NIHRDataInsights/HRCSData huggingface dataset:
Title: Low dose interleukin (IL)-2 in patients with a recent acute coronary syndrome
Funder: Medical Research Council

Abstract: Need: Coronary artery disease (CAD), caused by atherosclerosis, carries a substantial risk of morbidity/mortality due to atherosclerotic plaque disruption, which leads to severe ischemic cardiac events, called acute coronary syndromes (ACS). The latter define a spectrum of clinical manifestations, including unstable angina, non-ST-segment elevation myocardial infarction (NSTEMI) and ST-segment elevation myocardial infarction (STEMI). The occurrence of ACS (which may represent the first manifestation of CAD) further enhances the risk of recurrence and death. Although rates of in-hospital complications have dropped significantly, late consequences of ACS are largely underestimated and unrecognised with 5-year rates of death in the range of 20% despite the best of current therapeutic management [Fox KA, Eur Heart J 2010]. Out-of-hospital adverse events result from deleterious post-ischemic cardiac remodeling and progression of CAD, the determinants of which are instigated during the first months following the index event. Rationale: Immune dys-regulation, and more particularly defective regulatory T lymphocytes (Tregs), plays a central role in the pathophysiology of atherosclerosis and post-ischemic injury (see section 5 below). Unfortunately however, Tregs escape targeting by all of the current or tested therapies in CAD patients. Interleukin (IL)2 is essential for the development, survival, and function of Tregs. Interestingly, recombinant IL2 is available for drug re-purposing, and low dose (ld)-IL2 therapy preferentially induces Treg expansion in humans. Solution: Enhance Tregs through supplementation with ld-IL2 to suppress cardiovascular (CV) inflammation, with the aim to ultimately promote tissue repair and limit adverse CV events. Main question addressed here (which will form a go/no-go milestone for potential phase III clinical outcome trials): Does ld-IL2 safely enhance Treg levels and reduce vascular inflammation in patients with a recent ACS?


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR
Title: GLUCOCORTICOID RECEPTOR IN THE EARLY LIFE PROGRAMMING OF CARDIAC RESILIANCE
Funder: Medical Research Council

Abstract: Glucocorticoids are essential to mature fetal organs and tissues in preparation for life after birth, the reason they are used clinically in pregnant women at risk of preterm delivery. Conversely, excessive prenatal exposure to glucocorticoid increases risk of cardio-metabolic disease in adulthood. We have used glucocorticoid receptor (GR) knockout mouse models to show a previously unappreciated and essential role for GR to functionally, structurally and biochemically mature the fetal heart. Experiments in primary fetal mouse cardiomyocytes suggest that this occurs through remodelling of mitochondria. Mitochondrial mechanisms underlie the perinatal switch in cardiomyocytes from hyperplastic growth to cell cycle exit, binucleation and hypertrophic growth. Pilot data in our 'SMGRKO' mice that lack GR selectively in cardiomyocytes and vascular smooth muscle point to a delay in this switch, resulting in greater cardiomyocyte endowment in adulthood. This suggests that glucocorticoid induced maturation of the fetal heart is coupled to, and at the expense of, cardiomyocyte endowment in adulthood. To test our hypothesis, we will (i) establish if mitochondrial mechanisms underlie all aspects of glucocorticoid-induced maturation of cardiomyocytes, supporting a coupled mechanism behind glucocorticoid effects on cardiomyocyte maturation and growth; (ii) investigate whether prenatal administration of dexamethasone (used clinically) reduces cardiomyocyte proliferation and promotes cell cycle exit and binucleation in vivo and (iii) restrict GR expression in cardiomyocytes to the fetal period to test whether this promotes both cardiomyocyte maturation and exit from the cell cycle, confirming GR dependent mechanisms. If similar mechanisms operate in human fetal development, then appropriate understanding will highlight areas for improvements in therapy, for example to avoid overtreatment of babies and to limit adverse effects, whilst optimising the benefits of treatment.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Deep phenotyping to improve understanding of causal mechanisms and underlying gene mutations in primary lymphoedema and lymphatic malformations
Funder: Medical Research Council

