NIHRDataInsights/HRCSData huggingface dataset:
Title: FOOD-BASED BIOMARKERS, DIET QUALITY, AND CARDIOVASCULAR HEALTH
Funder: Medical Research Council

Abstract: Coronary heart disease (CHD), the leading cause of deaths in the U.S., is a preventable disease. Largely through smoking cessation promotion and improved control of hypertension and dyslipidemia through diet and medications, the U.S. has witnessed a decline of CHD incidence and mortality in the past decades,1 although such a decline has plateaued.2 The role of diet in the prevention of CHD has become more critical for a further reduction in CHD incidence and mortality. The current dietary guidelines recommend eating higher-quality diets, especially those enriched with plant-based foods, such as fruits, vegetables, and whole grains, and low in animal products, such as red meats, for lowering the risk of CHD,3, 4 although research is needed to further characterize healthful diets tailored toward individuals’ preference and dietary habits. Objective biomarkers that can reliably capture intakes are needed to further substantiate the link between healthful dietary patterns and CHD risk, monitor compliance. In addition, food biomarkers can be used to characterize an individual’s dietary pattern5 and to develop personalized dietary advice. In this regard, metabolomic profiling techniques are instrumental in identifying novel molecules that can serve as highlyspecific, objective biomarkers of food intake. We and others have recently identified several novel markers of sugar-sweetened beverages (SSBs), citrus fruits, chicken, red meats, and other foods, using metabolomics approaches.7-10 Despite these advances, few studies have attempted to demonstrate doseresponse relationships with food intake, discover markers for other important foods, systematically examined biomarkers that jointly can capture overall diet quality, evaluated associations of food biomarkers with CHD risk, or tailored dietary interventions toward specific food biomarkers to improve overall diet quality. To fill these knowledge gaps, we propose to conduct multiple, complementary, inter-connected projects that bridge novel food biomarker discovery, examination of dietary biomarkers in relation to CHD risk, and evaluation of the efficacy of using biomarker-based personalized advice to improve diet quality. This grant is highly responsive to the US-Ireland R&D Partnership Programme that encourages “tri-partite” collaborations among investigators in U.S., Republic of Ireland, and Northern Ireland. We have assembled a strong and interdisciplinary investigator team with expertise in metabolomics profiling, nutritional and cardiovascular epidemiology, bioinformatics, public health nutrition, and clinical research.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Fully Automatic Segmentation and Assessment of Atrial Scars for Atrial Fibrillation Patients Using LGE MRI
Funder: Medical Research Council

Abstract: The main objectives of this proposal are to (1) develop a novel data harmonisation method based on recently proposed domain adaptation and generative adversarial models; (2) carry out an initial two-centre cross-national validation study on the retrospectively collected LGE MRI data; (3) independent testing of a multicentre study consists of data collected from four centres, i.e., Brompton (UK), Anam (South Korea), KCL (UK), and Utah (USA), where the data from KCL and Utah are with open access; (4) strengthen further teaching, training and research collaboration links between UK and South Korea clinicians and technicians to gain more understanding about LGE MRI data and deep learning based fibrosis assessment; and (5) enable large-scale basic science and technical development projects and prospective clinical trials at two nations and further international studies.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Computational Cardiac Imaging
Funder: Medical Research Council

Abstract: Cardiovascular diseases are a diverse range of conditions that affect 8 million people in the UK with a cost to the UK economy of £16 billion each year. Cardiac imaging provides a rich source of data for understanding the structure and function of the heart in health and disease but conventional approaches to analysis do not capture the complex pathophysiology of heart disease. Our program harnesses advanced computer vision techniques for cardiac motion analysis coupled with innovative machine learning (ML) algorithms to model the genetic basis of complex cardiac traits, to provide automated approaches for personalised risk stratification and to prioritise molecular pathways for drug development. This is achieved by analysis of human cardiac MRI data acquired in diverse populations including 100,000 participants in UK Biobank. We will model pre-cardiomyopathic and disease-state rare variants using 3D computational models of genotype-phenotype interactions which will objectively map the expressivity of cardiomyopathy-associated variants before disease is established. ML also has the potential to model disease heterogeneity and identify cohesive disease groups based on morphology, function, and genetic variation. With the availability of whole exome sequencing in UK Biobank we will study the effects of predicted loss of function variants using ML phenotyping and 3D association modelling to anticipate the physiological consequences that could arise from therapeutic inhibition. Taken together this program will develop transformative technologies for diagnosis, prediction and therapy development in cardiovascular medicine.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: HAVEN: Hydroxychloroquine in ANCA Vasculitis Evaluation, a Phase II Multicentre, Randomised, Double Blind, Placebo Controlled Trial
Funder: Medical Research Council

