NIHRDataInsights/HRCSData huggingface dataset:
Title: Sodium reduction in Malawi
Funder: Medical Research Council

Abstract: Hypertension is a major cause of morbidity, disability and mortality, causing 7.5 million deaths worldwide. Globally, approximately 25% of adults are hypertensive, and rates are highest in sub-Saharan Africa(SSA) – up to 40% of adults are affected and blood pressure levels are nearly 10mmHg higher than in high-income countries1. High dietary salt may cause 30% of hypertension. Reducing salt intake would reduce strokes and cardiovascular diseases,2,3 and was nominated a ‘best-buy’ at the UN High-Level non-communicable diseases(NCD) meeting. Wealthy countries have tackled salt reduction through regulations, public education and food industry collaboration, but effective strategies to reduce salt intake in SSA (where most salt intake is from home food preservation or cooking) need development. We are conducting large urban/rural studies to determine NCD risk factors in Malawi; establishing a platform for interventions (Malawi Epidemiology and Intervention Research Unit/Karonga Prevention Study http://www.lshtm.ac.uk/eph/ide/research/kps/). Preliminary data reveal high salt consumption (11g/day). Engaging with policy-makers and community leaders, we will design and study the acceptability of, novel, cost effective and culturally-acceptable community-based salt reduction interventions. In this early phase we will 1)capitalise on our existing datasets and population-research platforms; calculating the population attributable risk fraction of excessive salt intake for hypertension and planning a cluster-randomised trial (accounting for cluster nature and between-cluster variation); 2)using published data, calculate the effects-size/sample-size; 3)test interventions/evaluation feasibility including salt reduction/substitution acceptability.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: CARDIOVASCULAR
Title: Phase 2 randomised trial of early versus delayed future care planning for patients with advanced heart disease
Funder: Marie Curie

Abstract: Patients with cancer have well developed palliative care services while patients with advanced heart disease, with a prognosis worse than many cancers, do not. It is widely recognised that this needs to change. However, there are no clinical trials that have assessed the effectiveness of better supportive care for people with advanced heart disease who are approaching the end of life. There are complex challenges in designing and running such a trial. This feasibility study aims to assess those challenges by asking patients, doctors and nurses about their views on how such a trial could be designed and run. A pilot study will also randomise a small number of people with advanced heart failure to a complex intervention which will include a detailed care-plan outlining support available and what should be done in the event of a sudden deterioration. The findings of this pilot study will help in the design of a much larger clinical trial.


Research activity codes: 7.2 END OF LIFE CARE;7.3 MANAGEMENT AND DECISION MAKING
Health categories: CARDIOVASCULAR
Title: VINDICATE: VitamIN D treating patIents with Chronic heArT failurE
Funder: Medical Research Council

Abstract: DESIGN: Two-centre double-blind randomised placebo-controlled study of 250 patients with stable CHF. INCLUSION CRITERIA: 1. Class II and III heart failure with left ventricular (LV) systolic dysfunction (LV ejection fraction </= 45%) 2. Stable symptoms for 3 months on optimally tolerated medical therapy 3. Vitamin D deficiency (50nmol/L). EXCLUSION CRITERIA: 1. Currently taking (or in the previous 3 months) calcium or other vitamin supplements 2. CHF due to untreated valvular heart disease 3. Indications for vitamin D supplementation 4. History of primary hyperparathyroidism, sarcoidosis, tuberculosis or lymphoma 5. Heart failure due to anaemia or thyrotoxicosis 6. Renal failure (GFR<30 l/min) 7. Inability to perform 6 minute walk test (6MWT) 8. Cognitive impairment. We will not exclude patients with a contraindication for cardiac magnetic resonance (CMR) or those unwilling to perform peak exercise testing from VINDICATE. INTERVENTION: 100mcg per day of vitamin D3 (or placebo). OUTCOME MEASURES: Primary endpoint: change in 6MWT (baseline to 12 months). Secondary endpoints: change in cardiac function (by CMR) and peak oxygen uptake. FOLLOW-UP: Safety and efficacy visits at 3, 6, 9 and 12 months. SAMPLE SIZE & STATISTICAL ANALYSIS: The SD of change in 6MWT has been estimated from the pilot study; the upper limit of the 80% confidence interval (estimated using bootstrapping) has been used in these calculations to allow for the small sample size in the pilot. 30m is assumed to be clinically important improvement in walk distance. 210 patients are required to have 90% power to show a difference in change in 6MWT of 28m or more with 5% significance (SD=62). 250 patients will be recruited to allow for ~15-20% dropout. Change in 6MWT will be compared between groups using Analysis of Covariance, adjusting for baseline 6MWT, diabetes, device therapy and centre. Similar methods will be employed to compare secondary endpoints between groups.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR
Title: DJ-1 as a novel target for cardioprotection
Funder: Medical Research Council

Abstract: The overall research objective will be to investigate DJ-1 as a novel mitochondrial target for protecting the heart against the detrimental effects of ischaemia-reperfusion injury (IRI). 1) Investigation of DJ-1 Function (In Vitro): The first objective will be to characterise the cardioprotective effect of DJ-1 using the HL-1 cardiac cell-line. We will investigate the effects of ablating DJ-1 using siRNA on mitochondrial function and susceptibility to IRI. Using different DJ-1 mutants, we will also determine how its subcellular localisation influences its cardioprotective effect. 2) Investigation of DJ-1 Function (In Vivo): The second objective will be to investigate the effect of endogenous DJ-1 in the adult heart. We will investigate the effect of DJ-1 ablation & DJ-1 over-expression in the adult murine heart on in situ myocardial infarct size & post-MI remodelling and the development of heart failure using cardiac MRI to assess these endpoints. 3) Investigation of Mechanism of Cardioprotection bt DJ-1: The third objective will be to investigate the mechanisms underlying the cardioprotection elicited by DJ-1. We will investigate the effect of DJ-1 on mitochondrial function by measuring the production of oxidative stress during IRI (confocal microscopy), mitochondrial respiration (SeaHorse Biosciences Analyzer), & mitochondrial morphology (confocal microscopy). In addition, we will investigate the effect of DJ-1 on an anti-apoptotic mechanism in which Akt downregulates the pro-apoptotic DAXX-ASK-1 pathway. 4) Investigation of effects of pharmacological modulation of DJ-1: The fourth & final objective will be to investigate pharmacological modulation of DJ-1 as a novel therapeutic cardioprotective strategy using a recently described small molecule activator of DJ-1 called phenylbutyrate. We will investigate whether this drug can protect the heart from IRI using adult murine cardiomyocytes and an in vivo murine model of acute & chronic MI.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: IDENTIFYING CARDIAC SUBSTRATES OF p38alpha MITOGEN-ACTIVATED PROTEIN KINASE
Funder: Medical Research Council

Abstract: The activation of the alpha isoform of p38 mitogen-activated protein kinase (p38) during myocardial infarction worsens injury. Under other circumstances its activation ensures cardiac adaptation to stress. Clinical trials of p38 inhibition have been unsuccessful due to a combination of toxicity and escape from inhibition with prolonged therapy. These observations suggest downstream targeting of p38 substrates may both enhance efficacy and reduce toxicity. We plan to use chemical genetic approaches to identify proteins phosphorylated by p38 during myocardial ischaemia and other stresses. Firstly we have created an analogue-sensitive (AS) form of p38 that can use expanded ATP analogues to transfer a thiophosphate affinity tag to substrate proteins. Secondly we have characterised a targeted mouse line in which p38 is resistant to pharmacological inhibition (IR). Recombinant active ASp38 will be used to tag proteins in heart homogenate. The tagged residues within proteins will be identified by affinity purification and mass spectrometry. These post-translational modifications will then be validated in cultured cells using ectopic expression of ASp38. Further validation will occur in whole heart by comparing IR and wild-type hearts subjected to pathological stresses in the presence of a pharmacological inhibitor of p38. Phosphopeptides from these heart samples will be identified based on inclusion lists generated using ASp38 and quantified by direct evaluation against matching peptides from stable isotope labelled heart. The relevance of dynamic changes in phosphorylation will then be determined in primary heart cells subjected to pathophysiologically-relevant stresses in culture following adenovirally-driven expression of prioritised proteins harbouring key substitutions. Based on this screen the most promising phosphoacceptor substitutions will be knocked into the relevant mouse allele for in-vivo characterisation and estimation of the spectrum of benefit.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Unipotency of Tbx5+ embryonic cardiac progenitor cells to cardiomyocytes.
Funder: Medical Research Council

Abstract: This project aims to study the fate and the character of Tbx5-expressing cardiac progenitor cells (CPCs). The results obtained will enable a full re-assessment of the subpopulations of CPCs and will facilitate in vitro time-lapse observation of Tbx5-expressing CPCs and the harvesting of pure Tbx5-expressing CPCs in the future. In this project, we will use two different genetically modified animals. BAC Tbx5-CreERT2 transgene is the bacterial artificial chromosome (BAC) clone containing 210 kb of the Tbx5 gene genome locus. CreERT2 is transcribed from this transgene in the region where Tbx5 should be expressed. The combination of this BAC Tbx5-CreERT2 transgenic mice and ROSA26-eYFP Cre reporter mice allows us to genetically label embryonic Tbx5-expressing CPCs with eYFP only when tamoxifen is administered to the pregnant females. To trace the initial Tbx5-expressing CPCs in the BAC Tbx5-CreERT2/ROSA26-eYFP embryos, we will use whole embryo culture. This model enables tighter labeling of Tbx5-expressing CPCs strictly due to easier control of TAM concentration To identify which type of cells are derived from Tbx5-expressing CPCs, we will perform immunofluorescence on histological sections or RT-PCR for the cells derived from embryonic cell culture or ES cell culture to detect the marker genes' expression specific for the cell type. To trace a clone of Tbx5-expressing CPCs in vitro, the cells labeled with eYFP will be isolated by Becton Dickinson Aria II Fluorescence-Activated Cell Sorting after the embryo or embryoid body is dissociated with trypsin. Individual cells will be seeded and cultured on a feeder layer in differentiation medium. To establish a novel experimental system to trace Tbx5-expressing CPCs in vitro without using animals, we will derive ES cells from BAC Tbx5-CreERT2/ROSA26-eYFP mouse blastcysts. Derivation is carried on by culture of blastcysts on feeder cells and iSTEM (Stem Cell Sciences) medium.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CARDIOVASCULAR
Title: Transcriptional regulation of the Notch and Vegf signalling pathways during angiogenesis and arterio-venous differentiation
Funder: Medical Research Council

Abstract: The correct formation of blood vessels is essential for embryonic growth and development, but this process can also be co-opted by a number of pathological conditions. The Notch and VEGF signalling pathways play a significant role in vessel differentiation and angiogenic vascular growth, and are consequently attractive candidates for anti-angiogenesis therapy. However, resistance to VEGF inhibitors, in part mediated by the Notch pathway, is emerging as a major clinical limitation to current anti-angiogenic therapies. Consequently, in order to develop effective, targeted interventions to pathological vessel growth, it is increasingly important that we understand the biology of these two pathways in endothelial cells. The aim of this proposal is to understand the regulatory networks that control the transcription of genes within the Notch and VEGF pathways during vessel growth via the systematic identification, validation and characterization of regulatory enhancer elements. These will be identified in silico, validated in transgenic zebrafish and characterized using targeted single-copy transgenic mouse models. Key regulatory factors will be identified through a combination of validated phylogenic footprints, mutations of cis-motifs and identification of binding factors e.g. with SILAC. The role of novel vascular factors will be further investigated via gene knock-down or knock-out strategies in both in vivo and in vitro models. In conclusion, this investigation will delineate the entire transcriptional pathway regulating the Notch and VEGF pathways during angiogenic sprouting and vascular differentiation, and identify key transcription factors involved in these processes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CARDIOVASCULAR
Title: The molecular function of the Popeye domain containing genes in the heart
Funder: Medical Research Council

Abstract: The Popeye domain containing (Popdc) genes are involved in adrenergic signaling in the heart. In order to overcome genetic redundancy, mice will be generated that lack the entire gene family and will be phenotypically assessed by ECG analysis. In order to assess the phenotypic consequences, a point mutation will be introduced into mice, which interferes with cAMP binding, and a nonsense mutation, which is present in patients with severe early onset bradycardia. In order to identify ion channels with which Popdc proteins might interact, we will analyze the action potentials of cardiac myocytes isolated from different null mutants. Alterations in ion channel anatomy might lead to the identification of malfunctioning currents and ultimately to ion channels, which directly interact with Popdc proteins. Candidates will be further assessed by co-localization and immunoprecipitation analysis. This study is likely to provide novel opportunities for rational drug design.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Genetic modifiers of hypertrophic cardiomyopathy in the Old Order Amish
Funder: Medical Research Council

Abstract: Hypertrophic cardiomyopathy (HCM) is the commonest inherited cardiovascular disorder and cause of sudden cardiac death in the young. Characteristic features include unexplained ventricular hypertrophy, myocyte disarray and interstitial fibrosis and several hundred causative mutations mainly in genes encoding sarcomeric proteins have been identified. Significant variation in phenotypic expression exists even amongst carriers of the same mutation within one family. Although the mechanisms underlying this phenomenon are poorly understood, they are likely to involve genetic modifiers. We have previously described a cohort of 10 infants in the Amish community in Ohio affected by severe HCM which were found to be homozygous for a splice site mutation (c.3330+2T>G) in MYBPC3. Our investigation of heterozygous gene carriers indicates that 11/41 (27%) had an intraventricular septal thickness in diastole (IVSd) over 15 mm and 3/41 (7%) had an IVSd over 20 mm, compared to none in the control group. The Amish are a founder population with a very homogenous life-style, complete genealogical records and large families and therefore constitute an ideal human model for modifier studies. We intend to recruit an additional 200 gene carriers who can all be interlinked through an extensive pedigree and evaluate them with ECG, ECHO and ambulatory monitoring which will result in the phenotypic description of the largest familiar cohort to date sharing the same HCM mutation. With a combined strategy of whole exome sequence analysis and a genome wide association study we will then identify genetic modifiers of the phenotype. This will improve our understanding of the pathophysiological mechanisms involved in the disease process and potentially identify novel targets for the development of treatment strategies to influence the natural history of HCM. Putative modifiers will then be investigated in a replication cohort of 340 unrelated genotyped HCM patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Manufacture scale up of human pericyte progenitor cells for regenerative medicine
Funder: Medical Research Council

Abstract: This proposal aims to develop a novel cell product for regenerative vascular medicine. The prototype of the cell product, consisting of saphenous vein-derived pericyte progenitor cells (SVPs), proved to be therapeutically effective in preclinical models of peripheral or myocardial ischaemia. Supplementation of pericytes stabilises the peri-infarct neovascularisation which is otherwise prone to leak and break. Furthermore, SVPs exert a spectrum of reparative actions including recruitment of pro-angiogenic monocytes and cardiac progenitor cells and inhibition of apoptosis and fibrosis. No safety concerns were reported. We propose now to validate the capability of a defined system of technical procedures to increase total throughput of cells and obtain a reliable, reproducible and quality-assured cell product in view of performing a first-in-man clinical trial with autologous SVPs in coronary artery disease patients unresponsive to medications and not amenable to revascularization. The project comprises 3 work-packages (WP), 6 milestones (M) and a contingency plan for prevention, troubleshooting and alternative solutions. The goal of WP1 is to scale up current protocol to improve the yield of extraction/expansion (M1) and introduce clinical-grade and xeno-free reagents (M2). The goal of WP2 is to transfer the protocol to the GMP facilities of the National Health Service-Blood and Transplant (NHSBT) for clinical-grade manufacture of at least 6 SVP lines (M3), followed by quality control of antigenic and genomic/epigenetic stability (M4). The goal of WP3 is to test the performance of individual SVP lines (WP5) and assess the therapeutic efficacy in a mouse model of myocardial infarction using a randomised factorial protocol (WP6).


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CARDIOVASCULAR
Title: A school-based education programme to reduce salt intake in children and their families
Funder: Medical Research Council

Abstract: The first phase of our proposal is to carry out a cross-sectional study in 400 primary school children with age of 7 to 11 years, to assess salt intake by measuring 24h urinary sodium excretion. We will also measure blood pressure (BP), height, weight, hip and waist circumference using a standard protocol. The second phase is to carry out a cluster randomised controlled trial in 240 children aged 10-11 years. After baseline assessments including 24h urine, BP and anthropometry, schools will be randomly allocated to either the control or intervention group. Additionally, both parents and grandparents of the participating children will be invited to take part in the study. Intervention group: Our target is to lower salt intake by 20% for both children and their families. The intervention will be delivered to school children who will be empowered to persuade their parents and grandparents to reduce the amount of salt used during food preparation. The intervention consists of two components, i.e. classroom and family. Control group: All children, their parents and grandparents in the control group will have the same measurements as those in the intervention group, but no salt awareness education will be given. Duration and follow-up: The duration will be one school term, i.e. 5 months. All measurements made at baseline will be repeated at mid-term and again at the end of the trial. The biochemist who performs the measurements of urinary electrolytes will not be told which group the participant is allocated. The use of automatic BP device will minimise observer bias with BP measurement. Outcomes: The primary outcome is the difference between the intervention and control group in the change in 24-h urinary sodium from baseline to the end of follow-up. The secondary outcome is the difference between the two groups in the change in BP.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: CARDIOVASCULAR
Title: Treating hypertension in rural South Africa: Comparative effectiveness of two different patient outreach models.
Funder: Medical Research Council

Abstract: South Africa has a high prevalence of hypertension, but it is often undiagnosed, or, if diagnosed, untreated. Deficiencies in hypertension management are mostly due to poor functioning of primary care services, which focus on acute conditions. Aware of these problems, South Africa is in the process of re-orientating primary health services to provide integrated care for chronic disease. The intention is to provide a new cadre of community health workers (CHW) delivering outreach integrated chronic care. There is concern that the proposed model is resource intensive and not sustainable in rural areas. We aim to compare the cost-effectiveness of the proposed model with a lower resource intervention using lay health workers based in the clinics and supporting patient self-help groups. Final plans for the intervention will be developed with local communities. The research will be conducted across 8 clinical facilities in the Agincourt Health and Demographic Surveillance site, using a cluster randomised trial, where the unit of randomisation is a facility and its catchment population. The intervention will include lay support workers in the clinic to raise awareness, increase patient health literacy, provide adherence counselling and encourage six monthly attendances at the clinic, as well as developing patient self-help groups. Outcomes will be measured at patient-, facility- and population-level (primary outcome: proportion with successfully controlled hypertension). A cross-disciplinary approach will capture patients' and health care workers' experiences using qualitative methods and exit interviews. This proposal aims to influence local and national policy, providing decision makers and practitioners with information to make an informed choice of an outreach model for providing integrated care, and specifically for improving the awareness, treatment and maintenance of hypertension.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: CARDIOVASCULAR