Inorganic Nitrate as a Treatment for ANOCA: NO-ANOCA (NO-ANOCA)

April 23, 2025 updated by: Patricia Rodriguez Lozano, University of Virginia

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

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Estimated)

8

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • Virginia
      • Charlottesville, Virginia, United States, 22903
        • University of Virginia
        • Contact:
          • Patricia Rodriguez-Lozano, MD
        • Contact:
        • Contact:
        • Contact:
          • Jason Allen, Ph.D.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Health Services Research
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Beetroot juice followed by placebo
70mL Nitrate Rich Beetroot Juice for 14 days followed by placebo (70mL nitrate depleted beetroot juice) for 14 days
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 (Nitrate depleted beetroot juice) for 14 days
Other: Placebo followed by Beetroot juice
Placebo (70 mL nitrate depleted beetroot juice) for 14 days followed by Nitrate rich Beetroot juice for 14 days
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
From enrollment to day 14

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Submaximal Exercise Economy
Time Frame: From enrollment to day 14
Submaximal Exercise Economy is calculated by a change in oxygen consumption (VO2 in mL/kg/min) from baseline to day 14.
From enrollment to day 14
Angina
Time Frame: From enrollment to day 14
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.
From enrollment to day 14
Dyspnea Symptoms
Time Frame: From enrollment to day 14
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.
From enrollment to day 14

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Virginia

Investigators

  • Principal Investigator: Patricia Rodriguez-Lozano, MD, University of Virginia

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

May 1, 2025

Primary Completion (Estimated)

May 1, 2026

Study Completion (Estimated)

June 1, 2026

Study Registration Dates

First Submitted

April 16, 2025

First Submitted That Met QC Criteria

April 23, 2025

First Posted (Actual)

April 29, 2025

Study Record Updates

Last Update Posted (Actual)

April 29, 2025

Last Update Submitted That Met QC Criteria

April 23, 2025

Last Verified

April 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 302494

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

There is no plan to make IPD available to other researchers

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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