Coronary and Valvular Heart Disease Research Projects

There are around 915,000 survivors of myocardial infarction (MI, heart attack) currently living in the UK, many will have sustained damage to their heart that increases the likelihood of developing heart failure (HF) in the longer term. This project investigates the potential for drugs that inhibit intracellular regeneration of glucocorticoid to modify repair after heart attack by preventing infarct expansion and reducing the stimulus for the subsequent maladaptive remodeling that leads to HF.

Globally air pollution is believed to be responsible for several million premature deaths every single year. Many megacities see the continuous exposure of many millions of people to extremely high levels of air pollution, and represent a priority for interventions to reduce pollution, exposure or the associated health effects.

Current strategies for the assessment for coronary heart disease are imprecise with unacceptable consequences for many patients including prescription of unnecessary life-long therapies or failure to identify and treat those at greatest risk of myocardial infarction and death. Using complementary experimental, clinical and epidemiological approaches, this project is evaluating high-sensitivity cardiac troponin testing as a tool for precision medicine to improve the diagnosis, risk stratification, investigation, and treatment of patients with stable coronary heart disease.

There has been an exponential increase in the production and development of manufactured nanomaterials (MNMs) for wide-ranging applications. However, there is potential for MNMs to harm the cardiovascular system (as environmental nanoparticles do). This possibility remains largely unexplored.

Air pollution is responsible for several million deaths worldwide per year, predominantly through cardiovascular mortality. The nanoparticles in traffic exhaust are especially harmful, although the biological mechanisms by which they induce detrimental cardiovascular effects remain to be fully established.

Despite the accumulating experimental evidence, the complexity of miRNA-based phenotype remains yet to be fully understood. Thus, we set to identify miRNAs that are able to regulate endothelial cell function, by performing high-throughput phenotypic screening using a whole-genome miRNA library. Furthermore, bioinformatics and network analysis demonstrated that top hit miRNAs regulate common pathways in endothelial cells, such as BMP and TGF beta signalling pathway.

Aortic stenosis is a condition whereby one of the heart valves (aortic valve) becomes narrowed, due to calcium deposition, over time. This can lead to chest pain, heart failure and sudden death. It is the commonest valve disease requiring surgery in the developed world and as the population becomes increasingly older, it is predicted that the prevalence of aortic stenosis will double in the next 20 years. Currently the only treatment is replacement of the aortic valve. Whilst this is excellent treatment, not everyone is suitable for it.

We have developed a method to generate large numbers of vascular endothelial cells from human ES cells. We use this to achieve two aims: (1) to understand the molecular and cellular processes that drive endothelial maturation and specification and (2) to assess the therapeutic potential of derived cells for therapy of ischemic conditions. 

Embryonic and adult zebrafish are able to regenerate their hearts after injury. Using specific transgenic lines labelling immune cells and cardiomyocytes, we can use the translucent embryonic zebrafish to provide unparalleled in vivo 4D imaging of immune cell-cardiomyocyte interactions in the beating heart for up to 48 hours. Our group is characterising and manipulating these inflammatory cell events, seeking therapeutic approaches to human heart repair following injury.

The Magnetic resonance imaging for Abdominal Aortic Aneurysms to predict Rupture or Surgery (MA3RS) study was the culmination of 10 years’ work exploring the use of a ‘smart’ magnetic resonance contrast agent (an ultrasmall superparamagnetic particles of iron oxide (USPIO) called ferumoxytol) to identify cellular inflammation and disease activity in abdominal aortic aneurysms.

In the SCOT-HEART trial, we demonstrated the clinical effectiveness of computed tomography coronary angiography (CTCA) in patients attending the rapid access chest pain clinic with suspected angina pectoris due to coronary heart disease. This study demonstrated that CTCA increased diagnostic certainty, changed treatments and investigations, and halved the rate of future myocardial infarction. This trial has been highly influential, has received several awards (Queen’s Anniversary Prize 2014-2016; British Medical Journal Imaging Team of the Year Award 2017), and has informed the 2016 NICE guideline (CG95) on the investigation of patients with stable chest pain.

This is a multi-centre international observational cohort study funded by the Wellcome Trust (WT103782AIA): the Prediction of Recurrent Events with 18F-Fluoride to Identify Ruptured and high-risk coronary artery plaques in patients with myocardial infarction (PRE18FFIR; NCT02278211). It is assessing whether the positron emission tomography (PET) tracer 18F-sodium fluoride is as a marker of coronary plaque vulnerability and can detect culprit and non-culprit unstable coronary plaques in patients with recent myocardial infarction.

Randomised controlled trial of early surgery in asymptomatic patients with severe aortic stenosis and objective evidence of left ventricular decompensation (myocardial fibrosis on magnetic resonance imaging) clinicaltrials.gov NCT03094143

Manganese holds great promise for cardiac MRI. As a calcium analogue, manganese-enhanced MRI provides direct imaging of viable calcium handling, with potential to define myocardial viability more accurately than with current gold-standard methods, as well as detect calcium-handling dysfunction in failing cardiomyocytes.

Post ischemic angiogenesis requires rapid establishment of repair machinery to enhance pro-angiogenic gene expression, as a primary requisite for vascularisation and tissue regeneration. A small number of studies have identified long non-coding RNAs (lncRNAs) that have importance for endothelial cell biology in general, but their function and consequences in angiogenesis are poorly defined. One of the major functions of lncRNAs is to regulate the target-coding gene expression by association with chromatin.

The primary aim of our research is to characterise the molecular mechanisms through which resident cardiac endothelial cells contribute to vascular regeneration in the post-ischaemic heart.

The main aim of this project is to study extracellular vesicle mediated cell-to-cell communication between human smooth muscle cells and endothelial cells, evaluate its relevance in vascular injury in an in vitro model of pulmonary arterial hypertension, and determine the significance of long non-coding RNA in this crosstalk.

Considering the key role of long non-coding RNAs in gene expression, we aim to identify lncRNAs showing a change in expression during vasculature development or in pathology. The lncRNA regulation and potential mechanism of action is then investigated based on genome-wide data generated by our group or publicly available.

Artificial intelligence has the potential to transform the way that we practice medicine. Our aim is to harness routine data from electronic health records, using signal processing and statistical machine learning, to develop clinical-decision support tools that will aid in the diagnosis and targeting of treatments for patients with myocardial infarction.

The High-STEACS research group are performing a series of stepped-wedge cluster randomised controlled trials (ClinicalTrials.gov Identifier: NCT01852123 and NCT03005158) to evaluate whether implementation of a high-sensitivity cardiac troponin I assay will reduce recurrent myocardial infarction and cardiovascular death in patients with suspected acute coronary syndrome across  tertiary and secondary care hospitals in Scotland.

Advanced in vivo imaging is key to cardiac phenotyping as well as for identification of myocardial injury and characterisation of structure, function and  molecular processes during remodelling of the heart in disease.

Heart failure has a poor prognosis and affects over 38 million patients worldwide. Humans have only a limited capacity to regenerate cardiomyocytes following injury. However, zebrafish possess a remarkable capacity to completely and efficiently regenerate the heart. Our goal is to identify and understand endogenous mechanisms of heart regeneration in zebrafish, and apply them to humans to promote heart regeneration following injury.

The central hypothesis of VascmiR is that microRNAs (miRs) fundamentally control pathological remodelling of the vasculature. The complexity of vascular bed heterogeneity and subsequent response to injury, the potential importance of miRNA in vascular pathology, and the paucity in knowledge relating to many facets of miRNA function in the vessel wall including target pathways, mechanistic features of miRNA-mediated cell:cell communication mediated by miRNA export and uptake etc. provides an excellent opportunity for groundbreaking basic and translational research in the field. 

Adenovirus Vector Technology: Next Generation Systems for Medical Therapy (AD-VEC)