NIHRDataInsights/HRCSData huggingface dataset:
Title: Functional trajectories and cardiovascular ageing
Funder: Medical Research Council

Abstract: Understanding pathways to cardiovascular (CV) ageing are important because, although deaths from heart and circulatory disease are falling, they remain the main cause of premature mortality in the UK. The overall aim of this programme is to identify possible novel intervention strategies and screening opportunities at all stages of the life course which would promote good CV function for as long as possible, and thus prevent or delay the onset of disease, extend the healthy lifespan and improve wellbeing and quality of life. In order to do this we have collected a comprehensive set of measures of cardiac and vascular structure and function as well as repeat measures of CV risk factors in the MRC National Survey of Health and Development, a cohort study of men and women followed since their birth in March 1946. We have previously shown how factors acting during gestation, childhood, adolescence and adult life affect body mass index (BMI) and blood pressure (BP) trajectories and other CV risk factors in the NSHD and across cohorts. With the new NSHD data, our objectives are: to identify life course predictors of BMI, BP and resting heart rate (RHR) lifetime trajectories; to identify the life course risk and protective factors associated with the vascular and cardiac phenotypes at 60-64 years and to understand their cumulative and interactive effects; and to investigate the biological pathways and mechanisms underlying CV ageing and its relationship with ageing of other body systems. In the longer term, the objectives are to assess the predictive power of the cardiac and vascular phenotypes on CV function decline and progression to disease, and the impact of CV ageing on quality of life and wellbeing. This programme will provide key evidence to inform clinical guidelines for the prevention of CVD for the early identification and more targeted management of individuals at risk, and aims to improve CVD risk prediction by incorporating longitudinal trajectories of risk factors and novel biomarkers. This programme addresses the MRC strategic research priority for 2009-14 to improve the chances of living a long and healthy life by taking a life course approach to the investigation of CV ageing.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Development and evaluation of a yoga-based cardiac rehabilitation programme (Yoga-CaRe) for secondary prevention of myocardial infarction
Funder: Medical Research Council

Abstract: Cardiac rehabilitation (CR) programmes aim to restore functioning and reduce the risk of adverse vascular outcomes in cardiac patients by improving their physical fitness, reducing stress, and bringing about lifestyle change. CR programmes have been shown to be highly effective, but they are virtually non-existent in developing countries such as India, because the large, multidisciplinary teams required for CR programmes are considered unaffordable. Yoga practice leads to similar outcomes as a CR programme (improved physical fitness, stress reduction and lifestyle change), but entails considerably fewer resources (single yoga teacher). In the UK, yoga may appeal to certain disadvantaged groups (e.g. ethnic minorities, women and the elderly) that currently have low CR uptake. We will summarise existing knowledge on yoga's cardiovascular health effects from scientific literature and yogic texts, and apply that knowledge to a model of CR to develop a yoga-based CR programme (Yoga-CaRe). Then, we will evaluate the effectiveness and cost-effectiveness of Yoga-CaRe in a large clinical trial in India, randomising 4,000 patients with acute myocardial infarction (AMI) to receive Yoga-CARE or enhanced standard care, and follow them for quality of life and cardiac morbidity and mortality over one year. In the UK we will perform a mechanistic study which will provide complementary information to the clinical trial in India; 80 patients with AMI will be randomised to receive yoga classes in addition to CR (routinely offered in the UK), and assessed for the acute (after first yoga class) and chronic (after 3 months) effects of yoga on neuro-endocrine pathways, cardiovascular risk factors and sub-clinical outcomes. Providing a sound scientific mechanism for observed clinical effects is vital for traditional therapies to gain wider acceptance. The expected outcomes of this research include a scalable intervention and greater collaboration between India and UK researchers.


Research activity codes: 5.7 PHYSICAL
Health categories: CARDIOVASCULAR
Title: Mechanisms underlying the development of pulmonary arterial hypertension
Funder: Medical Research Council

Abstract: This study seeks to determine novel genetic and environmental factors that contribute to the initiation and/or progression of pulmonary arterial hypertension (PAH). Idiopathic PAH is a rare but devastating condition, predominantly affecting females (2.3:1) in early middle age. The condition continues to carry a poor prognosis (40% mortality at 3 years) despite modern vasodilator therapies. Existing treatment does not target the abnormal vascular cell phenotype that characterises PAH. A major breakthrough in our understanding of the pathobiology was the identification of heterozygous disease-causing mutations in the gene encoding the bone morphogenetic protein type II receptor (BMPR-II) in families with PAH. Although research over the last 10 years has provided important clues, the precise cell and molecular mechanisms leading to disease manifestation remain incompletely understood. In addition, the penetrance of this mutation in families appears low, on average approximately 20%. The existence of discordant monozygotic twins points to important environmental factors. A further 15-26% of apparently sporadic cases of idiopathic PAH harbour mutations in BMPR-II. Identification of the critical environmental and additional genetic factors leading to disease manifestation will lead to strategies for disease prevention and may identify pathways for the development of novel therapies, and provide a basis for reverse translational studies in vitro and in vivo. This study will harness the expertise and unique resources of the UK National Pulmonary Hypertension Centres and allied NIHR BRC next generation sequencing capacity and bioinformatics to identify novel genetic variation underlying PAH. Concurrent epidemiology and biomarker testing will provide clues to environmental triggers. We will derive patient-specific induced pluripotent stem cells to test hypotheses and facilitate target/drug discovery and provide proof-of-concept for targeting the BMPR-II pathway in PAH.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: CARDIOVASCULAR
Title: The role of heterodimerisation between VEGFR-1 and VEGFR-2 in the regulation of vasculogenesis, angiogenesis and endothelial cell homeostasis
Funder: Medical Research Council

Abstract: Aberrant angiogenesis occurs in numerous pathologies, as a direct cause of disease, as well as contributing to condition severity and clinical outcome. Therapies aimed at promoting angiogenesis to tackle ischemic disease and reducing angiogenesis in cancers, would have tremendous clinical impact. Vascular endothelial growth factor (VEGF), its receptors, VEGFR-1 and VEGFR-2 are essential for developmental vasculogenesis and angiogenesis, physiological and pathological adult angiogenesis and endothelial homeostasis, but targeting this system for therapeutic angiogenesis has had limited success. Anti-VEGF antibodies and specific receptor inhibitors have proved to be disappointing therapeutically. However, the VEGF system is fundamental for blood vessel genesis, as such is unlikely to be the wrong target, it is paucity in the knowledge of the fine regulation of the VEGF system and feedback mechanisms necessary to inform, when, where and how to deliver the appropriate therapy to target this system effectively. Receptor heterodimerisation is a mechanism used to precisely regulate cell signal and function. Heterodimerisation of VEGF receptors has been widely demonstrated, but poorly studied. To investigate the function of the heterodimer between VEGFR-1 and VEGFR-2 (VEGFR1-2), I have generated a novel VEGFR1-2-specific ligand. Using this ligand I have shown that the heterodimer receptor mediates responses previously thought to be via VEGFR-1 homodimers and that VEGFR1-2 can negatively regulate VEGFR-2-mediated functions. Thus, it appears that VEGFR-1 subunits regulate VEGF activity predominantly by forming heterodimer receptors with VEGFR-2 subunits. This is a paradigm shift in the current thinking on the mechanism of action of VEGFR-1 and VEGFR-2 and will have a significant impact on the field. I am in a unique position to systematically characterise and explore the role of VEGFR1-2 in physiology and pathology and to ascertain its potential as a therapeutic avenue.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CARDIOVASCULAR
Title: Large-scale integrative studies of risk factors in coronary heart disease: from discovery to application
Funder: Medical Research Council

Abstract: With separate funding, we have established a consortium of 50,000 first-onset CHD cases and 50,000 controls, including ~25,000 incident CHD cases and ~25,000 controls from "nested" case-control or case-cohort subsets in population-based prospective studies. All are sharing extensive individual participant data. For all 100,000 participants, we are assaying a novel gene array (Exome+), as well as CardioMetabochip and genomewide association arrays in ~60,000 participants. These arrays furnish complementary data, enabling: i) study of >310,000 coding variants ii) dense fine-mapping of 360 priority loci (eg, >100 loci nominated by pharma, reflecting industry's priorities) iii) deep replication of previously identified promising variants and iv) imputation of 15 million additional variants. In large subsets, we are assaying ~200 soluble biomarkers of potential vascular relevance, eg: i) a panel of phospholipid fatty acids ii) pro-atherogenic and/or pro-inflammatory lipids iii) adipocytokines, endocrine factors iv) carotenoids and vitamins. We now propose to conduct lipidomics, metabonomics, and detailed inflammation biomarker assays in key subsets of these participants, capitalising on recent strategic investment in MRC labs. This combination of exceptional statistical power, access to individual-level data, extensive genotyping, and extensive phenotyping should provide great opportunities for: i) discovery ii) causal analysis (using Mendelian randomisation analysis) and iii) advancement of disease prediction strategies. To meet the challenges of analysing such exceptionally large and detailed datasets, we have assembled a world-leading analytical team led by the current, and the recent former, Directors of the MRC Biostatistics Unit. To hasten translation of findings, we have made arrangements for a variety of follow-on studies. To execute our plan, we seek support to maintain a core subset of our existing scientific team.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: How to assemble the cardiovascular system: instructions from the genome
Funder: Medical Research Council

Abstract: Regulatory information controls the expression of genes, and drives development, disease and evolution. The aim of this proposal is to decode the regulatory information that controls development of the outflow tract of the heart (OFT) and great vessels in humans, and link this information to human disease. Abnormal development of the outflow tract of the heart and the great vessels can lead to congenital heart disease, and increased risk of cardiovascular disease in adulthood. We will: (1) identify the regulatory regions that control the formation of the OFT and the great vessels in mouse, integrating a developmental time course of chromatin modifications, transcription factors binding and gene expression data; (2) obtain similar sets of data from two critical developmental windows in human embryogenesis, and map the regulatory information (mouse and human) on the human genome; (3) link the identified regulatory information to human genetic variation, including genome-wide association (GWAS) signals, and available data from our collaborators on congenital heart disease (CHD). Our results will be stored into a searchable, open-access web application to facilitate wider interpretation of GWAS datasets and of rare DNA variants identified in CHD.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Significance of Piezo1 in endothelial physiology and patho-physiology
Funder: Medical Research Council

Abstract: The molecular mechanisms enabling endothelial cells to sense and respond to shear stress or other mechanical forces are unclear and controversial. Our unpublished/pilot data suggest that the newly-discovered Piezo1 (FAM38A) membrane protein (ion channel subunit) plays a critical and previously unrecognised role. We therefore propose to investigate the significance of Piezo1 for relevant cardiovascular parameters in vivo and to learn more about the signals upstream and downstream of Piezo1. To this end we have put in place complementary mouse genetic approaches for the in vivo manipulation of Piezo1. Using these mice we propose to apply our in vivo, ex vivo and in vitro expertise to learn about Piezo1 in the context of cardiovascular physiology and patho-physiology. Specifically we will investigate embryonic and postnatal vascular development, VEGF-induced angiogenesis in the adult mouse, and reperfusion after ischaemia. We will measure blood pressure and heart rate and characterise the in vitro contractile properties of a resistance artery. We will measure the generation of nitric oxide and reactive oxygen species because of evidence they are tightly linked to mechanical force and Piezo1. We will measure the response to mechanical injury delivered to the endothelium via a guide-wire. We will measure vascular permeability because it is linked to mechanical force and because there is evidence suggesting Piezo1 is a regulator of cell-to-cell contact. In parallel, tissues and cells from the mice will be used in ex vivo studies to deliver knowledge about downstream pathways linked to Piezo1, identified through a phosphoproteomic strategy validated in pilot studies. Factors relevant to cardiovascular physiology and disease will be tested to determine if they promote or suppress contributions of Piezo1 to mechanical sensing events in endothelial cells.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Angiotensin-(1-7) and angiotensin-(1-9): assessment as therapeutic targets in acute vascular injury and remodelling
Funder: Medical Research Council

Abstract: The renin angiotensin system (RAS) is key to cardiovascular diseases, including cardiac and vascular remodelling. Pathophysiological effects via angiotensin (Ang) II are established, while Ang-(1-7), which signals via Mas, antagonises Ang II via the counter-regulatory RAS axis. We recently published Ang-(1-9) as an active peptide at the angiotensin type 2 receptor (AT2R), inhibiting cardiomyocyte hypertrophy and cardiac fibrosis. This highlighted Ang-(1-9) as a new counter-regulatory RAS axis member. Here we have assessed the effects of Ang-(1-9) in human endothelial cells (EC) and smooth muscle cells (SMC). Ang-(1-7) and Ang-(1-9) prevent SMC migration and proliferation via Mas or the AT2R, respectively without affecting EC growth and movement. SMC migration and proliferation are central to neointima development which leads to occlusion of arteries that have undergone percutaneous intervention via a balloon catheter leading to restenosis, or failure of vein grafts following coronary artery bypass procedures. As proof of concept we delivered Ang-(1-7) and Ang-(1-9) into wire injured carotid arteries in mice and observed that Ang-(1-9) was more efficient than Ang-(1-7) at inhibiting neointimal hyperplasia and furthermore that in vivo each peptide acted via its specific receptor. Since Ang-(1-7) and Ang-(1-9) demonstrate favourable attributes in the setting of acute vascular injury, here we will intensely investigate our initial findings in relevant in vitro, ex vivo and in vivo models of vein graft failure. The findings will enhance counter-regulatory RAS axis understanding by investigations into the mechanisms of action of these peptides and highlight therapeutic targets in vascular remodeling which can be further developed in the future.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: iPSC-derived cardiomyocytes to model estrogen receptor modulation of stress cardiomyopathy and arrhythmic syndromes
Funder: Medical Research Council

Abstract: Our hypothesis is that beta2AR switching from Gs-adenylyl cyclase-cAMP signaling to Gi-p38 MAPK signaling decreases cardiac contraction at the same time as conferring protection against arrhythmias and cell damage, and that estrogen signalling modifies this. The aim is to investigate the effect of estrogen on the biased agonism of the beta2AR and the relationship of this to the genotype of the SCM patient. We will investigate separately the cardioprotective (anti-arrhythmic, cell survival) and cardiodepressive effects of the beta2AR -Gi switch using human pluripotent stem cell derived cardiomyocytes (hPSC-CM) from human embryonic or induced pluripotent stem cells. Contraction, calcium transient and action potential duration will be used as readouts of function and to detect arrhythmia occurrence (early or delayed after-depolarisations). cAMP levels will be measured using transfected EPAC2 FRET sensor. These methods have been validated, are in routine use in the UK laboratory, and will be scaled up to high throughput assays in most cases. Cardiotoxicity experiments for apoptosis and necrosis will use the high content automated microscopy system, Cellomics ArrayScan, with readouts including loss of mitochondrial membrane potential, caspase 3 activation, nuclear condensation, increased cell permeability and decreased cell number. We are developing in a parallel project a number of hPSC-CM lines, either by CRISPR gene editing or by reprogramming of lymphoblasts from available subjects with the correct haplotype. These include lines overexpressing the main beta2AR SNPs with fluorescent (SNAP tag) labelling to allow monitoring of beta2AR movement during catecholamine/beta-blocker challenge. Our goal is to find a difference in signalling between cardiodepression and cardioprotection which could be exploited in design of beta2AR -Gi agonists to produce an antiarrhythmic and cardioprotective effect without depression of cardiac function.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Understanding gender differences in cardiometabolic risk across the life course
Funder: Medical Research Council

Abstract: Aim To study gender differences in measures of cardiometabolic risk from birth through to adulthood and to identify potential underlying mechanisms Objectives 1)To describe gender differences in measures of cardiometabolic risk across childhood and adolescence 2)To examine whether the stronger relationship between adiposity and measures of cardiometabolic risk seen in adult males is observed in contemporary children and adolescents 3)To examine whether the stronger association between measures of metabolic risk and measures of cardiovascular risk in females is already present in adolescence 4)To examine whether gender differences are explained by adiposity, lifestyle factors (smoking, diet, physical activity) and pubertal development 5)To identify biological mechanisms underlying gender differences by examining the role of metabalomics, DNA methylation, hormones and hepatic fat Methods: I will use data from two contemporary longitudinal cohort studies from very different settings; ALSPAC, a birth cohort of over 14,000 children which began in 1991/1992 in the south west of England and APCAPS, a prospective cohort study of 2,601 babies born in India between 1987 and 1990. I will examine gender differences in cardiometabolic risk across the life course in each cohort separately using multilevel models and structural equation models. I will examine the role of potential lifestyle mediators of associations in each cohort and biological mechanisms in ALSPAC including differential DNA methylation and metabolomics. I will draw on causal analysis methods developed at the MRC IEU and conduct cross cohort comparisons to improve causal inference. Scientific Opportunities My findings will increase understanding in the aetiology of gender differences in cardiometabolic health by identifying the origin of gender differences in cardiometabolic risk, how they change with age, and the intermediate processes that drive the gender differences.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: CARDIOVASCULAR
Title: In silico Investigation of the Mechanisms of Abnormal Spontaneous Excitation from Cell to Organ - Insights on the Development of Atrial Fibrillation
Funder: Medical Research Council

Abstract: The mechanisms underlying the initiation and development of atrial fibrillation (AF) are not well understood. Ectopic activity can mediate the development of re-entrant excitation and has been implicated in the genesis and recurrence of AF. This project aims to investigate the mechanistic link between malfunctions of the intracellular calcium handling system and the development of ectopic activity, and their translation into organ scale dynamics. This will be achieved through the development of mathematical models of the rabbit and human atria in three stages. Firstly, 3D single cell models of the coupled atrial intracellular calcium handling and membrane ion current systems will be developed, incorporating realistic intracellular micro-architecture. A finite element method incorporating Gillespie's algorithm will be implemented. The models will be used to investigate the role of electrical remodelling and sympathetic activity in the genesis of triggered behaviour. Secondly, mesoscopic physics techniques will be applied to reduce the resolution of the single cell models while preserving behaviour originating from stochastic processes at the microscopic scale. This will be achieved primarily through introducing stochastic noise terms to deterministic equations, such that the effect of stochastic processes on localised collections of ion channels and intracellular processes can be accounted for. Multiple cells will then be coupled together to investigate the mechanisms underlying synchronisation of triggered activity. Finally, the mesoscopic approach will be extended to translate synchronised triggered activity into organ-scale models. Combined with realistic reconstructions of atrial anatomy, the role of ectopic activity in the development of AF will be investigated. The project will produce deep understanding of the mechanisms of AF, facilitating improved treatment of the disorder, as well as a multi-scale framework for the investigation of cardiac arrhythmias.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: CARDIOVASCULAR