NIHRDataInsights/HRCSData huggingface dataset:
Title: International comparisons of 'big' health record data: application to cardiovascular diseases
Funder: Medical Research Council

Abstract: Aims and objectives (i) Clinical research: to address research questions in the prevention and progression of cardiovascular diseases across two or more countries. (ii) Informatics methods: To facilitate the discovery and documentation of contemporary electronic health records (HER) sources for cardiovascular disease (CVD) research in different. Methodology In clinical investigation, I will define strategies of handling data quality and comparability issues, harmonize patient inclusion/exclusion criteria, disease ascertainment, study variables, missing data and analytical protocol across different countries. Statistical analyses steps include: 1) descriptive statistics, 2) survival analysis and longitudinal analyses for observed and adjusted risk estimates, 3) prognosis analysis, 4) estimating missed opportunities burden and its association with excess adverse outcomes between countries. Between country analyses could be implemented via a) secure remote access, b) site visit, and c) a common protocol. Computationally intense analyses, including imputation and multi-level approaches will exploit the Farr high performance computing infrastructure. In contributing to informatics method, I will be first to build an interdisciplinary, international network of investigators and resources seeking to make EHR data sources discoverable and sharable for cardiovascular research. Second, to contribute to the creation of an international searchable meta-data catalogue of EHR data from different health care settings through the Farr Institute and the Health Informatics Network. Impact By focused on CVD, research results may provide insights on effective health system and care strategies for better health and wellness of the population in the UK and worldwide. In methodology, the research will contribute to our knowledge on research collaboration, study coordination and information governance for international studies based on linked electronic health records.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: CARDIOVASCULAR
Title: INVESTIGATING THE ROLE OF RUNX1 IN THE HEART POST-MYOCARDIAL INFARCTION
Funder: Medical Research Council

Abstract: Mortality of patients with MI and HF remains high despite optimal current medical therapy. New options that limit adverse cardiac remodelling and preserve LV function post-MI are urgently required. Runx1 is a transcription factor essential for the normal functioning of numerous organs and tissues, the most well-known of which is its critical role in haematopoiesis and Acute Myeloid Leukaemia. Recently discovered in the heart, Runx1 is increased in cardiomyocytes in the border zone myocardium of both patients with MI and in animal models of MI. Until now the function of Runx1 in the heart remained unknown. We have utilised CreLoxP technology to generate tamoxifen-inducible cardiomyocyte-specific conditional Runx1 knockout mice. One week following a single intra-peritoneal injection of tamoxifen, we induced MI (with an infarct size of 30-35% of LV) in adult Runx1 knockout mice and phenotyped them using echocardiography and pressure-volume catheters. Remarkably, whilst control mice demonstrated the expected decrease in LV contractility, wall thinning, eccentric hypertrophy and impaired cardiomyocyte calcium handling, Runx1 knockout mice with MI were protected from these adverse effects. We have therefore identified a novel target with therapeutic potential in the setting of MI. This proposal will provide mechanistic insight into the improved cardiac phenotype observed in Runx1 knockout mice and thereby enhance our understanding of cardiac remodelling post-MI, providing a platform for future translational studies to develop new therapeutic options for post-MI patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Structure-function studies on human Angiotensin-I converting enzyme (ACE)
Funder: Medical Research Council

Abstract: This project addresses key unresolved issues concerning the structure and activities of the angiotensin converting enzyme (ACE) using a combination of structural molecular biology, homology modelling and biochemistry and is a natural extension of our ongoing research. Our structure biology centred research work on ACE has been highly successful on the structures of different forms of the ACE protein, their substrate and inhibitor selectivity, and biological and potential clinical relevance. Key questions, however, remain unanswered and are the subject of the present proposal: what is the structure of the entire somatic ACE protein with both its active sites present? This is a considerable challenge for such a large and heavily glycosylated membrane protein. Encouraging preliminary data has been obtained in this direction. Can we design domain selective ACE inhibitors? Again, this should certainly be feasible and significant proof-of-principle work has already been achieved but more structural data are needed to refine the information available. To achieve these ends, our laboratory is very well placed from the structure determination viewpoint and we have put in place some key international collaborations over the recent years [with Profs Ed Sturrock, Kelly Chibale at UCT, South Africa (ACE biochemistry, compound design and synthesis) and Dr. Vincent Dive, CEA, Paris (protease inhibitor design and synthesis)]. Although the aims are challenging, much novel and potentially exploitable data should emerge from the project as we make progress through the next ambitious stage of the work as described in the proposal.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Determination of left atrial wall thickness and its influence on electroanatomic properties in the human atrium
Funder: Medical Research Council

Abstract: Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting approximately 2% of the UK population. It is associated with stroke, heart failure and death. The electrophysiological mechanisms underlying AF remain incompletely understood. Published data suggest left atrial wall thickness (LAWT) affects atrial electrophysiological properties and varies with presence of cardiac pathology. In appropriate patients, AF can be effectively treated by radiofrequency catheter ablation (RFCA). Successful RFCA requires delivery of transmural lesions to the left atrium. A fundamental determinant of transmurality of lesion formation is LAWT, which can vary from <1mm to 8mm. LAWT measurements are not currently available during RFCA. Hypotheses: Whole chamber LAWT can be reproducibly assessed using cardiac CT (CCT) LAWT increases with the presence of AF-associated cardiac conditions and predicts progression of AF Atrial electrophysiological profile varies with LAWT Knowledge of LAWT will inform personalised AF management strategies We have developed a novel method for measuring LAWT throughout the atrium from a CCT dataset. We will recruit to two studies. For the first study we will recruit patients with AF (not planned for RFCA) who will undergo CCT. Clinical parameters will be monitored and correlated with LAWT measurements taken from CCT. For the second study we will recruit patients planned for RFCA who will undergo CCT. At ablation we will assess intracardiac electrophysiological properties which we will correlate with LAWT. In patients undergoing repeat RFCA we will identify LAWT at sites of treatment failure to define the relationship between the two. LAWT is a critical biophysical parameter on which atrial electrophysiology as well as efficacy and safety of AF treatment is likely to depend. Our results have the potential to impact on treatment outcome while simultaneously illuminating the mechanisms responsible for AF.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Relationship between early and late events in the cardiac cycle as control points for therapeutic intervention
Funder: Medical Research Council

Abstract: This integrative study aims to produce new insight into the complex interplay between early and late events in electrical excitation and Ca metabolism of healthy hearts and those in heart failure (HF). We will elucidate processes that lead to a reduced repolarization reserve in cardiomyocytes from an animal model chosen for similarity to humans. In particular we will examine: (1) the interplay of Ito with other currents and the effects of CaMKII and adrenergic stimulation on the time course of Ca release from the SR; (2) how modulation of early currents by drugs and expression changes impact later currents. We will develop drug combinations to limit early after-depolarization generation, control action potential (AP) duration and improve the uniformity of the Ca transient to improve cell contractile performance in HF. Dynamic clamping will be used to measure AP responses to ionic current changes by injection or withdrawing currents generated by Hodgkin-Huxley model formulations. AP clamping will be used to directly measure repolarization reserve. Changes in ion channel expression in epi- and endo-cardial cells will be measured by qPCR and Western blotting. For both tubulated and detubulated regions of the cells (since failure also leads to t tubule loss), local RyR sensitivity will be probed by 3 dimensionally resolved 2-photon flash photolysis and measurement of release latency and its L-type Ca current dependence. This will be repeated in the presence of CaMKII stimulation, PKA stimulation for cells derived from both normal and failing hearts. Changes in location of proteins will be measured by immunocytochemistry and confocal microscopy. The interplay of subunit expression between ion channels will be examined by forced expression or knockdown of selected ion channel subunits in short term culture and IPSCs. Dose response curves for selected phamcological agents with be obtained in isolated myocytes and IPSCs.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;3.3 NUTRITION AND CHEMOPREVENTION
Health categories: CARDIOVASCULAR
Title: Understanding the Mechanistic Links Between Mid-Wall Fibrosis and Arrhythmic Risk in Non-Ischemic DCM Using a Combined Modelling & Clinical Approach
Funder: Medical Research Council

Abstract: Non-ischemic dilated cardiomyopathy (NIDCM) is a common, yet complex, form of structural heart disease characterised by pathological ventricular dilation and tissue remodelling. Despite its strong association with cardiac arrhythmia and sudden death, risk stratification in this population remains a significant challenge. Recent MR imaging studies have highlighted a strong correlation between identification of regions of mid-wall fibrosis in NIDCM patients and arrhythmia incidence and related death. However, the physiological mechanisms underlying these empirical findings are, as yet, unknown, limiting further application and use of this information for early identification of those patients at elevated arrhythmia risk. We aim to use state-of-the-art image processing and analysis techniques upon both extensive existing, and prospective, MR data cohorts to define specific structural and morphological quantitative metrics linking mid-wall fibrotic tissue remodelling with arrhythmic risk. Advanced computational simulations will be performed with idealised models to gain an in-depth understanding of how the presence of a mid-wall fibrotic region relates directly to arrhythmia burden as well as a detailed understanding of the parameters that govern these effects. A series of patient-specific image-based models will then be created, validated by in-vivo EP measurements from the prospective cohort, to provide key mechanistic insight underlying these associative links, specifically aiming to understand the relative importance of structural and electrophysiological remodelling upon arrhythmia risk. Uncovering these associative links between more specific structural metrics defining mid-wall fibrosis and arrhythmia risk, along with the in-depth mechanistic insight provided by the modelling, will help advance the direct use of these identified quantitative MR metrics to inform catheter ablation therapy and as a tool for clinical risk stratification and therapy optimisation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Role of miR96 in Pulmonary Arterial Hypertension
Funder: Medical Research Council

Abstract: MicroRNA(miR)96 targets the 5HT1B gene and is under-expressed in pulmonary artery smooth muscle cells (PASMCs) with a BMPR-II mutation; 5HT1B protein and mRNA expression and serotonin-induced proliferation is increased in these cells. MiR96 is also down-regulated in hPASMCs from female pulmonary arterial hypertension (PAH) patients where increased 5HT1B expression causes increased proliferation. This increased proliferation can be reversed by pre-miR96. This suggests that miR96 may play a role in the pathobiology of PAH and that a mimic may be a novel therapy for PAH. Delivery of miR96 to pulmonary arteries in vivo prevents/reverses PH in mouse models via decreased 5HT1B expression and increased BMPR-II signalling. Here we will fully determine the molecular mechanisms behind the oestrogen/BMPR-II /miR96 axis and evaluate the potential of a miR96 mimic as a treatment for PAH. We will examine effectiveness of a miR96 mimic in a robust PH rat model after optimizing pulmonary specific delivery and dosage. We will determine off-target and side-effects and determine if a combination approach optimises the therapeutic effect.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: RobotReviewer: development and evaluation of a machine learning tool to speed up evidence synthesis in cardiovascular diseases
Funder: Medical Research Council

Abstract: Background Systematic reviews (SRs) are the bedrock of evidence-based practice. However, due to the exponential increase in available research, it is becoming increasingly difficult to keep SRs up-to-date, and keep pace with the primary literature. This problem is compounded in the rapidly moving area of cardiovascular diseases (CVDs), where most reviews are out of date within 2 years of publication. Aims and objectives To extend and evaluate RobotReviewer, a machine learning (ML) system to semi-automate the extraction of data from PDFs reporting clinical trials in CVDs. The system should extract information on the population, interventions, outcomes, statistics, and risks of bias. The accuracy of the system for each variable will be evaluated via a comparison with published systematic reviews. This will allow the user to determine when the system is accurate enough for use, and to what extent. Methodology The system will use an emerging method, distant supervision, in which a text-mining algorithm extracts pertinent text having learned to do so from existing published systematic reviews. A corpus will be developed which links the full text of clinical trials in PDF format with structured data from the Cochrane Database of Systematic Reviews (CDSR), and ClinicalTrials.gov. Methods will be developed to label the target data elements in the PDFs using data from the CDSR and clinicaltrials.gov. ML algorithms will be developed and trained using this data. The system performance will be evaluated against accuracy standards to enable a judgment about whether the system is ready for use, and in what capacity. Scientific and medical opportunities For those conducting systematic reviews, an accurate automation system could reduce the huge time and cost burden in conducting SRs. For clinicians and patients, increased coverage of SRs and quicker production time would ensure that health decision-making is based on the highest quality and up-to-date evidence.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: CARDIOVASCULAR
Title: MICA: Prevention of Aortic Stenosis (PAS) Pilot Trial
Funder: Medical Research Council

Abstract: We plan to conduct a pilot randomised placebo controlled double-blind cross-over trial to determine whether sevelamer lowers serum phosphate in patients with aortic stenosis. Aortic stenosis is a serious heart condition with no known means of prevention. It is caused by progressive deposition of calcium phosphate crystals on the aortic valve, leading to obstruction of blood flow from the heart. Death follows symptoms of cardiac insufficiency in most cases unless the valve is surgically replaced. About 1.3 million people over age 75 have aortic stenosis in the UK, about one quarter of whom are severely affected. This number is expected to double over the next few decades as the population ages. The phosphate binding drug, sevelamer, reduces blood phosphate by blocking dietary absorption. Treatment is licensed in kidney failure to lower the high phosphate (2-3 x physiological levels) which results from failed renal excretion and leads to bone disease. Treatment reduces calcium phosphate, raising the possibility of extending its use in the prevention of aortic stenosis, by slowing or arresting valve calcification, in all people with the disorder. It is not known whether sevelamer lowers serum phosphate in patients with aortic stenosis whose phosphate levels are within the physiological range. In the proposed pilot trial, sevelamer, at low dose (2.4g/day) and high dose (7.2g/day) will be compared with placebo in 72 patients with aortic stenosis. The cross-over design (each person is their own control) provides the statistical power to assess efficacy in lowering phosphate with few subjects and the 2 doses allow the trade-off between efficacy and tolerability to be assessed. The pilot study, in addition to assessing efficacy, will also develop the recruitment pathways for a definitive trial, to assess the effect of sevelamer on the progression of aortic stenosis, with a view to repurposing this drug for the prevention of aortic stenosis in the population.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR
Title: The genetic architecture of heart rate and the electrocardiogram at rest and during exercise
Funder: Medical Research Council

Abstract: Rate and autonomic dependent changes in cardiac electrophysiology are fundamental in the genesis of many cardiac arrhythmias, including atrial and ventricular fibrillation. Genetic factors are known to be important, however we have limited knowledge of their identity. We wish to study the effects of exercise on cardiac excitability and establish the genetic architecture of dynamic electrophysiological parameters apparent on exercise. The results will reveal genes influencing our cardiovascular response to exercise and recovery. This knowledge will provide new insights into the molecular mechanisms of arrhythmias, and has the potential to identify drug targets for arrhythmia, and may also permit risk stratification for patients. Hypothesis: There is a specific set of genetic loci that determine human cardiac electrophysiological parameters influenced by exercise. Aims: 1.To derive resting and exercise ECG traits using bespoke algorithms. 2.To perform heritability analysis of dynamic electrophysiological parameters. 3.To perform GWAS to further understand the genetic architecture of resting and dynamic ECG traits. Methodology: UK Biobank has exercise ECG data acquired from ~ 95,000 individuals who have corresponding genomic data, this offers a unique opportunity to test this hypothesis. In a pilot study, we have successfully extracted a range of dynamic ECG parameters from data on 89 individuals using bespoke algorithms. This project will expand analysis to all exercise ECGs enabling heritability analyses for ECG dynamic phenotypes for the first time. This will be complemented with existing work, particularly regarding resting heart rate data from genetic consortia (where we co-lead analyses).


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CARDIOVASCULAR
Title: Understanding novel disease processes underlying cerebral small vessel disease and determining whether they can be therapeutically modified
Funder: Medical Research Council

Abstract: Cerebral small vessel disease is a major cause of stroke and the major cause of vascular dementia. Despite its importance we have limited understanding of its pathogenesis and this gap in knowledge has hampered development of new therapies. There are few proven treatments for this important condition. Recently it has been suggested that increased blood brain barrier (BBB) permeability and neuroinflammation may play a role in the disease. In an animal model a pathophysiological cascade has been suggested involving these disease processes, and excitingly a drug which inhibits these processes (minocycline) resulted in reduced white matter damage and improved cognitive function. In this Challenge grant we will apply state of the art imaging techniques which allow detection of BBB permeability in individual patients (using a contrast based MRI technique) and neuroinflammation (using 11C-PK11195 PET). In the first phase in an observational study we will determine the patterns of BBB permeability and neuroinflammation, whether these two processes overlap, and whether areas of increased permeability and inflammation progress to damaged brain tissue. We will study 20 patients with sporadic SVD. In addition we will study 20 patients with the younger onset genetic form of SVD, CADASIL; this will allow us to study presymptomatic individuals to determine the role of these processes very early in the disease. In the second half of the study we will perform a randomised controlled trial determining whether minocycline, the drug which has been used successfully in the animal model and which has been demonstrated to have effects on both stabilisation of the BBB and reducing neuroinflammation, results in a reduction in BBB permeability and neuroinflammation as measured by these imaging techniques. For the RCT we will study 44 patients, 22 given minocycline and 22 given placebo, in a double blind design.


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