NIHRDataInsights/HRCSData huggingface dataset:
Title: ENDOTHELIAL GATA4 IN ATHEROSCLEROSIS PROGRESSION
Funder: Medical Research Council

Abstract: Background. Disturbed blood flow promotes rupture of atherosclerotic plaques which causes myocardial infarction and stroke. The mechanisms of this link were unknown but we recently demonstrated a role for the transcription factor GATA4 which is induced by disturbed flow and abundantly expressed in plaque endothelial cells (EC). We found that GATA4 amplifies atherosclerosis and drives multiple pathogenic changes in EC that are known to promote plaque rupture (inflammation, excessive proliferation and apoptosis). We hypothesize that GATA4 is a master regulator of EC pathogenic change and an essential driver of plaque progression towards rupture. Scientific objectives. We will define the role of GATA4 and its downstream targets in the progression of atherosclerotic plaques towards rupture. GATA4 is pleiotropic with the ability to induce divergent transcriptional programmes that vary according to cell type, and we therefore propose to identify transcriptional targets of GATA4 that specifically play a role in atherosclerosis but are not involved in tissue homeostasis. Plan of investigation. The role of endothelial GATA4 in atheroprogression will be elucidated using human coronary artery plaques and conditional knockout approaches in mice. We will identify GATA4 gene regulatory networks controlling EC pathogenic changes by single cell RNAseq analysis. To focus on mechanisms that are exclusively pathogenic, we will deselect GATA4 networks involved in homeostasis. Potential future applications. The proposed research will elucidate GATA4 gene regulatory networks that are specifically involved in atherosclerosis progression, thereby identifying molecules that could be safely targeted to benefit patients at risk of myocardial infarction or stroke. Importantly, the GATA4 pathway has not been studied previously in atherosclerotic plaques and it therefore represents a novel and valuable resource in terms of potential new drug targets.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Cardiac and vascular disease prevention after hypertensive pregnancy: insights from AI-derived, multi-organ, hypertensive disease progression models
Funder: Medical Research Council

Abstract: Women who have a hypertensive pregnancy, and their children, are at significantly increased risk of cardiovascular disorders, including hypertension and stroke, in later life. Imaging studies show both the woman and child have identifiable cardiovascular changes decades before the development of these acute medical events. We will study whether distinctive patterns in these imaging markers can be used to describe disease progression and, thereby, provide a clinical tool to identify optimal times and approaches to intervene and slow disease progression. First, we will expand our existing post-partum imaging datasets to include older women and distinct demographic groups to form a harmonised dataset of complex, multi-modal, multi-organ phenotypic data extending from 6 months to 25 years post-partum. In addition, to understand early disease progression we will expand our existing young adult imaging datasets with additional follow up of a cohort at age 25-35 years with detailed pregnancy information. We will then use novel unsupervised machine learning to learn the multi-dimensional disease progression landscape across heart, brain and vasculature related to hypertensive pregnancy in young adults and postpartum. Vascular disease patterns will then be compared to those more broadly related to hypertension identified within the UK Biobank imaging cohort using similar computational approaches. Finally, we will investigate optimal ways to present this disease progression within clinical workflows to describe the relative position of individuals within the disease landscape. We will also determine whether models based on simple clinic measures can approximate to the complex imaging phenotypes. At the end of this programme we hope to have used artificial intelligence to map the life course of disease progression in families affected by hypertensive pregnancy and identified simple clinical approaches to characterise and manage disease progression.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: CARDIOVASCULAR
Title: Healthy longevity gene inspired therapy to rescue cardiovascular disease in progeria
Funder: Medical Research Council

Abstract: The study investigates the use of the longevity-associated variant of the human BPIFB4 gene (LAV-BPIFB4) for the treatment of cardiovascular complications of Hutchinson-Gilford progeria syndrome (HGPS). The applicants showed that LAV-BPIFB4 gene therapy alleviates cardiovascular disease and atherosclerosis in animal models and provided extensive mechanistic insight into the pathways underpinning the therapeutic benefit. Pilot data indicate that there is a strong overlapping between the targets of LAV-BPIFB4 and progerin, thus suggesting LAV-BPIFB4 could rescue cellular dysfunction at multiple levels. The experimental plan includes 3 WPs. In WP1, imaging studies using echocardiography and PET/CT scan will determine the efficacy of LAV-BPIFB4 gene therapy in progeric mice. In WP2, histology and immunohistochemistry analyses will be conducted in harvested murine cardiovascular tissues to verify the benefit of LAV-BPIFB4 gene therapy on the structural alterations that affect blood vessels and the heart. Moreover, we will assess the effect of therapy on the expression levels of BPIFB4/lamins in the heart and blood vessels. In WP3, we will analyse underpinning mechanisms in murine tissues and human HGPS cells. The simplification has resulted in ~ £40K saving as compared with the previous application. Ethical approvals and technical procedures are in place and the research environment is very supportive.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CARDIOVASCULAR
Title: Targeting the oxidative activation of PKG Ialpha as a treatment for HFpEF
Funder: Medical Research Council

Abstract: Heart failure is a common medical condition that causes the deaths of 200,000 people a year in the United Kingdom. Up to half of heart failure patients have a form known as Heart Failure with Preserved Ejection fraction (HFpEF), which is increasing in prevalence because people are living longer and comorbidities (e.g. diabetes, metabolic syndrome, hypertension) that may causally contribute are also escalating. There are no evidenced-based therapies for the generic treatment of HFpEF, although emerging clinical trial studies at the time of writing show early promise. Clearly. there is an unmet clinical need, which we will address by evaluating drugs that stimulate the disulfide activation of PKG Ialpha as a novel therapy for HFpEF. This application seems funds to develop and test drug G1 and chemical derivatives we are currently generating as potential therapies for HFpEF. We developed drug G1 from a screen of compounds that induce the oxidative targeting and activation of PKG Ialpha, which has a regulatory and redox active cysteine 42. We already have pilot data indicating that drug G1, which we developed as a novel anti-hypertensive, improves myocardial diastolic function in old mice with diastolic dysfunction, but not in C42S PKG Ialpha transgenic knock in mice that lack the cysteine G1 targets. We now want to test drug G1, and improved derivatives of this drug that we are currently making, in other in vivo murine models of HFpEF. We will also increase our mechanistic understanding of how oxidation of PKG Ialpha mediates relaxation during diastole.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR
Title: Systo-diastolic coupling as a therapeutic target for heart failure with preserved ejection fraction
Funder: Medical Research Council

Abstract: Heart failure with preserved ejection fraction (HFpEF) forms up to 50% of cases of heart failure, has similar high mortality to other forms of heart failure yet has few evidenced based treatments. HFpEF is thought to be due to impaired relaxation and filling of the left ventricle with contractile function and hence ejection fraction preserved. New data from ourselves challenge this view and suggest that a major cause of HFpEF is failure of the ventricle to contract efficiently early in systole with overall ejection fraction preserved at the expense of sustained contraction into late systole which impacts relaxation in diastole through an impairment of systo-diastolic coupling. A new metric of early systolic function, first-phase ejection fraction (EF1), is powerfully predictive of prognosis in HFpEF and in other conditions, the change of EF1 in response to treatment predicts outcomes. EF1 and systo-diastolic coupling therefore present an entirely new therapeutic target for HFpEF. In the present proposal we will use experimental probes to obtain a detailed understanding of the role of systo-diastolic coupling in HFpEF. This has the potential for near-term patient benefit through using established drugs to optimise EF1 and will validate EF1 for use as a target for novel drugs.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Mechanotransduction in vascular physiology and pathology
Funder: Medical Research Council

Abstract: The frictional force per unit area of shear stress is an essential regulator of vascular homeostasis and pathology. Endothelial cells that line blood vessels sense and decode shear stress patterns using mechanoreceptors expressed on their surface. Areas of disturbed shear stress are prone to development of atherosclerotic plaques due to chronic activation of pro-inflammatory pathways in endothelial cells. In contrast, straight regions of arteries that are exposed to laminar shear stress are largely protected from disease. We have recently identified the cell guidance receptor, Plexin D1 (PLXND1), as a novel mechanoreceptor in endothelial cells. We have shown that endothelial PLXND1 is required for sensing shear stress and activation of inflammatory pathways that will ultimately lead to development of atherosclerosis. We therefore hypothesise that PLXND1 is a central regulator of endothelial mechanotransduction and therefore represents a novel target for atherosclerosis. To test this hypothesis, we propose three work packages (WPs) that will determine the molecular mechanisms by which PLXND1 regulates mechanotransduction; the role of PLXND1 in physiological flow-mediated remodelling; and its role in human atherosclerosis and association of PLXND1 variants with coronary artery disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Prospective observational study investigating genomic determinants of outcome from cardiogenic shock (GOlDilOCS)
Funder: Medical Research Council

Abstract: Mortality from cardiogenic shock (CS) has remained at 30-50% over the last two decades. A more comprehensive understanding of the pathobiology of CS, specifically the heterogeneity of the host response, is needed to guide development of targeted therapies and inform clinical trial enrolment. Objective The aim of this project is to understand the heterogeneity of both the immune consequences and treatment responses in CS. We will explore this heterogeneity through identification of transcriptomic sub-phenotypes and their association with outcomes, including therapeutic responses. Design This is a prospective observational cohort study across 5 cardiac centres. We will recruit patients presenting with acute myocardial infarction (AMI) and CS who are supported medically (n=100); with extracorporeal membrane oxygenation (n=50); and with the Impella Device (n=50). We will also enrol patients who present with either AMI and no evidence of CS (n=50) or CS due to non-ischaemic pathologies (e.g. myocarditis: n=50) as comparators. Methods Blood samples will be collected at presentation, 24 hours, and 5 days to generate a biobank for initial focused genetic, transcriptomic and inflammatory mediator profiling, and for future multi-modal deep phenotyping. Clinical data will be retrieved from patient records and transcribed into an electronic case report form. Inter-individual heterogeneity in whole blood gene expression will be analysed using unsupervised hierarchical cluster analysis. Gene expression and inflammatory mediator profiles, and their evolution, will be correlated with clinical endpoints including survival. Enrichment of biological pathways and functions, and upstream regulators will be determined. Context- specific regulatory genetic variants involving gene networks central to the pathogenesis of CS will be identified. Impact These data will enable a personalised medicine approach and inform clinical trial design in CS.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR
Title: Implications of the Cardiac Hepcidin/Ferroportin axis for the Management of Iron Deficiency in Heart Failure
Funder: Medical Research Council

Abstract: Iron deficiency (ID) is a recently-recognised co-morbidity in chornic heart failure (CHF), and new guidelines recommend using I.V iron to treat it. These guidelines do not distinguish between different types of ID. One type of ID, most common in chronic conditions, is driven by raised levels of the hormone hepcidin. Hepcidin is raised by inflammation and causes ID by blocking the iron exporter ferroportin FPN in the liver and spleen, respective sites of iron storage and recycling. My lab has recently discovered new functions for hepcidin and FPN in the control of iron export within cardiomyocytes and demonstrated that this control is required for normal heart function. This discovery has important implications. First, raised hepcidin levels affect heart function directly by increasing cardiomyocyte iron retention and maginifying the impact of I.V iron on myocardial iron levels. Second, patients with raised hepcidin levels would benefit from a hepcidin-lowering approach to restore both serum iron levels and normal cardiac iron control. Aims- 1)To establish the direct effects of raised hepcidin on cardiac iron and function in the setting of heart failure, 2) Identify and target the factors that raise hepcidin in this setting, 3) Determine if serum hepcidin levels modify the outcomes of I.V iron treatment. Methodology- We will combine mechanistic experiments in an established mouse model of CHF with targeted sub-studies within a relevant patient cohort. Scientific & medical opportunities- Our studies will generate new mechanistic understanding of the role of raised hepcidin in the pathophysiology of CHF. One clinical application of this understanding is to use hepcidin-lowering drugs to restore both serum iron levels and normal cardiac iron control. FPN is also present in the kidney and lung. The tools and understanding generated by our work will pave the way for studying the role of local iron retention in the chronic conditions that affect these tissues.


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: Manganese Enhanced Magnetic Resonance Imaging (MRI) in Ischaemic and Takotsubo Cardiomyopathy.
Funder: Medical Research Council

Abstract: Cardiac magnetic resonance imaging is used to assess myocardial structure, function and tissue composition. This can be further enhanced using contrast media that target certain biological functions. As an analogue of calcium, manganese is readily taken up into viable cardiomyocytes where it increases T1 relaxivity. In previous work at the Centre for Cardiovascular Science at the University of Edinburgh, we have conducted proof-of-concept studies demonstrating that manganese-enhanced magnetic resonance imaging can delineate myocardial infarction better than gadolinium and is associated with alterations in myocardial T1 values in patients with dilated cardiomyopathy. We here propose to extend our findings to patients with either ischaemic myocardium or takotsubo cardiomyopathy, and to explore the recovery of transiently dysfunctional myocardium. We hypothesise that manganese-enhanced T1 mapping will identify substantial alterations in calcium handling during the early phases of ischaemic and non-ischaemic left ventricular systolic impairment, and that these will reverse following recovery of the myocardium. This has major potential to assist in the understanding, diagnosis and potential treatment of these conditions and establish a role for manganese-enhanced T1 mapping for myocardial viability. We believe that this will form an outstanding project for Dr Singh's Clinical Research Training Fellowship.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Characterising disease mechanisms and tailoring therapies for coronary microvascular dysfunction
Funder: Medical Research Council

Abstract: AIMS: Elucidate the pathogenesis of CMD subtypes and study the effects of subtype-stratified treatment on patients' exercise capacity and quality of life. OBJECTIVES: 1. Investigate why patients with functional CMD have elevated basal coronary blood flow (CBF); 2. Investigate whether subtype-stratified treatment yields superior outcomes compared to empirical treatment regimens. METHODOLOGY: According to our power calculations, 50 patients will need to be recruited to address the first objective and 78 patients for the second objective. 50 patients will undergo intracoronary physiology assessment during rest, bicycle exercise, peripheral infusion of adenosine, and intracoronary infusions of substance P followed by S-methyl-l-thiocitrulline (SMTC) or N(G)-monomethyl-l-arginine (L-NMMA). Adenosine is used to determine the coronary flow reserve and substance P tests endothelial function. CBF will be measured before and after the infusions of intracoronary vasoactive agents (substance P, SMTC and L-NMMA) to evaluate the microvascular response to these agents. The same 50 patients will undergo cardiac MRI to assess indirect and direct (blood oxygen level dependent) measures of myocardial ischaemia. These 50 patients, along with 28 patients already confirmed to have CMD on intracoronary assessment, will be invited to partake in a randomised, blinded, crossover trial investigating the effects of Ranolazine and Sildenafil on patients' exercise time, release of post-exertion cardiac biomarkers, angina-specific questionnaire scores and number of steps on a FitBit monitor. The primary outcome measure will be exercise duration on the exercise treadmill test. SCIENTIFIC AND MEDICAL OPPORTUNITIES: Improving our understanding of the pathogenesis of CMD subtypes is important in order to develop novel therapies for patients with CMD. A subtype-stratified therapeutic approach is likely to improve patients' exercise capacity and quality of life.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: What is the mechanism of action of the Coronary Sinus Reducer in refractory angina? A randomised placebo-controlled study
Funder: Medical Research Council

Abstract: Background: The coronary sinus reducer (CSR) is a novel device for the treatment of angina which is refractory to all conventional therapies and has shown placebo-controlled angina relief in a randomised trial. It has been used in humans for many years, with an excellent safety profile and is now in the European Society of Cardiology guidelines. Use of the CSR remains very limited and the mechanism of action is poorly understood. Aims: 1. To discover the mechanism of action of the CSR in refractory angina 2. To identify patients who are most likely to receive benefit from the CSR Methods: I will conduct a randomised, double-blinded, placebo-controlled study. I will enrol 40 patients with refractory angina. They will undergo baseline assessment with angina and quality of life questionnaires and exercise time. A smart phone symptom app will be completed daily throughout the study. Participants will also undergo quantitative, Kellman sequence cardiac perfusion MRI scans and non-invasive coronary flow measurement with pulsed-wave spectral doppler. In the catheterisation laboratory, after establishing auditory isolation with headphones and a deep level of conscious sedation, participants will be randomised 1:1 to the CSR or placebo. The follow-up will be six months, at which point, participants will repeat their baseline assessments and be unblinded. Outcomes: The primary endpoint will be the difference in myocardial perfusion reserve (MPR) increment on MRI, between the CSR group and the placebo group. A secondary endpoint will be the correlation between baseline MPR and exercise time increment. Opportunities: This fellowship will demonstrate the true placebo subtracted effects of the CSR on the ischaemic myocardium, defining the mechanism of action. It will advance the use of placebo control in mechanistic studies and stimulate new research in the role of the cardiac venous system in ischaemia.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR
Title: Determining the role of Wnt signalling & IGFBP6 in enhanced atherosclerosis risk in periodontal patients: biomarker & therapeutic potential evaluation
Funder: Medical Research Council

Abstract: Periodontitis and atherosclerosis are highly prevalent, chronic inflammatory disorders that share risk factors. The precise mechanism by which periodontitis gives rise to atherosclerosis is yet to be fully explicated. There are three components to the Fellowship. The first builds on an original pilot study conducted by myself which showed that the protein expression of monocytes/macrophages is significantly altered in patients with periodontitis. A significant change in the expression of Insulin-like Growth Factor Binding Protein 6 (IGFBP6) associated with an alteration in the downstream IGF signalling pathway and monocyte invasion/migration was detected and linked with altered expression of proteins within the Wnt signalling pathway. My hypothesis, to be tested in this project, is that the reduced expression of IGFBP6, together with a modification in the Wnt signalling pathway, is responsible for altered monocyte/macrophage behaviour. Moreover, these modifications contribute to atherosclerosis, making IGFBP6 a suitable biomarker of atherosclerosis progression. The second component is to compare the expression of IGFBP6 and Wnt pathway proteins in mice with/without atherosclerosis. Using a Wnt inhibitor, I will ascertain whether atherosclerosis is reduced in these mice. These investigations will reveal the translational potential of such a treatment in patients. Thirdly, IGFBP6 and Wnt pathway proteins in patients pre-and post-periodontal treatment will be quantified and compared with healthy controls to assess their potential use as biomarkers. The main benefit of this research will be a fuller understanding of the pathogenesis between periodontitis and atherosclerosis, and in the longer-term, the identification of new treatments and biomarkers, for better diagnosis, management, and life quality for patients. The findings will be transferrable to other inflammatory conditions, such as stroke, diabetes mellitus, and rheumatoid arthritis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR