Oxford - Fibrates in Aortic Stenosis (OxFAST)

The Effect of Altering Myocardial Lipid Content on Cardiac Physiology in Patients With Aortic Stenosis

Aortic stenosis (AS) is characterised by left ventricular (LV) hypertrophy and altered myocardial substrate metabolism. Peroxisome proliferator-activated receptor (PPARα), a regulator of lipid metabolism is deactivated in pressure overload hypertrophy such as in AS and can lead to dysregulation of fatty acid oxidation, myocardial triglyceride accumulation (steatosis) and lipotoxicity. The investigators propose a proof-of-concept study to investigate the effect of altering myocardial triglyceride (MTG) using a PPARα agonist, fenofibrate on cardiac physiology in patients with asymptomatic moderate-severe AS. The primary endpoint is a change in MTG assessed by magnetic resonance spectroscopy at baseline and after 6 months of treatment. Exploratory endpoints are changes in cardiac physiology including myocardial deformation (strain) as assessed by cardiac magnetic resonance imaging. The investigators hypothesise that pharmacological reduction of MTG with a PPARα agonist will result in steatosis regression and changes in cardiac physiology.

This is a single-centre, proof-of-concept study to investigate the effect of altering MTG content using fenofibrate on cardiac physiology in patients with asymptomatic moderate-severe AS. All patients will participate in a randomised, double-blind, placebo- controlled design for 6 months. AS will be graded according to the British Society of Echocardiography's transthoracic echocardiography guidelines. Sixty two eligible patients will be recruited in total, of which forty nine patients will be randomised to receive 200 mg daily oral fenofibrate and thirteen patients will receive matching placebo for 6 months. All patients will undergo 1H-MRS to assess MTG, 31P-MRS to assess myocardial energetic (Phosphocreatine-to-ATP ratio - PCr/ATP), standard cardiac magnetic resonance imaging to assess LV strain, LV mass, late gadolinium enhancement (fibrosis), physiological exercise assessments to measure maximum oxygen consumption (VO2 max) and 6-minute walking distance. Bloods will be drawn for cholesterol, renal and liver function, glucose and free fatty acids. All tests will be done at baseline and after 6 months' treatment with fenofibrate/placebo.

Change in myocardial triglyceride (MTG) content as assessed by cardiac magnetic resonance (CMR) spectroscopy

All participants will undergo blood tests (full blood count, renal and liver function, lipid profile, free fatty acids and NT- proBNP), CMR cine imaging for assessment of cardiac volumes, function including strain (myocardial tagging), aortic valve imaging and late gadolinium enhancement will be undertaken. MTG will be assessed using cardiac 1H-MRS (proton spectroscopy), which utilises the abundant hydrogen (1H) protons. For 1H-MRS, data are typically acquired at breath hold during diastole from a single voxel (14-16mL) localised in the myocardial septum and take 10-15 minutes to acquire. Myocardial lipid content is calculated as myocardial lipid/water ratio and expressed as percentage. It is hypothesised that Fenofibrate, PPAR alpha agonist will shift the cardiac metabolism back to mainly using free fatty acids and hence the investigators may see a reduction in myocardial lipid content.

Change in myocardial energetics (PCr/ATP ratio) as assessed by Phosphorous magnetic resonance spectroscopy

31P-MRS (Phosphorous Spectroscopy) allows the in vivo quantification of phosphorus (31P)-containing metabolites involved in energy metabolism, such as Phosphocreatine and ATP (Adenosine Triphosphate). PCr/ATP ratio is a reliable indicator of myocardial energetics. It is hypothesised that fenofibrate will increase fatty acid metabolism in the heart and subsequently improve the energetic status of the heart.

The investigators will assess the effect of altering cardiac metabolism using Fenofibrate and study its effect on cardiac physiology, mainly left ventricular function using CMR imaging. Strain assessment using myocardial tagging analysis will be used to detect subclinical dysfunction. The strain values are expressed as percentage.

Inclusion Criteria: Asymptomatic moderate to severe AS (with at least two of the following: aortic valve area <1.5 cm2, peak pressure gradient >36 mmHg or mean pressure gradient >25 mmHg) Not planned aortic valve replacement or transcatheter aortic valve implantation (TAVI) Age >18 No other significant valvular pathology No contraindication to magnetic resonance imaging. Exclusion Criteria: Known coronary artery disease, history of angina, myocardial infarction or presence of regional wall motion abnormalities Other underlying cardiomyopathy Left ventricular ejection fraction<50% Uncontrolled hypertension Diabetes Mellitus Liver impairment Pregnancy and lactation Body mass index >35 kg/m2 Renal impairment (eGFR<30 ml/min) Intolerance to or concurrent use of fibrates or PPARα agonists.