NIHRDataInsights/HRCSData huggingface dataset:
Title: The role of mevalonate derived metabolites (isoprenoids) in statin-related and mitochondrial myopathies
Funder: Department of Health (England)

Abstract: The statins, inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase, are the mainstay of the treatment of hypercholesterolaemia, atherosclerosis and coronary artery disease. However, some patients develop myopathy which may be related to pre-disposing factors such as high cellular statin uptake or effects on other, non-sterol, isoprenoids (ubiquinone, prenylation and geranylgeranlyation of proteins, and dolichols). Mitochondrial dysfunction has been associated with statin-related myopathy and it is possible that this arises secondary to inhibition of ubiquinone biosythesis or pre-existing impaired mitochondrial function. I propose to examine isoprenoid metabolism in patients with statin-related myopathy and in patients with myopathy due to mitochondrial disorders. My hypothesis is that modulated isoprenoid metabolism, whether due to treatment with statins or to inherited defects, is involved in the aetiology of myopathy. I propose to investigate this by direct measurement of the intermediates and products of the mevalonate pathway in tissues and body fluids.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR
Title: Cytokine profiling and inflammatory cell immunophenotyping in Pulmonary Arterial Hypertension (PAH) - next generation biomarkers
Funder: Department of Health (England)

Abstract: Pulmonary hypertension is a disease affecting the blood vessels that supply the lungs, where high blood pressure (hypertension) in the lungs greatly increases the strain put upon the heart. Currently the most accurate way to measure this pressure is by inserting a balloon (catheter) into the right side of the heart. This measurement is combined with others (including how far a patient can walk in 6 minutes) to predict the severity of disease and how best to manage the patient in the future. We propose to take an additional blood sample and measure the levels of certain chemicals (interleukins). We hope that this measurement may provide a better, or more accurate prediction of how severe the disease is. Using the remaining blood samples we also hope to measure different types of immune cells (normally important for fighting infections). We think that some of these immune cells may not work properly and may actually working against the blood vessels in the lungs. Importantly, the maturation and function of many immune cells are regulated by interleukins. Finally we plan to look in diseased lung tissue from patients who have received lung transplants for pulmonary hypertension. We plan to look for the expression of certain proteins (STAT proteins) related to interleukin signalling in diseased blood vessels. Together we hope that this study will result in a new range of tests that provide a better prediction of how severe a particular patients disease is and how well they might respond to different drugs.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Totally automated blood pressure monitoring at home to improve care of patients with Heart Failure or Pulmonary Hypertension.
Funder: Department of Health (England)

Abstract: Many older people suffer from the long-term disabling illnesses of Heart Failure and/or Pulmonary Hypertension. The symptoms are shortage of breath and severely restricted walking range. Without medication, patients get progressively worse until the disease kills them. With medication a combination of three types- the symptoms can be successfully alleviated. Both over-medication and under-medication can be medically dangerous and costly, either a waste of drugs, side effects or the patient requiring rehospitalisation. The vital measurement for controlling medication is Pulmonary Artery Pressure which currently can only be measured by catheterisation, involving a hospital procedure and risk. We propose that while first measuring PAP, a tiny pressure sensor should be placed securely in the artery. Measurements can then be made at any time by interrogating the sensor by radio from a pocket-sized reader. The reader will be permanently, wirelessly linked to the hospital. Close control of the medication is therefore possible, leading to improved patient condition, slower progression of the disease and reduced re-hospitalisation. Measurement quality is guaranteed and measurements during normal activity are better than current catheter-based measurements in a clinic or hospital bed. The patient will know that they have 24/7 care.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: CARDIOVASCULAR
Title: Virtual coronary physiology: an angiogram is all you need.
Funder: Department of Health (England)

Abstract: Doctors make better decisions regarding when and how to treat patients with coronary artery disease if they have these blood pressure measurements Currently, Doctors have to insert a metal wire inside the heart to measure artery pressures which is time-consuming and requires special equipment, staff and medicines. Although this invasive technique saves lives and money, more than 95% patients do not receive the procedure or the benefits it provides patients. SOLUTION: VIRTU provides a solution to this problem since it only needs X-ray pictures and does not require any wires, drugs, or additional time, equipment or staff. VIRTU has been tested and works but needs improving before it can be used in all patients. GOALS: Improve VIRTU's accuracy, Improve VIRTU's speed, Test VIRTU in patients with more complicated coronary disease. BENEFITS: This research will make VIRTU 'patient-ready'. VIRTU will deliver all the advantages of the current invasive technique (i.e. reduced deaths,


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Combined magnetic resonance coronary angiography and positron emission tomography in patients with coronary artery disease
Funder: Academy of Medical Sciences

Abstract: Coronary heart disease is the commonest cause of death worldwide. It is therefore essential to develop imaging techniques to identify coronary heart disease and patients who are at risk of having a heart attack. In the blood vessels that surround the heart the build of a “plaque” in the wall of the blood vessel can put people at risk of having a heart attack. A magnetic resonance imaging (MRI) scanner uses magnets to generate images of the inside of the body. When we inject a contrast agent into a vein in the arm we can use the MRI scanner to look at the blood vessels around the heart. A positron emission tomography (PET) scanner uses a tracer labeled with a radioisotope that is injected into a vein in the arm. The images from a PET scanner tell us where in the body the tracer is distributed and we can use this to tell us more about the processes that cause coronary heart disease. With a new type of scanner, a PET-MRI scanner, we will look at the blood vessels around the heart in healthy volunteers and patients with coronary heart disease. This will enable us to develop this combined imaging technique that can give us more information about the development of plaques in the blood vessels around the heart.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Alcohol Harms: The relationship between alcohol consumption and cardiovascular risk - A life-course perspective
Funder: Alcohol Change UK

Abstract: The relationship between alcohol consumption and cardiovascular disease (CVD) is complex and controversial. Meta-analyses suggest that those who consume alcohol in moderation have a lower risk of developing CVD than heavy drinkers and those who abstain. However, the majority of studies measure alcohol at only one point in time and therefore fail to take into account variation in drinking over time. This approach means that important transitions, such as from heavy drinking to abstinence or low-drinking are not captured. This particular change has been put forward as a potential explanation for the apparent U/J-shaped relationship between alcohol and CVD, as it may be that that those classified as non-drinkers are actually former heavy drinkers who quit due to ill-health (referred to as "sick-quitters"). Recently efforts have been made to quantify the extent to which changes in alcohol consumption are related to CVD, however, these studies have typically relied on crude conceptualisations of life-course consumption and have also failed to explicitly link changes in alcohol intake to changes in the hazard of an event occurring over time. Jointly examining the relationship between longitudinal typologies of drinking and CVD will improve our understanding of the association between changes in alcohol consumption over time with respect to developing CVD. In doing so, our findings can be used to develop dynamic predictive tools accounting for repeat measures of alcohol consumption across the life-course and thus provide individualised/age-specific drinking guidelines. We will use our existing infrastructure of 9 UK cohorts (sample size 59,397 with 163,710 alcohol observations) with harmonised alcohol measures, and with linkages to external outcome databases (mortality, GP, hospital records), to explicitly examine the role of alcohol consumption in the development of CVD using a life-course perspective. We will also add more cohorts with lifetime alcohol data.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: CARDIOVASCULAR
Title: Disintegration of the cerebral matrisome: a central mechanism leading to small vessel disease and vascular cognitive impairment
Funder: Alzheimer's Society

Abstract: Cerebral small vessel disease (SVD) affects the small blood vessels in the brain, which become abnormal and do not regulate blood flow properly to brain. SVD is a major cause of stroke and vascular dementia. There are no good treatments for SVD because we do not fully understand what causes SVD. This research programme will develop new disease models which we will use to better understand what causes SVD, develop possible treatment approaches and provide a platform for future studies to screen new drugs that might be useful in treating SVD. Our research will focus on a part of the brain called the neurovascular unit which is made of different types of brain cells. This unit controls the blood supply to brain cells ensuring there is sufficient ‘fuel’ for normal cell function. The brain cells and blood vessels are supported by a scaffold called the extracellular matrix. New evidence suggests that risk factors for SVD (genes, high blood pressure) may result in damage to the matrix. We identified that mutations in the gene, COL4A1, which encodes a protein that is a major component of the matrix, leads to increased risk of stroke. We will utilise an animal model that has a COL4A1 mutation and develops strokes similar to patients, to study SVD and stroke onset and progression. We will also determine the molecular changes that occur during disease development from the earliest stages. We will investigate these molecular changes further in human cell models with the aim of identifying if they can be modulated and establish if they are potential treatment targets. For this we will use stem cells, generated from patients with COL4 gene mutations, to make the cells of the neurovascular unit which then form a new human platform to investigate the neurovascular unit and test drugs.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Vascular dementia: failure of fluid drainage from cerebral white matter
Funder: Alzheimer's Society

Abstract: One of the main features of Vascular Dementia is a condition known as small vessel disease (SVD) that also results in bleeding in the brain. During life, vascular dementia and SVD have characteristic features on brain scans: small vessel changes and bleeds in the grey matter, accumulation of fluid in the white matter and enlargement of spaces around the vessels. The exact cause for these changes is not known and therefore it is difficult to identify a target for treatment. Apart from providing blood to feed the brain, the arteries also have a very important function in removing the fluid waste from the brain. We have demonstrated that the elimination of waste from the brain is along tiny channels embedded in the walls of arteries and this fails in the ageing grey matter. These channels are called “basement membranes”, as they form the base upon which other cells are layered. Basement membranes are formed by networks of proteins and they are anchored to the cells. One important anchoring molecule is alpha-dystrobrevin. In this project, we aim to demonstrate that failure of drainage of fluid from the grey and white matter of the brain is a mechanism underlying SVD. Methods: Using post-mortem brains from the CogFAST stroke study perfomed in Newcastle, we will characterise their anchoring system of alpha-dystrobrevin comparing with scans of the brains to identify the affected areas of white and grey matter. We will also use a novel system of microscopy that enables the three-dimensional view of the vascular tree of the brain in different regions. In order to test the elimination of fluid from living systems with disturbed basement membranes, we will use two types of genetically modified mice. The outcomes should provide the elements of failed elimination of fluid from the brains with SVD, enabling thus the development of efficient treatments.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Effects of n-3 polyunsaturated fatty acids on the generation and functional activities of microparticles
Funder: Biotechnology and Biological Sciences Research Council

Abstract: N-3 polyunsaturated fatty acids (PUFA) have well-characterised effects on some aspects of cardiovascular (CV) risk, such as blood triacylglycerols, but there is considerable controversy regarding other endpoints, particularly those associated with thrombosis, inflammation and endothelial dysfunction. Microparticles (MPs) are small, cell-derived particles, which carry with them not only bioactive cell components, but also cell membranes whose fatty acid composition could be modified by dietary fatty acids. MPs are therefore more than just markers; they carry bioactive cargo, which can initiate thrombosis, potentially influencing a wide range of atherothrombogenic processes. We have recently demonstrated, for the first time, that supplementation with n-3 polyunsaturated fatty acids (PUFA) dramatically reduces numbers of circulating MPs in subjects with mild CV risk, and this may be one of the mechanisms for the protective effects of these fatty acids in CV disease. There is very little other data relating to the effects of diet on MP numbers and almost no information about how diet might influence the activities of MPs. This project will examine the effects of dietary n-3 PUFA on the generation and functional activities of total circulating MPs and on the mechanisms underlying these effects using both established methods and newly emerging technology (nanoparticle tracking analysis; NTA) in two main strands with the following overarching hypotheses: (i) MPs derived from subjects supplemented with n-3 PUFA will have altered fatty acid composition and reduced pro-coagulant activities (Strand 1); (ii) platelets derived from subjects supplemented with n-3 PUFA will generate fewer platelet-derived MPs (PMPs) upon stimulation due to alterations in PS exposure and intracellular calcium release (Strand 2); (iii) PMPs generated in vitro from n-3 PUFA-enriched platelets will have reduced pro-coagulant activities (Strand 2).


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CARDIOVASCULAR
Title: Cardio-oncology: A high resolution national electronic health record investigation of the interplay between cancer and heart disease
Funder: Cancer Research UK

Abstract: As treatments for cancer and cardiovascular disease improve and survival increases, more patients are living with both conditions. These patients are frequently excluded from clinical trials and there is relatively limited current data on how these conditions interact to inform guidelines and ensure optimal patient care. The presence of co-morbidities is a key determinant of clinical decision making and patient outcomes for both conditions. For example, the presence of inter-current cancer may impact the risk, management and outcome of cardiovascular events. Likewise the presence of ischaemic heart disease may alter the threshold for curative surgery, chemotherapy or radiotherapy approaches in cancer patients. Furthermore, it is known that cancer and its treatment increases the risk of cardiovascular disease states including heart failure, valvular heart disease and ischaemic heart disease (IHD). Equally there is also growing evidence that treatments for cardiovascular disease can increase the risk of cancer (e.g. fluoroscopy) or conversely may improve cancer outcomes (e.g. aspirin or statins). Many of these adverse sequelae have a long latency period, beyond the scope of clinical trial follow-up and to date there have been no clinical trials developed aimed at reducing these long term risks. A better understanding of the interplay between cancer and cardiovascular disease in the population will enable current management to be optimised and future clinical trials aimed at reducing the risk of long term adverse sequelae to be developed. We propose a programme of work using national data derived from linking the UK cardiovascular audits and cancer registries to address key focused hypothesis-driven cardio-oncology research questions, using a large national dataset. Importantly we plan not just to undertake a single analysis of the linked datasets but to establish the processes for rolling linkage to enable UK researchers to access a unique ongoing data resource to undertake research for the benefit of patients. As a collaborative partnership between researchers and leading figures in the key stakeholders (National Institute of Cardiovascular Outcomes Research (NICOR), the National Cancer Intelligence Network (NCIN) , the National Cardiovascular Intelligence Network (NCVIN) and Public Health England (PHE)), we are uniquely placed to deliver on the ambitious aims of this research programme, to widely disseminate the study findings and to use the study findings influence the development of future patient guidelines and clinical trials.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: CARDIOVASCULAR
Title: Fabrication and validation of a remote controlled cardiovascular biosensor
Funder: Chief Scientist Office, Scotland

Abstract: Cardiovascular disease and blocked heart arteries are common in Scotland and responsible for the majority of heart attacks and strokes. Medical stents are devices used to reopen these sites which often silently re-block. Our aim is to develop a new self-reporting stent1,2 that senses these changes and clears the blockage to improve their effectiveness and benefit to patients. We have a well-developed model that can detect and invoke the necessary cell changes however the bulky electronics now need to be miniaturised into a device that can report this information wirelessly. A self-reporting stent would be transformative to Scottish healthcare.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: CARDIOVASCULAR
Title: Leveraging the 25 year follow-up of the WOSCOPS trial
Funder: Chief Scientist Office, Scotland

Abstract: Two pivotal trials conducted in Scotland (WOSCOPS and PROSPER) showed the beneficial effects of lowering cholesterol in men who had not had a heart attack and in the elderly. Long-term follow-up in WOSCOPS showed additional benefits in reducing heart disease. We will extend follow-up to 25 years in WOSCOPS and 15 years in PROSPER. We will apply for funding to explore long-term benefits in the peripheral arteries and in heart failure and to develop risk models for coronary heart disease, heart failure and peripheral artery disease, using clinical, laboratory and genetic information. We will also study the natural history of vascular disease in these populations.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: CARDIOVASCULAR
Title: Molecular THoracic imAging and bioiNformatics Approaches TO Sudden death (THANATOS) Study
Funder: Chief Scientist Office, Scotland

Abstract: The primary aim of the current proposal is to determine whether 18F-fluoride PET CT imaging of coronary atherosclerotic plaques identifies areas of micro-calcification and plaque rupture in sudden death victims. This study will address the following questions: (1) Does coronary 18F-fluoride activity identify coronary plaque rupture in sudden cardiac death victims? (2) Does coronary 18F-fluoride activity co-localise to areas of microcalcification in coronary arteries?


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Developing a behavioural Intervention to Improve the Effectiveness of CPR training for Lay People
Funder: Chief Scientist Office, Scotland

Abstract: In Scotland, ~3,500 people/year experience out-of-hospital cardiac arrest; only 5% survive to home. Early cardiopulmonary resuscitation (CPR) from lay bystanders is essential for survival. However, most (65%) CPR-trained lay-people do NOT attempt resuscitation when required. CPR is behaviour, yet behavioural science has not yet been systematically applied to this problem. We will use behavioural science to identify behaviour change techniques 1) demonstrated to increase CPR initiation in existing evidence. 2) delivered within existing training programmes. This will inform the content of an NIHR application to develop and test a text-messaging behavioural-intervention to prolong lay-trainees’ competence and increase willingness to initiate CPR


Research activity codes: 5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: CARDIOVASCULAR