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.
Plan of Investigation: a randomised double-blind placebo-controlled parallel two-limb study in New York Heart Association (NHYA) class II-III HF patients. Patients with left ventricular ejection fraction (LVEF) \<50% and elevated NT-proBNP/ BNP levels will be enrolled and stratified by degree of hyperuricaemia. 92-patients will receive a once daily dose of nitrate-rich beetroot juice (versus nitrate-deplete beetroot juice) for 12-weeks. The study is powered for significant reductions in hyperuricaemia. Powered secondary outcomes include circulating nitrite/nitrate levels, nitrite reductase activity, and a difference in LVEF from baseline by contrast echocardiography. A number of mechanistic exploratory outcomes will also be reported, including assessments of oxidative stress, erythrocytic XOR activity, 6-minute walk test, quality of life questionnaire and levels of NT-proBNP/BNP as surrogate measures of cardiac dysfunction.
Benefits: This trial if positive will identify a new, safe and easy-to-deliver therapeutic option for HF patients. The NHS would benefit by providing a new inexpensive pharmacotherapy for a disease with significant unmet need and increasing burden to the health service.
