NIHRDataInsights/HRCSData huggingface dataset:
Title: Automated retinal microvascular quantification as a predictor of cardiovascular disease risk in later life
Funder: Medical Research Council

Abstract: Overt changes in retinal vessels (particularly arterioles) have long been associated with disease. Growing evidence, including longitudinal evidence, suggests morphological changes in retinal vessels (including changes in tortuosity and width) are early physio-markers of cardio-metabolic risk and outcome (as well as other disease processes). Despite rapid advances in image capture and computational assessment of retinal vessels, considerable operator involvement limits investigation in large population studies. This project brings together a multidisciplinary group, with the shared aim of developing reliable, automated, efficient, freely available retinal image analysis (RIA) software, generating a rich quantitative characterization of the retinal vasculature in large volumes of fundus images. Previous work carried out by the investigators, including width and tortuosity measures, will ensure appropriate and novel use of the large-scale data generated from RIA from thousands of participants. An automated approach to retinal image analysis building on software already developed will be extensively validated against clinical assessment of vessel features, and applied to retinal images from large MRC funded prospective cohort studies in adulthood, including the European Prospective Investigation of Cancer (EPIC Norfolk - a richly phenotyped data source with 8623 participants), and UK Biobank (a prospective study of 500,000 middle aged adults, 70,000 with retinal images using the same image capture method as EPIC, i.e., a Topcon non-mydriatic fundus camera), allowing its performance in prediction of CVD events in middle aged and older age groups to be examined. Examination in the larger UK Biobank cohort will allow both cross-sectional and future prospective associations with CVD risk to be explored definitively (due to improved statistical power). Re-examination of the cohort (in 10,000 participants) will also allow analysis of repeated retinal imaging over time.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: MICA: Developing novel human antibodies targeting the OPG/TRAIL axis for the treatment of pulmonary arterial hypertension (PAH)
Funder: Medical Research Council

Abstract: Pulmonary Arterial Hypertension (PAH) describes a group of rapidly progressive conditions sharing a common haemodynamic diagnosis that results in right heart failure. The disease is driven by progressive pulmonary vascular remodelling that comprises a combination of sustained vasoconstriction and the obliteration of small pulmonary arteries through a process of cellular proliferation, intimal fibrosis and the formation of angio-proliferative (plexiform) lesions. Current treatments carry an annual cost per patient of between £5000-£300000, and target vasoconstriction via the prostacyclin, endothelin or nitric oxide pathways. These drugs do little to address the underlying proliferative vascular disease and there remains no curative pharmacological treatment for PAH. We have identified that increased expression of OPG and TRAIL are found within remodelled tissue from patients with PAH, and animal models. We have subsequently demonstrated that both are regulated by multiple pathways important in PAH pathogenesis (e.g. BMP/5-HT/Inflammation). Both OPG and TRAIL stimulate PA-SMC proliferation and migration in vitro suggesting an active role in disease. Studies in pre-clinical rodent models have demonstrated that both proteins are required for disease, and critically, that targeting OPG or TRAIL with antibodies reverses established disease in rodents. These studies are the first to demonstrate the critical importance of both OPG and TRAIL, and highlight their potential as therapeutic targets. New data demonstrates that bone marrow-derived OPG is predominant in driving disease, and that OPG stimulates TRAIL expression in PA-SMCs. We have previously reported that tissue TRAIL is critical to disease progression. Since OPG is upstream of TRAIL, the aim of this proposal is therefore to develop and screen novel therapeutic human anti-OPG antibodies for efficacy utilising both in vitro and in vivo disease models to identify a lead antibody for further translational studies.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR
Title: Cardiac arrhythmogenesis in the PGC-1alpha -/- murine system
Funder: Medical Research Council

Abstract: Sudden cardiac death is a major cause of death worldwide. The total number of deaths attributable to sudden cardiac death is second only to all cancer types combined. Arrhythmogenesis most frequently results from ischaemic conditions; however accumulating evidence implicates energetic dysfunction, particularly metabolic syndrome, diabetes and obesity as independent risk factors. I will link metabolic abnormality to cardiac arrhythmogenesis in the PGC1alpha-/- murine system. This system contains a gene deletion associated with disrupted mitochondrial bioenergetics, altered calcium homeostasis and cardiac failure in a background of diabetogenic changes. I will establish and quantify electrophysiological instabilities by testing for arrhythmic substrate with electrocardiographic and monophasic action potential recordings at the whole heart level. I will then identify the electrophysiological and cellular basis of the arrhythmic phenotype with a dissection of the causal relationship between arrhythmia triggering and perpetuating events, mechanistic studies of ion channel behaviour using patch clamp electrophysiological techniques and confocal microscopy to assess Ca2+ homeostasis in isolated cells. Having clarified arrhythmic mechanisms in this system, I will translate these findings to the development of two novel therapeutic agents undergoing clinical trials; the sarcoplasmic reticular Ca2+-ATPase (SERCA) activator, istaroxime and the late Na+ current blocker ranolazine. This will extend their use to the management of cardiac arrhythmia in metabolic conditions.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Defining the Functional Effects of Titin Gene Mutations on the Pathophysiology of Dilated Cardiomyopathy and their Clinical Significance
Funder: Medical Research Council

