NIHRDataInsights/HRCSData huggingface dataset:
Title: Can targeting local steroid regeneration reduce cardiac remodelling and the development of heart failure after myocardial infarction?
Funder: Wellcome Trust

Abstract: Although more people now survive following a heart attack, the heart often sustains damage that increases the risk of developing debilitating loss of heart function in the longer term. It has been shown that in mice the prevention of steroid hormone formation within cells prevents the loss of heart function after heart attack by increasing blood supply to the damaged area during repair. In this project we will test the ability of a medicine that blocks steroid hormone regeneration to prevent loss of heart function in a more clinically relevant model of heart attack in the pig. Tissues from the pigs will also be analysed for indicators of increasing blood supply. Finally, we will be looking in more detail at what our drug does within the heart muscle using the new technique of mass spectrometery imaging.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Targeting oxidised low-density lipoprotein in atherosclerotic plaque with antibody-based constructs for imaging and therapeutics
Funder: Wellcome Trust

Abstract: Background Oxidised LDL (oxLDL) forms a significant component of fatty plaques, or atherosclerotic lesions, that accumulate in coronary artery disease and can cause heart attacks or strokes. We have recently developed an antibody to oxLDL, LO1,that can target atherosclerotic plaques. Approach I aim to harness LO1 and other antibody fragments for targeting of nanoparticles to atherosclerotic plaque. I will develop nanoparticles that are capable of carrying a drug, that will be released when it reaches its destination (i.e. the atherosclerotic plaque). I will produce varying designs with different drugs and targeting agents and aim to demonstrate effective delivery of the nanoparticles. I will test these nanoparticles in mouse models of atherosclerosis, as well as a newly developed original experimental model using an amputated human limb. I will then fill the nanoparticles with the drug and aim to demonstrate a beneficial effect. Expected Impact The novel nanoparticles targeted to atherosclerotic plaque will provide a means of local delivery of drugs directly to diseased areas. This will permit much smaller drug doses to be used, with therefore fewer unwanted side effects. In addition, the drugs can be tailored to an individual, utilising the most suitable drug to treat each patient’s atherosclerotic plaques.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR
Title: Mitochondrial Mechanisms And Therapeutics In Heart Transplantation
Funder: Wellcome Trust

Abstract: Heart transplantation is the best available and life-saving treatment for end-stage heart failure. Unfortunately, there are far more patients in need of a heart transplant than there are suitable donor hearts and many patients die every year due to this shortage. When a heart is donated for transplantation, it can spend several hours outside the body without any oxygen supply, before it is transplanted into the recipient patient. During this period, a molecule called succinate builds up in cells. When the oxygen supply is restored to the heart, succinate is rapidly broken down, leading to injury and ultimately death of heart cells. We will use mouse, pig and human hearts to explore the events that damage donor hearts. This will help confirm that what we have learned from animal experiments are relevant to humans. We have also developed drugs that prevent succinate from building up in heart cells, and may be able to reduce damage during transplantation. We will test whether these drugs are safe and effective in reducing succinate build up, reducing damage to heart cells and improving donor heart function after transplantation. This treatment could result in more donor hearts being available and ultimately save lives.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CARDIOVASCULAR
Title: Development of novel computational approaches for human cardiac mapping data - Improving understanding and treatment of atrial fibrillation
Funder: Wellcome Trust

Abstract: Cardiac arrhythmias are a common pathway for multiple cardiovascular diseases, the leading cause of death in the world. Ablation of cardiac arrhythmias is a recommended and common treatment option for arrhythmia patients, but success rates are poor. Cardiac electroanatomical mapping systems (EAMs) are used to identify ablation targets. EAMs generate a wealth of raw data that is ideal for developing algorithms to tailor treatments to an individual patients’ pathophysiology and improve treatment options. However, no platform exists for developing and testing algorithms. Specific groups have developed closed-source software to identify ablation targets however, these results have not been widely reproducible. There is an acute need for an open-source and cross-vendor EAM analysis software to facilitate sharing methods, increase rigor and transparency and increase access to advanced processing tools. I will develop expandable open-source software for analysis of EAM data. I will incorporate established and novel analysis methodologies, including machine learning approaches. Algorithms will be robustly validated using clinical, pre-clinical and in silico datasets. The software I will develop will enable myself and others to utilise routinely collected clinical data, to better treat cardiac arrhythmia. I will apply these approaches to identify mechanistic drives of atrial fibrillation as an exemplar application.

Lay abstract: Cardiac arrhythmias, diseases where the heart beats irregularly, present a huge healthcare burden. Atrial fibrillation (AF) for example is an arrhythmia that affects over 30 million people worldwide. In AF, the heart's two upper chambers contract randomly and quickly. People with AF are at higher risk of stroke, heart attack and sudden death, so live with huge anxiety. A common treatment is “ablation”. Here we stop part of the heart working. Alas, this fails approximately half the time, so AF recurs. We don’t know why this happens. Electrical maps of the heart during ablation may hold the answer. But we don’t have the tools to effectively explore these data. I aim to develop new software for this. My software will be state-of-the-art and freely available. This will help us improve AF treatment. That will make patient quality of life better and reduce stroke, heart attack and sudden death.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Tricuspid Heart Valve Implantation To Help Patients Suffering From Carcinoid Tricuspid Regurgitation
Funder: Barts Charity

Abstract: Carcinoid heart disease (CHD) is a form of cancer affecting the heart. Patients can have severe tricuspid regurgitation (TR), a leaky valve in the right side of the heart. Patients suffer many unpleasant symptoms with a substantial loss of quality of life. For many there are no further surgical or medical treatments available. A new technology, a custom-made valve implant, appears to be a low risk alternative to surgery, and may reduce the severe symptoms for patients. The system is made to measure, guided by a conventional CT, and can be implanted through the femoral vein in a 30 minutes procedure. The team plans to treat 15 patients with carcinoid heart disease and severe tricuspid regurgitation. Symptomatic, inoperable patients will be screened with a CT, and if technically suitable will undergo a valve implant at the Barts Heart Centre. Aim is to document acute hemodynamic effects and the impact on symptoms. This will be the first patient series worldwide, and results could impact the treatment of severe tricuspid regurgitation in large cohorts of patients


Research activity codes: 5.3 MEDICAL DEVICES;6.3 MEDICAL DEVICES
Health categories: CARDIOVASCULAR
Title: Determining Novel SMURF1 Signalling Pathways and Precision Medicine Strategies in Patients with Pulmonary Arterial Hypertension
Funder: Wellcome Trust

Abstract: Pulmonary arterial hypertension (PAH) is a rare, but devastating disease that leads to increased pulmonary vascular resistance, right heart failure and death. Despite clear clinical and biological differences between individual patients with PAH the treatment is uniform, based on an algorithm that matches the number of vasodilator drugs to functional class. I aim to establish SMURF1 inhibition as a novel anti-proliferative therapy and pathway for precision medicine for patients with PAH. I have demonstrated that SMAD-specific ubiquitin ligase regulatory factor-1 (SMURF1) is critical to pulmonary vascular remodelling and experimental PAH, and that SMURF1 mRNA expression is detectable and increased in peripheral blood from patients with PAH. In November 2015 my collaborators (Novartis) patented a series of SMURF1 inhibitors. Through this Fellowship I will use cutting edge RNA and protein profling techniques to determine mechanism though which SMURF1 mediates disease pathology and, using samples and clinical data from the worlds largest and best genotyped-phenotyped cohort of patients with PAH (the UK National Cohort), investigate means of identifying patients with cellular abnormalities related to SMURF1 who may benefit from a SMURF1 targeted therapy.

Lay abstract: Pulmonary arterial hypertension (PAH) is a devastating disease caused by abnormal growth of cells in the wall of arteries that supply the lungs. Altered cell function leads to narrowing of the arteries, increased lung blood pressure and right heart failure. Patients suffer shortness of breath and premature death. Treatment options are limited to drugs that relax muscle in the blood vessel wall. Despite differences in the underlying disease process, current treatment guidelines are identical for all patients, matching symptoms to the number of drugs. Not all patients respond and many experience side effects. Targeting the cell growth that drives disease is an attractive treatment concept and novel drugs are required. I have recently demonstrated that SMURF1 levels are increased in patients with PAH and that SMURF1 is critical to cell growth and disease. I will examine how SMURF1 functions in disease using cutting-edge biological techniques and new SMURF1 targeted drugs, and investigate means of identifying patients most likely to benefit by examining available clinical samples and data from the worlds largest cohort of patients with PAH (UK National Cohort).

Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR
Title: CRYOSAT 2 Trial of effects of early, high-dose cryoprecipitate
Funder: Barts Charity

Abstract: A pilot study conducted by Barts Centre for Trauma Sciences (C4TS), demonstrated that the shortening of timelines to transfusion of cryoprecipitate has the potential to halve mortality from severe bleeding following major trauma. To assess the impact of early, high dose cryoprecipitate the applicants are proposing a randomised controlled trial, using existing trauma research networks across Europe, North America and Australia.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR
Title: Computational Modelling to Improve the Assessment and Management of Patients With Coronary Artery Disease
Funder: Wellcome Trust

Abstract: Coronary revascularisation decisions should be supported by physiological assessment of blood flow restriction. However, coronary flow measurement is difficult, inaccurate and labour-intensive. Instead, a pressure-derived index, fractional flow reserve (FFR), is used as a surrogate for flow. FFR is based on a number of physiological assumptions and has limitations. I have invented, developed and patented a prototype computer model that measures coronary flow and is practical for clinical use. My method is advantageous because, uniquely, it measures absolute flow (ml/min), requires no additional hardware, drugs or interventional effort and automatically provides integrated flow and pressure data. This provides a more accurate and complete coronary assessment and resolves the limitations of FFR. Potential clinical benefits include improved ischaemia detection, characterisation of patient-specific haemodynamics and therefore improved treatment allocation. Additionally, my method enables the quantification of microvascular resistance and therefore the diagnosis of microvascular dysfunction (common, prognostically important, but frequently overlooked). In this fellowship, I will learn from and collaborate with the world’s best engineers, clinicians and computational fluid dynamics experts in academia and industry, to improve the method’s accuracy and applicability. I will validate the method’s accuracy and generate clinical data to support future clinical trials, clinical translation and patient benefit.

Lay abstract: Coronary artery disease, the world’s leading cause of death, is caused by narrowings in the arteries of the heart. Patients do best when their treatment is based upon how much these narrowings restrict blood flow. This is challenging to measure, and rarely done. This results in the wrong treatment in more than 25% of cases. I have invented a computational method that accurately measures coronary blood flow during routine assessment. It requires no additional equipment, risk or expense, and enables ‘small-vessel’ heart disease to be diagnosed; a common condition which is frequently missed altogether. Working with world-leading cardiologists, engineers, and software companies, I aim to bring this concept forward to benefit as many patients as possible. After mathematical development, laboratory and initial patient testing, I plan to make the method available across the world to help doctors make more accurate diagnoses and select the most appropriate treatment for their patients.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Use of 68Ga-DOTATATE PET to identify the “inflammatory phenotype” in cardiovascular disease: a clinical translational programme
Funder: Wellcome Trust

Abstract: Inflammation drives atherosclerotic plaque rupture underlying most coronary events. While vascular inflammation can be visualised using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET), as a glucose analogue this method lacks cell specificity and is unreliable for coronary imaging owing to myocardial signal overspill. My research has shown that 68Ga-DOTATATE, a somatostatin receptor-2 PET ligand, provides a more accurate readout of macrophage-related atherosclerotic inflammation than 18F-FDG, with superior ability to distinguish high-risk versus lower-risk coronary lesions. In three parallel studies, I will test the clinical utility of 68Ga-DOTATATE PET to: i) quantify treatment response to high-intensity lipid-lowering with statins and proprotein convertase subtilisin/kexin type 9 inhibitors in patients with stable cardiovascular disease and familial hypercholesterolaemia; ii) predict disease progression post-myocardial infarction by identifying individuals with “residual” on-treatment coronary arterial inflammation; and iii) diagnose large-vessel vasculitis and monitor treatment response. 68Ga-DOTATATE imaging will also be compared to established MRI, CT, and intravascular imaging markers of atherosclerotic disease severity; and validated in vasculitis using autoradiography, histology and gene expression analyses. Moreover, transcriptomic and epigenetic profiling of monocyte-derived macrophages will be performed to better understand mechanisms underlying residual inflammatory risk defined by 68Ga-DOTATATE. This research will accelerate translation of 68Ga-DOTATATE inflammation imaging to the clinic.

Lay abstract: Every 3 minutes, a person in the UK suffers a heart attack. While doctors are good at diagnosing these potentially life-threatening events once they have occurred, we are less able to predict which individuals with heart disease are most at risk of future sudden events. We know that high-levels of inflammation occur in dangerous cholesterol deposits within the arteries that trigger heart attacks and strokes. My PhD research identified a new way of detecting these hotspots of inflammation, by using a scan called DOTATATE PET. In this new research, I will test whether DOTATATE PET can reveal people at high risk of heart attacks, whether it can be used to monitor the anti-inflammatory effects of new cholesterol-lowering drugs, and if it can help to diagnose a rare, but serious inflammatory disease called vasculitis. Ultimately, this research will help us to learn how to better prevent heart attacks before they occur.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: novel non-invasive Haemodynamic Methods in Heart Failure with Preserved Ejection Fraction
Funder: Wellcome Trust

Abstract: Heart failure with preserved ejection fraction (HFpEF) is prevalent, increasing and has a poor prognosis. Left ventricular (LV) haemodynamic assessment is needed to diagnose and manage patients with HFpEF. The reference method for it is an invasive study and is rarely done due to costs and risks. Doppler-derived velocity is used as a surrogate for LV pressure. However, because it is based on a number of assumptions, Doppler remains unreliable for detecting increased LV end-diastolic pressure (LVEDP). I have validated a four-dimensional flow cardiovascular magnetic resonance (4D flow CMR) acquisition which addresses issues with Doppler. I have further developed an accurate quantification method, which uniquely, measures intra-ventricular blood flow in 4D. Other advantages are that it does not require any additional hardware and has demonstrated superior associated with LVEDP. In this Fellowship, I will develop 4D flow techniques for an accurate assessment of LVEDP and pressure-volume loop in HFpEF. In addition, I will learn from and collaborate with the world-renowned clinicians, software/hardware engineers and modelling experts in academia and industry, to improve the method’s accuracy and applicability. I will validate the method’s accuracy and generate clinical data to support future clinical trials, clinical translation and patient benefit.

Lay abstract: Heart failure with preserved ejection fraction (HFpEF) is common and becoming one of the leading causes of death in patients with heart disease. Current non-invasive tests are not accurate enough to detect or diagnose HFpEF. This results in delayed diagnosis and early death for thousands of patients. I have developed cutting-edge, fast four-dimensional flow (4D flow) magnetic resonance imaging (MRI) techniques which can reliably assess three-dimensional blood-flow inside the heart over-time (the fourth dimension). I have also invented 4D flow MRI methods that can better detect raised pressures inside the heart associated with HFpEF. It requires no additional equipment, risk or expense, and enables accurate diagnosis of HFpEF. Working with world-leading cardiologists, engineers, scientists and companies, my ambition for the Fellowship is to further develop 4D flow MRI methods that will help doctors better detect; diagnosis and provide early treatment to patients with HFpEF and hence save thousands of lives.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: STRatifying Antihypertensive Treatments In multi-morbid hypertensives For personalised management of Blood Pressure (STRATIFY-BP)
Funder: Wellcome Trust

Abstract: Polypharmacy (five or more prescribed medications) is common in older people and is associated with an increased risk of adverse drug reactions. Preventative medications, such as those used to manage blood pressure and cholesterol, are common in polypharmacy and often require large numbers of people to be treated to prevent a small number of cardiovascular disease events. This leaves many individuals on drugs of little benefit, some of whom may be susceptible to side effects such as falls, kidney problems and muscle pain. As patients get older, the risks and benefits of their treatments may change, but doctors and patients have little information to inform their understanding of when this might happen. This proposal will use electronic health records with prediction modelling, causal inference and systematic review methods to establish the strength of association between antihypertensive therapy and side effects and build calculators which predict the likelihood of adverse events. These will be used to develop decision tools which predict an individual’s likelihood of benefit and harm from taking therapy. This approach will be applied to other preventative treatment areas and the resulting tools will help patients and doctors to make better informed decisions about starting or continuing these drugs.

Lay abstract: People are living for longer, with more long-term physical & mental conditions which worsen their health. One example is high blood pressure, where people can take 3-4 drugs to prevent stroke. However, between 65-125 people have to be treated for at least a year to prevent a stroke in one person. This is because these drugs only reduce possibility of stroke, they do not remove it altogether. Some of these patients may be prone to side effects such as falls and kidney problems. This proposal aims to use information from the medical records from 100,000s of patients to establish the link between blood pressure lowering drugs and side effects and develop a calculator which predicts a person’s risk of suffering harm. This information will be used to create a support tool which will help patients and doctors make better informed decisions about starting or continuing drugs.

Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: CARDIOVASCULAR