Abstract: There is an unmet need for therapies for ANCA vasculitis (AAV), an uncommon but serious group of autoimmune diseases, to reduce disease activity, prevent damage and minimise glucocorticoid toxicity. Hydroxychloroquine (HCQ) is an established, safe, effective and inexpensive therapy for lupus, rheumatoid arthritis and cutaneous vasculitis but has not been studied in AAV. HCQ has pleiotropic effects on cellular biology pathways central to AAV pathogenesis, providing a mechanistic rationale for its potential value in AAV. HCQ has useful effects on lipids, glucose, arterial stiffness and antithrombotic, antimicrobial and antineoplastic properties relevant to AAV patients. We propose a Phase II UK multicentre randomized double-blind placebo-controlled trial in active non-life threatening AAV patients with no major Birmingham Vasculitis Activity Score (BVAS) items, to investigate if HCQ treatment for 1 year ranks better than placebo at reducing uncontrolled disease, defined as BVAS>3. 76 subjects (38 in each arm) will be recruited from 10 UK centres over 2 years. Patients will be randomised 1:1 to adjunctive HCQ 400 mg daily or placebo with maintenance therapy, stable for 4 weeks pre-randomization, with azathioprine, equivalent methotrexate or rituximab>6 months ago. Both groups will receive oral glucocorticoids with a suggested schedule for maximum doses, tapering to a minimum according to disease activity. This trial will use outcome tools and research methodology validated by the European Vasculitis Society (EUVAS). The primary endpoint at 52 weeks will be the percentage of patients with BVAS>3. Secondary outcomes will evaluate HCQ effects on complete remission (BVAS=0), ANCA titres and flare rates, cumulative glucocorticoid dosage, vasculitis damage index (VDI), adverse events, health-related quality of life (SF-36, EQ5D) and fatigue (FACIT score). This trial addresses an unmet need for patients with AAV.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR
Title: Computational analysis of protein covariation for the identification of disease-associated variants in coding regions
Funder: Medical Research Council

Abstract: I will develop a series of computational tools for analysing the consequences of human variants taking into account the genetic background. My hypotheses are 1) that some protein residues tend to covary (i.e., residues are replaced simultaneously more often than expected if their variation were not correlated), and 2) that the risk posed for some variants is associated to the absence of compensatory variants affecting covarying positions. I will use evolutionary and population data in order to identify the covarying positions within and between human proteins. First, I will download or build multiple sequence alignments of the homologous sequences. Second, I will infer the phylogenetic tree associated to that alignment. Third, I will use a Maximum Parsimony approach in order to identify in which branches of the tree the residues change. For each pair of protein positions, I will count how many times the positions change in the same branch, and when there are only single changes. As the numbers of single and double changes are linearly related for each given position, I will use a regression analysis for identifying the pairs of residues with fewer single changes than expected. Statistical significance will be assessed through multiple Monte Carlo simulations. After that, I will identify which amino acid couplings are favoured in each of those covarying positions. In a second stage, I will use this information in order to analyse gene panels from patients of the Manchester Centre for Genomic Medicine and exome data from patients with Tetralogy of Fallot. The strategy will be to identify uncoupling variants that affect the normal pattern of variation within covarying positions. I will release the code for bioinformaticians interested in including my tool in their analytical pipelines.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: CARDIOVASCULAR
Title: L. Zuhlke, University of Cape Town: Etiological, intervention and outcome studies in African children, adolescents and young adults with heart disease
Funder: Medical Research Council

Abstract: In three areas of unmet need, we will examine specific scientific questions relating to healthcare delivery and disease mechanisms, which are directed towards providing better care for children with heart disease in Africa. In RHD we will identify the barriers to effective care for acute GAS infection through a situational assessment of healthcare for suspected GAS sore throat using a Needs Assessment Tool we have developed specifically for use in Africa. We will carry out a real world evaluation of an RADT as an adjunct to the diagnosis of GAS, quantifying sensitivity and specificity of the test and evaluating the value added in an urban African setting. We will conduct clinical evaluation, echocardiographic and cardiac MR imaging, and establish a tissue resource suitable for immunophenotypic evaluation of children and young adults with rapidly progressive RHD. In CHD we will establish a multi-centre registry focusing on the long-term outcomes of patients undergoing palliative and staged cardiac surgical procedures (for example, those with a Fontan circulation). We will carry out a baseline situational analysis of pediatric cardiology and cardiac catheter laboratory activities in collaborating African centres, and evaluate the impact of a quality improvement tool we have devised at Red Cross War Memorial Children's Hospital in these centres. We will extend our cohort study of congenital heart disease in Cape Town to at least five further African countries, and bank bioresources suitable for genetic and proteomic investigation of aetiology and outcome. We will apply advanced imaging including 3-D and 4-D Echo, and cardiac MRI to a sub-study of children, in the Cape Town Adolescent Antiretroviral Cohort, a unique group of 515 perinatally HIV-infected adolescents who have received prolonged antiretroviral therapy. We will quantify left ventricular diastolic function using echocardiography and myocardial fibrosis using CMR with late gadolinium enhanceme


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING;2.4 SURVEILLANCE AND DISTRIBUTION;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Strengthening primary care systems for prevention & control of cardiovascular diseases in Kenya: feasibility study of health kiosks in markets
Funder: Medical Research Council

Abstract: This is a feasibility study to explore whether the creation of public health kiosks in community markets, managed by nurses and community health workers (CHWs), can improve the prevention and control of cardiovascular diseases (CVD) in Vihiga county, a deprived rural setting in Kenya with rising CVD rates and poor health care access. The integration of health promotion and relevant practice into culturally-rich social spaces of markets is predicted to increase engagement, promote sustained behaviour change and function as a bridge to the health care system. Task-shifting strategies and collaborative community-based interventions are often advocated to reduce health inequalities and the NCD burden, but little evidence is available in LMICs. In collaboration with Vihiga County Health Department and WHO, the CHWs will be trained to provide health promotion and conduct screening using tablets programmed to identify those required for follow-up, while the nurse will provide feedback, probable 'diagnosis' and make referrals. Market champions will promote kiosk engagement in the community. Detailed developmental work will take place in 4 health centre-market clusters (2 intervention, 2 comparator). Evaluation will focus on understanding how sociocultural and organisational contexts of markets and health systems influence implementation. Based on the principles of realist evaluation and MRC guidelines for the evaluation of complex interventions, we will use a mixed methods approach including: 1) concept mapping with stakeholders to develop a model of factors that could affect implementation; 2) interviews with traders, market users, nurses and CHWs to understand barriers and facilitators; 3) simple mobile technologies to obtain live evaluation data on likely reach, effectiveness, adoption, implementation and maintenance. If the results are favourable we will hold policy workshops to discuss likely translational impact, and conduct wider testing of the intervention.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: CARDIOVASCULAR
Title: MICA: A Developmental Trial of Personalised Medicine for Repurposing Zibotentan, a Selective Endothelin A Receptor Blocker, in Microvascular Angina.
Funder: Medical Research Council

Abstract: We propose a randomised, double-blind, placebo-controlled, sequential crossover clinical trial of zibotentan in patients with microvascular angina (MVA) to gather information on safety, tolerance, efficacy and potential theragnostic biomarkers (treatment response, discontinuation). The primary outcome, treadmill exercise duration (s) on the Full Bruce protocol, is a measure of aerobic capacity that reflects disease severity. An improvement in exercise time is meaningful to patients and regulators e.g. FDA for licensing medicines for angina. Secondary - quantitative stress cardiac MRI (prioritised), blood/urine biomarkers, QoL & angina questionnaires (patient-orientated outcome measure (PROM)) and zibotentan levels/Pk/Pd. POWER - To achieve 80% power to detect a mean difference of 30s between treatments in a 2(x)2 crossover design 65 subjects will be needed with complete data. Taking account of test-retest reliability (10%), the final analysis population is n=72. Screen n=356, enrol n=144, randomise n=100. SETTING - A multicentre study (Cambridge, Glasgow, KCL, Oxford, Royal Free & Blackpool). Reserve sites will cover logistical problems. INCLUSION 1. Age >18 years 2. MVA confirmed with stress perfusion MRI and/or invasive tests of coronary function. 3. Effort intolerance (impaired exercise time vs. predicted) EXCLUSION 1. Vasospastic angina without MVA 2. Non-cardiac exercise-limiting problem 3. Women of child-bearing potential 4. Lack of consent 5. Inability to comply with the protocol 6. Genotype criteria not met INTERVENTION - Adjunctive treatment with zibotentan 10 mg based on efficacy in prior trials (AZ Investigator Brochure (IB)) or matched placebo, once daily for 3 months. Justification (dose): Zibotentan has been extensively studied in preclinical-, healthy volunteer- and phase 2/3 oncology studies. The IB supports safety (no liver toxicity), side-effects (mild-BP lowering, peripheral oedema) & efficacy (Pk-Pd models on vascular function.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR
Title: Using metabolomics to investigate the metabolic signatures and associated pathways linked to short-term exposure to air pollutants
Funder: Medical Research Council

Abstract: Air pollution contributes to 7 million deaths per year worldwide; the vast majority of those deaths are attributed to cardiovascular disease (CVD). The objective of this proposal is to examine the initial steps that lie on the causal pathway(s) linking exposure to air pollution and disease risk using multivariate metabolic phenotyping technologies (metabolomics) that have emerged as a powerful new method to capture biomarker information on a range of toxicological and disease processes. Our proposal takes advantage of existing data and samples from human chamber studies with three exposure scenarios (diesel, biodiesel, wood smoke), a 'real world' study of urban and peri-urban residents in Beijing with extensive personal exposure monitoring during winter and summer (AIRLESS and Oxford Street II with its extensive monitoring of air pollutants and already available metabolic data. We will use the metabolome-wide association study paradigm to investigate the metabolic fingerprint associated with (a) short- and long-term exposures to air pollutants and whether these are these replicated across different exposure scenarios. We will then apply chemometric, statistical and analytical chemistry approaches to structurally detect the significant metabolic features, followed by bioinformatics, statistical methods and analysis to identify the underlying metabolic pathways involved in different exposures and exposure scenarios, as well as exposure-specific pathways. The resulting data are expected to provide novel insights into the mechanisms underlying the adverse health effects of air pollution and provide a firm foundation for future work which addresses the possible links between these perturbations and early disease events.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: CARDIOVASCULAR
Title: Is there a difference between clinical angina and experimentally inducible angina? A placebo-controlled experiment in stable coronary artery disease
Funder: Medical Research Council

Abstract: Aims: ORBITA, the first placebo-controlled trial of angioplasty for stable angina, showed a weaker effect than hoped. One interpretation is that we cannot assume that all chest pain reported by a patient, with a coronary stenosis and objective evidence of ischaemia, is in fact angina. My principal aim is to improve patient selection for PCI by applying a novel symptom-based approach: I will determine whether symptoms, induced by confirmed experimental ischaemia can help us select patients who will truly derive benefit from PCI. Objectives: 1. I will discover the distribution of symptomatic response to low pressure balloon occlusion of the coronary artery. 2. I will discover the degree of match between the presenting clinical symptom and the symptom elicited by experimental balloon occlusion of the coronary artery (against placebo occlusion). 3. I will test the hypothesis that the degree with which experimentally induced symptoms match the presenting symptom of angina predicts the degree of symptomatic benefit from PCI. Methods: I will assess the symptomatic response to placebo-controlled low-pressure balloon occlusion of the coronary artery prior to PCI in 65 patients. Symptomatic response to PCI will be assessed by patient reported symptoms via a dedicated smartphone app for 1 month before and after PCI. Regression of ischaemia will be assessed with stress echocardiography and Fractional Flow Reserve. Opportunities: Despite 500,000 PCIs per year, cardiologists have not identified an evidence-based method of mapping ischaemia to angina in an individual patient. This research may offer a solution to this blind spot. If successful, this could lay the foundations for a novel direct diagnostic test, not for ischaemia, but for angina of ischaemic origin. Symptom-based personalisation of therapy for stable angina could maximise the therapeutic efficacy of PCI, helping us better tune the treatments to those most able to benefit from them.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: CARDIOVASCULAR
Title: Effects of recapitulating respiratory sinus arrhythmia by dynamic pacing with phasically varying cycle length on susceptibility to cardiac arrhythmia
Funder: Medical Research Council

Abstract: Respiratory sinus arrhythmia (RSA) is a naturally occurring periodic oscillation in heart rate in phase with the respiratory cycle that is prominent in athletes and neonates and is lost with age and cardiovascular disease. RSA represents the respiratory frequency component of heart rate variability, and its loss is a strong prognostic indicator of cardiovascular mortality, including sudden cardiac death, in patients. However, it is not known whether the loss of RSA increases propensity to arrhythmia. Oscillating bidirectional interaction between membrane potential and intracellular [Ca2+] has been causally linked with cardiac alternans, beat-to-beat variability of repolarisation (BVR) and the genesis of arrhythmias. It is well established that the action potential (AP) and Ca2+ transient (CaT) depend critically on cycle length (the reciprocal of heart rate) and that changes in pacing protocol alter responses of the AP and CaT to step changes in cycle length, known as short-term cardiac memory. Computer simulations indicate that imposing variation in pacing cycle length reduces the propensity to alternans, BVR and arrhythmia. This project examines the hypothesis that mimicking RSA through dynamic pacing with phasic variation of cycle length modifies coupling between the AP and CaT, producing short-term cardiac memory, and is protective against arrhythmia. The proposed research involves recordings of APs, membrane currents, CaT, SR Ca content and sarcomere shortening from isolated single cells using whole-cell patch clamp and fluorescence recording techniques. The effects of dynamic pacing on the electrophysiology and susceptibility to arrhythmia of Langendorff-perfused whole hearts will also be examined.


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