Heart Failure With Preserved Ejection Fraction, Type 2 Diabetes
Conditions
Brief summary
Heart failure with preserved ejection fraction (HFpEF) is a condition in which the heart cannot fill with blood effectively. As a result, people with HFpEF suffer fatigue, breathlessness, and develop swollen limbs. The condition often requires multiple admissions to hospital and is associated with a marked loss of lifespan. Despite being so common, very little is known about why people develop HFpEF and there are hardly any known treatments. Type 2 diabetes (T2D) is a major risk factor for HFpEF, and people with both HFpEF and diabetes are at a heightened risk of hospitalisation and premature death. It is unclear why the combination of diabetes and HFpEF is particularly harmful. This may be related to the hearts of people with type 2 diabetes being unable to take up the mineral calcium properly, as well as due to their hearts being less energy efficient. Both of these are vital to heart muscle pumping and filling, but until recently it has not been possible to assess these in humans. New advances in heart MRI scans, with dedicated scanner techniques and dyes (manganese contrast), now allow extremely detailed pictures of heart structure, function, calcium uptake and energy efficiency, all during the same scan. The investigators will enlist 40 volunteers with HFpEF (20 with T2D and 20 without T2D), and up to 20 healthy volunteers, to undergo a heart MRI scan with manganese contrast to assess calcium uptake and energy efficiency. This will allow the comparison of people with HFpEF with and without T2D, to see how their hearts are different to healthy volunteers.
Interventions
Self-administered, validated questionnaire to assess symptoms of heart failure
DIAGNOSTIC_TESTEchocardiogram
Resting transthoracic echocardiogram to exclude valvular pathology and the assess indices of systolic and diastolic function and speckle tracking for strain
DIAGNOSTIC_TESTSix-minute walk test
Standardised, objective assessment of exercise capacity
DIAGNOSTIC_TESTManganese-enhanced MRI and 31-P magnetic resonance spectroscopy
Using a 3-Tesla scanner, 31P magnetic resonance spectroscopy will be performed to obtain information regarding cardiac energetics. An intravenous infusion of manganese dipyridoxyl diphosphate (mangafodipir, MnDPDP) will be commenced at a rate of 1mL/min using a dose of 5µmol/kg (0.1mL/kg).
DIAGNOSTIC_TESTCardiovascular magnetic resonance scan
Scan including adenosine stress perfusion
DIAGNOSTIC_TESTBlood tests
Full blood count, Urea and electrolytes, Liver function tests, Glucose and HbA1c, Insulin and C-peptide, NTproBNP, High sensitive troponin I, storage of plasma for future analyses
Sponsors
University of Leicester
Study design
Observational model
CASE_CONTROL
Time perspective
CROSS_SECTIONAL
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Capacity to provide informed consent * Symptoms (e.g. breathlessness, orthopnoea, ankle swelling, fatigue), signs (e.g. elevated jugular venous pressure, peripheral oedema, third heart sound) or established diagnosis of HF with LV ejection fraction ≥ 50%, or * Meets HFpEF diagnostic criteria in accordance with the HFA-PEFF diagnostic algorithm form the Heart Failure Association of the European Society of Cardiology, in which a score ≥5 points confirms diagnosis of HFpEF
Exclusion criteria
* Known diagnosis of Type 1 Diabetes * Pregnancy or breast-feeding or females of child bearing age without a negative pregnancy test * Receiving an investigational drug or device within 30 days prior to participating in the study * Decompensated heart failure or pulmonary oedema * History of prolonged corrected QT interval or torsades de pointes * Second- or third-degree atrioventricular block * Abnormal liver function tests (\> 3x upper limit of normal) or history of liver disease * Baseline eGFR \< 30mL/min/1.73m2 * Any contraindications to MRI including implanted devices/pacemakers * Severe native valve disease, restrictive cardiomyopathy, constrictive pericarditis or hypertrophic cardiomyopathy, myocarditis or takotsubo cardiomyopathy. * Recent myocardial infarction within the previous 3 months * Known diagnosis of pheochromocytoma
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ki | Baseline | Manganese influx constant as measured by MEMRI scan |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Myocardial PCr/ATP ratio | Baseline | Phosphocreatine-to-ATP ratio as measured by 31P-magnetic resonance spectroscopy |
| Left ventricular ejection fraction | Baseline | %, measured by CMR |
| LV global longitudinal strain | Baseline | %, measured by CMR |
| LV global circumferential strain | Baseline | %, measured by CMR |
| LV PEDSR | Baseline | 1/s, measured by CMR |
| LV mass | Baseline | grams, measured by CMR |
| T1 values | Baseline | T1 values measured at 30 minutes post contrast on MEMRI scan |
| Myocardial fibrosis | Baseline | CMR assessed markers of LV myocardial fibrosis (extracellular volume) |
| Myocardial Perfusion | Baseline | CMR assessed markers of perfusion (myocardial perfusion reserve) |
| Associations of Ki with resting PCr/ATP | Baseline | Univariate and multivariate models to look for association between Ki and PCr/ATP ratio |
| Associations of exercise capacity with Ki and PCr/ATP in HFpEF | Baseline | Ki values as assessed by MEMRI, myocardial PCr/ATP as measured by 31P-MRS and six minute walk test distance. Associations will be assessed using univariate and multivariate models. |
| Plasma biomarkers of metabolic dysregulation, fibrosis and inflammation | Baseline | This exploratory outcome will assess the differences in a wide range of plasma biomarkers between groups and their association with Ki |
| 10-year outcomes | Baseline | 10-year outcomes including HF hospitalisation (time to first event and cumulative) and all-cause death. |
| LV mass/volume ratio | Baseline | Measured by CMR |
Countries
United Kingdom
Contacts
Backup ContactAbhishek Dattani, MBBS
Primary ContactGerry P McCann, MD
Outcome results
None listed