Cardiology ACF Projects 2021

A list of ACF 2021 projects within the speciality of cardiology.

Project lead: Professor Andre Ng: andre.ng@le.ac.uk

Arrhythmias and Cardiac Electrophysiology

The Arrhythmia and Cardiac Electrophysiology group led by Professor Andre Ng, based at the Department of Cardiovascular Sciences, University of Leicester and University Hospitals of Leicester NHS Trust focuses on the key areas of unmet clinical need sudden cardiac death (SCD) prediction and prevention as well as personalised interventional treatment for atrial fibrillation (AF). The cross-disciplinary team comprises preclinical scientists, clinical researchers and biomedical engineers as well as clinical trial personnel (research nurses and trial co-ordinators) to deliver the full bench-to-bedside translational research programme:-

1) Preclinical research – is supported by a British Heart Foundation Programme Grant (£994k, Jul’17-Jul’22) investigating into the mechanisms underlying ventricular fibrillation in causing SCD, in particular autonomic modulation and neurocardiac interactions.

2) Technology transfer – mechanistic knowhow of SCD mechanisms from preclinical studies have been translated into the development of novel ECG markers (LifeMap) which have strong prognostic predictive value, with the potential of significantly improving SCD risk stratification. The 2 markers developed thus far have patent granted (one in China, Japan, USA and Australia and the second in Australia). This work has ongoing support from NIHR Biomedical Research Centre funding and Heart Research UK as well as a newly awarded MRC DPFS grant (£1.02m, Oct’19-Oct’22).

3) Translational studies in the treatment for AF – collaborative work with engineering (see later) involve mechanistic studies in patients undergoing catheter ablation for AF aimed at understanding the underlying substrate and improving outcome by optimising ablation target. This has received funding from industrial partners and is supported by a new BHF Project Grant.

4) Clinical trials and studies in novel interventional procedures and medical devices – there is comprehensive work ranging from heart failure and hypertension devices to industry funded trials in neuromodulation.

The ACL is thus well supported by the interdisciplinary team working at the forefront in important areas of unmet clinical need in arrhythmias and cardiac electrophysiology. The Academic Clinical Lecturer post will provide an excellent platform for academic clinical training in Arrhythmia and Cardiac Electrophysiology, providing important key continuous bridge between the preclinical / clinical / biomedical engineering / clinical trial personnel within the team. There is opportunity to engage in the group’s strong and important industry collaborations as well as tabbing into the group’s expertise in successful exploitation of new intellectual property from research / technology transfer.

Training in relevant areas of expertise in arrhythmia and cardiac electrophysiology will be provided, depending on choice of research focus which could include:-

In-house:-

-           optical mapping in preclinical preparations

-           signal processing / biomedical engineering

-           machine learning techniques and artificial intelligence (collaboration with informatics)

-           bioinformatics and big data (CPRD and large databases)

-           plasma (proteomics) and other biomarkers in enhance prognostic and diagnostic assessment in relation to sudden cardiac death and atrial fibrillation pathology and response to treatment

National and international collaborations:-

-           GWAS in arrhythmias and arrhythmic syndromes

-           Multicentre clinical trials

 

 

Lead: Professor Salman Siddiqui  ss338@le.ac.uk

Co-applicant: Professor Chris Brightling  ceb17@le.ac.uk

Co-applicant: Professor Paul Monks   paul.monks@leicester.ac.uk

Co-applicant: Professor Toru Suzuki   tsuzuki@leicester.ac.uk

Co-applicant: Professor Paul Thomas– University of Loughborough, C.L.P.Thomas@lboro.ac.uk

 

Three project areas are available for the ACF. All three projects combine breath discovery science, quantitative methods, opportunities in trial design, opportunities in qualitative assessment of near patient breath testing and evidence synthesis methods e.g. systematic review methodology.

 

Several partners in the EMBER pathology node are capable of hosting trainees during industry placement including Owlstone Medical (Cambridge-UK), as well as opportunities to travel to partnering EU and US institutions active in the breathomics field for research placements.

 

 

(i) Breath signatures in severe asthma – stratification of biologic therapies

 

Current high costs therapies in airway disease such as severe asthma cost the NHS 1Billion Pa, however these therapies fail in 1 in 4 patients and the current biomarkers used to stratify them are imprecise (e.g. blood eosinophils) or affected by standard treatment such as inhaled steroids (exhaled nitric oxide). Treatment failure leads to ongoing harm to patients through oral steroids exposure and life-threatening attacks leading to hospital admission. The EMBER program has developed several early and promising biomarker signatures using breathomics of biologic therapy response (anti-IL-5, anti-IL-5 receptor therapies) in severe asthma that appear to (i) identify with high precision (sensitivity and specificity > 90%) patients that will fail treatment at initiation of therapy and (ii) allow monitoring of airway inflammation in a corticosteroid treatment effect independent manner.

 

The ACF/CL will develop research programs deploying these markers into clinical trials of biologic response considering all current biologic agents, supporting the design of these trials, positioning of the optimal sampling methods and breath analysis platform e.g. eNOSE vs GCxGC-MS for signature validation.

 

The projects are aligned to ongoing EU/UK severe asthma trials consortia (3TR-IMI-ADON, NIHR BEAT-SA) and offer opportunities for research placement within industry e.g. Owlstone Medical (Cambridge, UK).

 

(ii) Ex vivo, in vitro systems for breath biomarker validation

 

 

An important gap in the breath research field is to underpin breath volatile signatures to mechanisms of disease, enabling the development of future stratified medicines and robust biomarkers. Within the EMBER pathology node in vitro systems have been developed and are being optimised for sampling of headspace volatiles in primary cell cultures e.g. activated eosinophils and bacterial cultures and native matrices to the lung such as sputum.           The use of pharmacological antagonists for specific enzymatic pathways within cells and stable transfection methods e.g. lentivirus that target (overexpress/knockout) enzymes of key interest found in target cells provide a power method of identifying causal pathways of breath volatiles. The projects will focus on antimicrobial strategies that modify the microbiome and high cost therapies.

 

The ACF/CL will be trained in primary cell/matrix headspace volatile capture and analysis. Training in cell culture, stable transfection will be provided in the Leicester BRC. Access to large repositories of data within biologic and infection trials programs/observational cohort studies in EMBER will enable robust ‘lookup and validation’ of in vitro signatures identified in patients and clinical trials. The potential for secondments to industry partners within the EMBER partnership will be explored in this project (GSK, AZ and Chiesi).

 

(iii) Multi-metabolomics approaches in cardio respiratory disease

 

Acute cardio respiratory disease accounts for approximately 70% of emergency admissions in the NHS. Diagnostic uncertainty remains in 30% of patients despite available tools such as imaging and current pathology markers e.g. BNP, CRP. It is recognised that diagnostic uncertainty is related to adverse outcomes with prolonged length of stay, increased rates of treatment failure and increased morbidity and mortality. The EMBER program has identified promising breath volatile and plasma metabolomics signatures (> 550 patients, pragmatic Breathomics, GCxGC-MS acute care study) in patients with severe cardio respiratory admissions and high levels of diagnostic uncertainty – primarily presenting with overlap syndrome of acute heart failure, respiratory infection and COPD.  The further development and validation of these metabolomic signatures using near patient breath testing (e.g. eNOSE) and further molecular pathology e.g. sputum metagenomics in cases where infection is suspected, echocardiography in cases of suspected heart failure, will enable the development of potential point of care signatures at triage.

 

The ACF/CL will conduct acute care triage studies in patients with high levels of diagnostic uncertainty at triage for biomarker validation use point of care breath testing devices e.g. eNOSE, CMS, coupled with ReCIVA sampling onto thermal desorption tubes for GCxGC-MS target validation. Testing burden, patient acceptability will be further studied using qualitative assessments (semi-structured interviews). Health economic evaluation (in conjunction with the UoL Health Sciences group) will be initiated by developing a model of the acute care pathway and optimal positioning of breath testing devices.

 

Excellent support is available to deliver acute care studies in the BRC, this includes an established acute care platform for acute observational and intervention studies hosted by the Leicester NIHR-CRF, study nurses capable of supporting acute care studies, breath testing device are well established in the cardio respiratory admissions unit at University Hospitals of Leicester and several informatics tools in EMBER support sample curation, tracking and linkage to clinical care data.


 

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