NIHRDataInsights/HRCSData huggingface dataset:
Title: The Effect of Antiplatelet Medications on Innate Immune Activation
Funder: Medical Research Council

Abstract: Background Platelets have a central role in acute coronary syndromes (ACS). Ticagrelor is a novel antiplatelet drug that binds to platelet P2Y12 ADP receptors and also inhibits adenosine uptake, both of which have been shown to affect immune response. The Platelet Inhibition and Patient Outcomes (PLATO) study showed that ticagrelor reduces the incidence of pulmonary infections and has a differential effect on inflammatory markers compared to clopidogrel in patients with ACS. Hypothesis Ticagrelor and clopidogrel differ in their effect on innate immune activation, due to P2Y12 and non-P2Y12 dependent mechanisms Objectives 1.) Determine the in-vitro effects of ticagrelor on innate immune activation compared to other P2Y12 antagonists and inhibitors of adenosine reuptake. 2.) Determine the in-vivo effect of ticagrelor and clopidogrel on innate immune activation during experimental human endotoxaemia. 3.) Determine the effect of clopidogrel therapy on ex-vivo innate immune activation. Design/Methodology I will compare the effects of ticagrelor and other antiplatelet agents (including P2Y12 antagonists and inhibitors of adenosine reuptake) on innate immune activation in vitro and also in vivo using a safe, well-established model of experimental human endotoxaemia. I will study the effect of these compounds on key cellular functional pathways, including leukocyte expression of surface markers of activation, cytokine production, phagocytosis, pneumococcal killing, apoptosis and interaction with platelets. I will also investigate the effect of clopidogrel therapy on these pathways in patients with stable coronary artery disease ex vivo. Scientific and Medical Opportunities This will provide insights into the effects of ticagrelor and clopidogrel on innate immune responses and identify their effects on cellular pathways that may guide the development of novel antiplatelet strategies.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CARDIOVASCULAR
Title: The potential importance of Stromal Derived Factor-1 in the protection and repair of myocardium following simulated ischaemia-reperfusion injury
Funder: Medical Research Council

Abstract: OBJECTIVE Following ST-elevation myocardial infarction (STEMI), the therapeutic restoration of blood flow can itself inflict injury, known as Ischaemia-Reperfusion Injury (IRI). Remote Ischaemic Conditioning (RIC) describes the phenomenon whereby the application of brief non-lethal ischaemia and reperfusion to tissue remote from the heart protects the myocardium from a lethal episode of IRI. However, the mechanism remains elusive. The objective of this research is to elucidate this mechanism. AIMS Stromal Derived Factor-1-alpha (SDF-1) has been identified as a prime candidate and this application attempts to evaluate its role in the setting of IRI. SDF-1 is thought to have a dual function. Firstly, it regulates diverse cell functions that have previously been implicated in myocardial protection from IRI seen in RIC, namely the Reperfusion Injury Salvage Kinase (RISK) pathway. Secondly, it is thought to play a role in the trafficking of endothelial progenitor cells from bone marrow. It is therefore feasible that SDF-1 both protects the myocardium from IRI via the RISK pathway and contributes to its repair by homing stem cells to damaged myocardium. The key aims of my research, therefore, are to investigate the importance of SDF-1 in RIC acutely and to use a model of post-MI heart failure to investigate long-term benefit of increased SDF-1. METHODOLOGY Physiological in vivo and ex vivo rat and mouse models of myocardial IRI will be used in addition to in vitro cell models of hypoxia-reoxygenation injury, and a range of molecular biology techniques including Western blot analysis. Data will be analysed by one way ANOVA and Fishers' protected least significant difference test for multiple comparisons. SCIENTIFIC AND MEDICAL OPPORTUNITIES Finding the factor(s) responsible for the mechanisms of RIC is paramount for maximising its potential in patients undergoing both coronary artery bypass surgery and those presenting with STEMI.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Studies in the development of a novel side-branch stent
Funder: Medical Research Council

Abstract: Coronary artery disease (CAD) remains a major cause of mortality and morbidity. Percutaneous Coronary Intervention (PCI)-balloon inflation at the site of the narrowing with stent placed to keep the artery open-has become the dominant treatment for CAD. While PCI is a safe procedure with high success it can be more difficult and less predictable when disease occurs at branch points (bifurcation) as the angle between main and side branch can result in either a gap or overlap between the 2 stents used to treat each branch, due to the cylindrical stent ends being straight. Our aim is to develop a novel stent with a balloon modifiable proximal end conformed once placed in the bifurcation side arm allowing the end to accommodate the side branch/main branch angle. The main branch would then be stented with conventional stents for complete coverage of the bifurcation with no overlap/gap between the stents and no intrusion into the side branch stent. Initial work (previous NIHR grant) resulted in 2 early prototypes. The current proposal aims to build upon this work to allow the device to translate to clinical trials and practice We have specific plans to refine the design of our prototypes using computer modelling, Finite Element Analysis, and to laser cut improved prototypes to test in latex bifurcation models (stent behaviour under direct vision). After any needed re re-design, for stent prototypes to be successfully, repeatedly and reliably conformed in-vitro, an appropriately numbered pig bifurcation study will be undertaken. Assessment of in-vivo performance will use micro-CT to assess stent remodelling/relationships with the main vessel stent and histological studies early and at 28 days for tissue reaction to the implanted stent at bifurcation site (to ensure there are no downsides to the concept of in-vivo conformability eg a nidus for in-stent intimal hyperplasia or stent thrombosis) The ultimate aim is to develop a side branch stent for CE mark and testing in man.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: CARDIOVASCULAR
Title: Mechanosensitive regulation of cardiac excitation-contraction coupling: The role of localized beta-adrenergic receptors and calcium channels
Funder: Medical Research Council

Abstract: There is emerging interest in the potential of mechanical unloading of failing hearts using Left Ventricular Assist Device (LVAD) therapy to improve myocardial function. Recently it has been shown that LVAD support restores beta-adrenergic responsiveness and reverses receptor downregulation in failing human hearts. In this project we aim to study cAMP -beta receptors signalling in cardiomyocytes (CMs) isolated from rat hearts after mechanical unloading using a novel SICM/FRET technique. Mechanical unloading for periods of different duration will be induced in normal and failing rat hearts by heterotopic abdominal heart transplantation. The localized dynamics of cAMP-beta-receptors and the compatmentalisation of the signalling will be determined in isolated cardiomyocytes from control and unloaded hearts. In the second part of the project we will investigate the role of L type Calcium channels in the recovery of unloaded cells. We will look at the distribution of channels and correlate this with restoration of cellular architecture and membrane topography. This project will provide a mechanistic insight in the relationship between chronic changes in load and functional properties of the myocardium, and provide new information on the molecular and signalling effects of mechanical unloading during myocardial remodelling in heart failure.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Proteolytic cleavage of the low density lipoprotein (LDL) receptor: a novel regulator of plasma LDL cholesterol?
Funder: Medical Research Council

Abstract: Cardiovascular disease is, and will be for the foreseeable future, the leading cause of death in the world. One of the most significant risk factors for cardiovascular disease is elevated levels of plasma low-density lipoprotein (LDL) cholesterol. The number of functional LDL receptors (LDLRs) expressed on the surface of hepatocytes is the primary determinant of plasma LDL-cholesterol levels. LDLR binds plasma LDL particles, mediating their endocytosis, and thereby reducing plasma cholesterol. Using recombinant proteins, hepatic cell lines and ex vivo tissue, we have observed that human LDLR is proteolytically cleaved in its extracellular ligand binding domain by the secreted zinc metalloprotease bone morphogenetic protein-1 (BMP1). Critically, cleavage of LDLR by BMP1 reduces the endocytosis of LDL-cholesterol in a cellular system. These observations form the basis of a novel mechanism for the post-translational regulation of LDLR. We hypothesise that proteolytic cleavage of human LDLR by BMP1 regulates LDL uptake and hence plasma LDL cholesterol in vivo. To test this hypothesis our specific objectives are to quantitate the reduction in binding and cellular uptake of LDL by the BMP1 truncated LDLR; determine the effect of BMP1 regulation on LDLR proteolysis and plasma LDL cholesterol in vivo through complementary approaches of pharmacological inhibition and genetic modulation of BMP1 in mice expressing human LDLR; and understand the cellular and molecular mechanism of action of BMP1 on LDLR with particular emphasis on determining the subcellular compartment where BMP1 cleaves LDLR and whether BMP1 interacts with LDLR via an exosite. The results of this work will validate BMP1 as a novel regulator of human LDLR function, contribute to our understanding of the increasingly complex processes underlying the regulation of LDLR and plasma LDL cholesterol, as well as potentially identifying a new mechanism that could be a target for novel cholesterol-lowering drugs.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: 3D Free-breathing MRI with High Scan Efficiency for Assessment of Cardiovascular Disease: Combining Acceleration and Motion Correction Techniques
Funder: Medical Research Council

Abstract: A simple approach to reduce respiratory-induced motion artefacts in multislice 2D cardiovascular MRI is to perform the acquisition under multiple breath holds (~15-20s each). However this approach may suffer from slice-misalignment due to different breath hold positions and requires patient cooperation, which can be challenging in severely ill patients. To overcome these problems 3D free-breathing navigator 'gated' acquisitions have been introduced to minimize motion artifacts by estimating the respiratory signal from the foot-head translational motion of the diaphragm. Gating is used to acquire MR data only when the respiratory signal coincides with a predefined acceptance window, preferably end-expiration, while all other data are being rejected. This approach has shown to considerably reduce motion artifacts when small gating windows are employed (3-5mm), however it leads to prolonged scan times since only a fraction of the acquired data is accepted for reconstruction (referred to as scan efficiency). Another drawback of the navigator-gated approach is the use of an oversimplified and patient-independent model for motion correction. In this proposal we aim to develop, implement and test the clinical feasibility of an efficient (shorter scan time) and robust (neither planning nor patient collaboration required) respiratory motion compensation framework for late gadolinium enhancement (LGE) and whole-heart coronary MR angiography (CMRA). This method will achieve 100% scan efficiency by correcting all acquired data directly in the reconstruction after registration of high-resolution undersampled reconstructed 3D virtual image navigators. We hypothesize that this can be achieved by developing a new 3D approach that combines novel data sampling schemes, novel undersampling reconstruction techniques and a mathematical framework for simultaneous undersampled image reconstruction and motion correction of the free-breathing acquired data.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Investigating the relationship between active commuting and cardiovascular disease in the UK: Longitudinal and spatial analysis of four large datasets
Funder: Medical Research Council

Abstract: AIM: To produce a body of work investigating the causal relationship between active commuting (AC) and cardiovascular disease (CVD) outcomes through the lifecourse, using longitudinal and spatial approaches to the analysis of 4 large secondary datasets to unpack causality and process and situate the individual in their environmental and temporal context. OBJECTIVES: (1) To describe the prevalence and patterning of AC modes through time and across the lifecourse. (2) To determine whether a robust, independent association exists between AC and a range health outcomes on the CVD pathway. (3) To determine the direction of causality in these relationships and to explore causal pathways. (4) To investigate the ways in which socioeconomic and physical characteristics of the urban environment affect commuting mode choice and modify the effects of AC on BMI. METHODOLOGY: Outcomes of interest can broadly be split into 3 categories, reflecting their position on the causal pathway: (i) Biological antecedents of CVD; (ii) Diagnosed CVD-related conditions; (iii) CVD mortality. The exposure will be operationalised as a variable with three ordered categories of transport: Active; Public; Private. Four large longitudinal datasets will be exploited to illuminate distinct dimensions of the relationship between AC and CVD: (i) The ONS Longitudinal Study (ONS-LS); (ii) The UK Household Longitudinal Study (UKHLS); (iii) UK Biobank; (iv) The Olympic Regeneration in East London study (ORiEL). Complementary analyses of these 4 datasets will provide a comprehensive picture of the ways in which active commuting affects cardiovascular health in adults and young people in the UK. Analytical approaches will include longitudinal multilevel modelling, structural equation modelling and spatially explicit methods. This combination of longitudinal and spatial epidemiological approaches will provide a novel view of the relationship between AC and CVD, and yield key recommendations for policy.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: BHF Imperial Cardiovascular Regenerative Medicine Centre
Funder: Medical Research Council

Abstract: We plan a suite of high content/automated imaging platforms for the assessment of the cardiomyocyte phenotype with complementary capabilities at Imperial and Nottingham. This will allow complete phenotyping of a given endogenous, reprogrammed or pluripotent-stem cell derived cardiomyocyte by the Imperial/Nottingham Centre. The cardiomyocyte from embryonic (hESC-CM) or induced pluripotent (iPSC-CM) stem cells represents a human genotype-specific cell with an authentic morphological, electrical and contractile phenotype. For investigation of development, disease modelling and target discovery, the high throughput capabilities of stem cell-derived cardiomyocytes have the potential to produce a step-change in scale for the cardiac cell biology researcher. This will mesh with the increasing number of small- and large-scale initiatives to produce patient-derived pluripotent stem cells to model cardiac disease. Academics will also be well placed to transfer laboratory-based medium-throughput studies directly to Industry assays where similar platforms are used. We also ask for a contribution to the purchase and housing of new MRI scanner which will replace the instrument previously supported by the MRC CSC at Imperial. The proposed site for the MRI is the basement of the Imperial Centre for Translational and Experimental Medicine (ICTEM), where the majority of Imperial PIs are based. The proposed new facility will house Magnetic Resonance (MR), Positron Emission Tomography - Computed Tomography (PET-CT) and In-Vivo Imaging System (IVIS) scanning equipment together with associated support areas. The MRI is essential for the phenotyping of animals after interventions to increase cardiac stem-cell derived muscle integration, and we have developed state-of-the-art image analysis algorithms for these experiments in rodent disease models.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Development of a Gal-free Calcification Resistant Porcine Pericardial Heart Valve.
Funder: Medical Research Council

Abstract: Our final objective is to produce a new more durable bioprosthetic heart valve. Heart valve disease occurs due to birth defect, infection and age related degeneration. About 500,000 operations to fix or replace heart valves are performed annually worldwide. There are two types of replacement valves, mechanical heart valves (MHVs) which require lifetime anticoagulation and bioprosthetic heart valves (BHVs) made from biological tissues, typically human or porcine heart valve leaflets or animal pericardium. BHVs are preferred in older patients where they are more durable. Patients under 60 generally receive MHVs due to more rapid age-dependent BHV calcification and degeneration. Significant efforts have been devoted to develop calcification resistant BHVs which could be used in younger patients without chronic anticoagulation. BHV calcification is attributed to mechanical stress, passive calcium binding to phospholipids, and immune injury. Current anti-calcification treatments rely on phospholipid depletion. These processes are effective in animal models but have not improved BHV durability or permitted their routine use in younger patients. We have identified an antibody-mediated inflammatory process involving the dominant xenogeneic antigen galactose alpha 1,3 galactose (Gal) binding to universally present human anti-Gal antibody which enhances calcification of fixed Gal-positive (WT), but not Gal-free bioprosthetic materials. Growing evidence indicates that this antibody mediated inflammatory mechanism may significantly contribute to age-dependent calcification. Genetically modified pigs which do not make the Gal antigen (GTKO) are a potential new source for BHVs which resists anti-Gal induced calcification and may be more durable in younger patients. This study is designed to produce prototype BHVs made from WT and GTKO porcine pericardium and determine by in vitro testing their equivalence. This is an essential first step in commercial GTKO BHV development.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: CARDIOVASCULAR
Title: ATP sensitive potassium channels and cardiac arrhythmia
Funder: Medical Research Council

Abstract: My hypothesis is that inhibition of ATP-sensitive potassium channels in cardiac muscle is antiarrhythmic and it is feasible to differentially target sarcolemmal channels in the atria and ventricles. I aim to define the subunit expression and current characteristics in the atria and ventricles of mouse heart and to compare this with human atrial appendage. I will use quantitative real-time RT-PCR and western blotting to examine the differential subunit expression of Kir6.1, Kir6.2, SUR1, SUR2A and SUR2B in the various tissues and chambers of the heart. I will use patch clamping of single atrial and ventricular cells to examine any differences in pharmacology of the currents. My second aim is to examine the role of ATP-sensitive potassium channels in the genesis of abnormal rhythm using pharmacological approaches and in mice with cardiac specific deletion of Kir6.1. I will use programmed electrical stimulation to induce atrial fibrillation in the presence of ATP-senstive potassium channel openers and inhibitors and in Kir6.1 knockout mice. I will examine the electrical effects of the drugs in heart slices from the atria and ventricle of normal and Kir6.1 knockout mice and in slices of human atrial appendage.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: The role of ischaemia reperfusion injury and mitochondrial dysfunction in the development of chronic allograft vasculopathy
Funder: Medical Research Council

Abstract: Chronic allograft vasculopathy (CAV) is one of the major challenges facing solid organ transplantation and is critically dependent on the alloimmune response. Clinical studies suggest that the ischemia reperfusion injury (IRI) inherent to transplantation may also contribute to late allograft dysfunction, although this has not been definitively shown in an experimental setting. Furthermore, the mechanisms through which IRI may augment the alloimmune response to exacerbate CAV are not clear. Mitochondria are critical upstream mediators of IRI and may be central to augmentation of the immune response by IRI, through production of reactive oxygen species (ROS) and damage to mitochondrial DNA, lipids and proteins. We have developed a family of mitochondria-targeted therapies for IRI that have been shown to be safe and effective in extensive animal models and non-transplant Phase II human clinical trials. We have also developed well-characterised heterotopic mouse alloimmune models of CAV after cardiac transplantation, and shown that the indirect alloimmune pathway is likely to mediate development of CAV. This project examines the principal hypothesis that IRI exacerbates CAV through augmentation of the indirect alloimmune response. I also aim to show that amelioration of mitochondrial dysfunction abrogates the alloimmune response and the consequent CAV. To examine these hypotheses, I will quantify the influence of short and long cold ischaemia on mitochondrial dysfunction and cellular damage (including ROS production, DNA and protein damage), indirect alloimmunity (including CD4 T cell activation and alloantibody formation) and CAV using mouse models of chronic cardiac allograft rejection. I propose to show that treatment of the donor heart or recipient animal with mitochondrial-targeted therapies (the antioxidant MitoQ and the S-nitrosating agent MitoSNO respectively) ameliorates mitochondrial dysfunction, the indirect alloimmune response and ultimately CAV.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR