NIHRDataInsights/HRCSData huggingface dataset:
Title: Identifying Novel Opportunties for Translational Research, Precision Medicine and Drug Repurposing in Cardiovascular Disease Using Pharmacoepidemiology, Genetic Epidemiology and Bioinformatics
Funder: Chief Scientist Office, Scotland

Abstract: Cardiovascular disease (CVD) remains the main cause of death in Scotland. Despite the development of a number of new treatments which have improved survival and quality of life, there are still a number of areas which we do not fully understand, including the link between CVD and other associated conditions such as diabetes. In particular, we do not understand why certain patients respond better to certain treatments than others. One of the reasons for this is that the traditional approach to developing new treatments is to identify potential treatment targets in the laboratory and then use these treatments over the whole population. This method does not however take into account individual patient differences, therefore a new novel approach is needed. The approach of identifying which patients will respond to certain treatments and tailoring management to them is known as personalise or “precision” medicine. This approach has the potential to further benefit patients by identifying new diagnostic tools and treatment targets, particularly for patients in whom current treatments are not optimal. The addition of genetic data has further potential novel uses. The aim of this Lectureship is to utilise the expertise that Dundee has in precision medicine, combining use of genetic data and electronic health records to identify novel treatments and markers of illness in CVD. Using this available data will also potentially allow doctors to use current treatments in a more targeted manner, and perhaps identify new uses for medications that are currently used for other conditions. Dundee has access to a number of genetic and patient record databases, and has an outstanding track record of genetic studies in other fields such as diabetes. In this Lectureship, I aim to utilise the experience available in Dundee to conduct this technique in cardiovascular research, which has huge potential.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Constructing life beyond cancer with comorbid disease: a qualitative multi-perspective study
Funder: Chief Scientist Office, Scotland

Abstract: Not enough is known about the experience of living with cancer at the same time as one or more chronic illness such as diabetes, heart disease or mental ill health, and the impact this has on individuals, their quality of life and how they interact with doctors and nurses and use health services. This study will speak to people to find out in their own words how it is to experience this; for the patient themselves, and the main relative or carer alongside them. I also plan to speak to health professionals working in primary care and the community to gain insight into their views and experiences of working with and caring for these patients and their families. The findings from this study will inform structured community-based interventions aiming to support people with complex multi-morbidities and improve their health and wellbeing


Research activity codes: 5.7 PHYSICAL
Health categories: CARDIOVASCULAR
Title: Cardiovascular risk prediction in people with Type 2 Diabetes
Funder: Chief Scientist Office, Scotland

Abstract: Patients with T2DM are at increased risk of heart attacks and strokes compared to people without T2DM. Guidelines recommend that doctors and nurses use risk scores to identify people who are at high risk of these health problems and to suggest the best treatment. It is not clear whether these risk scores work well in people with T2DM today because they were developed using information from people without T2DM or were developed some time ago when people had different patterns of clinical characteristics such as hypertension. This research will find out whether the existing risk scores perform well or whether thay can be improved. A new risk score will be developed and its performance will be compared with existing scores. The identification of the best risk scores will facilitate that people with T2DM receive the best treatment to lower their risk of heart attacks and stroke.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Myocardial ischaemia in heart failure with perserved ejection fraction
Funder: Chief Scientist Office, Scotland

Abstract: Heart failure with preserved ejection fraction (HF-PEF) accounts for up to half of patients with heart failure (HF), and is becoming more common year-on-year. The underlying causes are not well understood and no treatments have been shown to improve symptoms or the poor outcomes associated with HF-PEF. A lack of blood getting to the heart muscle, known as myocardial ischaemia, may cause, or contribute to, HF-PEF in some patients. Myocardial ischaemia is caused by narrowings of the large heart arteries, known as coronary artery disease (CAD), and/or abnormalities of the small heart arteries, known as coronary microvascular dysfunction (CMD). We will investigate 150 patients admitted to hospital with HF-PEF to assess the prevalence of CAD and CMD (how common they are) and their role in real world patients with HF-PEF. Special heart scans (cardiac magnetic resonance imaging), heart artery dye tests (coronary angiography) and measurement of blood flow in the heart arteries (pressure wire studies) will be performed. With this information we hope to identify patients who, in the future, might benefit from treatment which could improve symptoms and life expectancy in a condition with poor outcomes and no current effective treatment options.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Pain management and patient education for physical activity in intermittent claudiction (PrEPAID):feasibility randomised controlled trial
Funder: Chief Scientist Office, Scotland

Abstract: Peripheral Arterial disease is a common condition which causes narrowing of the arteries. The most common symptom that patients with PAD experience is Intermittent Claudication (IC), pain in the lower limb(s) on exertion, which is relieved by rest. IC reduces patients’ quality of life (QoL) by limiting their ability to walk and engage in daily activities. Regular exercise and physical activity (PA) are central to the management of PAD and help to improve walking distances and reduce the risks associated with PAD such as heart attack and stroke. However, exercise and PA in this population is often limited due to pain. We have shown that Transcutaneous Electrical Nerve Stimulation (TENS) can help to reduce pain and increase walking distance in patients with PAD. We have also shown that educating patients about their condition and helping them to set goals has the potential to increase PA, and quality of life. This study will examine the feasibility of designing a definitive trial that investigates whether TENS can improve the physical activity of patient with PAD when delivered alone and/or alongside a patient education programme.


Research activity codes: 6.3 MEDICAL DEVICES
Health categories: CARDIOVASCULAR
Title: Glycaemia and chronic disease: harnessing UK Biobank and eHealth linkage to quantify risks, explore mechanisms and determine treatment impacts
Funder: Diabetes UK

Abstract: The global burden of diabetes, and of people at high risk of diabetes (pre-diabetes) is increasing rapidly. Significant questions remain unanswered. As HbA1c replaces glucose testing for diabetes diagnosis, and as chronic disease, including heart failure, cognitive decline, and cancer replace microvascular disease as major causes of morbidity and mortality, what is the optimal HbA1c threshold at which to diagnose diabetes and intervene? Why are women and ethnic minorities with diabetes particularly susceptible to the cardiovascular consequences of diabetes, and does this susceptibility extend to other chronic conditions? How does medication influence chronic disease risk in association with hyperglycaemia? We will address these questions using UK Biobank data on 500 thousand participants recruited from general practice, aged 40-69 years between 2006-10, with measurement of HbA1c and other risk factors, and extensive record linkage to capture events. Our findings will help inform understanding of the optimal HbA1c at which intervention should be considered. We will determine disease consequences for high risk groups, and identify explanations, informing targeted intervention strategies. Finally our analysis of treatment impacts by glycaemic status will clarify the role of medication in the aetiology of chronic disease, and highlight questions for focussed trials to inform clinical practice.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: CARDIOVASCULAR
Title: Promoting healthy ageing by improving autonomic function through transcutaneous vagus nerve stimulation
Funder: Dunhill Medical Trust

Abstract: Ageing is characterised by a shift in autonomic balance towards increased sympathetic and decreased parasympathetic activity. This change is associated with impaired function of cardiovascular and gastrointestinal systems and an increased risk of depression and mortality. We can non-invasively reverse autonomic changes through an innovative approach of stimulating the auricular branch of the vagus nerve - transcutaneous vagus nerve stimulation (tVNS). In the general population tVNS applied acutely increases parasympathetic influence and reduces sympathetic nervous outflow. These beneficial effects are positively correlated with increasing age. Here we aim to establish the degree of influence of daily tVNS on people aged 60-90 years. We will measure effects on: cardiovascular function through heart rate variability and baroreceptor reflex sensitivity; gastric motility by electrogastrography; sympathetic nervous outflow via microneurography and changes in mood through a questionnaire and interview. We predict that tVNS will redress the shift in autonomic balance with ageing.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CARDIOVASCULAR
Title: SCTS data analysis project
Funder: Heart Research UK

Abstract: In 2009 Heart Research UK awarded the SCTS a grant of £150,000 to employ an analyst to undertake research from the National Adult Cardiac Database. This resulted in 10 publications in high impact journals. The database now contains 15 years of data. In this time there have been significant reductions in mortality and increases in age and complexity of operations. We believe that it is time to undertake another analysis to understand in more detail these changes in survival and patient demographics.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: CARDIOVASCULAR
Title: Developmental Clinical Studies - Gene Therapy For Vein Graft Failure
Funder: Medical Research Council

Abstract: Our clinical trial application is based on a gene therapy approach for prevention of vein graft failure. The long term failure of bypass grafting using autologous saphenous vein remains a major clinical burden on the NHS. Preventing neointima formation in the immediate time points post-grafting is likely to have a major impact on the frequency of long term graft failure. We have developed a gene therapy approach using a replication-defective adenovirus vector that overexpresses the therapeutic gene ?tissue inhibitor of metalloproteinases-3 (TIMP-3)? that significantly attenuates neointima formation in human saphenous vein ex vivo and pig vein grafts in vivo. We propose a phase I/II clinical trial to assess the safety and efficacy of this approach in patients undergoing elective coronary bypass graft surgery. This first-in-man ex vivo approach maximises target vascular gene transfer while minimising systemic vector dissemination post-grafting. Our trial is designed with key milestones with firm efficacy endpoints.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: CARDIOVASCULAR
Title: Selective S-nitrosation of mitochondrial complex I by MitoSNO as a new therapy for cardiac ischaemia-reperfusion injury
Funder: Medical Research Council

Abstract: Ischaemia-reperfusion (IR) injury underlies the tissue damage during heart attack, often leading to death of the patient or to long term heart damage and health problems in those who survive the initial heart attack. Ischaemia occurs when the blood supply to an organ is interrupted, for example by a blood clot and if the blood supply is restored the tissue can recover. However, reperfusion of the ischaemic organ with oxygenated blood leads to extensive tissue damage that worsens the long-term prognosis for the patient. This injury is initiated largely by the production of damaging free radicals from mitochondria during reperfusion that leads to cell death. We have developed a novel mitochondria-targeted drug called MitoSNO that prevents free radical production from mitochondrial complex I during IR injury. MitoSNO comprises a lipophilic cation that facilitates its rapid and extensive uptake into mitochondria within the heart immediately following its intravenous injection during reperfusion. Within mitochondria MitoSNO selectively transfers its nitric oxide moiety onto a particular cysteine on respiratory complex I, thereby preventing the mitochondrial free radical production that normally occurs during reperfusion. This modification is reversed after 5-10 min allowing the mitochondria to return to full activity. Rodent studies have shown that MitoSNO prevents cardiac IR injury in clinically relevant in vivo models, thereby greatly enhancing the long-term recovery of heart function. MitoSNO is unique as no current protective therapies can be applied to organs at reperfusion to inhibit mitochondrial free radical production. In this proposal MitoSNO will be taken through studies in a pig model in preparation for first-in-man Phase I/II studies. As similar IR injury is found in other situations, such as stroke and organ transplantation, MitoSNO may also prove useful for a range of other indications.


Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR
Title: Creating building blocks for better treatment & control of NCD in poor & vulnerable households in Malaysia & Philippines
Funder: Medical Research Council

Abstract: We want to provide the knowledge needed to overcome health system barriers to optimal management of hypertension in Malaysia and the Philippines. This is important because it is a major cause of disability and premature death yet is easily detected and treated. Moreover, such knowledge can inform policies to improve management of all chronic diseases. Yet although evidence on its clinical management is universal, to overcome the health systems barriers, especially those faced by the poor, we need local knowledge. This, in turn, requires local capacity in health systems research and knowledge transfer. This project brings together all these elements in a partnership between leading research institutions in Malaysia, the Philippines and the UK. We will use mixed methods to understand barriers to hypertension control faced by low-income households over 12-18 months. We will use innovative open-source mobile technology to capture participantgenerated content (video, audio, text, etc.) on their lived experience, coupled with assessment of formal and informal providers. The project will generate analytical and methodological insights of relevance to Malaysia and the Philippines, and the global community, specifically low and middle income countries seeking to implement patient-centred and pro-poor responses to the growing burden of noncommunicable disease.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: CARDIOVASCULAR
Title: Molecular Cardiology
Funder: Medical Research Council

Abstract: "In the UK, approximately 150,000 people a year suffer from a myocardial infarction (MI), for which left ventricular hypertrophy is a major risk factor. The molecular mechanisms controlling the interplay between heart growth, infarct size and post-MI heart failure are poorly understood and are a major focus of the group. ||To address the mechanisms controlling heart growth, we have applied integrated genetic, genomic and functional studies in the rat and mouse and translated our findings to human populations. Our work has identified the genetic control points for thousands of genes in the rodent heart, which were used to identify an extra-cellular matrix protein, Ogn, as a primary determinant of left ventricular mass in mice, rats and humans. Identification of genes, such as Ogn, may lead to new treatments for human heart disease.||In other studies we have used cardiac magnetic resonance imaging guided human heart biopsies to determine the activity of key protein kinases in the hearts of patients with post-MI heart failure. These kinase studies have revealed unappreciated perturbations of the insulin signalling module in heart and skeletal muscle, which have implications for the treatment of diabetes and heart failure.||Overall, our data demonstrate the power of cutting-edge imaging, genomic and molecular approaches in rodents and humans, which can be used to identify robust candidates for disease pathogenesis with a view to developing new molecular insights and treatments for human heart disease."


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Clinical Lectureship in Cardiology
Funder: Medical Research Council

Abstract: Background and Aims The genetic and environmental factors that define cardiovascular structure and function, particularly at the intersection between health and the earliest stages of disease, remain poorly characterised. Conventional cardiovascular imaging provides limited, semi-quantitative and global metrics of the heart leading to underpowered imaging-genetics studies. We have demonstrated that three-dimensional (3D) cardiac magnetic resonance (CMR) imaging with computational quantitative phenotyping provides methodological, statistical and scaling advantages for epidemiological and genetic studies of the heart. The aim of my research is to use state-of-the-art cardiovascular imaging and computational techniques to identify the common and rare genetic variants associated with cardiac hypertrophy and dysfunction in humans. Our research found that truncating variants in titin (TTNtv) are present in 15-20% of dilated cardiomyopathy cases and, surprisingly, in ~1% of the general population. Methods Volunteers without self-reported cardiovascular disease are being recruited prospectively via advertisement to the UK Digital Heart Project (https://digital-heart.org/). We excluded participants who had known cardiovascular or metabolic disease and standard safety contraindications to MR imaging were followed. This study was approved by a research ethics committee and all participants gave written informed consent. So far 1950 volunteers (55% females; 70% Caucasian; mean age 41 years, SD 13) have had CMR imaging performed on a 1.5T Philips Achieva system (Best, Netherlands). In addition to conventional cine balanced steady-state free precession (b-SSFP) imaging, a high-spatial resolution 3D b-SSFP cine sequence was used that captures the whole-heart phenotype in a single breath-hold (reconstructed voxel size 1.2 × 1.2 × 2 mm). A cardiac atlas-based software was developed to quantitatively analyse 2D and 3D phenotypes (eg, wall thickness and function) at over 46 000 points across the heart. Ambulatory 24 hour blood pressure (BP) / pulse wave velocity (PWV) monitoring was used to supplement standard BP and ECG measurements. Detailed social and family histories were collected and anthropometric variables measured. Blood samples were taken for genotyping, whole-exome sequencing and serum biochemistry. Associations between phenotypes, clinical variables and genotypes were studied with 3D regression models and Bayesian latent factor analysis. Research plans We are using high-resolution quantitative phenotyping combined with computational modelling and advanced statistical analysis to identify the genes and biological pathways that determine cardiovascular morphological and physiological features. Following on from encouraging preliminary data we will carry out a 3D genome-wide association study. In addition we will carry out a study to clarify the penetrance and pathogenicity of TTNtv in humans.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Methods for joint modelling of multiple longitudinal and survival outcomes
Funder: Medical Research Council

Abstract: In many clinical applications we are interested in statistically modelling more than one outcome. These might be multiple longitudinal outcomes, such as the risk factors blood pressure, total cholesterol and high-density lipoprotein cholesterol for cardiovascular disease (CVD), or they may include a time-to-event, such as the first CVD event. The aim of this research programme is to develop and explore statistical methodology for the analysis of multiple outcomes. One area of focus will be dynamic risk prediction, where an individual’s prediction for the risk of an event occurring is updated in response to new measurements made of time-varying risk predictors. Methods for modelling repeated measurements of multiple risk predictors and a time-to-event outcome include joint modelling, where all outcomes are modelled simultaneously, and landmarking, where past repeated measurements are modelled separately from future times-to-events in a two-stage approach. A clinical application which motivates this work is cardiovascular risk prediction. We are using data from electronic health records to develop a risk prediction tool for cardiovascular disease and to provide recommendations for the optimal scheduling of cardiovascular risk assessments. By projecting the risk of cardiovascular disease into the future we will aim to determine whether a person will likely be at high risk of cardiovascular disease in the future, and thereby to obtain a personalised recommendation for the time to schedule the next risk assessment. Using data from electronic health records for clinical research can be challenging because this data has not been collected for research purposes. We will explore the impact of informative observation of risk factor measurements because these measurements may have been taken in response to the state of health of the individual. There will also be computational challenges in the application of complex statistical methods to such big data. Additional questions we will explore in this context include the improvement in predictive accuracy that could be achieved by including other aspects of the risk factor trajectory in a prediction model, such as the slope of the longitudinal trajectory, or the variability in the repeated measurements, and the use of decision theory in obtaining the personalised recommendations. This work will have important implications in the management of the risk of cardiovascular disease. Another application which motivates this programme of research is to understand the relationship between lung function and survival in cystic fibrosis. We are using joint modelling to assess whether the effect of sex on survival in cystic fibrosis patients is mediated by lung function, and will further explore the role of body mass index.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR