Cardiology

Medication compliance in patients with heart failure referred for device therapy

Supervisors:Dr Shirley Sze (kyss1@leicester.ac.uk) and Professor Ian Squire (is11@leicester.ac.uk)

Medication non-compliance is associated with a higher risk of recurrent HF hospitalisation and poorer survival. It also increases the need for costly advanced device therapies and even cardiac transplantation. The prevalence of medication non-compliance has been reported to range between 5 and 60% in different cohorts of HF patients, but it is uncertain which subgroups of HF patients are at highest risk of medication non-compliance. Many factors have been postulated to contribute to poor compliance and these include higher number of comorbidities, complexity of medical regimen, cognitive impairment, depression and socio-economic status, but the evidence has been inconsistent. Despite its significant relation to adverse clinical outcomes, medication compliance is not assessed routinely in clinical practice.

Leicester is a national centre for drug adherence and has established a novel technique to directly measure drug levels using liquid chromatography-tandem mass spectrometry (LC-MS) assays to provide objective evidence of medication non-compliance. We have demonstrated its diagnostic and therapeutic utility along with its cost-effectiveness in patients with hypertension.

In this project, the ACF will aim to use this technique to explore medication compliance in HF patients referred for device therapy. We will also aim to identify factors related to poor compliance and study the relation between poor compliance and clinical outcomes.

Findings from this study would build towards a competitive doctoral research fellowship to the British Heart Foundation (BHF) or National Institute for Health and Care Research (NIHR), investigating strategies to optimise medication compliance and improve clinical outcomes in patients with heart failure.

Phenotyping patients with frailty and heart failure

Supervisors: Dr Shirley Sze (kyss1@leicester.ac.uk) and Professor Ian Squire (is11@leicester.ac.uk)

Multimorbidity, the presence of 2 or more chronic medical conditions in an individual, is highly prevalent in patients with heart failure (HF) and frailty. Polypharmacy is inevitable in these patients. Multimorbiditycontributes to the progression of HF and frailty and may alter the response to treatment. Both cardiovascular and non-cardiovascular comorbidities maybe determining factors in the differentiation of the different types of HF and frailty and their impact on health outcomes.

Most prior clinical studies have focused on individual comorbidities in isolation without considering the interrelations among them. There is a real need to investigate the multimorbidity patterns that cause the greatest burden in HF. 

In this project, the ACF will perform a large-scale population study based on electronic health records from real world patients with an aim to characterise the comorbidities of HF in men and women, to explore their clustering into multimorbidity patterns, and to measure the impact of such patterns on negative health outcomes. Patients with frailty and heart failure is a heterogenous population, we hypothesize that the heterogeneity may be partially attributable to a difference in comorbidity patterns. Understanding how comorbidities cluster in HF patients and its impact on patient outcomes may be an important step towards personalizing HF treatment strategies for better outcome.  

In silico modelling of RCTs of prehabilitation interventions using routinely collected healthcare data

Supervisors: Professor Gavin Murphy (gjm19@leicester.ac.uk) ,Dr Muhammed Rashid (mr467@leicester.ac.uk) ,Dr Weiqi Liao (weiqi.liao@leicester.ac.uk)

1. To develop key skills in the use of routinely collected healthcare data, modern machine learning methods, and in silico clinical trial design.

2. To prepare a high quality submission for an external fellowship application within the lifetime of the post.

3. To pilot a novel research resource for trial development as part of the National Cardiac Surgery Clinical Trials Initiative

Research question: Can pharmacological prehabilitation in people with cardiovascular disease prevent organ injury and death following major surgery.

Interventions: Weight loss interventions including GLP-1 antagonists, anti-ageing interventions including SGLT2i and metformin, and interventions targeting chromatin remodelling including sodium valproate.

Data Sources: CPRD and HES data in partnership with the Leicester Real World Evidence Centre

Statistical Methods: The research will develop the in silico trial methods developed by our team (doi:10.1093/eurheartj/ehac670), that capitalise in the regional variation in the roll out of interventions to model potential RCTs of pre-surgery interventions in cardiac and other major surgical procedures.

Research Team

The research is undertaken in partnership with the Leicester CTU, the Leicester Real World Evidence Centre and statisticians based in the Department of Cardiovascular Sciences at the University of Leicester.

The use of pathway analysis to explore the trajectory of immune cells in inflammageing using bone marrow and myocardial tissue from cardiac surgery patients

Supervisors: Professor Gavin Murphy (gjm19@leicester.ac.uk), Professor Veryan Codd (vc15@leicester.ac.uk) and Professor Tom Webb (tw126@leicester.ac.uk)

The clinical problem: Inflammageing is a key determinant of outcome following cardiac surgery but the underlying processes are poorly understood.

Hypothesis: Chromatin adaptations to biological ageing in bone marrow cells determine cellular lineages and the development of inflammageing in cardiac tissue.

Aims

1. To develop key skills in the use of high precision transcriptomics and genomic data and modern bioinformatic methods to study immunosenescence and biological ageing in human tissue.

2. To use modern informatic methods to identify underlying disease processes in bone marrow and myocardium, and to identify novel therapeutics.

3. To prepare a high quality submission for an external fellowship application within the lifetime of the post.

Participants: People undergoing coronary artery bypass grafting who have provided simultaneous myocardial biopsies and sternal bone marrow isolates for analysis.

Data sources: single nuclei RNA sequencing (snRNAseq) and transposase-accessible chromatin with sequencing (ATAC-Seq) data from bone marrow and myocardial tissue from previous studies.

Methods: Bioinformatic methods will include differential gene expression analysis, pathway analyses, cell-cell interaction, and regulon analyses. Pathway analysis will assess changes in cellular gene expression and chromatin remodelling over pseudotime (PhenoAge, a biological ageing score).

The results will be validated using Mendellian Randomisation in UK Biobank.

Research Team

The research is undertaken in partnership with the internationally leading Cardiovascular Genomics (Codd, Samani) and Functional Genomics (Webb Solomon) groups at the University of Leicester. External collaborators include the Universities of Oxford and Humanitas in Milan.

Maternal Cardiovascular profiling for precision stratification of pregnant women with early onset type 2 diabetes (EOT2D)

Supervisors: Professor Tommy Mousa (hm282@leicester.ac.uk) and Professor Claire Meek (cm881@leicester.ac.uk)

Background: Diabetes mellitus is one of the most common medical disorders in pregnancy, affecting up to 5% of pregnancies in the United Kingdom (UK). Pregnancy in women with early-onset type 2 diabetes (EOT2D; diagnosis <40 years old) is increasingly common and associated with increased risk of placental-mediated diseases, such as pregnancy-induced hypertension (PIH) and preeclampsia (PET), and features of endothelial dysfunction, even in the absence of obesity or hypertension. This suggests that maladaptation of the cardiovascular system in pregnancy may be an important pathophysiological mechanism in EOT2D.

Our Leicester Maternal Haemodynamic Research Group have examined and reported on changes in maternal haemodynamic profiles, including arterial stiffness, a recognised cardiovascular risk factor, among pregnant women with gestational diabetes. We observed unique changes in arterial stiffness suggesting that vascular health may also be important in the development of complications in EOT2D. 

Aims: This project will assess longitudinal changes in maternal haemodynamics among pregnant women with EOT2D and will evaluate its role in the aetiology of pregnancy complications, as part of a large multicentre observational study (Leicester Diabetes Research Centre project led by Prof Meek; DOMINO study).

Hybrid closed loops and risk of placental-mediated diseases in women with type 1 diabetes (T1D) in pregnancy.

Supervisors: Professor Tommy Mousa (hm282@leicester.ac.uk) and Professor Claire Meek (cm881@leicester.ac.uk)

Background: Women with type 1 diabetes (T1D) in pregnancy have increased risk of placental-mediated diseases (Hypertension, pre-eclampsia, fetal growth restriction), preterm delivery, birthweight extremes, congenital anomaly, stillbirth and neonatal death. Hybrid closed loops (HCL), novel automated insulin delivery systems, are now the standard of care for pregnant women with T1D. HCLs improve maternal glycaemia, but their effect upon perinatal outcomes has not been assessed in real-world clinical practice.

Our Leicester Maternal Haemodynamic Research Group have identified that the type of therapy influences longitudinal changes in maternal haemodynamic profile among pregnant women with diabetes. However, it is unclear if HCLs are associated with improved maternal haemodynamics and reduced rates of vascular complications.

Aims: This project will assess the real-world effect of HCL use on perinatal complications, maternal glycaemia and cardiovascular health in women with T1D. This project will be embedded in a large multicentre observational study (Leicester Diabetes Research Centre project led by Prof Meek; DOMINO study) providing opportunities for publications, presentations and to learn about the end-to-end clinical research process.

Understanding progression from asymptomatic type 2 diabetes towards heart failure with preserved

ejection fraction through multidimensional phenotyping

Supervisors: Professor Gerry McCann (gpm12@leicester.ac.uk) , Dr Emer Brady (emb29@leicester.ac.uk), Dr Gaurav Gulsin (gg149@leicester.ac.uk)

Type 2 diabetes (T2D) is a major risk factor for heart failure with preserved ejection fraction (HFpEF), with an insidious, progressive and multifactorial pathophysiology. Several imaging studies have

demonstrated early deleterious myocardial alterations that precede HFpEF symptomology (termed stage B HF (SBHF)). We have been awarded £1.387million in funding from the British Heart Foundation to characterise the trajectory of SBHF in T2D towards symptomatic HFpEF and identify specific biological pathways that drive progression.  This work is an extension to our recently completed clinical cohort study the “Prevalence and Determinants of SubclInical Cardiovascular Dysfunction in Adults with Type 2 Diabetes – The PREDICT Study” (NCT03132129). In PREDICT, over 500 people with T2D (stage A and SBHF) were comprehensively phenotyped with advanced multidimensional multi-organ imaging, cardiopulmonary exercise testing and multi-omics. We will be inviting 200 participants back for repeat testing to assess disease progression and central and peripheral drivers of exercise intolerance, the signature and debilitating symptom of HFpEF.

The successful candidate will contribute to the development of, and have access to, this world-leading bioresource. They will use this rich data for the identification of distinct endotypes in T2D with variable progression of SBHF to inform targeted intervention trials for the prevention of symptomatic HF.

Investigating the clinical pheontypes and pathophysiology of uncommon coronary artery diseases

Supervisor: Professor David Adlam (da134@leicester.ac.uk)

We are interested in improving our understanding of the pathophysiology of rare causes of acute coronary syndromes. We have had British Heart Foundation funded research project to study patients with SCAD, a condition which primarily afflicts young women, particularly in the peri-partum period. We are also seekimg to expand this approach to study patients with CAE. CAE and SCAD have a spectrum of clinical presentations ranges from chest pain syndromes to myocardial infarction and sudden death. 

The UK/EU SCAD research portal (http://scad.lcbru.le.ac.uk/) was established in 2013 and is operated by the NIHR Leicester Cardiovascular BRU. More than 2000 patients have registered for research and consenting patients are now undergoing comprehensive clinical and imaging-based phenotyping, epidemiological follow-up and biobanking. This ACF would be focused on enhanced clinical phenotyping of patients from the SCAD study and working with the European SCAD Study Group to collate data from the ESC-EORP SCAD study, particularly in light of our increased understanding of the genetic predisposition to this condition, recruiting patients to the SCAD and CAE studies including clinical trials. Precise details can be moulded to candidates clinical and research interests and to the state of the art at the time point of commencement of research work.