Developmental clinical studies- Effect of elafin on myocardial injury and inflammation in coronary artery bypass surgery

Lead Research Organisation: University of Edinburgh
Department Name: Centre for Cardiovascular Science

Abstract

Heart muscle cells are susceptible to injury and death following interruption of blood flow (myocardial ischaemia). A mild form of injury occurs during coronary artery bypass surgey and can be measured using a sensitive blood marker (troponin) providing a helpful model to study drugs that may reduce ischaemic injury. Neutrophils are circulating blood cells that contribute to ischaemic injury by releasing destructive enzymes (elastases). Humans produce a protein called elafin that reduces neutrophil elastase injury. Extensive preclinical work from different international centres indicates that elafin has a therapeutic role in diseases of the arteries and heart characterised by neutrophil mediated injury. We believe that administering elafin to patients undergoing bypass surgery will reduce neutrophil mediated myocardial injury and the rise in post-operative inflammatory activity. The degree of heart muscle damage occurring during ischaemia determines clinical outcomes. No therapies are available to address neutrophil mediated heart muscle injury and development of a drug to reduce this offers substantial clinical benefit.

Technical Summary

During coronary artery bypass graft surgery, the myocardium receives an immediate ischaemic insult, exacerbated by post-ischaemic inflammatory responses following reperfusion that lead to increased myocardial injury. Elafin is a potent endogenous anti-elastase with wide ranging anti-inflammatory properties that inhibit destructive post-ischaemic inflammatory pathways. We hypothesise that elafin will reduce peri-operative ischaemic myocardial injury and systemic inflammation in elective coronary artery bypass graft surgery. Myocardial injury will be quantified over the first 48 hours using serial measurements of plasma troponin T concentrations. Subsequent myocardial infarct volume will be quantified by cardiac magnetic resonance imaging. This proof-of-concept study will establish whether elafin has cardioprotective effects in a clinical model of predictable myocardial injury. It has implications for the treatment of ischaemic heart disease, myocardial infarction and other diseases of ischaemic origin.

Publications

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Alam S (2013) INCIDENCE OF TYPE 5 MYOCARDIAL INFARCTION BY THE THIRD UNIVERSAL DEFINITION in Journal of the American College of Cardiology

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Alam SR (2015) Vascular and plaque imaging with ultrasmall superparamagnetic particles of iron oxide. in Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance

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Henriksen PA (2014) The potential of neutrophil elastase inhibitors as anti-inflammatory therapies. in Current opinion in hematology

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Williams MC (2019) Using radiation safely in cardiology: what imagers need to know. in Heart (British Cardiac Society)

 
Description ELHF Research Grants
Amount £14,145 (GBP)
Funding ID Dr Peter Henriksen 
Organisation Edinburgh & Lothians Health Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2013 
End 01/2014
 
Description Project Grant R11/A135
Amount £74,200 (GBP)
Funding ID R11/A135 
Organisation Chest Heart & Stroke Scotland 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2010 
End 12/2013
 
Description MRC Industrial Collaboration 
Organisation Proteo Biotech AG
Country Germany 
Sector Private 
PI Contribution Set up and recruitment into a randomised controlled trial studying the effect of Elafin in coronary artery bypass surgery patients. Patient testing including blood tests and cardaic MRI scanning. Recruitment of 87 patients.
Collaborator Contribution Provision of clinical grade Elafin. Measurement of circulating elastase activity and Elafin concentrations. Shipment costs
Impact The trial completed recruitment of 87 patients in September 2013. Results will be reported February 2014. 2 abstracts at American College of Cardiology Scientific Sessions 2013.
Start Year 2010
 
Title Use of Elafin for disorders associated with elastase independent increase in troponin 
Description The present invention relates to the use of elafin for the treatment and/or prevention of diseases or disorders associated with an increase in troponin levels, which are non elastase dependent.. The present invention in a preferred embodiment relates to a method and composition, using elafin, for protecting the heart muscle or other muscles from damage induced by abnormal blood flow and/or inflammation, which may result from, for example, a heart infarction. The present invention additionally or concomittantly relates to the use of elafin for the treatment and/or prevention of disorders or diseases which are associated with a rise in the level of troponin I and/or T. 
IP Reference WO2016030323 
Protection Patent granted
Year Protection Granted 2016
Licensed Yes
Impact NONE
 
Title EMPIRE study 
Description The EMPIRE study is examining whether the anti-inflammatory drug Elafin can reduce peri-operative myocardial ischaemia and inflammation in patients undergoing coronary bypass surgery. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2011
Development Status Under active development/distribution
Clinical Trial? Yes
Impact The EMPIRE trial has completed recruitment of 87 patients. Results will be available February 2014 
URL http://www.controlled-trials.com/ISRCTN01253916
 
Title EMPIRE trial- Imaging sub-study 
Description The use of ultrasmall paramagnetic iron oxide particles as a smart contrast agent to detect inflammation within the myocardium in patients undergoing coronary bypass surgery. 
Type Diagnostic Tool - Imaging
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2013
Development Status Under active development/distribution
Clinical Trial? Yes
Impact We have been able to demonstrate increased USPIO signal in patients undergoing coronary bypass surgery. This represents myocardial inflammation. We will examine whether treatment with Elafin reduces myocardial inflammation and USPIO signal when EMPIRE study analysis is complete February 2013 
URL http://www.isrctn.com/ISRCTN82061264
 
Description Talk on medical research at international science festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact 75 members of the public attended the lecture as part of a series of talks at The Edinburgh International Science Festival

The talk resulted in useful audience discussion including discussion from patients about participating in clinical trials
Year(s) Of Engagement Activity 2014
URL http://www.sciencefestival.co.uk/uploads/Festival2014/EISFPROGRAM2014small5.pdf
 
Description Talk to patient and funder support group for Chest Heart and Stroke Scotland 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Supporters
Results and Impact This was a talk outlining how research funding had been used. It was given to supporters and fund raisers for CHSS.

There was useful discussion on the cost of running clinical trials and the challenges with recruitment
Year(s) Of Engagement Activity 2014