Abstract: Lymphoedema is a chronic debilitating condition characterized by disabling swelling and life threatening infections. Primary lymphoedema often results from a genetic fault whereas secondary lymphoedema develops from an identifiable cause. There is no evidence that drug or surgical therapy is effective and treatment is largely palliative. Improved treatment will only come through better understanding of disease pathophysiology. The finding of causal genes has allowed specific diagnoses to be made. Further study of these genes in animals has informed on their roles in lymphatic development and function. Our group has discovered 8 of the 12 known causal genes for human lymphoedema through gathering cohorts of patients with similar physical characteristics (phenotypes). To understand the mechanisms causing the lymphoedema more informative methods of investigation are needed. We plan 4 lines of enquiry in genotyped human lymphoedema: (1) better imaging to investigate the main collecting vessels within a limb. We have developed MR lymphangiography in breast cancer related lymphoedema and have recently applied ICG Lymphography to study lymphatic vessel pumping. (2) the use of 3D ultramicroscopy of skin biopsies. With our project partners in Germany we have already demonstrated how visualization of the entire vascular network of the samples at the cellular resolution level permits a far more detailed description of initial lymphatic network morphology compared to traditional 2D sections. (3) to investigate the immune dysfunction in genotyped lymphoedema using FACS analysis and proliferation studies using isotope labelling of T cells, as well as primary and secondary immune response rates in vivo. (4) functional studies of causative genes and their mutations in mosaic forms of primary lymphoedema and lymphatic malformations to inform on causal genes and disease mechanisms.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: CARDIOVASCULAR
Title: Population-based salt intake survey to support the national salt reduction programme for Malaysia
Funder: Medical Research Council

Abstract: We will carry out a cross-sectional study in 1100 adults aged over 18 years. The participants will be randomly selected by a multi-stage stratified cluster sampling of Living Quarters (LQs) throughout Malaysia. The data collection will include (1) Complete a general questionnaire on basic demographics, disease history and medication use. (2) Complete a questionnaire which assesses knowledge, attitude and practice about salt. (3) Complete the food frequency questionnaire (FFQ). Trained dietitian or nutritionist will interview the participants using a pre-tested and validated FFQ including 94 food items. (4) Do a brief physical examination including blood pressure, body weight, height, waist and hip circumference using a standardised protocol. (5) Complete one 24h urine collection which is the gold standard method in determining the level of dietary salt intake. All participants will be given both oral and printed instructions on how to accurately collect 24-h urine. We will measure urine volume, sodium, potassium and creatinine. Ion-selective electrode method will be used for sodium and potassium analysis and Jaffe method for creatinine. Twenty-four hour urinary creatinine together with urine volume will be used to determine if the collection is likely to be complete. The primary outcome of the study is salt intake as measured by 24-hour urinary sodium excretion. The secondary outcomes are the main sources of salt in the diet, knowledge levels, attitude and current practices relating to salt.


Research activity codes: 4.4 POPULATION SCREENING;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: CARDIOVASCULAR
Title: Genetic, lipid and other risk factors in early-onset acute myocardial infarction in Malaysia.
Funder: Medical Research Council

Abstract: Coronary heart disease (CHD), with myocardial infarction (MI) as the main manifestation, is the single leading cause of death worldwide1 and is the leading cause of death in Malaysia.9,10 It is estimated that in Malaysia and other South-East Asian countries, nearly a quarter of CHD events occur in people younger than 50, resulting in a significant loss of productive working years due to death and disability. This background provides the rationale for the current Malaysia-UK funding call for research into "cardiovascular disease, especially young myocardial infarctions". We propose to establish the first large-scale CHD bioresource in Malaysia, ie, a case-control study that, in the first instance, will comprise 5000 participants (2500 MI patients aged <50 years). The overarching goal is to advance understanding of risk factors for CHD in Malaysia both to enrich mechanistic understanding and to inform public health action. We will initially focus on genomic and lipid-related risk factors, harnessing Malaysia's population's distinctive features of multi-ethnicity and consanguinity. The key objective of this study is to establish the first large-scale CHD bioresource in Malaysia to enable: (1) assumption-free discovery science that leverages Malaysia's unique history of multi-ethnicity and consanguinity through genomic studies of MI and cardiometabolic traits, with potential implications of results for downstream studies to elucidate the mechanistic basis of CHD and inform therapeutic target identification and prioritisation; (2) detailed evaluation of candidate cardiovascular risk factors of specific relevance to the Malaysian population, such as indigenous forms of tobacco consumption and local dietary patterns, with potential implications of results for public health policy; and (3)enduring collaboration between Malaysian and UK scientists, who will jointly manage and harvest the dataset and bioresource of this distinctive and important research platform.


