NIHRDataInsights/HRCSData huggingface dataset:
Title: Ultrafast contrast enhanced ultrasound for imaging and quantifying flow and tissue perfusion
Funder: Engineering and Physical Sciences Research Council

Abstract: Imaging and quantifying blood flow and perfusion are critical to the diagnosis and management of a range of major diseases including coronary heart disease, valvular heart disease, carotid, cerebral and peripheral vascular diseases, cancer, and chronic in


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Effect of blood versus crystalloid cardioplegia on cardiac dysfunction and patient outcome following cardiac surgery with cardiopulmonary bypass in children: Investigation of clinical outcome and myocardial molecular biology.
Funder: Chief Scientist Office (Scotland)

Abstract: Surgical repair of congenital heart defects requires temporary suspension of heart contraction, a period of myocardial ischemia followed by reperfusion resulting in timerelated myocardial injury. The choice of cardioplegia by surgeons to limit injury is not evidence based but has evolved without consensus in the paediatric population. Our research proposal is a randomised controlled trial comparing the efficacy of blood versus a new crystalloid cardioplegia in children undergoing cardiac surgery using cardiopulmonary bypass. The project will be ‘translational’ in design. By determining which molecular markers of damage are altered in myocardium in vitro by cardioplegia exposure, as well as determining effects of cardiolegia on sensitive markers of heart function, we will determine which method of cardioplegia will emerge as superior in improving patient outcome, reducing the inflammatory response and cardiac damage. This study will help surgeons decide better the choice of cardioplegia protection, hence improve patient outcome and reduce health service costs.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Investigating the therapeutic potential of cathepsin-L inhibition to limit ischaemiareperfusion injury in the heart.
Funder: Chief Scientist Office (Scotland)

Abstract: Coronary Heart Disease (CHD) is the main cause of death in Scotland. CHD leads to reduced myocardial blood flow (ischaemia) resulting in contractile dysfunction. In order to limit ischaemic-induced damage, myocardial reperfusion is required but paradoxically this can exacerbate cardiac dysfunction in a phenomenon called ischaemia-reperfusion (I/R) injury. Effective therapeutic strategies to limit I/R injury require identification of novel therapeutic targets. We have identified a novel target called cathepsin-L which is a protease that directly impairs cardiomyocyte function. Our novel ex vivo data demonstrate that cathepsin-L is increased during I/R and when inhibited prior to I/R improves myocardial function. We aim to advance this exciting ex vivo data along the translational pathway to characterise (a) the effect of a cathepsin-L inhibitor on I/R injury in vivo and (b) establish for the first time in CHD patients the cathepsin-L activity before and after reperfusion and its implications for myocardial function.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR
Title: Understanding the genetic regulation of adrenal steroid hormones in cardiovascular disease - developing a stratified approach to cardiovascular care.
Funder: Chief Scientist Office (Scotland)

Abstract: We will use large scale Scottish cohorts (Go-DARTS and Generation Scotland) to understand how variation at three key loci determining adrenal steroid synthesis - CYP11B2 (aldosterone synthase), C Y P l l B l (lip-hydroxylase) and CYP17A1 (17a-hydroxylase) - affect cardiovascular risk, outcome and response to therapy. To do so, we will first carry out a programme of discovery to define tag single nucleotide polymorphisms, allowing subsequent rapid genotyping to be performed on the three genes. We will use existing phenotypic and health outcome data, including response to cardiovascular drugs, to link genotype data and define predictors of risk and therapeutic responses, particularly to drugs that affect the renin/angiotensin/aldosterone system. These data could enable the definition of novel diagnostic tests that permit stratification of patients and lead to personalised care. This approach therefore has the potential to improve significantly the management of several common cardiovascular conditions, including high blood pressure.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: 18f-sodium fluoride imaging of abdominal aortic aneurysms
Funder: Chief Scientist Office (Scotland)

Abstract: Ruptured abdominal aortic aneurysms (AAAs) have a 90% mortality rate but there are currently no accurate methods of establishing the risk of rupture for an individual patient with an asymptomatic AAA. In vascular disease, microcalcification occurs in response to necrotic inflammation. Using computed tomography and positron emission tomography, we can identify early microcalcification using uptake of the radiotracer 18F-sodium fluoride. This can identify high risk-lesions in the aorta, coronary and carotid arteries, and appears to be indicative of necrotic and heavily inflamed tissue. We therefore propose to evaluate the ability of 18F -sodium fluoride to identify regions of necrotic inflammation in AAA and predict AAA expansion. We will also explore its additive value as part of an ongoing clinical trial assessing the identification of macrophage activity using magnetic resonance imaging. If successful, this could become an invaluable clinical tool to determine patients at high risk of rupture and requiring elective aneurysm repair.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Advanced Clinical Cardiovascular MR Imaging and Spectroscopy at 7 Tesla
Funder: Medical Research Council

Abstract: MR imaging of the cardiovascular system (CMR imaging) has made a huge clinical and scientific impact. Currently, CMR is performed at field strengths of either 1.5 or 3 Tesla (T). Here, CMR allows analysis of cardiac anatomy, function, viability and perfusion. CMR can offer much deeper insight into cardiac pathophysiology, as it is capable of providing accurate information about cardiac metabolism and oxygenation, coronary lumen anatomy and atherosclerotic plaque. However, these advanced CMR applications currently are severely limited by their low resolution and reproducibility. While 3T, compared to 1.5T, provides resolution gains in the right direction, these are insufficient. Our understanding of the major epidemic diseases in Cardiology, ischemic heart disease and heart failure, would benefit greatly from reliable and highly reproducible non-invasive characterisation of these advanced parameters. This would allow fundamentally novel insights into disease mechanisms and treatment effects. We aim to be at the leading edge of this new development by obtaining a high-field (7T) imaging system as a platform from which these highly desirable goals can be made a reality. In a collaborative effort (with local, national and international MR Physics partners), we will develop CMR methods at 7T, the first such effort in the UK (and probably in Europe). MR physics research will initially focus on coil design, SAR and B1 management, RF pulse optimisation, regional shimming. High resolution quantitative MR spectroscopy (MRS) will be developed, to measure cardiac high-energy phosphates and the novel parameters CK flux and free energy change, regionally resolved, with high reproducibility, making true metabolic imaging of the heart by MRS a reality for the first time. Clinical research applications will include ischemic heart disease, heart failure and hypertrophic cardiomyopathy. Coronary lumen and wall imaging will be developed with unprecedented resolution, allowing reliable non-invasive serial assessment of coronary artery disease in application studies. The BOLD effect is greatly enhanced at 7T, and we will develop robust imaging of myocardial oxygenation, allowing assessment of the interrelations amongst cardiac function, perfusion, oxygenation and metabolism in patients. Such a development has the potential to transform CMR imaging of cardiac metabolism, oxygenation, and coronary plaque from a niche research tool into a mainstream diagnostic measure that can treat the patient as an individual, enabling doctors to monitor the progress of a disease or the response to therapy. Such new MR techniques would contribute significantly to improving cardiovascular health and to relieving the burden of cardiovascular disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Characterisation of the United Kingdom thrombotic thrombocytopenic purpura (TTP) patient cohort
Funder: Medical Research Council

Abstract: Thrombotic thrombocytopenic purpura (TTP) is an acute life threatening disorder. It typically affects females between 30-40 years, but can present from birth to 80 years. TTP results from a deficiency of the enzyme ADAMTS 13, required for the cleavage (on secretion) of von Willebrand Factor (VWF) converting it from ultra large (ulVWF) molecular forms with excessive platelet reactivity, to normal forms Lack of ADAMTS13 results in platelet clumping and multi-organ microvascular thrombosis, with resultant clinical sequelae. Identification and treatment is the key to survival; without therapy mortality is 90%; with plasma exchange mortality is 15-20%. Plasma is a source of the missing/dysfunctional enzyme, ADAMTS 13, and plasma exchange using cell separators allows large volumes to be given as well as assisting in removal of ulVWF and ADAMTS13 antibodies. The majority of cases are acquired idiopathic (antibody mediated), but congenital TTP (identified in childhood or adults) and TTP secondary to other conditions make up 20% of all cases. We have presented a local, non-funded, observational, South East England TTP registry, but want to extend this throughout the UK. The aim is to gather important epidemiological information about patient characteristics, mortality/morbidity and treatment availability in the UK. After a review of this data, we the aim to extend multicentre trials to all centres treating TTP. The availability of recombinant ADAMTS13 (rADAMTS13) will be assessed for congenital TTP cases, who would be more easily identified from a UK registry. The adaptation of therapy to individual phenotypes will not only serve to assess the efficacy of rADAMTS 13, but prevent long term sequelae of no treatment. Statistically powered, randomised, controlled trials can only be undertaken when an appropriate cohort of patients are available. It is imperative to attain remission as quickly as possible in acute episodes to prevent long term morbidity or mortality. As idiopathic autoimmune TTP accounts for the majority of the cases, this will be the other primary focus using monoclonal antibody therapy (directed against autoantibody production). Assessment of the baseline and remission ADAMTS13 levels via central analysis will provide more information on the importance of antibody titres and epitope specificity in relation to precipitation of disease. Involving all UK sites and cases will provide a large DNA bank for analysis of ADAMTS13 gene mutations/polymorphisms and allow their importance in the risk of TTP subtypes to be assessed. Ultimately, this will improve the scope of treatment for patients with this devastating disease.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CARDIOVASCULAR
Title: Prevention IMPACT: developing and evaluating economic models for planning optimal cardiovascular prevention strategies
Funder: Medical Research Council

Abstract: The prevention of future cardiovascular disease (CVD) remains problematic. Planning and prediction challenges include: complex causes, diverse manifestations, increasing costs, population ageing and conflicting trends in obesity, diet, smoking and inequalities. Our multi-disciplinary group will therefore: # systematically review the scientific evidence; # elicit the views of NHS decision-makers; # identify a range of policy options; # further develop a validated coronary policy model to include stroke and other CVD; # compare the effectiveness and cost-effectiveness of different risk factor reduction strategies in high risk individuals and in entire populations; # share results with planners, policy-makers, professionals and patient groups.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: CARDIOVASCULAR
Title: Development and Validation of Cardiovascular MR Imaging and Spectroscopy at 7 Tesla
Funder: Medical Research Council

Abstract: This programme of work develops the tools and methodology for clinical cardiac MRI at 7 Tesla, from building the hardware right through to running studies with our clinical researchers. Existing grants have funded the equipment for 7Tesla whole body imaging in Oxford (the only UK cardiac capable ultra-high-field imaging system). The present proposal builds on this technology with sufficient man-power to allow our group to lead in this field. Owing to the challenges of cardiac imaging at 7Tesla and the expense of such a system, longer term Programme Grant funding is sought, this will enable a small but focused team to transition these techniques from being ?theoretically valuable? to actually being present on clinical systems, providing new, useful tools for research and clinical practice. The objective of our work is to develop tools that improve our ability to evaluate the heart in humans. The 7T scanner provides substantially increased signal to noise ratio (SNR) over present technology. We will investigate three areas where 7T shows great promise but is limited due to insufficient SNR at lower field strengths; 1) Coronary Magnetic Resonance Angiography (MRA). 2) BOLD imaging of the heart. 3) Phosphorus spectroscopy of the heart. There are several technical challenges in this work that are mostly related to the transmission of radiofrequency (RF) pulses. The first goal will be to translate the state-of-the-art proton RF coil designs developed by our collaborators (T.Vaughan, Minnesota University) onto our 7T system. To achieve this, we have invested time working in Minnesota, and they will provide hardware and support as part of our research collaboration. Enabling routine proton imaging of the heart at 7T is essential, and once in place will allow us to investigate coronary imaging at 7T with our expert collaborator (D.Li, Northwestern University, Chicago), and will provide the platform for our cardiac BOLD imaging methods. The second goal is to implement Phosphorus spectroscopy at high resolution for regional metabolic imaging of the heart. We will re-engineer a 3Tesla 32-channel proton coil to operate at 7T for 31P, and build a transmit coil. High quality coronary MRA without ionizing radiation; fast regional metabolic imaging; and localised measurements of cardiac oxygenation deficits would all have direct clinical and scientific impact, and are within the scope of this project. With an MRC programme grant, we would have the technical ability and infrastructure to be a world leading 7T cardiac imaging centre.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CARDIOVASCULAR
Title: MRC-BHF Cardiovascular Stem Cell Research Strategic Development Grant
Funder: Medical Research Council

Abstract: In humans and other mammals, the inability of adult myocardium to overcome cell death with equivalent muscle cell creation makes heart muscle cell number unusually well-posed as a therapeutic target. Notwithstanding a few exemplars, the clinical aspirations arising from this biological limit have led to a plethora of largely repetitive empirical trials with weak outcomes overall, little proven impact on myocyte formation and, typically, weak scientific underpinnings. The need is unequivocal for better, deeper, more systematic knowledge?including genomic, post-genomic and functional characterization of relevant cardiopoietic cells, if a step change is ever to occur in progress towards cardiac regeneration as a workable clinical goal. Inherently, the problem requires a team-based or consortium approach, as is sought by the present MRC-BHF call. This Cardiovascular Stem Cell Research Strategic Development Grant at Imperial College London is a coordinated effort of the National Heart and Lung Institute (NHLI) headed by Prof. Michael Schneider FMedSci, an innovative pioneer in cardiovascular stem cell biology, and the MRC Clinical Sciences Centre (CSC) headed by Prof. Amanda Fisher FMedSci, a distinguished authority on stem cell epigenetics. Members of the proposed Cardiovascular Stem Cell Research Strategic Development Grant include key experts in mouse genetics, genomics and epigenetics, focused collectively on a series of essential fundamental problems: (1) fate-mapping to define the embryological origin of cardiac progenitor cells and their subsequent contribution to the heart in health and disease; (2) sirtuins and insulin-like growth factor-1 as epigenetic modulators of cardiac repair; (3) chromatin profiling and epigenetic reprogramming of cardiac progenitor cells; (4) high-throughput high-content analyses of cardiac progenitor cell differentiation and function; and (5) next-generation genomics for gene, pathway and chromatin studies in cardiac progenitor cells. A 6,0000 m2 Cardiovascular Research Centre is under construction at Imperial?s Hammersmith campus, adjacent to expanded MRC facilities, and a highly robust recruitment drive is already underway. Apart from the specific questions to be addressed, the overriding goal of this proposal is alignment, integration and capacity-building, establishing an internationally competitive cardiovascular stem cell community that would help lead UK science in this realm and warrant a full-scale Centre in three years? time.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.2 CELLULAR AND GENE THERAPIES
Health categories: CARDIOVASCULAR
Title: An interactive in vivo and molecular investigation of the arrhythmogenic mechanisms of sudden cardiac death
Funder: Medical Research Council

Abstract: Sudden cardiac arrest (SCA) due to ventricular arrhythmias claims over 300,000 lives per year in the U.S and 50,000 lives per year in the UK). Prior to cardiac arrest alternating changes on the surface ECG frequently occur which are thought to arise from fluctuations in the electrical currents on the surface of the heart. These fluctuations are initially in phase with one another (concordant alternans) and then become out of phase (discordant alternans) before degenerating into ventricular fibrillation (VF). Although animal studies have demonstrated this, it has not been possible to study these events in man. We have developed a unique strategy to investigate these phenomena in patients undergoing cardiac surgery. This involves multielectrode mapping of the whole heart in combination with cellular electrophysiology & gene expression studies of tissue biopsied from sites susceptible to and resistant to alternans identified by our new on line analysis algorithms of alternans. We will use these data to (1) improve risk stratification of patients for implantable defibrillators based on ECG microvolt T wave alternans (2) improve our understanding of mechanisms underlying discordant alternans in patients with cardiac disease, (3) attempt to identify targets for pharmacological therapy, (4) identify novel pacing strategies to be implemented on implantable devices to prevent ventricular fibrillation, (5) provide unique human whole-heart and molecular data as a first stage in informing a computer model for future on-site, on-line interaction with combined whole-heart / cellular electrophysiology patient studies. This ?virtual heart? model could be employed to predict beat by beat events in the evolution of ventricular arrhythmia and test pacing strategies to abort the transition of alternans to VF. It could also be used to develop & evaluate the effects of new anti-dysrhythmic drugs and minimise the use of testing in animals.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.3 MEDICAL DEVICES
Health categories: CARDIOVASCULAR
Title: Cell-matrix biology of the vascular progenitor cell niche.
Funder: Medical Research Council

Abstract: This proposal is to define the cell-extracellular matrix biology of the vascular mesenchymal progenitor cell (MPC) niche, as a basis for developing effective new cardiovascular therapies. MPCs offer immense opportunities for treating cardiovascular disease, given their accessibility, immunosuppressive and anti-inflammatory properties, paracrine contributions to tissue repair and potential to differentiate along vascular lineages. However, their underlying biology remains poorly defined and a major obstacle to realising their therapeutic potential. Signals across the cell-matrix interface control numerous aspects of cell biology, including survival, proliferation, migration and differentiation. This timely interdisciplinary proposal is to exploit our combined unique international strengths in cell-matrix and mesenchymal progenitor cell biology, state-of-the-art proteomics and glycomics, and in vivo models to define the MPC cell-matrix niche and apply this knowledge therapeutically. We will undertake systematic analysis to define the cell-matrix niche of MPCs from bone marrow and umbilical cord, generating a comprehensive (open access) database. This knowledge will allow us to determine how cell-matrix niche molecules control MPC fate decisions, to select MPCs reproducibly and track them during vascular regeneration in vivo, and to exploit the niche to enhance MPC-mediated repair of damaged blood vessels in injured hearts and the performance of engineered vascular grafts. Our studies will underpin a future pipeline of interlinked basic and translational studies of lead target proteins as determinants of cell fate and MPC-based cardiovascular therapies. The ultimate goal is to direct revascularisation of ischaemic heart and peripheral tissues. Thus, we offer a timely and exceptional opportunity to advance novel progenitor cell therapies for cardiovascular repair.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.2 CELLULAR AND GENE THERAPIES
Health categories: CARDIOVASCULAR