Investigation of Dietary Nitrate Optimisation by Hyperuricaemia Stratification in Heart Failure
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 2
- 试验地点
- 1
- 主要终点
- Change in serum uric acid levels
研究概览
简要总结
This study evaluates the addition of inorganic dietary nitrate to the optimal treatment of patients diagnosed with heart failure with reduced ejection fraction. Some vegetables contain large amounts of inorganic nitrate, and research suggests that this nitrate has beneficial effects on the heart and blood vessels. We have shown in lab experiments that nitrate has positive effects on the heart. We wish to test whether dietary nitrate might be useful in halting deterioration and/or improving heart function in patients with heart failure, with a specific focus on a marker of poor outcome in heart failure: high uric acid levels. Half of the patients will receive nitrate-rich beetroot juice, and the other half a nitrate-deplete placebo beetroot juice.
详细描述
Background: Heart failure (HF) affects 1-2% of those under 70 years, and 10-20% of those over 70 years in developed countries; approximately 900,000 people in the UK suffer with HF. Despite several promising pre-clinical targets, clinical translation has been disappointing, with very few successful phase 3 studies of new HF therapeutics. Dysfunction of the classical pathways that underlie endothelial nitric oxide (NO) production, with deficient cardiac constitutive NO supply, are thought to play a major role in the pathogenesis of HF. It has been mooted that novel strategies that replace/restore this diminished NO have therapeutic potential.
The organic nitrates, as a method of NO delivery, provide an efficacious treatment in the acute HF setting. However, the development of tolerance, tachyphylaxis, and endothelial dysfunction with long-term use severely limits their utility in chronic heart disease. Alternative methods for sustained NO delivery without tolerance are therefore of interest.
Recent clinical research demonstrates that inorganic nitrate offers this possibility through sequential chemical reduction, first via the enterosalivary circuit to nitrite, and subsequently from nitrite to NO. In particular, pre-clinical research suggests that delivery of NO via this pathway imparts benefit in HF models. Dietary inorganic nitrate is known to provide a safe and non-invasive method to elevate NO in humans, and a once daily dose (5-6mmol), in the form of a beetroot juice, can improve vascular function and reduce blood pressure in hypertensives.
Inorganic nitrate as a HF treatment is particularly exciting since a key pathway involved in the generation of NO from nitrate is xanthine oxidoreductase (XOR); an enzyme upregulated in HF. Conventionally, XOR is considered detrimental as it generates superoxide and uric acid; both exert negative effects on cardiac function, and are associated with worse outcomes in HF. However, XOR also plays an important role in the second step of nitrate bioactivation: conversion of nitrite to NO in the heart. Importantly, we have hypothesised that in an environment of elevated XOR activity, such as HF, delivery of inorganic nitrate to the body would result in reductions in superoxide/uric acid with concomitant elevations in NO. This might prove more efficacious than simply inhibiting the enzyme using classical inhibitors. Importantly, a recent study (EXACT-HF) has shown a trend for reduced HF re-hospitalisations in those with XOR inhibition via allopurinol; it has been suggested that greater benefits might be seen if these effects are coupled with NO delivery.
Research Hypothesis and Aims: We aim to investigate whether dietary inorganic nitrate provides benefit in patients with HF. We will determine whether inorganic nitrate delivery by elevating nitrite, delivers substrate to XOR resulting in a two-fold benefit: increasing NO production, whilst concomitantly reducing superoxide and uric acid levels.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Double-blind study, with randomisation undertaken by Barts Cardiovascular Clinical Trials Unit
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥18 years
- •Diagnosed with heart failure with reduced ejection fraction on the basis of:
- •LVEF ≤50% as assessed by Echocardiography (or cardiac MRI)
- •raised BNP and/or NT-proBNP levels placing patients in the "high risk" category, to ensure heart failure is the cause of symptoms:
- •stable heart failure: NT-proBNP >600pg/mL and BNP >150pg/mL
- •hospitalisation within 12 months: NT-proBNP >400pg/mL and BNP >100pg/mL
- •NYHA Class II-III symptoms
- •On optimally-tolerated, stable (>12 weeks) prognostic medical therapy (beta-blocker, ACE-inhibitor or ARB, mineralocorticoid therapy if deemed necessary)
- •No heart failure-related hospitalisation for >12 weeks
- •Clinic systolic blood pressure ≥95mmHg
- •Able and willing to give written informed consent
- •The intervention with dietary nitrate is intentionally designed to be in addition to the patient's own lifestyle. There will be no restrictions placed on diet, anti-oxidant supplements or prescription medications, other than those listed in the exclusion criteria below.
排除标准
- •Use of anti-bacterial mouthwash or tongue scrapes (current or unwillingness to cease such mouthcare for at least one month prior to entering the study, and for the duration of the trial) as this interrupts the enterosalivary circuit and thus prevents the bioactivity of nitrate
- •History of recurrent symptomatic gout or current treatment with xanthine oxidase inhibitors for hyperuricaemia
- •Concomitant use of long acting organic nitrates or phosphodiesterase inhibitors (not including on an as required basis)
- •Angina at CCS Class III/IV, requiring regular use of sublingual GTN (considered >twice/week), or awaiting revascularisation
- •If LVEF in the range 40-50%, impaires systolic function secondary to uncorrected valve disease, primary pulmonary hypertension, active myocarditis, constrictive pericarditis, restrictive cardiomyopathy or hypertrophic cardiomyopathy
- •Renal failure with eGFR<30 at screening
- •History of symptomatic renal stone disease
- •Current life-threatening condition that might prevent a patient-subject completing the study
- •Allergy to SonoVue Echo contrast
- •Pregnancy, breast feeding or planned pregnancy
- •Anaemia, defined as Haemaglobin <80g/L
- •Subjects with any acute infection, or recent systemic antibiotics (oral or intravenous) within 3 months of screening, or significant trauma (burns, fractures)
- •The subject has a three-month prior history of regular alcohol consumption exceeding an average weekly intake of > 28 units (or an average daily intake of greater than 3 units) for males, or an average weekly intake of > 21 units (or an average daily intake of greater than 2 units) for females. 1 unit is equivalent to a half-pint (284mL) of beer/lager; 25mL measure of spirits or 125mL of wine
- •Mobility thought to be restricted significantly by other illnesses apart from heart failure
- •Any other subject whom the Investigator deems unsuitable for the study (e.g. due to other medical reasons, laboratory abnormalities, expected study medication noncompliance, or subject's unwillingness to comply with all study-related study procedures)
结局指标
主要结局
Change in serum uric acid levels
时间窗: 12 +/- 2 weeks
Uric acid is a prognostic marker in patients with heart failure. The intervention proposed acts on the enzyme, xanthine oxidoreductase (XOR), that produces uric acid. We will therefore measure the change in serum uric acid level from baseline to assess whether dietary nitrate treatment decreases hyperuricaemia. We will stratify uric acid levels and undertake analysis between strata.
次要结局
- Changes in plasma nitrite(12 +/- 2 weeks)
- Changes in plasma nitrate(12 +/- 2 weeks)
- Changes in cGMP as a marker for Nitric Oxide(12 +/- 2 weeks)
- Changes in cardiac pump function(12 +/- 2 weeks)