Research activity codes: 4.4 POPULATION SCREENING;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: CARDIOVASCULAR
Title: Understanding the role of fatty acids in the aetiology of cardiovascular disease using novel causal inference methods
Funder: Medical Research Council

Abstract: Aim: To assess whether fatty acids are involved in the aetiology of cardiovascular disease (CVD) and to identify potential underlying mechanisms. Objectives: 1) To examine whether circulating fatty acids are causally related to CVD risk 2) To explore potential underlying mechanisms by which circulating fatty acids could be linked to CVD 3) To synthesize the literature on the relation between dietary fatty acids and CVD and extensively explore the presence and potential explanations of biases Methodology: I will use data on genetic variants, fatty acids, other metabolites, and CVD (coronary artery disease and stroke) from UK Biobank and four study consortia (UCLEB, METASTROKE, CARDIoGRAMplusC4D, Metabolomics GWAS). The exposures of interest are fatty acids (saturated, monounsaturated, omega-3 and omega-6 fatty acids). To assess the potential causal effect of circulating fatty acids on CVD risk (Objective 1), genetic variants strongly associated with circulating free fatty acids will be used as instrumental variables in a Mendelian randomisation framework (n = 540,00-750,000 individuals). Causal mediation analysis will be used to better understand pathways by which fatty acids might be linked to CVD through a broad interrogation of various lipoproteins, lipids, and low molecular weight molecules that collectively constitute the metabolome (high throughput metabolomics profiling) (Objective 2). The literature on the association between dietary fatty acids and CVD will be appraised using novel techniques in meta-analytical research (overview of reviews and triangulation) aimed at providing an overview of the evidence and exploring the presence and reasons for potential biases (Objective 3). Scientific and medical opportunities: My findings will provide important causal evidence regarding health effects of fatty acids that can be used to inform research, clinical practice and make appropriate public health policy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Development of a fluorine-18 radiopharmaceutical to enhance and establish adrenal imaging by positron emission tomography
Funder: Medical Research Council

Abstract: .At least one quarter of the adult UK population has hypertension, a major risk factor for heart attacks and stroke. Primary hyperaldosteronism (PHA), a treatable form of hypertension, accounts for 5-10% of all cases, and 20-25% of those with difficult to control ('resistant') hypertension. Determining whether one (potentially curable with surgery) or both (requiring long-term drug treatment) adrenal glands are the source of PHA in any given patient remains challenging. Existing lateralising procedures include computed tomography or magnetic resonance imaging, which often lack appropriate sensitivity, while the highly invasive adrenal vein sampling (AVS) is time-consuming, technically demanding, and fails in 20-50% of cases. Therefore, there is an urgent need for an accurate and more widely available method for reliably diagnosing the cause of PHA. To address this need our solution is to use positron emission tomography (PET) coupled with the radiopharmaceutical [11C]metomidate for molecular adrenal imaging. We have previously shown PET can be a sensitive and specific alternative to AVS for the management of PHA. However, [11C]metomidate is labelled with the short-lived radioisotope carbon-11 (t1/2 =20 min), which limits this technique to the few PET centres in the UK with on-site radiopharmacies with cyclotrons for its manufacture. Therefore, our objective is to overcome this barrier to wider expansion of this technique by developing a radiopharmaceutical labelled with the longer-lived radioisotope fluorine-18 (t1/2 =110 min), which can be supplied to external centres. To achieve this, our objective is to develop [18F]CETO, a fluorine-18 analogue of metomidate, through a structured workplan with go-no go milestones, consisting of preclinical characterisation followed by PET imaging in patients. Subsequent roll out of this radiopharmaceutical would facilitate the creation of a national NHS network for molecular imaging in PHA.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Furthering our understanding of the redox regulation of Protein Kinase A in the cardiovascular system
Funder: Medical Research Council

Abstract: We originally discovered that Type I PKA protein, which is crucially important in cardiovascular function, is susceptible to oxidation. This kinase, which is expressed widely in the cardiovascular system, forms a homo interprotein disulfide within the kinases regulatory RIalpha subunits during oxidant stress. Our primary objective is to increase the understanding of the redox regulation of this isoform of PKA in the heart and in blood vessels. We want to do this because dysregulated PKA is broadly implicated in the pathogenesis of cardiovascular disease, times when the kinase may encounter elevated oxidative stress which promotes its oxidation. We have developed methods allowing us to routinely monitor PKA oxidation and will use biochemical methods and physiological measurement of cardiac function to monitor the changes in the heart or in blood vessel resulting from oxidation of this kinase. We have developed a transgenic knock in murine model in which the redox sensor cysteine thiols in this specific kinase are replaced to make the PKA RIalpha 'redox inactive'. By comparing the responses of these C17S PKA RIalpha knock in mice to wild type controls, we will be able to more clearly define the role of PKA oxidation in the development of cardiovascular disease - aiding our long term aim of trying to combat this prevalent and escalating, global healthcare burden.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CARDIOVASCULAR
Title: Aircraft Noise and Cardiovascular Outcomes (ANCO)
Funder: Medical Research Council

Abstract: We will use data from SAHSU national postcode and address-level hospitalisation and mortality data, the SABRE cohort (in west London, followed up twice since 1988) and UK Biobank cohort (~120,000 living in conurbations with major airports; repeated measures on 20,000 with potential noise exposure from Manchester airport). We will generate annual aircraft noise exposure estimates for 2006-15 for average (LAeq,16hr, Lnight, Lden), maximum (LAmax) and N70 metrics, and also estimates for Heathrow back to the 1980s at place of residence, using information from the Civil Aviation Authority. An integrated programme of analyses will be conducted to investigate if exposures are associated with CVD morbidity/mortality and intermediate outcomes related to physiological responses to noise. These will include heart rate variability as a measure of autonomic nervous system activation (SABRE), BP and sleep disturbance (both SABRE and UK Biobank), possible intermediate routes by which noise may affect CVD. In addition in SABRE and UK Biobank we will undertake exploratory hypothesis-generating analyses concerning possible metabolic impacts of aircraft noise stress based on limited previous investigations. We will account for potential confounding by road noise and air pollution applied to small areas near airports and to recent cohort follow-ups using estimates already integrated into UK Biobank and SABRE cohorts by the applicants. Road traffic estimates come from the CNOSSOS-EU road noise model developed at Imperial and air pollution exposures from the EU European Study of Cohorts and Air Pollution Effects (ESCAPE) project. We will also perform a novel investigation of associations between aircraft noise and ultrafine particles (UFP) from jet engines using mobile monitoring near Gatwick and Heathrow airports and develop models to predict UFP from NO2 and other variables. Sensitivity analyses will examine alternatives to metrics using noise averages and potential confounding by UFPs.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: CARDIOVASCULAR
Title: A North-South Partnership in Congenital Heart Disease (CHD)
Funder: Medical Research Council

Abstract: Building on the existing clinical cardiovascular research expertise in Cape Town, we will create a comprehensive registry and database of both adult and child CHD patients, with capacity for the integration of genotypic data, and develop the infrastructure necessary for prospective follow-up. We will carry out detailed clinical and echocardiographic characterisation of all participants at enrolment. We will biobank samples from probands (and their parents where available) for DNA extraction and downstream 'omics analyses. We will obtain cardiac tissue from study participants who undergo a cardiac surgical procedure during the period of the study. We will aim to enrol at least 1200 patients. We will conduct focused candidate gene studies using next-generation sequencing panels to explore the contribution of rare variants in genes previously implicated in CHD risk in Europeans, in an African population. We will undertake patient specific studies to investigate the potential for computational fluid dynamics (CFD) modelling to contribute to personalised medicine in two CHD conditions: repaired tetralogy of Fallot (TOF) and coarctation of the aorta (CoA). Structural and flow data will be extracted from CT, echocardiography and serial cardiac MR scanning. We will identify the baseline haemodynamic features in each patient using standard flow derived metrics and map this to a detailed morphological characterisation of the geometry. The genetic and CFD study results will establish the feasibility of our approach and provide justification for a more substantial, and possibly pan-African, follow-on award. Establishment of the resource will provide a foundation for African researchers to address pressing questions regarding the lifecourse epidemiology and optimal treatment of CHD in an African context in future applications.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CARDIOVASCULAR
Title: Defining the biology of human cardiac stem/progenitor cells for their use as an allogeneic cell therapeutic agent for myocardial repair & regeneration
Funder: Medical Research Council

Abstract: The adult myocardium, including human, harbours multi-potent cardiac stem cells (CSCs), which give rise to new cardiomyocytes and vasculature. We can efficiently isolate CSCs from human, pig, mouse and rat hearts and clonally-derive and expand at least 1 x 1011 from a single CSC. When administered systemically, clonal CSCs have a natural homing capacity to the damaged heart. Moreover, CSCs secrete a repertoire of pro-survival and regenerative growth factors, which mediates a 'paracrine' effect on the recipient's myocardium including activating the endogenous, resident CSCs. The proposed allogeneic CSC therapy is conceptually and practically different from any presently in clinical use. The approach is a modulated form of growth factor therapy, where the cells naturally home to the damaged myocardium, deliver a complex mixture of growth factors, which elicit a 'paracrine' effect and activate the endogenous target regenerative cells within a short time frame of 1-2 days. In this project, we will assess the phenotypic and genomic stability of human CSCs (hCSCs) over long term culture. We will validate the homing capacity of hCSCs in the clinically-applicable MI injury model and track the hCSCs utilising dual-mode radionuclide-fluorescence reporter gene whole-body multi-modal imaging (e.g. by SPECT/PET-CT-fluorescence imaging) in vivo. We will employ Laser Capture Microdissection to extract the transplanted hCSCs from the heart tissue and measure the expression of regenerative growth factors expressed by the hCSCs once they have homed to the damaged heart. This project will advance the development of an allogeneic, homogeneous cell product which is affordable, readily and widely available and compatible with the current clinical standard of care.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES;6.2 CELLULAR AND GENE THERAPIES
Health categories: CARDIOVASCULAR