Inorganic Nitrate as a Treatment for ANOCA: NO-ANOCA
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 入组人数
- 8
- 试验地点
- 2
- 主要终点
- Change in Coronary Flow Reserve
研究概览
简要总结
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
详细描述
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-.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Health Services Research
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
结局指标
主要结局
Change in Coronary Flow Reserve
时间窗: 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
次要结局
- Submaximal Exercise Economy(From enrollment to day 14)
- Angina(From enrollment to day 14)
- Dyspnea Symptoms(From enrollment to day 14)
研究者
Patricia Rodriguez Lozano
Principal Investigator
University of Virginia