An exploration of the Heart – Liver axis: using MRI to understand how and why measurements taken in the liver relate to adverse cardiovascular outcomes

Commercial partner: Perspectum Ltd

Aim: To determine the pathophysiological mechanisms associated with changes in liver MRI biomarkers, and which relate to adverse cardiovascular outcomes.

Background: Metabolic dysfunction associated steatotic liver disease (MASLD) is the hepatic manifestation of the metabolic syndrome. MASLD affects a quarter of the population globally and is associated with adverse cardiovascular outcomes. A variety of biomarkers of MASLD have been developed and these have been shown to predict all-cause mortality and liver related events. Our centre has been instrumental in the development of liver T1 and iron corrected T1 (cT1) as biomarkers of chronic liver disease in general and MASLD in particular. We are therefore particularly interested in the observation that liver T1 and cT1 are associated with adverse cardiovascular outcomes in the wider general population. Cross-sectional studies comparing cT1 to liver histology show that fibrosis and inflammation are the pathophysiological mechanisms related to the changes in cT1 in people with liver disease. However, it is unclear whether the same pathophysiology underpins the observed increase in liver T1 / cT1 in participants from the general population such those in the UK Biobank.

We have previously shown that in healthy people liver cT1 and T1 is closely associated with changes in fluid status and validated the ratio of the cross-sectional area of the inferior vena cava to the cross-sectional area of the aorta (IVC/Ao ratio) as a surrogate of fluid status. We therefore hypothesise that in the general population, changes in liver T1 / cT1 are most likely related to fluid congestion, that in turn may be related to subclinical heart failure with with preserved ejection fraction (HFpEF).

Plan of work

1. UK Biobank study

We will use imaging data collected from more than 50,000 participants from the UK Biobank study to evaluate any associations between metrics of right ventricular function and liver T1 / cT1. We will assess whether T1 measured in other tissues has the same predictive value as cT1 measured in the liver. We will also evaluate the association between liver cT1 and IVC/Ao ratio. We will develop imaging analysis pipelines to allow the (semi-)automated analysis of large numbers of data sets. The fellow will therefore develop skills in image analysis including the use of machine learning tools.

2. In-depth evaluation of dynamic changes in liver T1 in people with heart failure and preserved ejection fraction (HFpEF)

We have previously shown that cardiac function in subclinical HFpEF is better evaluated during exercise, and we have established a cardiac MR (CMR) protocol to do this. We will recruit 20 patients with HFpEF to be assessed with our exercise CMR protocol. We will measure cardiac parameters and also liver T1 before and during exercise. We hypothesise that the right heart pressure increases during exercise (which defines HFpEF seen as RA dilation and reduced RV systolic augmentation on CMR during exercise) causes reduced liver venous drainage, and therefore liver congestion (leading to an increase in liver T1). This would be similar to the transient lung congestion that is now being described in HFpEF during exercise.

Value of the results

Understanding the underlying pathophysiology that drives adverse cardiovascular outcomes will have significant implications on the choice of potential treatments and preventive strategies. In particular, evidence of an association between fluid congestion or subclinical cardiac dysfunction and adverse cardiac outcomes, but none, or only weak evidence of an association between liver inflammation or fibrosis and adverse cardiac outcomes will propel the adoption of treatments aiming to improve cardiac function over treatments aiming to address liver inflammation or fibrosis in the wider population.

Apply using course:  DPhil in Medical Sciences

MRC INDUSTRIAL CASE STUDENTSHIPS 2025

Designed to nurture the academic entrepreneurs of the future, the Enterprise studentship programme offers a stimulating educational experience as part of the Oxford-MRC DTP cohort, with the additional benefit of working closely with an industrial partner. This will provide entrepreneurial training opportunities and an insight into how commercial science is conducted alongside a superb academic base within the University. Students will work for at least 3 months in the associated company.

ELIGIBILITY

They are open to both UK and non-UK nationals and will follow the UKRI student eligibility requirements. UKRI will normally limit the proportion of international students appointed each year through individual training grants to 30% of the total intake each year.

FUNDING PACKAGE

Each iCASE studentship is fully-funded – it includes four years of stipend at the UKRI stipend level + £2,500 p.a., course fees, and a generous research training support grant.

APPLICATIONS DEADLINE

Applications must be received by 12 noon (UK time) Tuesday 3 December 2024.

For details of entry requirements please go to the Oxford-MRC DTP iCASE 2025 Projects page.

HOW TO APPLY

Before applying for this project we recommend you contact the lead supervisors for informal discussion.

To make a formal application, please complete the University’s online application form for the DPhil course specified under the project description above. Please indicate the iCASE project clearly by inserting ‘iCASE’ before the project title and by using the reference code iCASE. You will need to provide a personal statement (500 words max if applying for a project hosted by one of Medical Sciences departments – please note that this limit might be different if a project is hosted by one of MPLS departments in which case follow their requirement) detailing your interest and fit for the studentship. Note that no project proposal is required for the iCASE studentship applications.

If you wish to apply for a combination of iCASE and other projects within the hosting department, this can be done on the same application form (max number of projects you can apply for on one application depends on the department you wish to apply to). If you wish to apply for iCASE projects within different departments, you will have to make separate applications directly through those departments.

If you have any queries about the iCASE application process (questions about the project should be directed to the lead supervisor), please email mrc@medsci.ox.ac.uk.