NIHRDataInsights/HRCSData huggingface dataset:
Title: New Horizons in Clinical Cardiac Diffusion Magnetic Resonance Imaging
Funder: Wellcome Trust

Abstract: Remodelling of the heart is linked to a poor prognosis for patients with cardiac disease. While the mechanisms underpinning this process are only poorly understood, changes in the microstructural architecture of the myocardium are considered to play a key-role. Cardiac diffusion tensor imaging (cDTI) has enabled insights into the microstructure non-invasively through the assessment of the diffusion of water molecules in the myocardium. cDTI provides quantitative diffusion metrics such as Fractional Anisotropy, Mean Diffusivity and Helix Angle, which can serve as biomarkers of disease. Nevertheless, cDTI is technically challenging due to its sensitivity to motion, strain and perfusion. Moreover, the diffusion tensor is an oversimplified representation of the underlying tissue structure. More realistic tissue models as developed for the brain are presently prohibited by MR scanners hardware limitations, particularly magnetic field gradient strength. The aim of this project is to establish cardiac diffusion MRI on the Connectome scanner, which features gradients 4x stronger than those available on clinical scanners, in order to develop next generation MRI techniques for the non-invasive, microstructural characterisation of the beating heart in humans, with the ultimate aim to detect subtle remodelling of cardiac tissue earlier, and with higher accuracy than ever before.

Lay abstract: Remodelling of the heart is characterized by changes of its size and shape. The more it remodels, the worse is the outcome for patients with heart disease likely to be. The mechanisms underlying remodelling are not known, but changes in the microstructure of the heart muscle are important. Cardiac Diffusion Magnetic Resonance Imaging (cDMRI) can measure this microstructure, but despite ongoing developments, it is not yet used for clinical management. This is due to technical challenges and to MRI scanner hardware limitations, particularly gradient strength. The Human Connectome Project, designed to provide unparalleled assessment of the brain, developed highly-specialised MRI scanners with gradients 4x stronger than those available on clinical scanners. This technology has never been exploited outside of the head. The proposed project combines leading expertise in cDMRI and microstructural imaging with access to one of only 3 such scanners worldwide, to develop next generation assessments of human hearts.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR;NEUROLOGICAL
Title: Neural circuits regulating appetite in an uncertain environment
Funder: Wellcome Trust

Abstract: Dietary sodium – typically, common salt – is essential to all animals for health and survival, but when consumed in excess it is profoundly damaging, being a leading risk factor for cardiovascular morbidity and mortality worldwide. Eating salty foods is often a pleasurable experience, leaving many individuals struggling to keep their diet healthy.Whether the taste of salt is rewarding or not depends on the brain’s reward pathways, which make salt less rewarding when the body needs it less. However, periods of sodium deprivation can subvert this, often leading to consumption beyond physiological requirements. This response to a period of deprivation may explain why some individuals are unable to regulate their sodium intake in daily life.To better understand the brain circuitry regulating sodium appetite, I will use a combination of animal behavioural and neuroscientific techniques. My focus will be on dopamine, a key neurotransmitter involved in the brain's reward pathways, in addition to electrical activity in the wider brain. I will observe these aspects of brain function during periods of sodium deprivation to shed light on their role in overextending the sodium appetite beyond healthy consumption, delivering new insights about the brain’s role in nutritional disorders and appetite regulation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CARDIOVASCULAR;NEUROLOGICAL;MENTAL HEALTH
Title: Human pluripotent stem cell cardiomyocytes and hepatocytes with engineered genotypes for drug safety evaluation
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Safety assessment of each new drug developed requires up to 1800 animals, which typically comprise non-rodent species (monkeys, dogs) and rodents (rats and mice). New EU regulations on toxicity testing (termed 'REACH') will use up to 54 million animals over the next 10 years to evaluate 30,000 compounds. Even with this level of animal use, preclinical assays are cited as only 71% predictive of whether a drug will be toxic in humans. Poor predictability is due to species differences and the inability to develop test platforms that mirror diverse human genotypes, particularly those associated with the high drug susceptibility seen in cardio- and hepato-toxicity. Adverse drug reactions account for 100,000 deaths per year in the US alone. To facilitate reduction and replacement of animal use, and to increase predictability to human toxicity, this proposal brings together a new consortium with skills in genome engineering (Skarnes, Rosen; Sanger Centre), human pluripotent stem cell biology & robotic automation (hPSC; Denning, Young; Nottingham) and toxicity testing (Goldring, Park; Liverpool). The aim is to engineer different patient-relevant mutations associated with drug susceptibility or resistance into the protein coding regions of otherwise genetically healthy hPSCs. Differentiating these cells will produce cardiomyocytes and hepatocytes that carry specific mutations within a common genetic background, allowing unbiased evaluation of how genotype-drug interaction affects cell structure, function and viability. Co-culturing cardiomyocytes with hepatocytes of different genotypes will allow the impact of altered hepatocyte function on cardiomyocytes to be assessed. Comparing these results with data from the literature and industrial partners will allow the predictive value of this humanised in vitro model to be determined. A 0.1% reduction in animal-based in vitro, ex vivo and in vivo tests has the potential to save up to 54,000 animals in Europe alone.


Research activity codes: 5.1 PHARMACEUTICALS;5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: CARDIOVASCULAR;ORAL AND GASTROINTESTINAL
Title: The role of vascular endothelial growth factors (VEGF) and angiopoietins (Ang) in endothelial dysfunction in children with chronic kidney disease (CKD) stage 5
Funder: Kids Kidney Research

Abstract: Drug treatment and kidney dialysis is now so successful for even the smallest children that most paediatric patients with long-term kidney failure survive until adulthood. Drugs and dialysis are not perfect, however, because they do not stop the children developing cardiovascular disease which increases their risk of dying from a heart attack or stroke by 800 times. The first step in cardiovascular disease appears to be damage to the lining of the blood vessels and we believe that circulating factors in the blood are involved in this process, particularly two compounds called VEGF and angiopoietin which normally control vessel number and stability. In this study, we will investigate vessels removed from children with long-term kidney failure during routine operations for insertion of dialysis catheters or kidney transplantation. We will measure levels of VEGF and angiopoietin in the circulation and within the removed vessels, and compare these results to other tests of cardiovascular function. We will also grow the vessels in the laboratory to test the effects of VEGF and angiopoietin on them. This study will help us understand the roles of VEGF and angiopoietin in vessel damage in kidney patients. Such data may allow us to develop therapies that manipulate VEGF or angiopoietin to prevent cardiovascular disease in children (and potentially adults) with long-term kidney failure.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR;RENAL AND UROGENITAL
Title: Genetics of renovascular malformations
Funder: Kids Kidney Research

Abstract: Narrowing (stenosis) of one of the arteries that supplies the kidneys causes the kidney to produce hormones that increase blood pressure. So the rest of the body is exposed to severely increased blood pressure and the risk of major complications. In children, stenosis is mostly due to an overgrowth of the fibrous and muscular tissue in the vessels. GOSH is an international referral centre for children with renovascular hypertension. They have already collected DNA from more than 30 affected children. This project plans to use genetic technology to identify variations in genes affecting patients. This will enable a precise diagnosis, provide insight into the disease mechanism and could be used to develop targeted treatments.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR;RENAL AND UROGENITAL
Title: Comprehensive characterisation of the cardiovascular effects of chronic renal disease in children – A novel cardiovascular magnetic resonance study.
Funder: Kids Kidney Research

Abstract: Patients on dialysis have a very high risk of developing heart and vessel (cardiovascular) disease. In 20-30 yr olds, the chance of dying from cardiovascular disease is the same as that of an 85yr old. In patients with high blood pressure (hypertension) we know that if left untreated that this can put a strain on the heart causing structural changes with thickening of heart muscles and eventually the heart function can be compromised.Previous studies have shown cardiovascular disease in patients with moderate and severe kidney failure (chronic kidney disease stages 3, 4 & 5). We have previously shown HD places a lot of strain on the heart. It can result in a drop in BP and symptoms such as headaches and stomach cramps. A low BP is a signal for the heart to work harder to deliver blood to all the organs in the body. The heart itself requires blood to work normally. If its blood supply falls below a critical level this injures the heart muscle (myocardial ischaemia). Injured heart muscle segments are unable to move (contract) normally, thereby reducing overall function. We have also demonstrated with conventional methods that about two thirds of children with diseases affecting the blood supply to the kidney (renovascular disease) have structurally and functionally abnormal hearts. This relatively low proportion has always been surprising, as these children often have massively raised blood pressure up to systolic 200 mm Hg or more.We at Great Ormond Street Hospital see the largest number of patients with renovascular disease. We have started a home haemodialysis (HD) service in 2010 and have recruited 15 patients. The advantage of home HD is that one can provide longer and more frequent dialysis treatments and these are though to be gentle on the body. Finally we now have access to a unique cardiac magnetic resonance test that is both sensitive and precise enough to detect subtle changes in the heart, non-invasively. We propose a study to determine: 1. Whether the heart is adversely affected in children with mild kidney failure (CKD stage 2).2. The deleterious effects on the heart from long standing hypertension in children with normally functioning kidneys 3. Compare the hearts of children on conventional in hospital HD compared with children on home HD. We will attempt to recruit i) normal children, ii) children with mild, moderate and severe kidney failure, iii) hypertension and renovascular hypertension, and iv) children on conventional in hospital HD and home HD All of these children undergo a series of tests using cardiac MRI.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR;RENAL AND UROGENITAL
Title: Mechanisms for an effect of N-acetylcysteine on renal function after exposure
Funder: Chief Scientist Office (Scotland)

Abstract: Radiocontrast-induced nephropathy is a major and increasingly common complication of contrast use, increasing the mortality of chronic kidney disease patients threefold. N-acetylcysteine (NAC) is widely used for prevention but recent meta-analyses indicate that the more than 20 RCTs performed so far have provided insufficient evidence with which to determine effectiveness. These RCTs have been performed without prior detailed clinical studies of NAC’s effect on renal function that would have guided the choice of outcome measure and regimen. We propose to set up a structured set of randomised cross-over and parallel-group studies to assess the effect of oral and IV NAC on normal and diseased kidneys, and then the effect of contrast with and without NAC treatment. The information gained should aid the design of a phase III study that uses a rational dose of NAC, given through the correct route, and assesses the correct outcome measure.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;3.3 NUTRITION AND CHEMOPREVENTION
Health categories: CARDIOVASCULAR;RENAL AND UROGENITAL
Title: The effect of resistance training and aerobic exercise on vascular stiffness, exercise capacity, muscle strength and incidence of complications following kidney transplantation.
Funder: Department of Health (England)

Abstract: The use of modern immunosuppressant therapies have improved the life-expectancy of kidney grafts, however, risks of secondary complications such as diabetes, cardiovascular disease and obesity are an associated risk. Aerobic exercise helps to prevent and treat cardiovascular disease and to prevent and reverse arterial stiffening. Resistance training can prevent or treat lifestyle-related functional limitations. This project will examine the individual effect of aerobic and resistance training exercise delivered in a 12-week supervised outpatient class setting, compared with usual care, on vascular stiffness; aerobic capacity; functional ability; transplant outcomes and quality of life in patients who have received a kidney transplant.


Research activity codes: 5.7 PHYSICAL;6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: CARDIOVASCULAR;RENAL AND UROGENITAL
Title: Genetic and molecular characterisation of sodium reabsorption by thiazide-sensitive pathways in the kidney
Funder: Medical Research Council

Abstract: Aims: To advance understanding of the thiazide-sensitive pathway(s) of sodium reabsorption by studying two clinical manifestations of dysregulation of this pathway: Gordon syndrome (GS) and Thiazide-Induced Hyponatraemia (TIH). Objectives 1.To establish the genetic basis for Gordon syndrome (GS) in patients without mutation in WNK1/4, CUL3 or KLHL3 mutation and explore phenotype-genotype correlations within GS 2.To build on pilot work in Nottingham to establish the genetic basis for predisposition to severe TIH and detailed description of the TIH phenotype 3.To investigate whether the identified genes are associated with blood pressure and sodium concentration in the general population using the UK Biobank 4. in vitro characterisation of identified genes and their variants, including novel CUL3, KLHL3 and TIH candidates already identified. Methods 1.Recruitment of GS patients with Professors Gordon and Jeunemaitre and TIH patients through an ongoing multi-site programme in the UK 2.A variety of genetic methods will be used to investigate GS and TIH including: -Whole exome reseqencing (GS) -Exon-directed beadchip analysis (TIH) -Targeted resequencing of candidate genes (TIH) 3. Association study of BP and serum sodium in the UK Biobank population. 4. Functional studies using Xenopus oocytes & cell culture. Scientific/Medical value of results 1.Further understanding of the molecular mechanisms regulating sodium trafficking will advance the understanding of: a.the regulation of human blood pressure b.additional mechanisms of action of thiazide diuretics c.predisposition to TIH 2.This will inform: a.The discovery of new anti-hypertensive drug targets b.The design of new diuretics less prone to induce hyponatraemia c.Functional and pharmacogenetic characterisation of hypertensive patients to avoid thiazides in those susceptible to hyponatraemia


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR;RENAL AND UROGENITAL
Title: Investigating the effect of AMPK activiation in vivo on the cardiovascular system, using a novel transgenic mouse model we have previously generated.
Funder: Medical Research Foundation

Abstract: Investigating the effect of AMPK activiation in vivo on the cardiovascular system, using a novel transgenic mouse model we have previously generated. Recent work has shown that AMPK activiation causes a developmental defect resulting in polycystic kidney phenotype that in turn leads to hypertension. Chronic hypertension causes secondary changes in heart function, including hypertrophy. We have now established a model with kidney-specific expression of the AMPK transgene and are using this to dissect the mechanisms leading to the polycystic kidney phenotype.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR;RENAL AND UROGENITAL
Title: Harnessing opportunities for quality improvement from Primary Care electronic health records.
Funder: Wellcome Trust

Abstract: Patients often don't get the best treatment available from their doctor. We know that if we tell doctors which of their patients did not receive the best treatment, along with a plan on how they could have given it to them, then they are likely to provide better treatment in future. Unfortunately, at the moment doctors are just told whether or not their patients receive good treatment - they aren't given plans to help them improve, so often patients keep getting poor treatment. This project w ill develop and test a new computer programme that will use patient's medical records to tell doctors when their patients don't get the best treatment AND what they could do in future to improve. Based on what we know already, we think this will help patients get better care, and live longer and healthier lives. The project will first look at the treatment of a heart and kidney condition by GPs in Salford. The computer programme will be created by finding patterns in patient's medical records with these conditions. Then it will be tested by getting GPs to use it and asking them questions about it.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: CARDIOVASCULAR;RENAL AND UROGENITAL
Title: MICA: Ancestry and biological Informative Markers for stratification of HYpertension: The AIM HY study
Funder: Medical Research Council

Abstract: Hypertension treatment within the UK is currently stratified according to age and self-defined ethnicity (SDE). Limitations of this are well recognised: wide inter-individual response to drug classes despite stratification by age/ethnicity; uncertainty in stratification of ethnic minorities other than those of African ancestry and in an increasingly admixed population; uncertainty in stratification to combination treatment required in most patients; This proposal aims to exploit ethnic variation in drug response to: 1) Determine whether ancestry informative markers (AIM) and metabolomic profiling can be used to effectively personalize anti-hypertensive treatment. 2) Provide evidence for selecting the best first-line and combination treatments. 3) Determine mechanisms that define the response to existing treatments and hence inform future approaches to resistant hypertension using non-standard combinations of existing drugs and/or new drugs. Prediction of response to treatment by AIM / metabolites (previously identified in a discovery program in Twins UK) will be examined in existing randomised clinic trial (RCT) cohorts. A RCT in a multi-ethnic cohort of newly diagnosed hypertensive subjects in the UK will prospectively test this prediction and provide definitive evidence for optimal drug regimes. Multi-dimensional 'omics data (genomics, transcriptomics and metabolomics) from Twins UK will be used to identify potential gene pathways determining metabolite signatures associated with drug responses. Specific pathways will then be tested using interventional studies in participants from the RCT. A final phase of the study will examine whether the predictors of response can be utilised in centres in in lower and middle-income countries (LMIC). The consortium and project thus supports the 3 strategic aims of the MRC to translate advances in basic science, apply it to individuals and to build global collaborations to address inequality in health care.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CARDIOVASCULAR;RENAL AND UROGENITAL;STROKE
Title: The Cardiac Role of the Exchange Protein Directly Activated by cAMP (Epac) During Postnatal Development
Funder: British Journal of Anaesthesia

Abstract: The vulnerability of the myocardium to cardiac insults changes during postnatal development. The underlying mechanism(s) are not presently known although developmental changes in Ca2+ mobilisation could be responsible. Key regulation of cardiac Ca2+ cycling is mediated via cyclic AMP (cAMP) /protein Kinase A (PKA) signalling pathway. Recent work has also identified guanine nucleotide exchange factor directly activated by cAMP (Epac) as an additional independent and parallel cAMP signalling pathway which also appears to regulate Ca2+ cycling in cardiomyocytes. Little is known about the role of Epac in health and disease with nothing known about the role of Epac during postnatal development. The aim of this project is to test the hypothesis that "postnatal developmental changes in cAMP /Epac signalling pathways alter Ca2+ cycling under normal conditions and during cardiac insults independent of the cAMP/PKA pathway". This work will answer fundamental questions relating to developmental changes in regulation of Ca2+ cycling and will aid the rational development of strategies to protect the developing heart.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR;REPRODUCTIVE HEALTH AND CHILDBIRTH