NIHRDataInsights/HRCSData huggingface dataset:
Title: An Intelligent Stethoscope
Funder: Medical Research Council

Abstract: Valvular heart disease (VHD) has become an epidemic that currently affects 1.3 million people in the UK. This number is expected to double by 2040 with ageing of the population. 800,000 of those affected by VHD are unaware of their condition. Early diagnosis is key to providing timely treatment, minimising morbidity and preventing premature death. We are developing an intelligent stethoscope to automatically detect heart murmurs and diagnose the underlying pathology, which would improve early diagnosis of VHD. Currently, heart murmurs are picked up as a part of a physical exam by a General Practitioner (GP) using a stethoscope. However, VHD is often identified late, when patients are symptomatic and when many have already developed irreversible complications (such as heart failure) or post-mortem. Our proof-of-concept system can detect 94% of the heart murmurs identified by doctors. With the collection of more clinical-data and matched echocardiograms, the system will be able to surpass the rate of identification and accuracy achieved by trained practitioners via auscultation. It could also be used by less-skilled healthcare professionals in a screening program for those at risk. This would reduce the number of missed diagnoses, reduce the burden on GPs of detection, and support early intervention to minimise morbidity and mortality.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Development of a successful novel technology for sudden cardiac death risk stratification for clinical use - LifeMap
Funder: Medical Research Council

Abstract: Sudden cardiac death (SCD) is responsible for over 3 million deaths worldwide annually. The majority are due to lethal heart rhythm disturbances which could be aborted with implantable cardioverter defibrillators (ICDs). However, selecting appropriate patients for ICDs is extremely difficult. The limiting factor is the poor performance of current SCD risk stratification largely based on the degree of cardiac dysfunction, heart failure status and QRS duration. 60 % of those deemed "high-risk" according to the crude guideline criteria and have ICDs implanted do not ever use them during the 4-5 years device lifespan at a cost of £10,000 per ICD. On the other hand, the majority of SCD occurs in a large population regarded as "low-risk" for which there is no risk assessment available. We have translated preclinical understanding of electrical restitution in ventricular arrhythmogenesis, into the development of LifeMap. This technology comprises 2 novel ECG markers - Regional Restitution Instability Index (R2I2) and Peak ECG Restitution Slope (PERS), supported by patent applications (R2I2 granted in 4 countries, PERS to be granted in Australia). Using predefined threshold cutoffs, patients positive for both R2I2 and PERS had a relative risk of VA/SCD 21.6 times that of those negative for R2I2 and PERS. The high positive predictive value (80%) of LifeMap markers for SCD/ ventricular arrhythmia (VA) supports that they will be of clinical utility in the large intermediate risk population. This proposal aims to translate the current, laborious research technique into an effective clinical tool, to be used by medical professionals with minimal training and offer accurate risk assessment for SCD. A novel product will be developed, including automated software with user interface and customised proprietary modules which will produce LifeMap markers acquired during pacing or exercise. This would bring LifeMap to the next phase of development ready for a pivotal trial.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Pathways of calcium signalling in atrial fibrillation highlighted by genomic and transcriptomic studies
Funder: Medical Research Council

Abstract: There is mounting evidence that the Gq protein-activated phospholipase C/inositol triphosphate (PLC/IP3) pathway has functional importance in the development of atrial fibrillation in mammals. Ligands for receptors that activate Gq are known to be pro-arrhythmic as is knockout of protein inhibitors of Gq. In genome wide association studies (GWAS), polymorphisms in constituents of the PLC/IP3 pathway segregate with the atrial fibrillation (AF) phenotype and their levels of expression differ in recent transcriptomic studies comparing the atrial appendages of patients with and without AF. Therefore, this work aims to investigate the extent and mechanism by which the PLC/IP3 pathway contributes to the pro-arrhythmic state in mammalian atria. This will be achieved using three lines of investigation. Firstly, the effect of angiotensin and purinergic receptor activation on single cell calcium handling including the function of T-type calcium channels will be investigated. This will be done with HL-1 and dissociated murine atrial cells using patch clamp and calcium imaging techniques. Secondly, the effect of the same receptor activation on tissue level electrophysiology and calcium signaling using multielectrode arrays and florescent microscopy will be investigated. Finally, we will focus on CACNA1G and DAG beta as both genes are implicated in GWAS and transcriptomic studies. We will investigate the effect of overexpression of these proteins and siRNA inhibition in single cells. We will investigate single-cell and tissue level electrophysiology in the DAG beta knockout mouse using wildtype littermates as controls.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Discovering the causes of mutation-negative hypertrophic cardiomyopathy
Funder: Medical Research Council

