NIHRDataInsights/HRCSData huggingface dataset:
Title: Development of a Novel Angioplasty Catheter for Treatment of Calcified Arteries
Funder: Medical Research Council

Abstract: Coronary calcification is an inherent element of atherosclerotic coronary disease which poses significant challenges to percutaneous coronary intervention (PCI) procedures. Vascular mural calcification can prevent effective coronary dilation or lead to incomplete expansion of coronary stents. Extensive coronary calcification at present may preclude a PCI approach necessitating either open heart surgery or a palliative medical strategy. The number of procedures with coronary calcification is increasing as coronary intervention moves into an older population. We seek to address this need with a novel PCI compatible device. Currently two technologies are in use both having either limited efficacy or require training in a unique complex skillset not familiar to the majority of operators. Scored or 'cutting' balloons are bulky and delivery into calcific lesions is frequently impossible. Rotational atherectomy or rotablation is a technology where a rotating diamond coated burr is introduced to disrupt coronary calcification. Rotablation is effective but requires specific training distinct from traditional PCI techniques. It is notable that although this technology has been available for many years, the proportion of trained operators remains low. Both methods are associated with increased complication rates due to vessel injury, dissection and perforation. It is known from elementary mechanics that impulses can produce a great amount of force over a short time interval. This is the functional principle that instruments like impact hammer or impact wrench work very well. It is also well know from fluid mechanics that incompressible fluids can be used as a medium for rapid and efficient power transmission. Such fluids have been used in familiar hydraulic jacks. We propose to adapt these technologies to develop a catheterised device enabling localised endovascular therapy at a controlled depth and energy for disrupting the vascular calcium to facilitate subsequent PCI


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: CARDIOVASCULAR
Title: A foundation study of the effects of postnatal enalapril on maternal cardiac function following early-onset pre-eclampsia.
Funder: Medical Research Council

Abstract: Early-onset pre-eclampsia (EPE), is associated with postnatal (PN) maternal cardiac dysfunction and long-term cardiovascular risk. PN cardiac dysfunction is a strong predictor of PE recurrence. Mechanistic data linking EPE and cardiac dysfunction is limited and no PN interventional studies have assessed its reversibility. Soluble fms-like tyrosine kinase-1 (sFlt) is up-regulated in EPE and induces cardiac remodelling in rat models. Angiotensin-Converting Enzyme (ACE) inhibitors prevent cardiac remodelling following myocardial ischaemia in adult heart disease, but have not been used in PN EPE women. Hypothesis: sFlt mediates maternal cardiac dysfunction following EPE and this can be ameliorated by PN administration of an ACE inhibitor (enalapril). Objective 1: Characterise the pathophysiology of maternal cardiac dysfunction following EPE and determine if it can be modified by PN treatment with enalapril. Women will be randomised to enalapril or placebo in a double blind randomised controlled trial (RCT). Measured outcomes will be cardiac function measured by echocardiography and serum biomarkers. Objective 2: i) Explore the mechanism of sFlt-mediated cardiac dysfunction in an animal model of PE and ii) determine if it can be ameliorated by PN enalapril treatment. i) Pregnant rats will be treated with exogenous sFlt/vehicle. Cardiac damage will be investigated using a panel of cardiac and angiogenic biomarkers, echocardiography, macroscopic and microscopic assessment of left ventricular mass, capillary density, fibrosis and oxidative damage. ii) The same rat model will be used to determine whether cardiac damage is ameliorated by PN enalapril. These studies will provide novel data on the mechanism of cardiac injury following EPE and the potential benefit of PN enalapril treatment. If successful, this will lead to longer term PN intervention studies in this high-risk group, which have the potential to dramatically reduce the long-term consequences of EPE.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR
Title: Development of a Gal-free Calcification Resistant Porcine Pericardial Heart Valve: Establishment of Biological Tissue Equivalence.
Funder: Medical Research Council

Abstract: Of the 300,000/yr replacement heart valves (RHVs) implanted, there are two types, mechanical (MHVs) requiring lifetime anticoagulation, and bioprosthetic (BHVs), made from bovine or porcine valves or pericardium, which generally do not. Patients under 60 are chiefly treated with MHVs to avoid accelerated age-dependent BHV calcification/degeneration seen in younger patients. Trends in RHV surgery include increasing use of BHV's (from 40 to 60% of total) and the use of transcatheter valves (>200,000 to date) whose leaflets are made of bovine or porcine pericardium. Universal human anti-Gal antibody, binding to the Gal antigen on commercial BHVs, promotes calcification. GTKO pig tissue does not contain Gal and is not subject to immune mediated calcification. A GTKO BHV may potentially reduce calcification, improve durability, and make BHV's available to younger patients. To progress development of such a BHV we compared the physical, hydrodynamic and durability performance of pericardium from GTKO and wild type (WT) pigs in an in-house constructed BHV, detecting no significant differences between the two. This application now compares the biological properties of valves made from GTKO and WT pericardium. Objective 1 is to improve the durability of our in-house BHV to have predictable performance for in vivo testing. Manufacturing improvements in our in-house valves have already improved durability. Objective 2 is to compare the biological properties of GTKO and WT pericardial BHVs using the industry standard mitral valve replacement in juvenile sheep with 90-day survival. Primary endpoints are gross valve pathology, histological analysis of valves for evidence of cardiac thrombus deposition, pannus formation, inflammation, calcification or structural valve deterioration and quantitative calcium determination using atomic spectroscopy on valves at explant. This testing is the last step to de-risk commercial adoption of GTKO materials for future BHV development.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: CARDIOVASCULAR
Title: Thiol-disulfide redox switches in protein kinases and their role in cardiovascular health and disease
Funder: Medical Research Council

Abstract: We have previously discovered several proteins in the cardiovascular system that are regulated by changes in their oxidation state. These proteins play crucially important roles in the healthy function of blood vessels and the heart. However, these redox-regulated proteins can also become aberrantly stimulated during stress scenarios associated with increased oxidant levels (oxidative stress), events that can contribute causatively to disease pathogenesis. At the moment our understanding of how changes in oxidative stress regulate proteins in the cardiovascular system is far from complete, an issue that this application seeks to address. We have recently identified a host of proteins in the heart that were previously not known to be modified by oxidants, and our objective now is studying them to understand the impact this have on their enzymatic activities, as well for cardiovascular function. In addition to studying these proteins at the biochemical and cell biological level, we also have generated novel transgenic mouse models in which the redox sensing has been replaced so they cannot sense or transduce oxidant signals. By studying these redox dead mice, or tissues or cells isolated form them, and comparing their response to wild type controls, we will be able to define the roles these protein sensors play in the maintenance of cardiovascular health, and how they may be dysregulated during disease. To achieve our aims we will use a multidisciplinary approaches, with in vivo cardiovascular phenotyping (telemetric blood pressure, echocardiography, Pressure-Volume analysis) together with ex vivo functional tissue studies (isolated hearts, isolated blood vessels) and biochemical analyses (Western immunoblotting, kinase activity assays, histology). Protocol with mice will be randomised and blinded analysis and subject to full power analysis to ensure adequate sample size is utilised. Ultimately, these studies may provide important clues about new drug targets.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CARDIOVASCULAR
Title: IMPC: Investigating the role of Trichoplein (TCHP) in post-ischaemic vascular repair
Funder: Medical Research Council

Abstract: After the onset of ischaemia, hypoxia-related pathways, immunoinflammatory balance, as well as changes in hemodynamical forces within vascular wall trigger all the processes regulating vascular homeostasis, including vasculogenesis, angiogenesis, arteriogenesis which act in concert to establish a functional vascular network in ischaemic zones. In patients with ischemic diseases, most of the cellular and molecular mechanisms involved in the activation of vessel growth and vascular remodelling are markedly compromised. Moreover, impaired endothelial function due to cardiovascular risk factors such as obesity and diabetes leads to development and rapid progression of severe vascular diseases. Thus, the identification and characterization of novel genes/regulatory pathways to better understand the process behind vascular repair is therefore crucial. Based on prior work, we have demonstrated that microRNA-503 (miR-503) has a prominent role in the diabetes-induced impairment of post-ischemic neovascularization. Leading on from the characterization of miR-503 targets, we have identified a novel regulator of endothelial cells (ECs) function - Trichoplein (TCHP). Our preliminary data reveal that loss of TCHP function in ECs led to an impaired EC functions such as migration and angiogenesis. Accordingly, disruption of TCHP gene expression in zebrafish using morpholinos results in defective blood vessel formation. Finally, we see a decreased expression of TCHP in ECs of type 1 diabetic mice and ECs from patients with vascular dysfunction and premature coronary artery disease. However, very little is still known on the role of TCHP during post-ischaemic angiogenesis, how it regulates vessel dynamics, and whether it plays a role in blood vessel growth. We will therefore generate an endothelial lineage-specific TCHP knockout mouse, to determine the basal cardiovascular phenotype in these mice and to analyse the importance of TCHP during vascular injury.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Mechano-enzymatic cleavage of transthyretin in systemic amyloidosis: elucidation of mechanism and characterization of putative proteases
Funder: Medical Research Council

Abstract: We have identified a new pathway for TTR amyloidogenesis which is primed by proteolytic cleavage followed by TTR dissociation and fibril formation. We have compelling evidence that plasmin, the key proteolytic enzyme of the physiological fibrinolytic pathway, is central to TTR amyloid formation. In WP1 we will determine the rate constants for the 5 central reactions involved in the transformation of native tetrameric TTR into amyloid fibrils: 1. Selective cleavage of native TTR at the peptide bond Lys48-Thr49 (k1). 2. Proteolytic degradation of truncated 49-127 TTR fragment (k2). 3. Proteolytic degradation of full-length 1-127 TTR protomer (k3). 4. Oligomers formation (k4). 5. Aggregation of full-length and/or truncated protomer into amyloid fibrils (k5). In WP2 we plan to establish the intensity of shear stress required for the activation of the mechano-enzymatic cleavage for the most common amyloidogenic variants and investigate the relationship between the shear stress required for each individual variant and their corresponding thermodynamic stability. In WP3 we will test the effect of drugs, including those currently in clinical use, on the model of fibrillogenesis designed in WP1. We will carry out a comparative analysis of the efficacy of monovalent and bivalent TTR ligands in inhibiting the fibril formation. We will examine how TTR ligands can affect the composition of amyloid fibrils and whether they may reduce the amount of truncated TTR species which is converted into fibrils. In WP4 we will characterize how the physiological activation of plasminogen to plasmin can affect cleavage and amyloidogenesis of TTR. We aim to understand how modulation of this enzyme by its activators and inhibitors can affect the kinetics of the fibrillogenic pathway, the final yield of amyloid fibrils and their composition.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Genetic analyses of ventricular depolarisation and repolarisation and prediction of cardiovascular risk.
Funder: Medical Research Council

Abstract: Genome wide association studies (GWAS) for QT, JT and QRS interval have provided new information on the underlying mechanisms behind ventricular depolarisation and repolarisation. However, the heritability of these traits is not fully explained, and further investigation is required into the utility of adopting common genetic variants for cardiac risk prediction in the clinical setting. The aims of this project are to identify new variants to utilise in multi-biomarker risk prediction for adverse cardiac events. Methodology We will perform the largest meta-analysis of GWAS to date, of QT, JT and QRS intervals in ~300,000 individuals using 1000 genomes and HRC imputation in collaboration with the CHARGE EKG consortium. We will also derive spatial QRS-T angle from 12 lead resting ECGs acquired from UK Biobank, and perform the first ever heritability study and GWAS on this trait in ~100,000 individuals using BOLT-RMM and BOLT-LMM software respectively. Identified variants will be extensively annotated using bioinformatics methods and publically available datasets, which will provide insight into their putative function in electrophysiological pathways and identify candidate genes. Using identified variants, using genetic risk scores, we will test for association with cardiovascular outcomes including left ventricular measurements on cardiac MRI, hospital admissions for tachyarrhythmia and mortality. Scientific and medical opportunities This project will contribute to our understanding of the pathophysiology of arrhythmia generation and sudden cardiac death. It may identify new targets for medical therapy by novel drug development or existing drug re-profiling. The data will enable Mendelian Randomisation studies to test the effects of specific drug interventions on clinical outcomes. Finally through inclusion of new biomarkers and subsequent risk score development, risk prediction for adverse cardiovascular outcomes in the general population could be improved.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CARDIOVASCULAR
Title: The Effect of Inorganic Nitrite on Cardiac Function During Exercise in Patients with Heart Failure with Preserved Ejection Fraction (HFpEF)
Funder: Medical Research Council

Abstract: Patients with heart failure with preserved ejection fraction (HFpEF) suffer from reduced exercise capacity and life expectancy. The pathophysiology of HFpEF involves a combination of left ventricular stiffness, impaired diastolic function, and abnormalities in the peripheral circulation. There is currently no effective treatment for HFpEF. Inorganic nitrite represents a potential treatment for HFpEF, targeting abnormalities both in ventricular stiffness and in the peripheral circulation. In patients with HFpEF, inorganic nitrite improves pulmonary capillary wedge pressure during exercise. Beetroot juice is a source of inorganic nitrite (through the in vivo conversion of dietary nitrate found in the juice). A single shot of beetroot juice has been shown to improve exercise capacity in patients with HFpEF. Hypothesis: Inorganic nitrite improves myocardial performance and peripheral arterial indices in patients with HFpEF, leading to enhanced exercise capacity. Objectives: 1. To assess the effect of two weeks' treatment with beetroot juice on exercise capacity and left ventricular function in patients with HFpEF. We will perform a double-blind randomised, controlled, crossover intervention study assessing the effect of beetroot juice on exercise capacity, cardiac diastolic function and central haemodynamics, in 35 patients with HFpEF. The co-primary end-points are exercise capacity and change in E/e' on exercise 2. To assess the effect of inorganic nitrite on left ventricular end-diastolic pressure (LVEDP) during exercise. We will perform left ventricular pressure volume analysis during exercise in 22 patients with HFpEF. Patients will be randomised to receive intracoronary infusions of either nitrite or saline control. The primary end-point will be the effect of nitrite on LVEDP during exercise. Secondary end-points will include the effect of nitrite on exercise-induced changes in both diastolic performance and ventricular-arterial coupling.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR
Title: Yoga programme for type-2 diabetes prevention (YOGA-DP) among high-risk people in India: intervention development and feasibility study
Funder: Medical Research Council

Abstract: India has the world's second largest type-2 diabetes (T2DM) epidemic. Another huge population in India is at high-risk of T2DM (their blood sugar concentrations are higher than normal). They are more likely to develop T2DM and its complications than people with normal concentrations. Physical activity is effective in reducing blood sugar concentrations. However, physical activity levels are lower among Indians, especially among women and older people. Contemporary physical activities have some limitations. Yoga, an ancient Indian mind-body exercise, has some advantages over contemporary physical activities and can meet the aim of the recommended physical activity for T2DM prevention among high-risk people in India. The overarching aim is to explore whether a yoga programme can prevent T2DM among these high-risk people as compared to enhanced standard care. Group yoga sessions will be provided by yoga practitioners, for 75 minutes, twice a week for six months. The enhanced standard care will include a leaflet and a group session on routine physical activity advice, delivered by a different team member. Intending to following up this work with a future randomised controlled trial (RCT), the subsidiary objectives of this early phase study are: 1) To develop the intervention: A systematic iterative process will be followed to develop the intervention content. A systematic review will be conducted to generate a list of yogic practices that are recommended for managing diabetes. Then, yoga and exercise professionals will validate these yogic practices. The prototype intervention will be drafted and pre-tested among our study participants. 2) To determine the feasibility of undertaking the future RCT: Participants will be recruited and randomised to intervention and control groups. Quantitative data will be collected to estimate important parameters that are needed to design the RCT. Semi-structured interviews will be conducted to explore study-specific issues.


Research activity codes: 5.7 PHYSICAL
Health categories: CARDIOVASCULAR
Title: NoToNa: Tackling cardiovascular risk in the adolescent life-course through a schools' salt-reduction intervention in sub-Saharan Africa
Funder: Medical Research Council

Abstract: Hypertension, a risk factor for strokes, cardiovascular and renal disease, is increasing in sub-Saharan Africa, and starts young. WHO has identified salt reduction as one of the "best buys" to reduce cardiovascular disease in low income countries. In much of sub-Saharan Africa most sodium intake is from salt added at home, so measures tackling processed food that have worked elsewhere would have little impact. In Malawi we have already found hypertension in teenagers (5.1% males and 2.3% females aged 18-19) with levels increasing rapidly with age. Salt consumption is high: more than half of the adults exceeded recommended limits from plain salt alone. Working with the School Health and Nutrition Programme, we propose to conduct a cluster-randomized trial of an educational/behavioural intervention package in schools in rural and urban Malawi which aims to reduce salt consumption in adolescents and their families. Of 26 schools, half will be randomized to receive the intervention and half will receive the normal school curriculum. The intervention will take place over one school term and will be delivered to children in Year 6 (aged 11-14). It will include lectures, discussions, homework including food diaries, competitions, drama and family quizzes. It is modelled on a successful intervention in China, and will be adapted for local use. We will measure the effect of the intervention by measuring 24-hour urinary sodium and blood pressure in a random sample of 20 children per school and their parents/guardians at baseline, at the end of the intervention, and one year later (to assess persistence of any effects). We will compare the change in measurements from baseline in participants from intervention and control schools. Process evaluation will include identifying barriers and facilitators to the intervention, and we will also estimate cost-effectiveness. These factors will be critical in deciding whether and how to scale up the intervention.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: CARDIOVASCULAR