NIHRDataInsights/HRCSData huggingface dataset:
Title: Evaluation of Hypothermic Oxygenated Perfusion Ex-Vivo Heart Perfusion to Expand the Donor Pool and Improve Transplant Outcomes
Funder: Medical Research Council

Abstract: Heart transplant, the gold-standard treatment for patients with severe heart failure, is critically limited by the number of donor hearts. Only the best organs are accepted for transplant due to the concerns over heart's vulnerability to ischaemia reperfusion (IR) injury. The cold ischaemic time during static cold storage (SCS), the current heart storage method, adversely affects transplant outcomes. Selected donation after circulatory death (DCD) hearts, if provided with oxygenated reperfusion immediately after retrieval to reverse the initial warm ischaemic insult, can contribute to 30% increment of transplant activity. However, the high cost of the only available ex-vivo heart perfusion machine limits their utilisation. Hypothermic oxygenated perfusion (HOP) is a novel ex-vivo heart preservation method, which continuously perfuses the donor heart with hypothermic blood-based cardioplegic solution. It has been proven to be able to preserve porcine hearts safely for 24 hours before successful transplantation. We hypothesise that HOP is able to preserve extended donation after brainstem death (DBD) and DCD hearts for up to 12 hours, through minimising the IR injury induced cardiomyocyte necroptosis and mitochondrial damage. DBD and DCD hearts, declined for clinical transplant, will be preserved by HOP or SCS before being re-perfused with normothermic blood-based solution in the modified Langendorff testing rig. The tissues and perfusate samples collected will be analysed to reveal the mechanisms of IR injury in heart, compare the extent of cardiomyocyte necroptosis and mitochondrial damage after preservation by HOP vs SCS, and assess the role of promising biomarkers, such as cardiomyocyte cell-free DNA and flavin mononucleotide, a marker of mitochondrial reperfusion injury. Similar samples and post-transplant heart function will be collected from clinical heart transplants to validate the pathway observations, and novel biomarkers of allograft quality.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Redefining Unstable Angina with High-sensitivity Cardiac Troponin
Funder: Medical Research Council

Abstract: The widespread introduction of high-sensitivity cardiac troponin assays into clinical practice is having a major impact on the acute coronary syndrome. The incidence of unstable angina is falling, but varies markedly from 4% to 32% of patients reflecting a lack of objective diagnostic criteria. Whilst guidelines continue to define unstable angina in those below the diagnostic threshold (<99th percentile), we are now able to measure cardiac troponin concentrations within the reference range, where levels reflect the presence and extent of coronary artery disease, and predict future coronary events. I hypothesise that the diagnosis of unstable angina can be refined using serial high-sensitivity troponin testing and objective biomarker criteria. I will derive and validate these criteria in longitudinal and cross-sectional cohort studies, and evaluate their clinical utility in a substudy of a prospective randomised controlled trial. My aim is to improve the diagnosis, treatment and outcome of patients with unstable angina.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR
Title: Machine learning and the diagnosis of myocardial infarction
Funder: Medical Research Council

Abstract: High-sensitivity cardiac troponin assays are able to quantify troponin at very low concentrations and enable patients with acute chest pain to have the diagnosis of myocardial infarction ruled out earlier. However, these assays also increase the identification of patients with elevated troponin for many other reasons. In this fellowship, I hypothesise that a machine learning algorithm combining troponin with key clinical variables can improve the diagnostic performance for myocardial infarction. To address this hypothesis, I will conduct two studies: Study 1: Using supervised learning approaches I will train a variety of machine learning algorithms to determine a robust statistical model with maximal accuracy. This model will integrate high-sensitivity cardiac troponin concentrations with key clinical variables to calculate the probability of myocardial infarction. The model with be trained in a large cohort of consecutive patients with suspected myocardial infarction (n=48,282) who participated in a randomised control trial. The model will be validated thereafter in an unseen cohort of patients. Once the model is established, it will be incorporated in a clinical decision support tool available in a WebApp. Study 2: I will conduct a proof-of-concept randomised study to evaluate the performance of the above algorithm in real life. We will enrol 700 patients attending the Emergency Department with chest pain. Patients will be randomised to troponin only guided care based on the 99th centile or reporting the probability of myocardial infarction using our clinical decision support tool alongside the troponin result. The primary outcome will be the difference between pre- and post-test diagnostic certainty for myocardial infarction. Key secondary outcome measures will include the duration of stay, treatments initiated in the Emergency Department, cardiology referral, angiography and hospital admission in patients with and without myocardial infarction.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Understanding the predictors of heart muscle disease and sudden cardiac death in young athletes.
Funder: Medical Research Council

Abstract: Research question: What is the long-term significance of T-wave inversion (TWI) as a predictor of heart muscle disease and sudden cardiac death (SCD) in young white and black athletes? Specific aims: 1) ) To comprehensively clinically characterise 1010 white and black athletes who had TWI on ECG and a structurally normal heart on echocardiogram aged 16 years, after a median 14.8 years follow-up, with specific reference to development of cardiomyopathy. 2) To undertake genetic evaluation in all participants diagnosed with cardiomyopathy, conservatively estimated at 60% of those with baseline abnormal TWI. 3) To build a predictive model to determine which individuals with TWI go on to develop cardiomyopathy and place themselves at an increased risk of SCD. Participants: 1010 athletes (50% black and 50% white) who demonstrated abnormal TWI with a structurally normal heart at initial mandatory cardiac evaluation a mean of 14.8 years ago. Methods: Each participant will undergo: 1) 12-lead ECG to re-evaluate the TWI; 2) echocardiogram in accordance with national guidelines; 3) cardiac MRI to identify myocardial fibrosis and fatty replacement; 4) cardiopulmonary exercise testing to report functional parameters that may be reduced in cardiomyopathic cases; 5) gene testing using the Inherited Cardiac Conditions panel developed at the Manchester Centre for Genomic Medicine. The primary outcome would be detection of cardiomyopathy after evaluation and secondary outcome would be life-threatening arrhythmia. This would be a unique translational resource that can guide physicians to better inform young athletic people with TWI of both black and white ethnicities (and their families) on predicting the likelihood of developing a heart muscle disorder in the future and an increased risk of death. This risk can be modified through lifestyle measures, medications and in the highest risk cases, implantation of a defibrillator to protect the athlete.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Haemodynamic Determinants Of HYpertension In Children And Young People And Role Of The Sympathetic Nervous System: HY CYP
Funder: Medical Research Council

Abstract: Hypertension affects almost one in three of the adult population and is the largest single cause of mortality and morbidity worldwide. There is clear evidence of tracking of blood pressure (BP) from childhood into adulthood and understanding the aetiology of primary hypertension in children and young people (CYP) is therefore important to better prevent and treat hypertension at all ages. The established view of primary hypertension is that it is caused by increased peripheral vascular resistance. However, the majority of hypertension in CYP, particularly that associated with obesity is systolic hypertension and is likely to be due to increased cardiac activity (increased heart rate and increased ejection velocities) and/or stiffness of large arteries. In a preliminary study we found primary hypertension in CYP to result from increased cardiac activity and increased proximal aortic stiffness. This study will examine the haemodynamic aetiology of hypertension in untreated CYP using state of the art MRI methodology. Secondly it will address the likely cause of the cardiac overactivity - increased sympathetic nerve activity (SNA) by examining interventions that have specific effects on SNA: device guided breathing which reduces SNA and beta-1-adrenergic antagonists which block effects of raised SNA on the heart. Aims: 1. To characterise the haemodynamic phenotype of CYP with primary hypertension. 2. To investigate the contribution of cardiac overactivity and large vessel stiffening in this phenotype. 3. To investigate the role of the SNA in contributing to cardiac overactivity and large vessel stiffening in this phenotype.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Treating Primary Aldosteronism-induced Hypertension via Microwave Ablation
Funder: Medical Research Council

Abstract: In this tripartite US-Ireland R&D partnership program R01 research plan, we propose the development, optimization, and evaluation of a minimally-invasive microwave thermal therapy (MWT) system for definitive treatment of primary aldosteronism. Primary aldosteronism (PA) accounts for 5 - 12% of all hypertension and confers a higher risk for cardiovascular and cerebrovascular complications compared to age and blood pressure (BP) matched essential hypertension. Yet PA remains under-diagnosed and under-treated, largely due to the lack of definitive management options for the majority of affected individuals. The current definitive approach to unilateral PA is surgical adrenalectomy, while bilateral disease is managed medically; medical therapy is often poorly tolerated due to off target anti-androgen effects. Only ~30% of all individuals diagnosed with PA undergo surgery, and collateral resection of normal cortex limits the option of surgery to unilateral disease, given the inevitable risk for adrenocortical insufficiency with bilateral adrenalectomy. Therefore, the overall objective of this proposal is the development, optimization, and experimental evaluation of an image-guided approach for sub-ablative MWT of APAs, and for post-treatment assessment of adrenal function. First, we will employ a series of in vitro studies to determine the optimal range of thermal doses for rendering hyperfunctioning adrenal cells defunct, at sub-ablative thermal doses. We will then verify the ability to disrupt adrenal cell function at these thermal doses in an in vivo mouse tumor model, with thermal dose tracked via MRI temperature imaging. Next, we will develop a system employing microwave applicators with precise spatio-temporal control of microwave radiation to deliver MWT to hyperfunctioning adrenal cells. We will develop real-time techniques for identifying the targeted tissue from real-time imaging, informed by pre-procedural PET/CT imaging localizing the hyperfunctioning adrenal cells, in order to guide applicator placement and energy delivery. Finally, we will develop a non-iodinated contrast agent suitable for verifying adrenal cell function, immediately post MWT, thereby providing a means for assessing treatment outcome. The overall system will be evaluated in a large animal model. If successful, and translated to humans in future studies, this approach will, for the first time, extend definitive management of PA to individuals with unilateral and bilateral APAs. !


Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CARDIOVASCULAR
Title: Future Innovations in Novel Detection of Atrial Fibrillation (FIND-AF): Enabling regulatory approval for use of the FIND-AF machine learning algorithm in the NHS
Funder: Department of Health and Social Care

Abstract: Atrial fibrillation (AF) is increasingly common and associated with a five-fold increased risk of stroke.1 Over 300,000 people in the UK are living with undiagnosed AF leading to 15,000 preventable strokes a year.2,3 Improving early detection of AF is one of the three main cardiovascular priorities in the NHS Long Term Plan.4 However, untargeted screening has proven ineffective.5-7 FIND-AF, a machine learning algorithm, enables the early detection of AF through a targeted approach.8 FIND-AF uses routinely-collected data in primary care electronic health records (EHRs) to provide individual-level prediction of the risk of having AF within the next 6 months. Our clinical validation of FIND-AF in 440,000 EHRs demonstrated a negative predictive value of 95.5% with a predictive accuracy 6-fold better compared to current strategies.9 Given that FIND-AF is classified as software as a medical device, we now need funding to progress our work by achieving the necessary regulatory requirements for the technology to be used in the NHS. To do this we will sub-contract Ethos Ltd. to achieve the Digital Technology Assessment Criteria (DTAC), the DCB 0129 Standard, and Class I UKCA certification according to the Medical Devices Directive (93/42/EEC). As part of this process we will implement FIND-AF in SystmOne (one of the two main primary care EHR systems in the NHS) and perform design verification and validation. Regulatory approval would de-risk the technology for funding applications to the NIHR i4i programme, as well as the West Yorkshire Integrated Care System and Yorkshire and Humber Academic Health Sciences Network, for clinical utilisation in a single arm open label study to evaluate if the implementation of the algorithm will increase AF detection rates in a clinical setting. Importantly, it would also overcome the regulatory barrier for FIND-AF to be rapidly up-scaled and used across the NHS.


Research activity codes: 4.4 POPULATION SCREENING;7.3 MANAGEMENT AND DECISION MAKING
Health categories: CARDIOVASCULAR
Title: Prospective Longitudinal evaluation of AI-ECG in a Newly diagnosed Heart Failure (PLANE-HF)
Funder: Department of Health and Social Care

Abstract: Heart Failure: NHS Long Term Plan Priority Heart Failure (HF) is a condition in which the heart can no longer adequately pump blood. It is increasingly common, consumes >4% of the NHS budget and deadlier than most cancers1. The majority of patients have HF with reduced Ejection Fraction (HFrEF), treatment of which improves quality of life and survival2. However, 3 and 4. Easy home-based tracking of treatment response would be transformative. We have confirmed the accuracy of such a diagnostic to track HFrEF in >1000 patients5. Eko-DUO smart-stethoscope We have demonstrated that a &ldquo;smart stethoscope&rdquo; (Eko DUO) with artificial intelligence (AI) accurately categorises HFrEF severity after only 15 seconds of recording (electrocardiogram and heart sounds) during routine precordial placement5. Our preliminary demonstration that patients self-examination data is of comparable quality to clinicians (n=89, intraclass-correlation-coefficient= 0.887 [0.828-0.926]) creates a compelling opportunity for patient-led home monitoring of treatment response for newly diagnosed HFrEF. Potential benefits include: a. Individualised predictions of deterioration b. Proactive medication adjustment c. Enhanced triage for echocardiography Plan In 6 months we will complete a study of 80 patients with newly diagnosed HFrEF - 40 of coronary and 40 of non-coronary causes. Patients will receive an Eko DUO and instructions for twice-weekly self-examination for 3 months. Patients will be invited for echocardiography at 6 weeks post-diagnosis &ndash; window of maximal heart function changes with medication &ndash; followed by a final echocardiogram (routine care) at 3 months. This completes the 6-month time frame of this call, but with added value from longer-term follow-up of this cohort. We will test hypotheses that longitudinal trends and changes in AI-derived insights are associated with changes in, and possibly prediction of: Heart pump function on echocardiography Dosing of prognostic medication Hospitalisation


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Patient and Pubic Involvement and Engagement (PPIE) to inform design refinement and regulatory plan, including feasibility testing of innovative wearable device to monitor ankle swelling as an early warning of worsening Heart Failure.
Funder: Department of Health and Social Care

Abstract: In the UK, heart failure (HF) affects >900,000 people, accounting for 5% of acute hospital admissions (1,2,3,4). A key driver of worsening HF is fluid retention, or &quot;congestion&quot;, often leading to peripheral oedema (ankle swelling) as an early symptom, followed by breathlessness and fatigue causing multiple emergency hospitalisations. Peripheral oedema severity is an independent predictor of longer hospital stay and higher mortality (5). Early detection and correction of congestion can prevent hospitalisations and maintain patient wellness, but there is no sensitive or specific method to detect or accurately quantify congestion (6). Ergofigure s wearable digital device, Eye, is designed to monitor ankle swelling continuously, providing an early warning of worsening HF, enhancing patient self-management with occasional preventative intervention from healthcare professionals (HCP). Ergofigure conducted early patient and public involvement (PPI) with patients, HCPs and commissioners to confirm our approach. We have invested >&pound;120K in prototype development, which is now ready to test with our end users. However, we are at a critical point where we must ensure alignment of our solution with user needs to ensure our business viability. Ergofigure now needs financial support to lead a second critical PPI programme combined with real-world feasibility testing over 6 months to gain feedback on: 1) Device comfort, safety, function and usability. 2) Desired data reporting and alert format. Additionally, we need financial support to align our regulatory strategy (using consultancies), including technical file development and ISO13485 compliance for MDR CE/CA mark submission. This project will answer questions of design acceptability, usability, and effectiveness through engagement of 3 end-user groups: (a) HF Patients - with confirmed engagement of UK HF-Patient Charity, Pumping Marvellous; (b) HF Patient family members, (c) NHS HF teams &ndash; South Warwickshire NHS Trust engagement confirmed. Product and regulatory improvement at this stage will help ensure NHS and MHRA acceptance.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Leveraging technology for the assessment and monitoring of fragile infants with complex congenital heart disease in the community
Funder: Department of Health and Social Care

Abstract: Aim: To empower parents of infants with complex cardiac conditions to make life saving decisions wherever they are, using mobile application-based information and guidance, held on their smartphones Evidence gained from parents forums and studies about the Congenital Heart Assessment Tool (CHAT2)1-4 highlighted parental and clinicians fears about taking sick children home from hospital and venturing out into normal life. Additionally, barriers to the success of CHAT24 include the anxieties of parents in managing frequent monitoring and reliable transmission of data. The paper-based CHAT24 was developed for parents to monitor their infant s condition at home using a traffic light system to indicate healthcare intervention need, based on daily monitoring of key parameters and behaviours. CHAT24 provides a management plan for parents but relies on parents phoning the right person at the right time. Leveraging technology to transmit data enables immediate communication with healthcare professionals. This quality improvement project will be implemented with healthcare practitioners and parents at all stages, using readily available technologies through modern smartphone devices, whilst recognising digital poverty. Phase 1 &ndash; Scoping exercise (1 month) Focus groups with parents, Charity Little Hearts Matter (LHM) and healthcare professionals using CHAT24 as a guide, to identify essential functional (e.g. CHAT24 parameters) and non-functional (e.g. plain English) requirements to ensure the application meets everyone s needs. Phase 2 &ndash; Mobile application development (3 months) A mobile application will be specified, designed, and developed based on the requirements gathered in phase-1, ensuring relevant accessibility and usability guidelines are met, whilst taking advantage of the research team s technical, software development, study design, clinical and academic experience. Phase 3 &ndash; User testing (2 months) Undertake user testing with a group of healthcare professionals, technologists, parents and LHM using the developed application to ensure that it has the potential to address the concerns outlined above.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING;7.1 INDIVIDUAL CARE NEEDS
Health categories: CARDIOVASCULAR
Title: Non-vitamin K antagonist oral anticoagulants (NOACs) after acute myocardial infarction (AMI): a network meta-analysis'
Funder: Department of Health and Social Care

Abstract: Acute myocardial infarction (AMI) is one of the world largest health problems. Despite therapy, AMI remains a leading cause of death globally and the number one cause of death in UK. The global incidence of AMI is estimated to be 10 to 15 million episodes per year, and it is associated with great disease and economic burden. AMI costs the UK £3.6 billion in direct healthcare costs and economic losses each year. This significant burden of disease highlights the need to improve prevention, treatment and long-term management of individuals suffering from AMI. Balancing the risk of bleeding and thrombosis post-AMI is challenging and the optimal antithrombotic therapy remains uncertain. The role of NOACs after AMI is not fully understood and treatment decisions rely on limited evidence. Given the complexity of the condition and in the absence of RCTs comparing different types of NOACs against each other, it is essential to carry out a comprehensive and comparative evaluation of all available treatment options within the framework of a network meta-analysis (NMA). To our knowledge, no other systematic review and NMA has assessed the efficiency and safety of NOACs after AMI. We, therefore, aim for our review to present the most current and best available evidence to patients, clinicians, policy makers and researchers.

Lay abstract: See Plain English Summary

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR