Coronary Microvascular Dysfunction (CMD)NO-ANOCANCT06948201
Inorganic Nitrate as a Treatment for ANOCA: NO-ANOCA
A study of Coronary Microvascular Dysfunction (CMD) and Angina Patients With Non-obstructive Coronary Artery Disease, run by University of Virginia at 1 site in United States.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Coronary Microvascular Dysfunction (CMD), Angina Patients With Non-obstructive Coronary Artery Disease
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 8 participants
- Where
- 1 siteUnited States
- Study dates
- May 2025to Jun 2026
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
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 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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.
Show all 26Show fewer
- 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
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site
University of Virginia
Charlottesville, Virginia, 22903
Shuo Wang, 434-982-1058, JR7CE@uvahealth.org
Emily Planas, 434-982-1058, ejg9rb@uvahealth.org
About this study
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.
Read more
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
Read the detailed description
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).
- Conditions
- Coronary Microvascular Dysfunction (CMD), Angina Patients With Non-obstructive Coronary Artery Disease
- Being tested
- 70mL Nitrate Rich Beetroot Juice followed by placebo (Nitrate depleted beetroot juice), Placebo (70 mL Nitrate depleted beetroot juice) followed by 70mL Nitrate Rich Beetroot Juice
- Keywords
- angina, ANOCA, Non-obstructive Coronary Artery Disease, CMD, Non-Obstructive CAD, Chest Pain in Women
- Medical subject headings
- Angina Pectoris
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
70mL Nitrate Rich Beetroot Juice followed by placebo (Nitrate depleted beetroot juice)Dietary supplement
70mL Nitrate Rich Beetroot Juice for 14 days followed by placebo (Nitrate depleted beetroot juice) for 14 days
Placebo (70 mL Nitrate depleted beetroot juice) followed by 70mL Nitrate Rich Beetroot JuiceDietary supplement
Placebo (70 mL Nitrate depleted beetroot juice) for 14 days followed by 70mL Nitrate Rich Beetroot Juice for 14 days
| Study group | Role | What they receive |
|---|---|---|
| Beetroot juice followed by placebo | Other | 70mL Nitrate Rich Beetroot Juice for 14 days followed by placebo (70mL nitrate depleted beetroot juice) for 14 days Receives: Dietary Supplement: 70mL Nitrate Rich Beetroot Juice followed by placebo (Nitrate depleted beetroot juice) |
| Placebo followed by Beetroot juice | Other | Placebo (70 mL nitrate depleted beetroot juice) for 14 days followed by Nitrate rich Beetroot juice for 14 days Receives: Dietary Supplement: Placebo (70 mL Nitrate depleted beetroot juice) followed by 70mL Nitrate Rich Beetroot Juice |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Coronary Flow Reserve
Coronary flow reserve is calculated as the ratio of hyperemic myocardial blood flow to the resting myocardial blood flow using cardiovascular magnetic resonance myocardial perfusion imaging
Measured: From enrollment to day 14
Secondary outcomes (3)
Submaximal Exercise Economy
Submaximal Exercise Economy is calculated by a change in oxygen consumption (VO2 in mL/kg/min) from baseline to day 14.
Measured: From enrollment to day 14
Angina
Angina is measured using the Seattle Angina Questionnaire from baseline to day 14. Question measurements range from activities being extremely limited to not at all limited by symptoms (chest pain, chest tightness, or angina) with less symptoms associated with better health related quality of life.
Measured: From enrollment to day 14
Dyspnea Symptoms
Dyspnea symptoms are measured using the Rose Dyspnea Score comparing from baseline to day 14. Less dyspnea symptoms are associated with a better health related quality of life.
Measured: From enrollment to day 14
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Apr 2025
- Study startMay 2025 (estimated)
- Primary completionMay 2026 (estimated)
- Study completionJun 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (28)Papers the sponsor has linked to this study.
- Other trials for Coronary Microvascular Dysfunction (CMD)Studies of the same condition, open and under way.
- More trials run by University of VirginiaThe 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
- Health services research
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- single-site, double-blind, randomized crossover pilot study
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 8 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Virginia
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Patricia Rodriguez Lozano, University of Virginia
- Investigators
- Patricia Rodriguez-Lozano, MD, Principal investigator, University of Virginia
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06948201
- Sponsor's protocol ID
- 302494
- Acronym
- NO-ANOCA
- Status last verified
- Apr 2025
- First submitted
- 16 Apr 2025
- Last updated
- 29 Apr 2025
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: There is no plan to make IPD available to other researchers
Publications
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.
PubMed 37795531Hogwood 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.
PubMed 37732374Parker JD, Parker JO. Nitrate therapy for stable angina pectoris. N Engl J Med. 1998 Feb 19;338(8):520-31. doi: 10.1056/NEJM199802193380807. No abstract available.
PubMed 9468470Lyerly GW, Sui X, Church TS, Lavie CJ, Hand GA, Blair SN. Maximal exercise electrocardiographic responses and coronary heart disease mortality among men with metabolic syndrome. Mayo Clin Proc. 2010 Mar;85(3):239-46. doi: 10.4065/mcp.2009.0509. Epub 2010 Feb 16.
PubMed 20160139Lara J, Ashor AW, Oggioni C, Ahluwalia A, Mathers JC, Siervo M. Effects of inorganic nitrate and beetroot supplementation on endothelial function: a systematic review and meta-analysis. Eur J Nutr. 2016 Mar;55(2):451-459. doi: 10.1007/s00394-015-0872-7. Epub 2015 Mar 13.
PubMed 25764393Fejes R, Pilat N, Lutnik M, Weisshaar S, Weijler AM, Kruger K, Draxler A, Bragagna L, Peake JM, Woodman RJ, Croft KD, Bondonno CP, Hodgson JM, Wagner KH, Wolzt M, Neubauer O. Effects of increased nitrate intake from beetroot juice on blood markers of oxidative stress and inflammation in older adults with hypertension. Free Radic Biol Med. 2024 Sep;222:519-530. doi: 10.1016/j.freeradbiomed.2024.07.004. Epub 2024 Jul 5.
PubMed 38972612Kapil V, Milsom AB, Okorie M, Maleki-Toyserkani S, Akram F, Rehman F, Arghandawi S, Pearl V, Benjamin N, Loukogeorgakis S, Macallister R, Hobbs AJ, Webb AJ, Ahluwalia A. Inorganic nitrate supplementation lowers blood pressure in humans: role for nitrite-derived NO. Hypertension. 2010 Aug;56(2):274-81. doi: 10.1161/HYPERTENSIONAHA.110.153536. Epub 2010 Jun 28.
PubMed 20585108Kapil V, Weitzberg E, Lundberg JO, Ahluwalia A. Clinical evidence demonstrating the utility of inorganic nitrate in cardiovascular health. Nitric Oxide. 2014 Apr 30;38:45-57. doi: 10.1016/j.niox.2014.03.162. Epub 2014 Mar 18.
PubMed 24650698Del Buono MG, Montone RA, Camilli M, Carbone S, Narula J, Lavie CJ, Niccoli G, Crea F. Coronary Microvascular Dysfunction Across the Spectrum of Cardiovascular Diseases: JACC State-of-the-Art Review. J Am Coll Cardiol. 2021 Sep 28;78(13):1352-1371. doi: 10.1016/j.jacc.2021.07.042.
PubMed 34556322Zhang Z, Li X, He J, Wang S, Wang J, Liu J, Wang Y. Molecular mechanisms of endothelial dysfunction in coronary microcirculation dysfunction. J Thromb Thrombolysis. 2023 Oct;56(3):388-397. doi: 10.1007/s11239-023-02862-2. Epub 2023 Jul 19.
PubMed 37466848Barsky L, Merz CNB, Wei J, Shufelt C, Handberg E, Pepine C, Rutledge T, Reis S, Doyle M, Rogers W, Shaw L, Sopko G. Even "WISE-R?"-an Update on the NHLBI-Sponsored Women's Ischemia Syndrome Evaluation. Curr Atheroscler Rep. 2020 Jun 18;22(8):35. doi: 10.1007/s11883-020-00852-w.
PubMed 32556630Hosadurg N, Watts K, Wang S, Wingerter KE, Taylor AM, Villines TC, Patel AR, Bourque JM, Lindner JR, Kramer CM, Sharma G, Rodriguez Lozano PF. Emerging Pathway to a Precision Medicine Approach for Angina With Nonobstructive Coronary Arteries in Women. JACC Adv. 2024 Jul 4;3(8):101074. doi: 10.1016/j.jacadv.2024.101074. eCollection 2024 Aug.
PubMed 39055270Wu Y, Zhu H, Xu Q, Li Y, Tang L. Effect of exercise training in patients with angina with nonobstructive coronary arteries: a systematic review and meta-analysis. Coron Artery Dis. 2025 May 1;36(3):252-262. doi: 10.1097/MCA.0000000000001440. Epub 2024 Oct 24.
PubMed 39470145Gulati M, Khan N, George M, Berry C, Chieffo A, Camici PG, Crea F, Kaski JC, Marzilli M, Merz CNB. Ischemia with no obstructive coronary artery disease (INOCA): A patient self-report quality of life survey from INOCA international. Int J Cardiol. 2023 Jan 15;371:28-39. doi: 10.1016/j.ijcard.2022.09.047. Epub 2022 Sep 23.
PubMed 36162521Meeder JG, Hartzema-Meijer MJ, Jansen TPJ, Konst RE, Damman P, Elias-Smale SE. Outpatient Management of Patients With Angina With No Obstructive Coronary Arteries: How to Come to a Proper Diagnosis and Therapy. Front Cardiovasc Med. 2021 Nov 2;8:716319. doi: 10.3389/fcvm.2021.716319. eCollection 2021.
PubMed 34796207
Study at a glance
From the registry record, last updated by the sponsor on 29 Apr 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Inorganic Nitrate as a Treatment for ANOCA: NO-ANOCA
- ClinicalTrials.gov ID
- NCT06948201
- Acronym / sponsor ID
- NO-ANOCA / 302494
- Conditions
- Coronary Microvascular Dysfunction (CMD), Angina Patients With Non-obstructive Coronary Artery Disease
- Keywords
- angina, ANOCA, Non-obstructive Coronary Artery Disease, CMD, Non-Obstructive CAD, Chest Pain in Women
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 8 participants (estimated)
- Lead sponsor
- University of VirginiaUniversity, hospital or other
- Study start
- May 2025 (estimated)
- Primary completion
- May 2026 (estimated)
- Study completion
- Jun 2026 (estimated)
- First posted
- 29 Apr 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Detailed description
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).
Study design
- Primary purpose
- Health services research
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- single-site, double-blind, randomized crossover pilot study
| Arm | Type | Receives |
|---|---|---|
| Beetroot juice followed by placebo | Other | Dietary Supplement: 70mL Nitrate Rich Beetroot Juice followed by placebo (Nitrate depleted beetroot juice)70mL Nitrate Rich Beetroot Juice for 14 days followed by placebo (70mL nitrate depleted beetroot juice) for 14 days |
| Placebo followed by Beetroot juice | Other | Dietary Supplement: Placebo (70 mL Nitrate depleted beetroot juice) followed by 70mL Nitrate Rich Beetroot JuicePlacebo (70 mL nitrate depleted beetroot juice) for 14 days followed by Nitrate rich Beetroot juice for 14 days |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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.
Key exclusion criteria (26 listed)
- 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
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 |
|---|---|---|
| 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 | Dietary supplement | Beetroot juice followed by placebo |
| Placebo (70 mL Nitrate depleted beetroot juice) followed by 70mL Nitrate Rich Beetroot JuicePlacebo (70 mL Nitrate depleted beetroot juice) for 14 days followed by 70mL Nitrate Rich Beetroot Juice for 14 days | Dietary supplement | Placebo followed by Beetroot juice |
Primary outcome
Change in Coronary Flow Reserve
Time frame: From enrollment to day 14
Coronary flow reserve is calculated as the ratio of hyperemic myocardial blood flow to the resting myocardial blood flow using cardiovascular magnetic resonance myocardial perfusion imaging
3 secondary outcomes
Submaximal Exercise Economy
Time frame: From enrollment to day 14
Angina
Time frame: From enrollment to day 14
Dyspnea Symptoms
Time frame: From enrollment to day 14
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Apr 2025.
- Background: PubMed 37795531Hogwood 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.
- Background: PubMed 37732374Hogwood 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.
- Background: PubMed 9468470Parker JD, Parker JO. Nitrate therapy for stable angina pectoris. N Engl J Med. 1998 Feb 19;338(8):520-31. doi: 10.1056/NEJM199802193380807. No abstract available.
- Background: PubMed 20160139Lyerly GW, Sui X, Church TS, Lavie CJ, Hand GA, Blair SN. Maximal exercise electrocardiographic responses and coronary heart disease mortality among men with metabolic syndrome. Mayo Clin Proc. 2010 Mar;85(3):239-46. doi: 10.4065/mcp.2009.0509. Epub 2010 Feb 16.
- Background: PubMed 25764393Lara J, Ashor AW, Oggioni C, Ahluwalia A, Mathers JC, Siervo M. Effects of inorganic nitrate and beetroot supplementation on endothelial function: a systematic review and meta-analysis. Eur J Nutr. 2016 Mar;55(2):451-459. doi: 10.1007/s00394-015-0872-7. Epub 2015 Mar 13.
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- Individual participant dataSharing planned: No. There is no plan to make IPD available to other researchers
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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.
Patricia Rodriguez-Lozano, MD principal investigator
University of Virginia
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study of Coronary Microvascular Dysfunction (CMD) and Angina Patients With Non-obstructive Coronary Artery Disease, run by University of Virginia 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 7 inclusion and 26 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: opening soon, as of the sponsor's last update on 29 Apr 2025. 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?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Shuo Wang (434-982-1058, VJR7CE@uvahealth.org), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Coronary Flow Reserve (time frame: From enrollment to day 14). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06948201, which also lists 28 linked publications.
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 29 Apr 2025.