Abstract: Hypertrophic cardiomyopathy (HCM) is defined as left ventricular hypertrophy in the absence of abnormal loading conditions. It is the commonest genetic heart disease and a major cause of sudden cardiac death and heart failure. It is usually inherited as an autosomal dominant genetic trait. Yet, the yield of genetic testing is less than 60%, even in the ~50% of patients with a family history of the disease. A genetic cause is thus unknown in a large proportion of patients. Furthermore, even when the causal genotype is known, phenotype associations and predictions are still poorly defined and currently have limited clinical actionability. These gaps in knowledge expose individuals and families to uncertainty about diagnosis and their future health. It also means that the pathophysiology of the disease is unresolved and opportunities for disease-modifying therapeutic discovery are limited. New and integrated approaches are needed to diminish these evidence gaps. One major aim of this project is to explore the importance of previously understudied rare non-coding (NC) sequence variation, in a very large cohort of ~2000 HCM patients. My preliminary quantitative analysis of NC variants in HCM suggests a significantly increased burden of deep intronic variation in sarcomere genes, which might contribute to the disease phenotype. Secondly, I will seek to discover novel causal genes, using whole-exome and whole-genome sequencing approaches in ~2000 patients previously tested for mutations in established HCM genes. Thirdly, through a Genome Wide Association Study (GWAS) approach in the same cohort, I will test the hypothesis of a polygenic cause for mutation-negative HCM. Finally, I will use novel advanced cardiac imaging linked to outcomes to explore new HCM genotype-phenotype classifications.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: MICA: Novel inhibitors of Transglutaminase 2 (TG2), a new therapy to halt the progression of diabetic cardiomyopathy
Funder: Medical Research Council

Abstract: Cardiovascular disease remains the foremost cause of death across the industrialised world. The risk of developing heart failure is significantly increased in the presence of type 2 diabetes (T2D) which affects over 300 million people worldwide. T2D sufferers also have a higher risk of and worse outcome following myocardial infarction with metabolic and morphologic changes in the myocardium leading to fibrosis as a common final pathway.The term 'Diabetic cardiomyopathy' (DCM) summarises these complex changes. The mortality risk increases tenfold, and five-year survival is 12.5% in T2D patients with DCM. Targeted therapies of DCM are urgently needed. This project aims to halt the development of myocardial fibrosis in DCM by targeting the protein crosslinking enzyme Transglutaminase 2 (TG2). Aided by structure based drug design (SBDD) Aston has developed a series of highly potent and selective TG2 inhibitors. Our preliminary studies demonstrated the efficacy of these compounds in both cells and two animal models of cardiac fibrosis. Our objective is to improve the Pharmacokinetic (PK) characteristics of our lead series of compounds, while maintaining potency and selectivity. We will use a combination of synthetic chemistry,SBDD and in vitro screening to generate improved compounds that combine appropriate stability and aqueous solubility, TG2 activity, cellular efficacy and in vivo target engagement. Compounds will be tested in vitro using enzyme and cell screens and by DMPK and toxicity assays and in vivo for PK, Pharmacodynamics (PD) and toxicity. Lead compounds will be initially screened for efficacy in a mouse model of chronic fibrosis, i.e. the transverse aortic constriction model. DMPK characterisation will be performed throughout with more intensive studies expected in the final development stage. In the later stages of year 2, lead compounds will be tested for efficacy in a mouse DCM model and also tested for in vivo toxicity.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR
Title: Oestrogen and oestrogen metabolites in pulmonary arterial hypertension
Funder: Medical Research Council

Abstract: Pulmonary arterial hypertension (PAH) is a progressive disease that leads to right heart failure. The estimated survival rate at 3 years after diagnosis is only ~74% and the incidence of PAH is greater among women than men. Preclinical and clinical evidence suggest that manipulation of oestrogen (E2) synthesis, action and/or metabolism might offer a novel therapy for PAH. Indeed, four ongoing proof-of-concept clinical trials are investigating drugs that manipulate the synthesis and effects of E2. The principal investigators of these trials are collaborators in the current research proposal. It is unclear if the pathogenic effects of E2 are due to E2 itself or due to dysfunctional oestrogen metabolism leading to the accumulation of mitogenic metabolites that cause pulmonary vascular remodelling. The effects that novel drugs are having on E2 metabolism are also unclear. There are currently no blood-borne markers or non-invasive tests that can diagnose PAH. It is therefore important to investigate if unique blood-borne E2 metabolites are markers of the disease. We will examine E2 metabolism in plasma from patients. Preclinical and molecular studies in human pulmonary arterial smooth muscle cells from patients will further define the mechanisms behind the effects of E2 metabolites. We will apply a unique LC-MS/MS assay to determine the levels of E2 and its metabolites in the plasma from patients and stratify these with sex, BMI, disease status and severity. This will also be determined in patients registered into three clinical trials of drugs that affect E2 synthesis or E2 receptor function. We will determine transpulmonary gradients of plasma E2 and its metabolites in patients with PAH. Patients are very heterogeneous in age, environment, severity of disease, ongoing medication and responsiveness to drugs; therefore a reproducible animal model will allow controlled examination of the effects of sex, development of disease and novel therapies on E2 metabolism.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CARDIOVASCULAR
Title: Targeting immunomodulation following cardiac injury
Funder: Medical Research Council

Abstract: Regenerative medicine approaches to cardiovascular disease have largely centred on replacement of lost cardiovascular cells, with little attention paid to the local environment into which the new cells emerge: a cytotoxic mixture of inflammation and fibrosis which prevents engraftment and integration with survived heart tissue. We demonstrated previously that the cardiac lymphatic vasculature can respond to cardiac injury (Klotz et al., 2015. Nature) and more recently that increased lymphatic vessel sprouting (lymphangiogenesis) functions to clear immune cells to draining lymph nodes and constrain the inflammatory and reparative responses for improved outcome (Vieira et al., 2018. JCI). We now hypothesis that the cardiac lymphatics can be utilised to define functionally-relevant immune cell sub-types following cardiac injury. To test this, we will establish a time course of cardiac lymphatic vessel induction and analyses of lymphatic-compromised mouse models (Prox1-haploinsufficiency- a model of impaired lymphangiogenesis and Lyve-1 mutants- a model of impaired immune cell uptake) post-myocardial infarction (MI) to probe the temporal effects of immune cell clearance and resolution, focusing specifically on macrophages, dendritic cells and T-cells. Using combined single-cell transcriptomics and CYTOF imaging, we will identify precisely which sub-populations are cleared at which time points and how altered clearance correlates with outcome. To extrapolate to humans, we propose to study a model of human lymphatic vessels and their role in improving cardiac function post-MI. Finally, we will carry-out an unbiased chemical screen for novel activators of human lymphatics to establish the basis for promoting therapeutic lymphangiogenesis in human MI patients.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: CARDIOVASCULAR
Title: Reducing Premature Coronary Artery Disease in Malaysia by early identification of Familial Hypercholesterolaemia
Funder: Medical Research Council

Abstract: BACKGROUND: Premature coronary artery disease is increasing rapidly in Malaysia and Familial Hypercholesterolemia (FH) is an important cause. Most FH cases remain undiagnosed. The UK team has developed a new primary care approach (FAMCAT) that is upto 20% better at identifying FH than the established Simon-Broome (SB) and Dutch Lipid Clinic (DLCC) diagnostic criteria. But FAMCAT's performance needs to be validated in Malaysia. Combined with eliciting patients and primary care practitioners' opinions of the approach, the study aims to improve identification of FH in Malaysian primary care STUDY OBJECTIVES: 1. To compare detection rate of FH in Malaysian primary care population between FAMCAT and established clinical diagnostic criteria (SB and DLCC): Workstream (WS)1 2. To identify FH genetic profile in individuals with suspected FH in the Malaysian primary care population: WS2 3. To explore the experience, concerns and expectations of individuals with suspected FH who are referred for genetic testing: WS3 4. To evaluate clinical utility of a new FH case identification tool in Malaysian primary care: WS3 DESIGN AND SETTING: Through an observational study, WS1 will identify individuals with suspected FH in the Malaysian primary care using FAMCAT, SB or DLCC, who will be offered genetic testing. WS 2 will use targeted next generation sequencing to identify FH-causing genetic mutations. WS 3 will use qualitative interview methods to explore the experience of patients with suspected FH and primary care practitioners' opinions on usability of FH case identification tool POPULATION:6800 patients complete 10 minutes assessment in 12 primary care clinics to identify 310 patients with suspected FH (WS1 &WS2). Up to 25 patients referred for genetic testing and 40 primary care practitioners (WS 3) OUTPUT: Primary care FH case identification tool, genetic testing regime and clinical pathway that is acceptable to patients, doctors and policymakers.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: LOng-Term anatomical fluid dynamics for new Univentricular heartS palliation (LOTUS)
Funder: Medical Research Council

Abstract: This project will take advantage of a unique partnership between USM and Hospital Raja Perempuam Zainab II, in Malaysia, and a world-leading team in the UK, blending together extensive clinical experience from both countries with engineering and mathematical modelling and High-Performance Computing (HPC) research. USM has a well-established research-active Unit of Paediatric and Congenital Cardiac Surgery, with state-of-the-art data acquisition capabilities and a unique and well-maintained data set of patients of all ages. This will be used for the calibration of the mathematical/computational model aimed at explaining the long-term impact of Univentricular Heart (UVH) palliation. The prediction of the morphological changes in the vascular system, as consequences of growth and modifications induced by the surgical procedures, will be achieved by a state-of-the-art artificial intelligence technology based on the generative adversarial neural networks. The project will make use of freely available specialised software, such as CRIMSON, SimVascular, VMTK, for image segmentation and geometry meshing, enhanced by advanced image segmentation software and novel geometric rendering of vascular alterations from surgery based on advanced parametric surface classes. New Computational Fluid Dynamics (CFD) approaches based on polyhedral discretisations will be developed for computational turnaround speedup and reduction of highly skilled time-consuming human intervention at the meshing stage. In particular, three incremental CFD solver will be released, of increasing fidelity, based on novel polytopic 3D meshes of the vessels, pipe-like curvilinear elements designed to reduce the computational costs inherent to standard 3D meshing, inclusion of fluid-structure interaction phenomena modelling compliant vessels.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: CARDIOVASCULAR
Title: Potential of acellular biological scaffold coated with chemokines and cytokines as tissue engineered small artery grafts
Funder: Medical Research Council

Abstract: Millions of coronary and peripheral artery bypass procedures are undertaken yearly worldwide using autologous saphenous veins (SVG) or synthetic grafts. However, >50% of these grafts get blocked after 5-10 years. Moreover, vein graft occlusion is more frequent in diabetic patients than non-diabetics. Infections at the harvesting sites, hospital re-admissions, and revascularizations are also common, which further reduces the success of the grafts. Arterial conduits are used only in ~20% of all cases, despite a >95% patency rate at 15-20 years and reduced long-term mortality. Bioengineering of small arterial conduits is a possible alternative approach to improve SVG patency. Our pilot suggests that implanting acellular biological grafts in a porcine carotid artery leads to in situ arterial bioengineering by host cells, although with a sub-optimal three-layered wall, asymmetric cell recruitment and matrix remodeling. In this application, we aim to improve our results by modulating cell recruitment and differentiation within the graft by coating scaffolds with chemokines and cytokines (monocyte chemoattractant protein-1 (MCP-1), fractalkine, pleiotrophin and tumour necrosis factor-alpha (TNF-alpha)). We hypothesize that the use of these chemokines will attract monocytes and the cytokines will promote differentiation into endothelial-like cells and produce more structured and functional arterial-like grafts. We will develop the coated acellular grafts and test their performance in vitro (bio-reactor) and in vivo (porcine carotid artery implantation). Our laboratories are highly experienced with in vitro and in vivo models of grafting and tissue engineering which are essential for the success of this project. The creation of this off-the-shelf graft will avoid the use of autologous vein which will save surgical time and money as well as eliminating the risk of infection and discomfort of the leg in addition to improving the function of the graft.


Research activity codes: 5.4 SURGERY
Health categories: CARDIOVASCULAR
Title: Evaluating the role of pharmacists and m-Health strategies in the management of hypertension in General Pueyrredon
Funder: Medical Research Council

Abstract: Hypertension is one of the main cardiovascular risk factors in Argentina, with a high prevalence (36%) and an important social, economic and health impact. Despite the availability of highly effective treatment and preventive strategies, only half of hypertensive patients are aware of their condition and the majority are not appropriately controlled. The incorporation of pharmacists and the use of information & communication technologies (ICTs), are two of the strategies that have shown to be effective in the improvement of hypertensive patients' management. This proposal is aimed at evaluating the access, acceptability, adoption and impact of an innovating program, which incorporates pharmacists, social marketing and the use of ICTs ("Health MGP" https://saludmgp.rpmplay.com/ and a mobile app) in the diagnosis, treatment, monitoring and control of hypertension in patients with different types of health coverage and from different social strata at the Municipality of General Pueyrredón, Province of Buenos Aires, Argentina. Adult residents of this city (>18 years old), excluding pregnant women, will constitute the eligible population. A mixed method study will be conducted.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: CARDIOVASCULAR
Title: Building a comprehensive aortic aneurysm and dissection prediction model incorporating genetic and non-genetic factors
Funder: Medical Research Council

Abstract: Aortic aneurysm and dissection (AAD) is a potentially devastating vascular condition that is often silent until a significant complication occurs. Monogenic, polygenic and clinical risk factors all play a major role in AAD susceptibility and prognosis. Screening and preventative interventions can reduce risk of death and disability from AAD but early identification remains a problem. It is possible that comprehensive risk models, based upon age, electronic health records, genetic data and/or imaging could stratify the population to enable provision of efficient personalised screening. These data could also inform individualised surgical treatment and post-operative surveillance strategies. We aim to evaluate the impact of genetic and other clinical factors on the risk of aortic diseases in the UKBiobank and then model risk distribution using primary incidence rates from the OxVasc study to generate data that could be used to inform screening policies. As an extension to this we aim to develop an ambitious recall-based study to evaluate advanced aortic imaging features of individuals with high genetic risk to evaluate presence of subclinical phenotypes that could guide preventative treatment strategies.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR