The Effect of Altering Myocardial Lipid Content on Cardiac Physiology in Patients With Aortic Stenosis
试验速览
- 阶段
- 不适用
- 入组人数
- 67
- 试验地点
- 1
- 主要终点
- Change in myocardial triglyceride (MTG) content as assessed by cardiac magnetic resonance (CMR) spectroscopy
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
Randomised double-blind placebo controlled study
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
- •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)
- •No other significant valvular pathology
- •No contraindication to magnetic resonance imaging.
排除标准
- •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.
研究组 & 干预措施
OxFAST Fibrate group
49 patients randomised to receive fenofibrate 200mg capsules.
干预措施: Fenofibrate Capsules (Drug)
OxFAST placebo group
13 patients randomised to receive placebo will act as controls.
干预措施: Placental Lactogen (Drug)
结局指标
主要结局
Change in myocardial triglyceride (MTG) content as assessed by cardiac magnetic resonance (CMR) spectroscopy
时间窗: 6 months
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.
次要结局
- Change in myocardial energetics (PCr/ATP ratio) as assessed by Phosphorous magnetic resonance spectroscopy(6 months)
- Change in left ventricular function measured using CMR imaging(6 months)