NIHRDataInsights/HRCSData huggingface dataset:
Title: In silico human-based methodologies for evaluation of drug cardiac safety and efficacy
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Cardiotoxicity is one of the leading causes of failure during drug development and also, more worrying, after marketing approval. Withdrawal due to cardiotoxicity has increased from 5.1 to 33%, including compounds to treat cardiovascular problems as well as drugs not intended to affect the heart such as antihistamines. Current used strategy to screen for adverse contractility effects involves a combination of preclinical in-vitro pharmacological profiling, cardiomyocyte assays and in-vivo cardiovascular (CVS) studies, and uses a variety of animal species (rats, mice, rabbits, guinea-pigs, dogs, pigs and non-human primates). In spite of the variety of animal methods for preclinical screening for drug safety, 20-50% of all advanced candidates have to be abandoned due to adverse outcomes, even late in the drug development process. The main aim is to accelerate the uptake of human-based in silico methodologies for evaluation of cardiac drug safety and efficacy in industry, regulatory and clinical settings. The specific objectives include: 1) Review, collation and implementation of a comprehensive database of human electrophysiology and contractility in silico multiscale mechanistic models for specific cardiac disease conditions. 2) Development and qualification of in silico human models for the prediction of adverse outcomes in human cardiac electrophysiology and contractility for specific disease conditions, based on existing models, and calibration with in vivo and ex situ recordings. 3) Evaluation studies to compare in silico human-based predictions to clinical outcomes, current animal methods, and in vitro methods including stem cell derived cardiomyocytes. 4) Workshops and dissemination activities to identify and overcome barriers for the uptake of in silico methods in industrial, clinical and regulatory settings. Project membership involves key partners across 11 countries who will raise the profile of in silico human models for the 3Rs.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR
Title: Use of induced pluripotent stem cell derived cardiomyocytes to test the consequences of genetic variants in atrial and ventricular arrhythmias
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Inherited cardiac conditions are caused by genetic mutations in cardiac genes. They are the most common cause of sudden cardiac death in the young through ventricular arrhythmias and also contribute substantially to heart failure, putting a major burden on health care systems. To develop specific therapies, it is necessary to understand the consequences of the genetic mutations at the molecular level. Model systems, such as cells, organoids and whole organisms are used to elucidate disease pathways. The animal models among them have a high ethical burden, therefore there is a need to replace them by cellular models.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Replacement of animal use in measuring cardiomyocyte response to drug safety profiling using a novel NMR metabolomics technology
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: The development of drugs for therapeutic treatment depends on animal testing to ensure that they are safe for people to use. In the past some drugs that were thought to be safe went on to cause serious heart problems, and even fatalities. Harmful drugs were found to stop the heart from functioning properly by altering the behaviour of molecules that control the electrical activity and energy required to work, and ultimately the ability of the heart to beat properly. In response to this, all drugs that are developed must be tested for harmful effects on animal hearts. Our project is focused on a new technology called NMR metabolomics, which can accurately identify changes in how the heart uses energy at the cell level, allowing us to study the harmful effects of drugs by monitoring human heart cells without the need to perform experiments on mice (and other animals).


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR
Title: ECHO-SENS: Externally CHarged CardiOvascular bioSENSors
Funder: Department for the Economy, Northern Ireland

Abstract: The project aims to transform current medical interventions and standards of care to develop externally-powered implanted technology for continuous health monitoring. The consortium will specifically focus on the development of advanced implantable microelectronic technologies capable of monitoring patient physiological performance, tracking nascent or progressing pathologies and delivering treatment.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: CARDIOVASCULAR
Title: Developing the Next Generation of Cardiac Organoid Systems
Funder: Department for the Economy, Northern Ireland

Abstract: The project aims to apply a new laser-enabled low temperature deposition process to create gold nanopatterns (thin films and lattice structures) which are critical to the fabrication of focal attachment points on thin fibrous tissue scaffolds, and optimisation of their conductive properties. Specific aims include the development and characterization of cardiac organoids from induced pluripotent stem (iPS) cells and testing their function in the developed patterned structures in vitro and in vivo.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Using wearable devices to monitor the symptomatic status of children with Hypertrophic Cardiomyopathy.
Funder: The Academy of Medical Sciences

Abstract: Childhood Hypertrophic Cardiomyopathy (HCM) is associated with significant long-term morbidity but symptoms are not easily assessed in clinical practice. Performance during traditional, symptom-limited exercise testing with metabolic gas exchange has been shown to correlate with symptoms in adults with the disease. However, exercise testing is not readily available for all children with HCM and cannot be reliably performed in younger children. Wearable devices could overcome these challenges improving clinicians’ ability to detect symptoms and improve quality of life. Daily step count has been shown to correlate with disease severity in adult patients but the use of these devices has not been explored in children with HCM. This study takes advantage of a large and unique clinical cohort of children with HCM seen at the Centre for Inherited Cardiovascular Diseases, Great Ormond Street Hospital to determine if wearable devices could be a useful tool to monitor the symptomatic status of children with HCM. The study aims include; to determine the relationship between wearable devices data and traditional measures of cardiopulmonary fitness in childhood HCM; to determine the relationship between wearable devices data and patient-reported symptoms; and to determine the acceptability of wearable devices for patients and families. An improved understanding of the relationship between wearable device data, traditional exercise testing and symptomatic status in childhood HCM would pave the way for future studies investigating the role of remote long-term monitoring of patients allowing rationalisation of hospital based investigations and prediction of adverse outcomes.

Lay abstract: Unexplained thickening of the heart (Hypertrophic Cardiomyopathy or HCM) is a rare disease in childhood that can significantly affect quality of life because of symptoms like breathlessness, chest pain and dizziness, which can be debilitating. Treatments are available to help but assessing symptoms in young children can be difficult. In adults with the disease, symptoms are often associated with a reduced exercise ability. However, exercise tests are not possible for all children with HCM and cannot be used in the very youngest patients (under 7 years). Wearable devices (such as smartwatches) could be used to overcome these difficulties by tracking activity levels in daily life and have shown some promise in adults with the disease. However, they have not previously been tested in children. The aim of this study is to explore if data from wearable devices (such as daily step count) could be used in children with HCM to monitor symptoms. This could allow for earlier treatment and an improvement in the quality of life for these children as well as avoid the need for unpleasant exercise tests. If successful in this disease, such technology could also be used in children with other heart conditions.

Research activity codes: 5.3 MEDICAL DEVICES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Developing a cell-free strategy for cardiac regeneration
Funder: The Academy of Medical Sciences

Abstract: The overarching aim of this project is to assess the benefit of a Myc-Cyclin T1 regenerative therapeutic in a heart failure setting and establish its potential for treating a broad range of heart failure patients. The scale of the disease, with 23 million heart failure patients worldwide, has an enormous socio-economic impact. Currently, the only effective treatment for end-stage heart failure is heart transplantation. Strategies to promote regeneration of the heart would be a powerful alternative treatment. Towards that end, our recent findings demonstrate that combined Myc and Cyclin T1 expression can elicit extensive cellular proliferation of adult mammalian cardiomyocytes. We have designed a modified synthetic messenger RNA (modRNA) as a transient prototypical therapeutic agent for combined Myc and Cyclin T1 delivery. Treatment with the therapeutic immediately following myocardial damage improves left ventricular function in the mouse, establishing its potential efficacy. Here, I will determine if a Myc-Cyclin T1 therapy could be used to treat later stages of heart damage using our pioneering “acutely switchable” mouse model. Fulfilment of the aims will enable the translation of our modRNA therapeutic for myocardial infarction, with the potential to treat millions of patients with heart failure worldwide.

Lay abstract: Cardiovascular disease is the leading cause of death worldwide, causing over 18 million deaths annually. Of these deaths, around 85% are attributed to heart attack and stroke. During a heart attack, the lack of oxygen to the heart causes the muscle cells (cardiomyocytes) to die. Adult mammalian cardiomyocytes do not have the capacity to regenerate by proliferating after injury and cannot repopulate the heart tissue after damage. Loss of these contractile cells causes reduced heart function, heart failure, and ultimately death. Major research efforts are therefore aimed at regenerating the heart, with limited progress to date from a clinical perspective. We have recently found that if we force the expression of two genes (Myc and Cyclin T1) in cardiomyocytes in mouse hearts via genetic manipulation, we can activate a substantial proliferative response in the cells. Furthermore, using a novel therapy that drives a short pulse of Myc and Cyclin T1 expression, we have shown that we can reduce heart damage when treating mice immediately following injury. These results represent a major step towards the development of a regenerative therapeutics based on stimulating cardiomyocyte proliferation in adult hearts. However, the vast majority of patients who present with symptoms of heart failure have had the disease for some time. The proposed project will determine whether our strategy could be expanded to treat a broader range of patients by assessing the benefit of Myc and Cyclin T1 expression in a heart failure setting.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR
Title: Clinical Translation of Optical Ultrasound Imaging
Funder: Royal Academy of Engineering

Abstract: This research aims to improve the diagnosis and treatment of cardiovascular patients by developing all-optical ultrasound imaging probes for real-time visualisation of tissues and medical devices from inside the body.A multidisciplinary, collaborative effort this project will focus attention and stimulate connections across many fields, including optics, ultrasound, materials science and medical device design, thereby creating a knowledge base to speed up the translation of future biomedical sensing innovations.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Improving acute cardiac care of patients with renal disease through linkage of national audits in the UK
Funder: The Health Foundation

Abstract: National audits significantly advance knowledge of how variations in clinical care impact patient outcomes across the NHS. However, they are often restricted by an organ-specific focus, despite many patients having conditions that affect more than one organ. Heart and kidney diseases are known to interact on multiple levels. People with reduced kidney function are at a high risk of heart attacks, but can develop acute kidney injury as a side effect of the dye that is injected during heart investigations. Evidence shows that these patients are therefore less likely to receive the potentially life-saving cardiology care they need. This project led by the London School of Hygiene and Tropical Medicine aims to provide information on how to improve acute cardiology care for people with reduced kidney function by investigating national variations in how different cardiology centres manage patients. Data from acute cardiology care, hospitalisations and deaths held at the National Institute of Cardiac Outcomes Research (NICOR) will be linked to data on acute kidney injury and dialysis held at the UK Renal Registry (UKRR) to create the largest cardio-renal national data resource to date. Analyses using the linked data will quantify the patient benefit and overall cost of managing patients with reduced kidney function at admission differently. Key project outputs will be disseminated by opinion leaders in the cardio-renal community and through ‘plain English’ summaries drafted by patient representatives. This project has the potential to improve health care and outcomes for patients with heart and kidney disease by highlighting areas of clinical need, investigating divergence from clinical evidence and guidelines, and identifying the benefits of changing practice.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: CARDIOVASCULAR
Title: LAUNCHES QI: Linking AUdit and National datasets in Congenital HEart Services fo
Funder: The Health Foundation

Abstract: Services for congenital heart disease (CHD) span a patient’s lifetime, from birth through to adulthood. However, the quality of these services is currently only measured by 30 day survival following children’s heart surgery. 30-day survival is now almost 98%, so this is no longer a good proxy for quality. Medical advances mean that adults with CHD now outnumber children with CHD, but there is no routine monitoring of adult services, nor of the important transition from child to adult services. This project, led by a team of clinicians, commissioners, patient representatives and academics from University College London, will address the gaps in how quality of CHD care is measured and reported in England. The work involves linking the national CHD audit dataset to four national datasets encompassing hospital admissions and life status. This will enable the trajectory of CHD patients through the NHS to be described over the course of their lives, for example analysing how many hospital admissions they have, and what happens when children become adults. It will include information on utilisation and outcomes. Variation in the provision of care across England will be assessed and opportunities for improvement identified. The project will produce the first comprehensive understanding of care received by a complex population from birth to adulthood. This will be the basis for a step change in how quality in CHD services is measured and improved. It will also be a template for how national datasets can be successfully linked and used to understand variation and drive quality improvement for other lifelong conditions, such as renal disease, haemophilia and cystic fibrosis.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: CARDIOVASCULAR
Title: Can leg blood pressure measurements predict brachial blood pressure? An individual participant data meta-analysis using data from the INTERPRESS-IPD Collaboration
Funder: Stroke Association

Abstract: Background: Hypertension, a key modifiable risk factor for the prevention of stroke, is diagnosed and managed by blood pressure (BP) measurement on the upper arm. Amputations, altered muscle tone after stroke or limb deformities may prevent this. Leg BP measurement is an alternative, but limited data exist to guide clinicians in interpreting such readings. Aim: Using data from the INTERPRESS-IPD Collaboration, which holds >34,000 individual records from 12 international studies, we will: i) examine the relationship between arm and leg BP; ii) develop and validate a multivariable model predicting arm BP from leg BP; iii) investigate the prognostic role of leg BP in cardiovascular event and mortality risk prediction. Methods: In an observational cohort design, individual participant data (IPD) meta-analyses will be undertaken to explore the cross-sectional relationship between arm and leg BP in multivariable models. Heterogeneity will be assessed using I2 and tau2. Prognostic models will also be derived for all-cause and cardiovascular mortality and cardiovascular events. Expected outcomes: We will provide the first evidence-based method for estimating individual brachial systolic BP, and cardiovascular risk, from leg measurements. Our findings will support clinicians and patients in detecting and managing high BP more effectively where leg measurements are required.

Lay abstract: Background: Hypertension, a key modifiable risk factor for the prevention of stroke, is diagnosed and managed by blood pressure (BP) measurement on the upper arm. Amputations, altered muscle tone after stroke or limb deformities may prevent this. Leg BP measurement is an alternative, but limited data exist to guide clinicians in interpreting such readings. Aim: Using data from the INTERPRESS-IPD Collaboration, which holds >34,000 individual records from 12 international studies, we will: i) examine the relationship between arm and leg BP; ii) develop and validate a multivariable model predicting arm BP from leg BP; iii) investigate the prognostic role of leg BP in cardiovascular event and mortality risk prediction. Methods: In an observational cohort design, individual participant data (IPD) meta-analyses will be undertaken to explore the cross-sectional relationship between arm and leg BP in multivariable models. Heterogeneity will be assessed using I2 and tau2. Prognostic models will also be derived for all-cause and cardiovascular mortality and cardiovascular events. Expected outcomes: We will provide the first evidence-based method for estimating individual brachial systolic BP, and cardiovascular risk, from leg measurements. Our findings will support clinicians and patients in detecting and managing high BP more effectively where leg measurements are required.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Decision making about implantation of cardioverter defibrillators (ICDs) and deactivation during end of life care
Funder: Department of Health (England)

Abstract: Implantable cardioverter defibrillators (ICDs) prevent sudden cardiac death in patients at high risk (primary prevention) and in survivors of cardiac arrest (secondary prevention). ICDs are effective at improving overall survival but have a range of adverse effects including inappropriate shocks increased hospitalisations anxiety and depression. One of the main concerns is the capacity of the ICD to prolong the dying process and cause unnecessary pain and distress to the patient towards the end of their life. Yet it is unclear if how and when the issue of deactivation is communicated to ICD recipients. We also do not know what types of information or support patients and their family members need in order to make implantation and deactivation decisions. To date much of the published literature is concerned with what happens in specialist centres with little consideration of earlier stages of decision making in secondary care. The dual focus of this project on both ICD implantation and deactivation decisions reflects the government’s stated commitment to shared decision making as well as the importance attached to advance care planning in the NHS. Against this background our study is timely particularly with the observation that much needs to be done in terms of understanding how best to implement shared decision making within existing services. We will address these knowledge gaps by establishing how patients are engaged in implantation and deactivation decisions and how this could be improved. The notion of device deactivation raises complex ethical legal psychosocial and emotional dilemmas for the patient their family members and the clinician. We will use non-participant observation and semi-structured interviews to understand how to improve decision making in ICD implantation and deactivation and to establish the information and support needs of patients family members and clinicians. These data will be used to develop initial brief decision support for ICD implantation as well as informing advance care planning for ICD recipients. To this end we will conduct two workshops with a mix of patients family members and clinicians to iteratively develop initial approaches to decision support and guidance for advance care planning. Our approach to knowledge mobilisation will involve dissemination of the study findings in peer review publications conferences patient organisation events and in a half day dissemination event involving patients family members representatives from patient organisations clinicians and academics.


Research activity codes: 7.2 END OF LIFE CARE;7.3 MANAGEMENT AND DECISION MAKING
Health categories: CARDIOVASCULAR