Cardiomyopathy, Hypertrophic
Conditions
Brief summary
Inorganic nitrate, which is found at high levels in green leafy vegetables, is reduced to nitrite by bacteria in the mouth, swallowed, and absorbed in the stomach into the blood. Studies have shown that increasing the blood levels of nitrite improves the way that muscles use oxygen and energy during exercise, and potentially blood flow. Some people (\ 1 in 500) suffer from a type of genetic heart condition known as hypertrophic cardiomyopathy (HCM). This condition means that the muscle in the heart does not use energy well and becomes larger than average, meaning that they have to tap into the heart's 'energy reserves'. It is not known if nitrite has the same beneficial effects on heart muscle as on other muscles in the body. Our study will explore the mechanism by which nitrite may improve the function and energy status of the heart in HCM.
Interventions
DRUGSodium Nitrate
Single dose of 14mmol oral inorganic sodium nitrate
DRUGPlacebo
Single dose of oral matching placebo
DIAGNOSTIC_TESTPhosphorous Magnetic Resonance Spectroscopy
On the first visit day of this arm, participants will be lie inside an MRI scanner to take pictures of the heart. The thigh muscle will then be imaged before, during, and after kicking exercises.
DIAGNOSTIC_TESTExercise Stress Transthoracic Echocardiogram
On the second visit day of this arm, participants will be asked to lie, semi-erect, on an exercise bed for up to 90 minutes. The echocardiogram will be performed at rest and during peak exercise. The exercise will be in the form of a pedal bike. The exercise levels will be worked out from an upright bicycle exercise test completed by the participants prior to randomization.
Sponsors
Norfolk and Norwich University Hospitals NHS Foundation Trust
British Medical Research Council
University of East Anglia
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
This will be a double blind study. The placebo and active treatments will appear identical and will be dispensed in identical containers. All trial patients, care providers, outcome assessors and data analysts will remain blind throughout the study.
Intervention model description
This is a placebo-controlled, random-order mechanistic study of oral inorganic sodium nitrate versus placebo in cross-over fashion in patients with non obstructive hypertrophic cardiomyopathy and exercise limitation.
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Male or female, aged between 18 and 80 years. * Able to provide informed consent. * Able to understand basic instructions in English. * A diagnosis of hypertrophic cardiomyopathy based on conventional transthoracic echocardiogram guidelines: left ventricular wall thickness \>1.5cm in the absence of sufficient alternative cause. * Exercise limited by symptoms on exertion (NYHA Class II symptoms or greater). * PeakVO2 \<80% on baseline CPEX. * The absence of resting LV outflow tract obstruction (peak gradient \<30 mm Hg) on TTE.
Exclusion criteria
* Significant medical, surgical or psychiatric disease that in the opinion of the patient's attending physician would affect subject safety or influence the study outcome. * Contraindications for undergoing MRI. * Hypotension with a systolic blood pressure \<90mmHg. * Severe anaemia with a plasma haemoglobin level \<8.0g/dL. * Known glucose-6-phosphate dehydrogenase (G6PD) deficiency or G6PD deficiency measured at screening in males of African, Asian or Mediterranean decent. * Female subjects of childbearing potential. * Haemodynamically significant valve disease. * Predisposed to acute on chronic limb ischemia evident from a history of claudication or known peripheral arterial disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cardiac Energetic Status | 3 hours post dose of drug or placebo | Change in cardiac PCr/ATP ratio on phosphorus MRS between inorganic sodium nitrate and placebo |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Skeletal Muscle Mitochondrial Oxidative Capacity/Energetic Status | 3.5 hours post dose of drug or placebo | Change in PCr recovery half-time on dynamic phosphorus MRS between inorganic sodium nitrate and placebo |
| Cardiac Diastolic and Systolic Function on exercise | 3 hours post dose of drug or placebo | Change in measures of diastolic and systolic function on transthoracic echocardiogram at submaximal exercise between inorganic sodium nitrate and placebo |
| Cardiac Diastolic and Systolic Function at rest | 3 hours post dose of drug or placebo | Change in measures of diastolic and systolic function on transthoracic echocardiogram at rest between inorganic sodium nitrate and placebo |
| Plasma levels of Nitrate/Nitrite/NOx | 3 hours post dose of drug or placebo | Change in blood plasma levels of Nitrate/Nitrite/NOx between inorganic sodium nitrate and placebo |
Countries
United Kingdom
Contacts
Primary ContactBrodie L Loudon, MBBS
Backup ContactMichael P Frenneaux, MD
Outcome results
None listed