Abstract: Background: Dilated cardiomyopathy (DCM) is the second commonest cause of heart failure and the leading indication for heart transplantation in the UK. Collaborative work from our group has shown that 25% of familial cases of 'idiopathic' DCM have a mutation in the TTN gene that encodes titin, the largest sarcomeric protein, which has key roles in the contractile process. Aim: To define the functional effects of the TTN gene mutation on the pathophysiology of DCM and evaluate what clinical significance this mutation holds. Objectives 1.Produce detailed phenotypic characterisation of DCM patients with TTN mutations by cardiac MRI (CMR). Determine if clear genotype/phenotype correlation. 2.Integrate genetic and CMR markers to determine prognostic significance of presence/type of TTN mutation in DCM. 3.Identify CMR early myocardial tissue markers of disease in TTN gene-positive/phenotype-negative patients (G+/P-). Methodology 1.CMR: Scanning of DCM/TTN positive patients, including assessments for myocardial strain, interstitial fibrosis and late enhancement to look for replacement fibrosis. Assessment for microvascular ischaemia using Hybrid-EPI quantitative perfusion analysis in TTN G+/P- individuals 2.Genetics: Construction of DNA libraries. Comparison between patients with truncation and single amino acid missense non truncation mutations in the TTN gene. 3.Epidemiological Analysis of Outcomes: Prospective follow up (questionnaires, primary care & hospital records, Office of National Statistics' flag and track mortality). Statistical comparisons to determine if presence/type of TTN mutation is independently associated with outcome. Scientific and Medical Opportunities of the Study -Benefit for DCM patients, cardiomyopathy researchers, and pharmaceutical industry. -Improved clinical monitoring of DCM patients and guided genetic counselling of their family members. -Future development of novel therapeutic targets in G+/P- individuals.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Prediction of human cardiotoxic QT prolongation using in-vitro multiple ion channel data and mathematical models of cardiac myocytes
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Thousands of animals are used across the world for the assessment of cardiac toxicity each year. Animals are used at multiple stages of drug development, in every pharmaceutical company (Pollard et al., 2010). This is primarily for detection of risk of Torsade-de-Pointes (TdP) cardiac arrhythmia. A leading cause of withdrawal of drugs from the market, TdP risk is one of the main causes of attrition during compound development. There are two major reasons that large numbers of animals have traditionally been required. (1) There are a large number of potential drug interactions in the heart, which we could not hope to screen without a representation of all of the possible targets in the whole system (with an animal model); and (2) the heart's electrophysiology has been considered "too complicated" to predict a drug effect - even given the full list of drug targets and affinities, the whole physiological system must be well represented (again, with an animal model). Technological advances mean that neither of the points above should remain a stumbling block, and in this project we will reduce animal use by taking advantage of the following techniques: (1) We will work with AstraZeneca (AZ) and GlaxoSmithKline (GSK) to assess compounds for multiple cardiac-ion channel interactions, using high-throughput in-vitro screens, to address the first point; (2) mathematical models, quantifying the complex processes involved in generation of cardiac electrical activity, address the second. We will compare our predictions with the human trial results, statistically quantifying the level of predictive power that simulations have for human clinical trials. We will provide all of the generated data, simulation and analysis tools as open-source. There will therefore be no major obstacle to the widespread use of simulation, instead of animal models, for proarrhythmic screening, with additional benefits in terms of more accurate prediction of effects in human physiology.


Research activity codes: 5.1 PHARMACEUTICALS;5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: CARDIOVASCULAR
Title: An in vitro model to investigate the role of oestrogen and oestrogen metabolism in pulmonary vascular disease
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Pulmonary arterial hypertension (PAH) is more prevalent in women than in men yet the reasons for this are unknown. Evidence from animal models suggest that oestrogen and oestrogen metabolites may contribute to PAH. Oestrogen metabolites can be either anti-proliferative or pro-proliferative and so it is imperative to understand how oestrogen metabolism is affected in the disease setting. ELISA approaches are used currently to measure oestrogen and oestrogen metabolites in tissues and blood from animals. This approach is, however, is severely restricted and limited. We have carried out feasibility studies for the development of a unique cellular model for examining oestrogen metabolism in human pulmonary arterial cells (hPASMCs) utilising HPLC and LC-MS techniques. This both reduces and replaces animal experiments and also increase the sensitivity and breadth of the metabolomic profile we are able to measure. This approach also increases the translational potential of the study as we can study cells from patients with PAH. Using animals, we have already shown therapeutic effects anastrozole (inhibitor of oestrogen synthesis), an ERalpha (major oestrogen receptor)-antagonist, a CYP1B1 (major metabolising enzyme of oestrogen) antagonist and ovariectomy. We wish to adapt our new methodology to measure oestrogen metabolites in lung tissue already harvested from these experimental animals. We will then determine which changes in oestrogen metabolite accumulation relates to the therapeutic effect. We will also expand our metabolic profiling to examine the synthesis and metabolism of testosterone. Using pharmacological, cell and molecular biological techniques the student will also carry out functional studies on the hPASMCs to determine the proliferative and signalling responses to key metabolic pathways that are described by these studies. The study will identify important mediators of PAH and the effects of these will be examined in animal models in vivo


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Why do patient outcomes from acute coronary syndromes vary by hospital in England and Wales?
Funder: Department of Health (England)

Abstract: Objectives: To investigate the causes of hospital variation in outcomes from acute coronary syndromes in England and Wales and develop recommendations for improving patient care. Design:1) Cross sectional study using linked national observational and administrative data relating to over 500,000 acute coronary syndrome events in England and Wales. 2) Longitudinal study following up 600 patients with acute coronary syndromes for 1 year from discharge from 2 hospitals in England. Systems: Acute coronary syndrome data from the following databases: Myocardial Ischaemia National audit Project (MINAP), General Practice Research Database (GPRD), British Cardiovascular Intervention Society (BCIS), Hospital Episode Statistics (HES), and University Hospitals of Leicester Coronary Care Unit (UHL CCU). Techniques / approaches: Generalised Linear Models, Latent Variable Modelling, Generalised Additive Models, geographical mapping, funnel plots, survey of trajectories of care using the EQ-5D health research quality of life tool. Outcomes: Quantification of hospital attributable effects relating to early and late mortality, hospital readmission, reinfarction, length of hospital stay, and delays to treatment. Describing trajectories of quality of life recovery patterns (outcome) and using them as predictors of outcome. Develop a Leeds Index of Myocardial Infarction (LIMI) severity score and a near-point risk ACS model. Development of a dedicated website that permits access to secondary data in the form of funnel plots and tabluated summaries, offers caluctors for estimating the risk characteristics of ACS patients, hospital effects, and has links to publications.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;7.4 RESOURCES AND INFRASTRUCTURE (DISEASE MANAGEMENT)
Health categories: CARDIOVASCULAR
Title: Pre-operative risk stratification, outcomes, post-operative surveillance and patient reported outcomes for endovascular aortic aneurysm repair
Funder: Department of Health (England)

Abstract: Outcomes research evaluates the impact of health care on the health outcomes of patients and populations. This research includes the evaluation of economic impacts linked to health outcomes, such as cost effectiveness and cost utility. An emphasis is placed on disease-oriented evaluations of care delivered in general, real-world settings using real-world data, setting it apart from the environment of randomised trials. There are a wide range of outcomes to study including mortality, morbidity, functional status and health-related quality of life. Outcomes research is a multidisciplinary field that examines the use, quality, delivery, and financing of health care services to increase knowledge and understanding of the structure, processes, and effects of health services for individuals and populations. Through this it provides the data to help solve critical problems that are faced in everyday clinical practice. The information learned can have an immediate impact on patient care and system improvement. The studies contained in this application aim to address key issues surrounding the provision of a specific surgical procedure in a number of ways. First, the studies will improve the quality of information available to surgeons and patients prior to surgery, leading to safer surgery and driving up the quality of care received. The studies include benchmarking national outcomes data and deriving risk prediction tools. Second, the stratification of surveillance schedules after surgery will tailor surveillance towards individual patients and address the issue of cost effectivness whilst ensuring safety. Finally, the responsiveness of healthcare services to patient experience will be improved through the development of a disease-specific PROM.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: CARDIOVASCULAR
Title: Optimizing RV diastolic dysfunction to improve outcome for patients with cardiopulmonary disorders
Funder: Department of Health (England)

Abstract: During diastole, blood fills the heart to ensure normal function. When there is diastolic dysfunction the heart becomes stiffer and is unable to fill correctly. The function of the ventricle can be assessed by measuring the change in pressure and volume during the heart cycle. Previously studies have focused predominantly on the left ventricle. We propose to study the right ventricle, specifically following drug, or surgical intervention. By understanding how pressure and volume change in the ventricle, these studies will improve our understanding of the mechanism of right ventricular diastolic dysfunction and optimise future patient treatment.


Research activity codes: 6.4 SURGERY;5.4 SURGERY
Health categories: CARDIOVASCULAR
Title: The impact of transcatheter aortic valve implantation (TAVI) on the health and quality of life of frail older people
Funder: Department of Health (England)

Abstract: Background The prevalence of aortic stenosis (AS) due to advanced age is increasing as the population ages. Mortality is high if untreated. Surgical aortic valve replacement is gold standard treatment but many frail older people are too high-risk to undergo this. TAVI is a new minimally invasive therapy which allows aortic valve implantation without major surgery. No trials comparing surgery with TAVI have been reported as yet, although NICE have produced interventional procedural guidance for TAVI. Nevertheless, it is being implemented enthusiastically in many UK centres, and is likely to be adopted widely in the near future. Clinical outcomes are being recorded on a national database, but little is known about other outcomes of importance to the patients concerned and their carers. Aims i) To monitor the impact of TAVI on patients’ and carers’ health and quality of life at 1 and 3 months post procedure. ii) To identify patient-generated outcomes of importance to supplement routinely monitored outcomes such as mortality, change in cardiac symptoms, cognitive status (MMSE), and health status (SF-12 and EQ-5D). iii) To identify key items for a quality of life related outcome measure specifically for frail older people undergoing TAVI. This may be refined and used in subsequent trials. iv) To make a preliminary assessment of the suitability and acceptability of TAVI for frail older people. Plan of Investigation All patients aged 65+ years referred for TAVI in the Leeds Cardiac Centre (estimated n=60) over two years will be invited to participate. Participants will be assessed one or two days prior to TAVI, and the SF-12 and EQ-5D completed. Post TAVI the SF-12 and EQ-5D will be posted at 1 & 3 months. Semi-structured interviews will also be conducted to record patients’ & carers’ descriptions of the impact of TAVI on their everyday life at selected time points. The structure of the interview will be informed by a literature review. Participants will be given the opportunity to describe factors that influence their quality of life. Data will be subjected to framework analysis to identify key outcomes of importance for this group. Potential Impact This formal scrutiny of this new and potentially revolutionary therapy may be used to: i) Assess the acceptability and feasibility of TAVI for a sample of older people. ii) Add to our knowledge of its impact on older people and their carers, enabling potential patients and carers to be better informed about the likely outcomes of the procedure. iii) Inform outcome measurement for this group, allowing the inclusion of patient/carer generated items in subsequent trials. iv) Contribute to improved screening and selection of older people for TAVI. v) Inform the use of outcome measures for older people undergoing similar types of intervention. vi) Inform the development of TAVI services in other NHS trusts and more widely.?


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: CARDIOVASCULAR
Title: A socioeconimic analysis of the decline in coronary heart disease mortality in Scotland between 2000 and 2012, with policy projections to 2020
Funder: Chief Scientist Office (Scotland)

Abstract: Objectives: To quantify the decline in CHD mortality between 2000 and 2010 in Scotland within the context of socioeconomic inequalities. To apportion this decline to treatments and risk factor changes using a cell based model, the IMPACTsec model. To then compare the potential future impact of public health interventions on predicted inequalities in CHD mortality in 2020. Design: Scottish linked health and population data will be used to develop an IMPACTsec model for Scotland. Techniques/approaches: Datasets will be sourced relating to the Scottish population, mortality, patient numbers, treatment uptake, risk factor changes and consequent mortality. Health data stratified by gender, age group and Scottish Index of Multiple Deprivation (SIMD) quintiles will be extracted, analysed, validated and then utilised in the IMPACTsec model. Measurements/outcomes: The fall in CHD deaths between 2000 and 2010 will be apportioned to specific treatments and risk factor changes using the IMPACTsec model. These mortality outcomes will be examined according to gender, age and SIMD quintile. The model will then be used to a) generate projections to 2020, b) compare proposed policy interventions on future CHD mortality and c) assess effects on deprivation gradients. Other valuable outcomes from the Scottish IMPACTsec model will include a) estimation of the CHD burden to health services and community prescribing for CHD in Scotland, including quantification of any inequalities, b) quantification of the contribution of treatments and risk factor levels to the excess CHD mortality associated with the most deprived groups, and c) detailed comparisons with results from the English model.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: CARDIOVASCULAR
Title: Prognostic Importance of Microvascular Dysfunction in Asymptomatic Patients with Aortic Stenosis.
Funder: Department of Health (England)

Abstract: Objectives: to compare whether MRI scanning or exercise testing can better identify patients with a narrowed heart valve (aortic stenosis) who will benefit from surgery. Design: we will measure blood flow to the heart with MRI scanning and also exercise test 170 patients with aortic stenosis and follow them for up to 2.5years. Expected outcomes: MRI scanning will more accurately identify those patients who will need surgery during this period. Anticipated benefits: improved selection of patients with aortic stenosis who are likely to benefit from early surgery. This study will inform National and International Guidelines and is likely to reduce deaths and health outcomes in such patients.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR