NIHRDataInsights/HRCSData huggingface dataset:
Title: Childhood hypertrophic cardiomyopathy: characterising early phenotypes and disease progression to identify novel therapeutic targets
Funder: Medical Research Council

Abstract: Hypertrophic cardiomyopathy (HCM) is a clinically and genetically heterogeneous condition characterised by unexplained left ventricular hypertrophy. Although rare in childhood (estimated prevalence <3:100,000), HCM is a leading cause of sudden cardiac death (SCD). The aetiology of childhood HCM is heterogeneous, includes inborn errors of metabolism, neuromuscular disorders and malformation syndromes. Most cases, however, are caused by mutations in the cardiac sarcomere protein genes, inherited as an autosomal dominant trait with variable and age-related penetrance. The last 3-4 decades have seen significant advances in our understanding of the genetic basis of HCM, but clinical management remains largely unchanged and focussed on symptom palliation, family screening and prevention of disease-related complications such as SCD and stroke. To date, little attention has been paid to modification of the underlying disease process. Recently, there has been increasing interest in the potential for pharmacological therapy to prevent disease expression in pre-phenotypic mutation carriers, but pilot studies have been hampered by a lack of understanding of the underlying pathophysiological mechanisms of disease expression and progression. Animal studies using novel small molecules targeting actin-myosin binding have suggested that they may prevent the development of LVH in pre-phenotypic mutation carriers. However, a better understanding of the early features of HCM is essential before this approach can be translated into the clinic. One of the greatest challenges remains to understand the relationship between genotype, pathophysiology and clinical phenotype. This work takes advantage of a unique clinical cohort and bioresource and aims to use deep clinical and molecular phenotyping techniques to characterise the early clinical and biochemical phenotypic features of childhood HCM and investigate the pathophysiological mechanisms of clinical disease expression and progression.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: School-based education programme to reduce salt: Scaling-up in China (EduSaltS)
Funder: Medical Research Council

Abstract: Based on the WHO's Conceptual Framework for Scaling up, our proposed research aims to conduct a scale-up study on the school-based education programme to reduce salt in China with an implementation science approach. We will use one group pre-post design with mixed (both qualitative and quantitative) methodology. The study will be carried out in 3 regions, i.e. Beijing (the capital of China), Shijiazhuang in the north and Zhenjiang in the south with a population of >1 million children and 2.2 million adults. The study will follow a 4-phase model of implementation spanning preparation (0.5 yr), pilot (0.5 yr), scale-up study (2 yrs), and national roll-out and sustainment phase (1 yr). During the scale-up study, a refined education programme will be implemented in grade 4 (aged approximately 10 yrs) in all primary schools. We will conduct 3 representative cross-sectional surveys to assess the changes in KAP (Knowledge, Attitudes and Practices) and salt intake (measured by 24h urinary sodium), at baseline (yr 0), at the end of the 1-yr intervention (yr 1), and after an additional year of follow-up (yr 2), with an aim of evaluating the effect of the intervention and its sustainability. KAP questionnaires will be completed in a randomly selected sample of 4050 children from 54 schools, and 8100 adult family members. Salt intake will be assessed by 24h urinary sodium excretion in a randomly selected sample of 726 children from 33 schools and 726 adult family members. The primary outcome is the change of salt-related KAP, and the secondary outcome is the change of salt intake in children and their families as measured by 24h urinary sodium. Process evaluation will be conducted to assess the uptake rate of the scale-up package, and to examine facilitators and barriers to implementation. For health economic evaluation, an incremental cost effectiveness ratio will be calculated.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: CARDIOVASCULAR
Title: MICA: CT-derived fractional flow reserve (FFRCT) for the improved management of chest pain patients
Funder: Medical Research Council

Abstract: Coronary Computed Tomography Angiography (CCTA) is recommended as the first-line diagnostic test for patients with suspected angina and coronary artery disease (CAD). The accurate diagnosis of CAD is important to allow the appropriate medical treatment and post-test risk stratification to identify patients that might benefit from revascularisation. FFRCT is a non-invasive physiological test that can assess flow limitation across a coronary stenoses with high diagnostic accuracy and good correlation to invasive FFR. FFRCT has been shown in trials to reduce the total number of inappropriate invasive coronary angiograms (ICAs) post-CCTA and increase the revascularization treatment rate. FFRCT has the potential to improve diagnostic certainty, reduce unnecessary downstream tests and the patients time to treatment. NHS trusts and clinical commissioning groups (CCGs) are hesitant to find alternative innovation technology funding due to the current budgetary constraints. This has resulted in significant delay in funding and adopting the technology. To address this issue, NHS England awarded HeartFlow an Innovation and Technology Payment (ITP) to increase the uptake of the technology.The NHS should benefit by reducing the number of invasive tests and the wider economy will benefit from fewer lost working days. The ITP programme will end in April 2020, and as yet only two CCGs have agreed to continue funding FFRCT. A key hurdle is that there remains a lack of 'real world practice' evidence to support the clinical trial data, particularly in the UK healthcare setting. This grant application is aimed at addressing this problem, using real world patient data, retrospectively collected to assess hard clinical outcomes and costs to determine the true impact of FFRCT within the NHS patient care pathway.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Improving control of Hypertension in a high HIV prevalence setting (CoHHP): A cluster-randomized feasibility trial in rural Botswana
Funder: Medical Research Council

Abstract: Hypertension is a leading risk factor for the 18 million cardiovascular deaths that occur each year around the world, yet hypertension is largely undiagnosed or inadequately treated in developing countries including in sub-Saharan Africa. While several multicomponent hypertension control interventions have been found to be effective in other developing regions, a remaining gap is assessing generalizability and tailoring these approaches to the African context, where shortages in skilled personnel are more extreme, and burden of other morbidities competing for limited siloed healthcare resources is high. We will conduct a future parallel cluster-randomized controlled trial (Hybrid 1c design) in 30-69 year old adults with uncontrolled hypertension to evaluate the effectiveness of an innovative multicomponent intervention versus usual care to reduce blood pressure (BP) and cardiovascular disease (CVD) risk. Based on evidence and our previous work, this intervention will be comprised of a) community-based screening and awareness, b) training and decision support for nurse-led treatment, c) remote phone-based navigation coupled with cash transfer for transport, and d) home-based accompaniment delivered by trained lay health workers. We propose a 24-months mixed methods feasibility project that aims to: 1) examine barriers to hypertension care from patient and provider perspectives, 2) assess design feasibility of a larger cluster randomized controlled trial 3) assess acceptability of phone-based navigation. Aim 1 will involve focus groups and in-depth interviews of 40 patient participants and ~20 providers. Aims 2 and 3 will involve parallel-group cluster randomized feasibility trial, enrolling 1218 participants across six clusters (communities in rural and peri-urban communities).


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: CARDIOVASCULAR
Title: The interactions between filamin C and small heat-shock proteins in cardiac mechanosignalling
Funder: Medical Research Council

Abstract: Mechanosignalling - the process of sensing and responding to changes in mechanical demand - is important for cardiac function and implicated in pathologies such as hypertension, aortic stenosis and heart failure. Current understanding of the mechanisms underlying mechanosignalling remains limited. In this project, we aim to produce a detailed mechanistic understanding of a novel putative cardiac mechanosignalling complex involving filamin C, an actin crosslinking protein that senses mechanical strain. Filamin C is associated with inherited cardiac diseases and up-regulated in cardiac models of biomechanical stress. It interacts with two molecular chaperones, HSPB1 and HSPB7, which are co-upregulated under biomechanical stress. We hypothesise that filamin C, HSPB1 and HSPB7 form a cardiac mechanosignalling complex that is modulated by phosphorylation. We will develop a detailed understanding of this putative cardiac mechanosignalling complex - from the atomic to the whole-organ level - using in vitro biophysics and structural biology, induced pluripotent stem cell derived cardiomyocytes and in vivo (mouse) models. First, we will resolve the structure of filamin C bound to HSPB7. Second, we will identify the phosphorylation events that regulate filamin C:HSPB1/HSPB7 interactions. Third, we will determine the complex's role in the response to biomechanical stress. Fourth, we will detail the aberrant mechanosignalling that occurs due to pathogenic variants in filamin C that are known to cause inherited cardiac disorders. Finally, to maximise the potential of our work to achieve impact through patient benefit, we intend to pilot an assay to screen for small molecules that can modulate interactions among the proteins in the complex, as a starting point for identifying potential therapeutic opportunities opened up by this work. Insights into mechanosignalling mechanisms are fundamental to our understanding of cardiac function and treating heart failure.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CARDIOVASCULAR
Title: Plug and play: an innovative bio-artificial artery for vascular reconstruction
Funder: Medical Research Council

Abstract: The shortage of autologous blood vessels for vascular constructive surgery has stimulated research into vascular tissue engineering. Natural artery provides the best template for tissue-engineered blood vessel (TEBV). However, previous designs of TEBV failed to replicate the mechanical and functional features of a natural artery, and were associated with a high incidence of thrombosis, stenosis and aneurysm. This investigation addresses the hypothesis that a viable, artery-like TEBV, generated using a combination of multidisciplinary approaches, exerts superior post-grafting performance comparable to artery graft. This will be achieved by building on an existing collaboration combining expertise in vascular biology and bioengineering. The proposed study aims to investigate the transnational potential of this TEBV as a vascular bypass graft, with a set of objectives to optimise the cell viability, investigate its ability to adapt the arterial pressure/flow and achieve artery-like post-grafting performance. Unlike previous bio-artificial grafts, the proposed TEBV will require minimum post-grafting remodelling and function well even in patients with severe cardiovascular disease.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CARDIOVASCULAR
Title: Artificial Intelligence 3D Biventricular Scar Modelling to Guide Precision VT Ablation
Funder: Medical Research Council

Abstract: Sudden cardiac death (SCD) claims 450,000 lives annually in the US with a likely similar inferred incidence due to comparable cardiovascular risk profile in Western Europeans. The most common cause of SCD is ischaemic heart disease (IHD) with 75% of cases linked to previous myocardial infarction (MI) causing left ventricular scarring. This predisposes to ventricular arrhythmias (VA) eg ventricular tachycardia (VT) or ventricular fibrillation (VF) leading to SCD. Holter monitor studies have confirmed VT as a precursor to VF in up to 60% of all cases, in comparison to primary VF in 8%, suggesting VT as the predominant precursor of SCD. Implantable cardioverter-defibrillators (ICDs) decrease mortality and are the mainstay of treatment in these patients however whilst ICDs save lives they do not prevent VA occurrence. ICD shocks used to treat VAs are painful, lead to significant morbidity and do not offer complete protection against arrhythmic death. Concomitant use of anti-arrhythmic drugs to suppress VAs is common practice however these are often ineffective or poorly tolerated. VT occurs due to slow abnormal conduction across living cells embedded within dead scar tissue leading to the formation of conduction channels (CCs) which perpetuate reentry. Radiofrequency ablation in the cardiac electrophysiology (EP) lab can be effective at transecting CCs in scar however due to the complex 3D architecture of scar VT ablation remains challenging with long procedure times and suboptimal recurrence rates of 40-50% at 2 years. Late Gadolinium enhanced cardiac MRI (LGE CMR) scans display high-resolution myocardial scar and there is an ample of published data confirming good correlation of CMR scar and intracardiac scar in canine histological and clinical human EP studies. With advances in artificial intelligence (AI) and our locally established cMR protocols performed in ICD patients we aim to develop an AI computational CMR derived 3D scar model to guide precision VT ablation


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: The role of DNA Methylation, Chromatin Remodelling and Histone Modification in Syndromic and Non-Syndromic Congenital Heart Disease.
Funder: Medical Research Council

Abstract: Congenital heart disease (CHD) is the commonest congenital defect, affecting 1% of live births. The genetic aetiology of a large proportion of congenital heart disease remains unexplained. DNA methylation and chromatin remodelling are important epigenetic mechanisms that play a key role in the regulation of gene transcription. As alterations in genes responsible for these processes cause congenital malformation syndromes with a high prevalence of CHD, we wish to further investigate the role of gene transcription in the aetiology of syndromic and non-syndromic CHD. To do this, we will assess whole genome sequencing data from patients with CHD recruited to the 100,000 Genomes Project and our own cohorts. We will use the expertise from our cellular modelling group, such as CRISPR-Cas9 gene-editing and induced pluripotent stem cell (iPSC) creation, generation of iPSCs from patient-derived dermal fibroblasts, and genome-wide DNA methylation analysis to confirm novel genetic associations. We have recently shown that a hotspot of mutations in a specific region of KMT2D, a histone lysine methyltransferase, cause a novel malformation disorder that has CHD as an important feature. We will knock-in missense mutations into induced pluripotent stem cells (iPSCs) to model the novel missense mutations identified in this disorder. iPSCs differentiated into neural crest lineages will be characterized by RNA-seq to identify differential gene expression signatures. Pathway analyses will identify important regulatory sub-networks, which are disrupted or activated by the action of KMT2D. Differentially-expressed mRNAs will be validated by quantitative rt-PCR. Together these studies will increase scientific knowledge of the link between gene transcription and CHD, with specific insight into the function of KMT2D, how this function is affected by the observed mutations, and how histone methylation and gene expression are altered across the genome.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Investigating the role of macrophage-deposited collagen in the injured mouse heart
Funder: Medical Research Council

Abstract: Following myocardial infarction (MI) acute wound healing and long-term tissue remodelling are mediated by fibrosis and scarring. This serves initially to prevent ventricular rupture but can progress to heart failure. The current dogma is that the scar consists of extracellular matrix proteins, predominantly collagens, produced by activated fibroblasts (myofibroblasts). In a recent study comparing regenerative and non-regenerative zebrafish and mouse models, we revealed that macrophages also deposit collagen within the forming scar following heart injury. Whilst this study implicated macrophages as direct contributors to fibrosis during heart repair, the question as to why macrophages produce collagen remains unanswered. Here we propose to investigate the role of macrophage-collagen during neonatal mouse heart injury in transition from regeneration to fibrosis and in the adult infarcted mouse heart. We will combine comprehensive ECM proteomics and cryo-Electron Microscopy (EM) to fully characterise scar content, ultrastructure and cell-matrix interactions across stages. We will use SC-RNA-Seq transcriptomics and spatial proteomics to identify which subsets of macrophages produce collagen as well as macrophage-tracking and conditional targeting of collagen isoforms to determine function. A comprehensive understanding of cardiac fibrosis, including the potential for targeting macrophage-induced pro-fibrotic pathways, will assist in the development of therapies for patients suffering from acute MI.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Determining patient-individualised placebo-controlled angina thresholds for invasive haemodynamic assessment
Funder: Medical Research Council

Abstract: - Background - Current guidelines advocate the use of an objective assessment of ischaemia, defined as a fractional flow reserve (FFR) of 0.80 or instantaneous wave-free ratio (iFR) of 0.89, to identify patients that will gain symptomatic benefit from PCI. Patients who fall within this clinical cut-point appear entitled to PCI, while those who fall above this threshold are not. The primary evidence-based aim of PCI in stable angina has now shifted towards symptom relief, not ischaemia. Yet no controlled experiment to date has validated the recommended FFR/iFR thresholds with angina (the symptom, as opposed to ischaemia) or justified the use of a predefined population level cut-point for symptoms. - Aims - 1. To measure the FFR/iFR threshold that causes symptoms 2. To determine how this threshold varies between patients 3. To determine how this threshold varies between exercise and rest for the same patient - Method - I will conduct a randomised double-blinded placebo-controlled study of 58 patients with stable angina eligible for PCI with anatomical evidence of significant single-vessel CAD and physiological evidence of ischaemia. Following PCI, the angina threshold will be established by progressively narrowing the coronary artery lumen with a balloon inside the stent, until angina develops. This will be done separately with exercise and with rest. Once recovered, the identical degree of narrowing will be re-introduced (without exercise) and FFR/iFR measurements with each will be obtained. - Endpoints - Primary- FFR/iFR value at the point of angina during: (a) Rest (b) Exercise Secondary- Angina severity score, similarity score and symptom type - Opportunities - 1. Enhance our understanding of the relationship between FFR/iFR values and symptoms. 2. Determine if there is variability between patients and whether a single clinical cut-off is appropriate. 3. Allow clinicians to contextualise FFR/iFR values for their patients.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: CARDIOVASCULAR
Title: Personalised care for older patients with myocardial infarction (MiRisk)
Funder: Medical Research Council

Abstract: Guidelines recommend the use of risk stratification tools to guide the management of patients with myocardial infarction. Frailty and multimorbidity are strong predictors of adverse outcomes following myocardial infarction and are increasingly common in older patients yet neither are objectively measured or used to guide patient management. There is evidence to suggest incorporating these measures into current risk tools improves discrimination in older patients. I aim to develop a personalised risk prediction model for use in older patients with myocardial infarction. I hypothesise that a risk prediction model which includes important non-cardiovascular factors such as frailty and multimorbidity will lead to improved risk stratification. I hypothesis that a risk prediction model capable of estimating the separate risks of myocardial infarction, cardiovascular death and non-cardiovascular death would greatly aid decision making in older patients. These hypotheses will be tested in three phases. Study 1: Analysis of the impact of patient age, frailty and multimorbidity on the management and outcomes of 48,282 consecutive patients with suspected myocardial infarction who participated in a randomised control trial. We anticipate frailty and multimorbidity are important factors in decision making and have an incremental impact on cardiovascular and non-cardiovascular outcomes. Study 2: Derivation, internal validation and independent external validation of a multiple outcome clinical risk prediction model (MiRisk). MiRisk will be derived and validated using a population database containing detailed primary, secondary and social care data on patients suffering a myocardial infarction between 2012-2019 in the South East Region of Scotland. Study 3: Comparison of MiRisk and the Global Registry of Acute Cardiac Events (GRACE) score in the 2,949 patients with myocardial infarction present in the HighSTEACS trial database.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR