
Intervention Type
DIETARY_SUPPLEMENT
Eligibility Criteria
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Inclusion Criteria
* Age ≥18 years.
* Female sex.
* Willing and able to provide written informed consent.
* Signs and symptoms of suspected ischemia prompted referral for further evaluation by cardiac catheterization or CCTA within two years of consent.
* No evidence of obstructive epicardial CAD (stenosis \>50%) of a major epicardial vessel or an FFR ≤0.80 by invasive catheterization or CCTA. Patients who have not undergone cardiac catheterization of CT angiogram within the last 2 years for chest pain can be scheduled for a screening CT angiogram of the coronary arteries to confirm eligibility.
* Impaired coronary flow reserve (cut-off values depending on methodology use between ≤2.0 and ≤2.5 by stress testing PET/CMR or Invasive assessment) or Abnormal index of coronary microcirculatory resistance (e.g., IMR \> 25)
* SGLT2i Naïve
* Female sex.
* Willing and able to provide written informed consent.
* Signs and symptoms of suspected ischemia prompted referral for further evaluation by cardiac catheterization or CCTA within two years of consent.
* No evidence of obstructive epicardial CAD (stenosis \>50%) of a major epicardial vessel or an FFR ≤0.80 by invasive catheterization or CCTA. Patients who have not undergone cardiac catheterization of CT angiogram within the last 2 years for chest pain can be scheduled for a screening CT angiogram of the coronary arteries to confirm eligibility.
* Impaired coronary flow reserve (cut-off values depending on methodology use between ≤2.0 and ≤2.5 by stress testing PET/CMR or Invasive assessment) or Abnormal index of coronary microcirculatory resistance (e.g., IMR \> 25)
* SGLT2i Naïve
Exclusion Criteria
* History of non-ischemic cardiomyopathy LVEF \<40% or hypertrophic cardiomyopathy.
* History of congestive heart failure, severe pulmonary disease, liver disease
* History of acute coronary syndrome (ACS) within previous 30 days
* Stroke within the last 180 days or intracranial hemorrhage at any time.
* Severe valvular disease
* Life expectancy \<3 years, due to non-cardiovascular comorbidity.
* Pregnancy or women who are breast-feeding
* Type 1 diabetes mellitus
* Symptomatic hypotension or systolic BP\<95 mmHg on 2 consecutive measurements
* Active malignancy requiring treatment at the time of visit
* Severe (eGFR \<30 mL/min/1.73 m2 by CKD-EPI), unstable, or rapidly progressing renal disease at the time of randomization
* History of recurrent UTI/bladder/kidney infections
* Asthma with ongoing wheezing
* Known or suspected bronchoconstrictive or bronchospastic lung disease (ARDS, emphysema)
* Greater than first degree heart block
* Implanted cardiac device
* Profound sinus bradycardia (heart rates\<40 beats per minute)
* Atrial fibrillation or supraventricular arrhythmias at time of imaging
* Known intolerance of nitrates (other than hypotension)
* History of reaction to iodinated contrast agents
* Any orthopedic, neurological, or other condition that prevents participant from exercising
* Individuals currently taking nitroglycerine (or inorganic nitrates), PDE-5 inhibitors (ex: Cialis, Viagra), and xanthine oxidase inhibitors (ex: Allopurinol)
* Smokers within the last 5 years
* Prisoners
* Cognitively impaired individuals
* Non-English Speaking
* History of congestive heart failure, severe pulmonary disease, liver disease
* History of acute coronary syndrome (ACS) within previous 30 days
* Stroke within the last 180 days or intracranial hemorrhage at any time.
* Severe valvular disease
* Life expectancy \<3 years, due to non-cardiovascular comorbidity.
* Pregnancy or women who are breast-feeding
* Type 1 diabetes mellitus
* Symptomatic hypotension or systolic BP\<95 mmHg on 2 consecutive measurements
* Active malignancy requiring treatment at the time of visit
* Severe (eGFR \<30 mL/min/1.73 m2 by CKD-EPI), unstable, or rapidly progressing renal disease at the time of randomization
* History of recurrent UTI/bladder/kidney infections
* Asthma with ongoing wheezing
* Known or suspected bronchoconstrictive or bronchospastic lung disease (ARDS, emphysema)
* Greater than first degree heart block
* Implanted cardiac device
* Profound sinus bradycardia (heart rates\<40 beats per minute)
* Atrial fibrillation or supraventricular arrhythmias at time of imaging
* Known intolerance of nitrates (other than hypotension)
* History of reaction to iodinated contrast agents
* Any orthopedic, neurological, or other condition that prevents participant from exercising
* Individuals currently taking nitroglycerine (or inorganic nitrates), PDE-5 inhibitors (ex: Cialis, Viagra), and xanthine oxidase inhibitors (ex: Allopurinol)
* Smokers within the last 5 years
* Prisoners
* Cognitively impaired individuals
* Non-English Speaking
Minimum Eligible Age
18 Years
Eligible Sex
FEMALE
Accepts Healthy Volunteers
No
Sponsors
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University of Virginia
OTHER
Sponsor Role
lead
Responsible Party
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Patricia Rodriguez Lozano
Principal Investigator
Responsibility Role
PRINCIPAL_INVESTIGATOR
Principal Investigators
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Patricia Rodriguez-Lozano, MD
Role: PRINCIPAL_INVESTIGATOR
University of Virginia
Locations
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University of Virginia
Charlottesville, Virginia, United States
Site Status
Countries
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United States
Central Contacts
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Facility Contacts
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References
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Hogwood AC, Ortiz de Zevallos J, Weeldreyer N, Clark JR, Mazzella V, Cain L, Myaing D, Love KM, Weltman A, Allen JD. The acute effects of exercise intensity and inorganic nitrate supplementation on vascular health in females after menopause. J Appl Physiol (1985). 2023 Nov 1;135(5):1070-1081. doi: 10.1152/japplphysiol.00559.2023. Epub 2023 Oct 5.
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Hogwood AC, Ortiz de Zevallos J, Kruse K, De Guzman J, Buckley M, Weltman A, Allen JD. The effects of inorganic nitrate supplementation on exercise economy and endurance capacity across the menstrual cycle. J Appl Physiol (1985). 2023 Nov 1;135(5):1167-1175. doi: 10.1152/japplphysiol.00221.2023. Epub 2023 Sep 21.
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Smilowitz NR, Prasad M, Widmer RJ, Toleva O, Quesada O, Sutton NR, Lerman A, Reynolds HR, Kesarwani M, Savage MP, Sweeny JM, Janaszek KB, Barseghian El-Farra A, Holoshitz N, Park K, Albadri A, Blair JA, Jeremias A, Kearney KE, Kobayashi Y, Miner SES, Samuels BA, Shah SM, Taqueti VR, Wei J, Fearon WF, Moses JW, Henry TD, Tremmel JA; Microvascular Network (MVN). Comprehensive Management of ANOCA, Part 2-Program Development, Treatment, and Research Initiatives: JACC State-of-the-Art Review. J Am Coll Cardiol. 2023 Sep 19;82(12):1264-1279. doi: 10.1016/j.jacc.2023.06.044.
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Other Identifiers
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302494
Identifier Type: -
Identifier Source: org_study_id
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Nitrite in Hypertrophic Cardiomyopathy (HCM) Study
NCT03251287
UNKNOWN
PHASE1
Investigating the Effects of Dietary Nitrate on Vascular Function, Platelet Reactivity and Restenosis in Stable Angina
NCT02529189
COMPLETED
PHASE2
Dietary Nitrate and Nitrite to Increase Nitric Oxide in Patients With Coronary Artery Disease
NCT00069654
COMPLETED
PHASE2
Effect of Beetroot Juice on Coronary Blood Flow and Walking Performance in PAD
NCT02553733
UNKNOWN
PHASE2
Acute Effects of Beet Extract on Autonomic and Cardiovascular Recovery After Exercise
NCT04094233
COMPLETED
NA
Effect of Nitrate-rich Beetroot Juice on Exercise Performance in Heart Failure Patients
NCT02223403
COMPLETED
NA
The Effects of Inorganic Nitrate on Cardiac Muscle in Angina
NCT02078921
COMPLETED
PHASE2
Effects of Dietary Nitrate Intake on Cardiovascular Performance in Response to Hand Grip Test in Bodybuilders
NCT05835401
COMPLETED
NA
Acute Effects of Beet Juice Consumption on Exercise Capacity in Heart Failure
NCT01946542
TERMINATED
PHASE1/PHASE2
Upregulating the Nitric Oxide Pathway To Restore Autonomic Phenotype (UNTRAP).
NCT03658174
COMPLETED
NA
The Role of Nitrite in Preconditioning Mediated Tolerance to Ischemic Stress
NCT00250185
COMPLETED
PHASE1
The Impact of Vericiguat on Microvascular Function in Patients with Documented Vasospastic Angina Pectoris
NCT06415227
NOT_YET_RECRUITING
PHASE2
A Prospective Study to Evaluate the Effect of Chronic Nitrate Therapy on Vasodilation Function in Coronary Heart Disease
NCT01430780
UNKNOWN
Effects of Nitrite on Blood Vessel Dilation in Normal Volunteers
NCT00048477
COMPLETED
PHASE2
Dietary Nitrate Supplementation and Thermoregulation
NCT03506646
COMPLETED
NA
Effect of Beta-blockers on Coronary Flow and Resistance in Patients With ANOCA
NCT06864234
RECRUITING
PHASE4
The Haem and Nitrite Study - The Effects of Haemoglobin NO-blockade on Nitrite-induced Forearm Vessel Dilatation
NCT03077763
UNKNOWN
PHASE1
The Nitrite and Coronary Flow Study
NCT04354051
COMPLETED
PHASE1/PHASE2
Local Antioxidant Therapy Vasoconstriction Effects in Different Races
NCT03684213
COMPLETED
PHASE1
Nitrite Infusion Studies
NCT00102271
COMPLETED
PHASE1
Pilot Study On The Role Of Nitric Oxide In Alpha 1-Adrenergic Vasoreactivity
NCT00240058
COMPLETED
NA
Assessing the Effect of the 'Wavy' Application, on Stress and Burden of Disease in Women With INOCA
NCT06171893
COMPLETED
NA
Physiologic Effect of Topical Nitroglycerin on Microcirculation Capacity in Patients With Circulatory Shock.
NCT05102734
COMPLETED
Clinical Trial of Sodium Nitrite for Out of Hospital Cardiac Arrest
NCT03452917
COMPLETED
PHASE2/PHASE3
Effect of Nitrite on Exercise Physiology and Metabolism
NCT00105222
TERMINATED
PHASE1