NIHRDataInsights/HRCSData huggingface dataset:
Title: novel multi-nuclear magnetic resonance spectroscopy approaches for the sensitive and robust assessment of human cardiac energetics
Funder: Wellcome Trust

Abstract: Altered cardiac metabolism is now recognized as an important component of many cardiovascular diseases, including heart failure. Accurate assessment of cellular energetics promises significantly better disease staging and treatment monitoring in such conditions. Current non-invasive techniques based on magnetic resonance spectroscopy (MRS) are not precise enough to reliably define cardiac energetics in individual patients. In this fellowship, I will develop new highly-sensitive MRS techniques for complete cardiac energetics assessment at 7T. The main goals of this research are: 1. To establish a robust, patient-specific platform for cardiac energetics quantification, by developing novel approaches to overcome a range of technical challenges associated with 31P-MRS; 2. To develop advanced methods that will allow for complete assessment of cardiac energetics, including quantification of Gibbs free energy of adenosine-triphosphate (ATP) hydrolysis (deltaG), and of complete myocardial ATP fluxes; 3. To demonstrate the sensitivity of these novel methods to measure impairments in total cardiac ATP dynamics in patients with type II diabetes and to detect changes in cellular energetics that accompany the transition to heart failure. These new measures will help provide unique insight into the pathophysiology of the failing heart and will be applicable in future studies monitoring novel metabolic therapies in cardiovascular disorders.

Lay abstract: The heart needs a lot of energy to function effectively, and we know that patients with heart failure have an ‘energy deficit’, which contributes to their disease. Currently available methods allow us to measure large energy deficits, but are not precise enough to be used for individual patients in a clinical setting, or to predict who will develop heart failure. I will develop new magnetic resonance-based methods, which can reliably measure how much energy is available to the heart from its reserves and how fast these reserves replenish. With this, I will be able to measure the extent of the ‘energy deficit’ much more precisely and, for example, observe the energetic changes that follow the transition towards heart failure in patients with diabetes. Importantly, techniques sensitive on a patient level basis would be ideal to develop, test and monitor novel therapies aimed at improving the energy state of the heart.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Understanding the role of myosin super relaxation in cardiac health and disease
Funder: Wellcome Trust

Abstract: A novel energy conserving mechanism, myosin super relaxation (SRX) has recently been discovered in cardiac muscle. SRX is a structural state of myosin, where myosin heads are folded away from actin, preventing force producing actomyosin interactions and contraction. Little is known about the key regulatory systems that govern the formation of myosin SRX in cardiac biology. It is evident that phosphorylation of key sarcomeric proteins play an important role, but the cellular signalling that underlies these changes is poorly defined. I aim to define these cellular signalling pathways and how they control sarcomeric protein phosphorylation. I will define how far reaching myosin SRX destabilisation is as a disease causing mechanism. To do this I will employ CRISPR/Cas-9 technologies to develop stem cell models of hypertrophic cardiomyopathy, HCM, a debilitating genetic condition that affects 1 in 500 people. I will augment these human stem cell models with human and murine tissue samples to define SRX abundance and regulation in acquired cardiovascular conditions including atrial fibrillation, heart failure, hypertension, myocardial infarction, and ageing. In doing so I will define sub-sets of disease pathomechanisms in inherited and acquired cardiomyopathies to allow precision targeting of therapeutics, which will bring significant benefit to patients.

Lay abstract: The heart circulates blood by the coordinated contractions of the cells of the heart. The contraction of these cells is driven by myosin, a molecular motor which uses cellular energy.~70% of myosin molecules in the heart are in an ‘off’ state. This ‘off’ state allows the heart to conserve energy. 'Off' myosin can be turned 'on' depending on how hard the heart needs to beat, but how this is done by the cell is not fully understood. In some inherited heart conditions, myosin is not able to switch off, due to mutations in a person’s DNA, which can cause heart failure. The amount of myosin in the ‘off’ state may also change in many common heart conditions including atrial fibrillation and heart failure. I aim to understand how the myosin ‘off’ state is regulated so that we can design new therapies for patients with heart conditions.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Cardiovascular disease in very low income sub-Saharan Africa: informing the response to an emerging epidemic
Funder: Wellcome Trust

Abstract: I will improve understanding of key determinants and the incidence of cardiovascular disease in low-income sub-Saharan-Africa, capitalising on my expertise in stroke epidemiology in rural and urban Malawi and the research infrastructure across seven sub-Saharan-Africa population cohorts. Information on the age- and sex-specific incidences of priority cardiovascular diseases is essential for health service planning in sub-Saharan-Africa. “Traditional” risk-factors (hypertension, type-2 diabetes and obesity) are highly prevalent and increasing in incidence and some, particular to low-income settings, such as chronic-infections, are not declining. The performance of diagnostic tools and risk prediction scores for cardiovascular disease developed in high-income settings need to be tested and adapted for use in low-income sub-Saharan-Africa. I will build on the urban/rural cohort in Malawi, extending community and clinic surveillance with population-level questionnaire-screening (followed by a diagnostic pathway in those with “possible cardiovascular disease”) to estimate the true incidence of various cardiovascular diseases. I will also extend the follow-up for our seven African cohorts and use this harmonised dataset to estimate the relative contributions of key drivers of cardiovascular disease and assess the performance of existing cardiovascular disease risk prediction scores. This work will inform the planning of evidence-based, health-systems responses and context-relevant, individual, and population-level interventions.

Lay abstract: Cardiovascular diseases (CVD), including heart attack, stroke and heart failure, are leading causes of death and disability worldwide. This burden is increasingly borne in low-income-countries where access to preventive interventions and health care is limited. Studies in high-income-countries show that CVD is largely preventable. In low-income-sub-Saharan Africa we lack critical basic knowledge of the incidence of non-fatal CVD and risk factors for CVD may be different to high-income-countries. There is an increasing burden of hypertension, adult-onset diabetes and obesity but also risk factors that differ from high-income-countries, such as chronic-infections, malnutrition, poverty and genetics. Using detailed population-based studies in rural and urban Malawi on non-fatal CVD, and across seven African populations on fatal-CVD, I will characterise the types of CVD, identify key drivers, and test risk prediction scores. Findings from this will inform planning of health systems and context relevant, individual and population-level interventions to improve prevention and case management.

Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: CARDIOVASCULAR
Title: Human in silico clinical trials in post myocardial infarction: mechanistic investigations into phenotypic electromechanical variability and response to treatment
Funder: Wellcome Trust

Abstract: The population of patients with ventricular damage following survival of myocardial infarction (MI) is rising, owing to the increased prevalence of coronary artery disease and improvements in treatment. Post-MI patients suffer from permanent myocardial damage, and this increases risk of sudden death and cardiac mechanical dysfunction, with potential progression to heart failure. Arrhythmic risk stratification is conducted using ventricular ejection fraction, a mechanical marker. However, a significant number of sudden deaths occur in patients with relatively preserved ejection fraction, and patients with low ejection fraction often do not experience serious arrhythmic events. In this Fellowship, I propose to unravel key mechanisms explaining phenotypic variability in post-MI, focusing on the interplay between electrophysiological and mechanical ventricular abnormalities, and their modulation by pharmacological interventions. I propose a Systems Biomedicine approach based on human ventricular computer modelling and simulation of coupled mechanical and electrophysiological function, in iteration with experimental and clinical studies. We will construct populations of thousands of human ventricular electromechanical post-MI models from ionic to whole-organ dynamics, calibrated and validated using rich experimental and clinical datasets. We will conduct in silico clinical trials to dissect key factors determining arrhythmic risk and degree of mechanical dysfunction post-MI, and effects of pharmacological interventions.

Lay abstract: Patients surviving a myocardial infarction suffer from a damaged heart, and are at risk of sudden death and impaired cardiac pumping action. Risk stratification for sudden death is conducted using primarily ventricular pumping efficiency. However a significant number of sudden deaths occur in patients with relatively preserved ejection fraction, and patients with low ejection fraction often do not experience serious arrhythmic events. In this fellowship, I aim to investigate mechanisms explaining the links between arrhythmic risk and mechanical dysfunction in post-myocardial infarction patients, and how they are modulated by pharmacological treatments. We will construct computer models of populations of human ventricles to simulate their electrophysiological and mechanical function, considering variability in ionic, cellular and tissue properties. We will calibrate and validate them using rich experimental and clinical datasets. We aim to ultimately inform the identification of more effective methods for risk stratification, and to improve treatment of patients at risk.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: South Asia Biobank
Funder: Wellcome Trust

Abstract: South Asians are not well represented in large-scale longitudinal studies including UK Biobank (Indian, n=6109, Pakistani, n=1905, Bangladeshi, n=240). We propose a South Asia Biobank of ~180,000 participants from UK and South Asia, underpinned by our; i. track-record in carrying out such studies; ii. existing infrastructure, investments, and partnerships in UK and South Asia, and iii. established frameworks for linkage to health records enabling identification of future outcomes. We will; i. increase recruitment into London Life Sciences Population (LOLIPOP) Study (32,183 South Asians, 2002-2008) to n~80,000 South Asians, from the lists of North-West London general practitioners ii. enhance LOLIPOP cohort by measuring additional exposures and phenotypes. In parallel, we will collect and store biological samples from ~100,000 South Asians being followed-up longitudinally, with high-quality standardised NCD surveillance data at 5 Centres of Excellence in India, Pakistan, Sri Lanka and Bangladesh, as part of our National Institute of Health Research (NIHR, £7M) Global Health Research Unit (sample collection not funded by NIHR). The South Asia Biobank will form a core part of UK’s portfolio of longitudinal studies made available to researchers world-wide for investigation of wide ranging scientific questions among South Asians, who comprise ¼ of the world's population.

Lay abstract: South Asians are at increased risk of heart disease, diabetes, renal failure and other chronic diseases. The reasons underlying this increased risk are not known. We will create a longitudinal population study comprising ~180,000 people recruited from the United Kingdom and South Asian countries (South Asia Biobank). We will assemble data on health, lifestyle, and environment factors. We will also collect and store biological samples. We will follow-up participants in the UK and South Asia for health outcomes over many years, including for cardiovascular disease, diabetes, chronic kidney disease and cancers. We will make the data and samples available to researchers worldwide, to understand prevent and treat a wide range of chronic illnesses that are important amongst South Asians, who comprise &frac14; of the world’s population.

Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: CARDIOVASCULAR
Title: AffeX Patient Management System - AffeX-PMS
Funder: Innovate UK

Abstract: Raised blood pressure (BP) or hypertension is the single most preventable cause of stroke, heart attack, heart failure and cardiovascular death. It is also a leading factor for an increased risk of dementia, and kidney failure. By lowering BP the combined risk of associated disability and death can be reduced by more than a half. However, despite the widespread availability of drugs that help lower BP, ~40% patients using these drugs fail to properly control their BP (2.5m in England). Importantly, for these patients, there are no other regulatory approved treatment options available. Studies have shown that electrically stimulating nerves (autonomic nerve) can reduce BP in these patients. Several companies are working on solutions, all involve invasive devices and/or in-hospital procedures that are costly. In contrast, Afferent has developed a solution which achieves the same effect non-invasively. By attaching electrodes to the skin of the outer ear using an approach called transcutaneous autonomic neuromodulation, BP can be effectively reduced. This is currently being tested in a clinical trial by Queen Mary University London (QMUL). Afferent's solution is low cost, very safe and patients can treat themselves at home. This project will investigate how we could make this technology easier to use at home and also manage patients rather than them visit their GPs to have their condition managed remotely. As we are using an electronic device we can easily check when the device was used and if it was used correctly. If we also get patients to check their BP using a home BP-monitor we can then use internet technologies to send this information to the GP who can see if the patient is managing control and advise if any change to treatment is needed. This project will build the computer system that will enable this and also a mobile app so patients can self-monitor their own condition. We believe this technology could help other patients. 90% of stroke victims are cannot be given medical treatments to remove the blood clot in the brain and for these patients there is no other medical treatment. We think Afferent's technology may also help these patients recover by helping restore the blood supply to the parts of the brain which have been starved of oxygen. Our colleagues at QMUL will undertake a proof of concept study to determine if giving this treatment on arrival at hospital helps stroke victim recovery.


Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;7.1 INDIVIDUAL CARE NEEDS
Health categories: CARDIOVASCULAR
Title: CCRATE - Cardiac Circadian Rhythm Automated Trend Establishment
Funder: Innovate UK

Abstract: The CCRATE project takes the results of the company's long running physiological signal AI programme and develops a consumer health system for the establishment of continuous Blood Pressure analysis. The project uses new advances in AI to generate a Blood Pressure reading every 10 beats of the subject's heart without the need for an inflatable cuff. For too many years diagnosis of hypertension have been made through wholly unreliable, inaccurate, uncomfortable inflatable cuffs. We aim to change that and to create a solution that works for consumers using their smartphones paired with already certified stick on sensors. At just 17g the chosen sensor solution can be worn for 7 days and is showerproof. In that 7-day period we analyse typically around 600,000 heart data points and generate up to 60,000 Blood Pressure readings. This level of analysis has never previously been achieved on a consumer health device. The project develops the end to end data network between stick-on sensor and user's smartphone. It bridges the gap between app and medical device, and provides a new and novel means to analyse people's cardiac performance, their Blood Pressure and links it all to their Circadian Rhythm. Blood pressure fluctuates with a pattern that follows a circadian rhythm, with a peak in the early morning hours and a trough during sleep. This rhythm originates in a "master oscillator" located in the brain. This is the cutting edge of consumer healthcare, blending AI algorithms with advances in high-fidelity physiological measurements. The output of the project will be commercialised through partnerships with specific industry organisations and sectors. It is time we moved away from the inflatable cuff Blood Pressure device that is responsible for the onset of white coat hypertension as well as providing numerous questions over its reliability/suitability as a consumer health device.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: University of Manchester (The) and Independent Vascular Services Limited
Funder: Innovate UK

Abstract: To develop and embed a Digitally Enhanced Advanced Services model, which will increase productivity and enable the establishment of an image analysis centre of excellence to serve NHS and other new markets.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: CARDIOVASCULAR
Title: Using zebrafish embryos to identify genes that protect against atherosclerosis
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Atherosclerosis, a disease of arteries leading to angina, heart attack and stroke, is the leading cause of death in the UK. It is initiated at branches and bends of arteries that display enhanced rates of endothelial cell (EC) proliferation associated with vascular leakiness and influx of cholesterol-rich lipoproteins. These sites are exposed to disturbed blood flow which generates low wall shear stress (WSS; mechanical drag) which promotes EC proliferation and atherogenesis. By contrast, high WSS protects arteries by inducing EC quiescence. Elucidating the molecular mechanisms linking WSS to EC proliferation could lead to the development of novel therapies to treat atherosclerosis. Studying EC responses to flow using in vitro flow bioreactors has had limited success because they do not generate physiological shear stress waveforms and EC lack cross-talk with smooth muscle and other vascular cell types. Because of these considerations, we have developed zebrafish embryo models to investigate vascular responses to flow. We recently used a zebrafish embryo model for functional screening of flow-responsive genes that regulate EC apoptosis, and found that shear stress regulation of EC proliferation was also conserved between murine and fish models (Serbanovic-Canic et al. 2017 ATVB;37:130-143 and Evans, unpublished). The proposed NC3Rs/BHF PhD Studentship will build on these observations by developing a zebrafish embryo model to identify genes that control EC proliferation under shear, thus enhancing the applicability and value of zebrafish models in studies of atherosclerosis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Development of E-Sense: a flexible in vitro platform to determine cardiovascular risk
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Cardiovascular disease causes more than a quarter of all deaths in the UK, costing the health service £11billion each year. Atherosclerosis, the underlying mechanism potentiating Coronary Heart Disease, develops focally at regions of disturbed (athero-prone) flow within coronary arteries and not within regions that experience laminar (athero-resistant) flow, clearly implicating the endothelium in the initiation of disease. Athero-prone flow activates the endothelium, priming them for inflammation, increasing permeability and leukocyte trafficking. The PREDICTION study, which used intravascular imaging to study disease development in patients with coronary heart disease, demonstrated that atherosclerotic plaques progressed in areas of low endothelial wall shear stress. Furthermore, 30% of heart attacks are caused by endothelial erosion of plaques, where the endothelium detaches, precipitating thrombus formation and arterial occlusion. Therefore, the endothelium and its response to flow and cardiovascular risk factors, plays a significant contribution to initiation, progression and clinical presentation of coronary heart disease. This suggests that creation of an endothelial-based in vitro detection system (E-Sense) will provide an ideal platform for detecting agents that cause vascular harm and promote atherosclerosis and coronary heart disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR