Effect of Dietary Nitrate Ingestion in Heart Failure

Heart Failure Clinical Trial

— DiNOmo-HF  

Official title:

Investigation of Dietary Nitrate Optimisation by Hyperuricaemia Stratification in Heart Failure

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03511248
• Other study ID #: 17/LO/1624
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: June 1, 2018
• Est. completion date: March 1, 2024

Study information

• Verified date: July 2022
• Source: Queen Mary University of London
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 92
• Est. completion date: March 1, 2024
• Est. primary completion date: December 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Age =18 years

2. Diagnosed with heart failure with reduced ejection fraction on the basis of:

1. LVEF =50% as assessed by Echocardiography (or cardiac MRI)

2. 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

3. NYHA Class II-III symptoms

4. On optimally-tolerated, stable (>12 weeks) prognostic medical therapy (beta-blocker, ACE-inhibitor or ARB, mineralocorticoid therapy if deemed necessary)

5. No heart failure-related hospitalisation for >12 weeks

6. Clinic systolic blood pressure =95mmHg

7. 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.

Exclusion Criteria:

1. 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

2. History of recurrent symptomatic gout or current treatment with xanthine oxidase inhibitors for hyperuricaemia

3. Concomitant use of long acting organic nitrates or phosphodiesterase inhibitors (not including on an as required basis)

4. Angina at CCS Class III/IV, requiring regular use of sublingual GTN (considered >twice/week), or awaiting revascularisation

5. 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

6. Renal failure with eGFR<30 at screening

7. History of symptomatic renal stone disease

8. Current life-threatening condition that might prevent a patient-subject completing the study

9. Allergy to SonoVue Echo contrast

10. Pregnancy, breast feeding or planned pregnancy

11. Anaemia, defined as Haemaglobin <80g/L

12. Subjects with any acute infection, or recent systemic antibiotics (oral or intravenous) within 3 months of screening, or significant trauma (burns, fractures)

13. 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

14. Mobility thought to be restricted significantly by other illnesses apart from heart failure

15. 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)

Related Conditions & MeSH terms

• Heart Failure
• Heart Failure, Systolic

Intervention

Dietary Supplement:
• Nitrate-rich Beetroot Juice
The beetroot juice contains approximately 100kcal per 100mL of juice, equivalent to a glass of orange juice; the volume of juice per day for the study is 70mL. Volunteers will be informed that an average woman weighing 65kg should not consume more than 2000kcal per day, and an average man of 75kg not more than 2500kcal per day.
• Nitrate-deplete Beetroot Juice
The beetroot juice contains approximately 100kcal per 100mL of juice, equivalent to a glass of orange juice; the volume of juice per day for the study is 70mL. Volunteers will be informed that an average woman weighing 65kg should not consume more than 2000kcal per day, and an average man of 75kg not more than 2500kcal per day.

Locations

Country	Name	City	State
United Kingdom	Queen Mary University of London	London

Sponsors (1)

Lead Sponsor	Collaborator
Queen Mary University of London

Country where clinical trial is conducted

United Kingdom, 

References & Publications (5)

Givertz MM, Anstrom KJ, Redfield MM, Deswal A, Haddad H, Butler J, Tang WH, Dunlap ME, LeWinter MM, Mann DL, Felker GM, O'Connor CM, Goldsmith SR, Ofili EO, Saltzberg MT, Margulies KB, Cappola TP, Konstam MA, Semigran MJ, McNulty SE, Lee KL, Shah MR, Hernandez AF; NHLBI Heart Failure Clinical Research Network. Effects of Xanthine Oxidase Inhibition in Hyperuricemic Heart Failure Patients: The Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure Patients (EXACT-HF) Study. Circulation. 2015 May 19;131(20):1763-71. doi: 10.1161/CIRCULATIONAHA.114.014536. Epub 2015 Apr 14. — View Citation

Jones DA, Pellaton C, Velmurugan S, Rathod KS, Andiapen M, Antoniou S, van Eijl S, Webb AJ, Westwood MA, Parmar MK, Mathur A, Ahluwalia A. Randomized phase 2 trial of intracoronary nitrite during acute myocardial infarction. Circ Res. 2015 Jan 30;116(3):437-47. doi: 10.1161/CIRCRESAHA.116.305082. Epub 2014 Dec 15. Erratum in: Circ Res. 2015 Mar 27;116(7):e55. — View Citation

Kapil V, Khambata RS, Robertson A, Caulfield MJ, Ahluwalia A. Dietary nitrate provides sustained blood pressure lowering in hypertensive patients: a randomized, phase 2, double-blind, placebo-controlled study. Hypertension. 2015 Feb;65(2):320-7. doi: 10.1161/HYPERTENSIONAHA.114.04675. Epub 2014 Nov 24. — View Citation

Khambata RS, Ghosh SM, Rathod KS, Thevathasan T, Filomena F, Xiao Q, Ahluwalia A. Antiinflammatory actions of inorganic nitrate stabilize the atherosclerotic plaque. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E550-E559. doi: 10.1073/pnas.1613063114. Epub 2017 Jan 5. — View Citation

Velmurugan S, Gan JM, Rathod KS, Khambata RS, Ghosh SM, Hartley A, Van Eijl S, Sagi-Kiss V, Chowdhury TA, Curtis M, Kuhnle GG, Wade WG, Ahluwalia A. Dietary nitrate improves vascular function in patients with hypercholesterolemia: a randomized, double-blind, placebo-controlled study. Am J Clin Nutr. 2016 Jan;103(1):25-38. doi: 10.3945/ajcn.115.116244. Epub 2015 Nov 25. Erratum in: Am J Clin Nutr. 2018 Apr 1;107(4):676. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Changes in markers of oxidative stress: MDA	Measured using ELISA and used collectively with oxidised LDL and TBAR assays to determine oxidative stress	12 +/- 2 weeks
Other	Changes in markers of oxidative stress: oxidised LDL	Measured using ELISA and used collectively with MDA and TBAR assays to determine oxidative stress	12 +/- 2 weeks
Other	Changes in markers of oxidative stress: TBAR	Measured using ELISA and used collectively with oxidised LDL and MDA assays to determine oxidative stress	12 +/- 2 weeks
Other	Measure of red blood cell XOR activity	We will measure expression and activity of XOR by red blood cells, as a marker of both nitrite reductase capacity as well as hyperuricaemia.	12 +/- 2 weeks
Other	Changes in blood pressure	Analysis of 24-hour blood pressure monitoring	12 +/- 2 weeks
Other	Change in NT-proBNP	Analysis of this important natriuretic peptide	12 +/- 2 weeks
Other	Change in BNP	Analysis of this important natriuretic peptide	12 +/- 2 weeks
Other	Change in high sensitivity C-Reactive Protein	Analysis of the highly sensitive marker of inflammation	12 +/- 2 weeks
Other	Change in lipid levels (LDL, triglycerides, HDL, total cholesterol)	Analysis of lipids	12 +/- 2 weeks
Other	Contrast Echocardiography: ventricular function	Measurement of cardiac ventricular function using cardiac MRI (ejection fraction)	12 +/- 2 weeks
Other	Contrast Echocardiography: ventricular volumes	Measurement of cardiac ventricular volumes using cardiac MRI	12 +/- 2 weeks
Other	Contrast Echocardiography: wall stress	Assessment of left ventricular wall stress	12 +/- 2 weeks
Other	Changes in resting cardiac electrical activity	As determined by electrocardiogram analysis	12 +/- 2 weeks
Other	6-minute Walk Test	Functional assessment of exercise capacity	12 +/- 2 weeks
Other	Minnesota Living with Heart Failure Quality of Life Questionnaire	Qualitative analysis of quality of life	12 +/- 2 weeks
Other	Stratification by Type II Diabetes Mellitus	All results will be stratified by the pre-existing diagnosis of Type II Diabetes Mellitus to determine whether this additional cause of oxidative stress impacts on the ability of inorganic nitrate to recover function in patients with heart failure	12 +/- 2 weeks
Other	Evidence of active dental caries	Pre-specified sub-group analyses by dental disease	12 +/- 2 weeks
Other	Measurement of methaemaglobinaemia	Safety measure	12 +/- 2 weeks
Primary	Change in serum uric acid levels	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.	12 +/- 2 weeks
Secondary	Changes in plasma nitrate	We will measure the change in nitrate levels in plasma using ozone chemiluminescence, which measures the consumed dose of inorganic nitrate consumed, as the first step in the enterosalivary circuit.	12 +/- 2 weeks
Secondary	Changes in plasma nitrite	We will measure the change in nitrite levels in plasma using ozone chemiluminescence, measuring the conversion of nitrate to nitrite which the enzyme XOR uses to form the biologically active metabolite, nitric oxide.	12 +/- 2 weeks
Secondary	Changes in cGMP as a marker for Nitric Oxide	We will measure the change in cGMP levels using an ELISA assay, as a stable and measurable surrogate of the biologically active product, nitric oxide.	12 +/- 2 weeks
Secondary	Changes in cardiac pump function	Using contrast Echocardiography, we will measure the change in left ventricular ejection fraction from baseline following intervention.	12 +/- 2 weeks