Magnetic Resonance Imaging Using Ultrasmall Superparamagnetic Particles of Iron Oxide to Predict Clinical Outcome in Patients Under Surveillance for Abdominal Aortic Aneurysms

Lead Research Organisation: University of Edinburgh

Abstract

The aorta is the main blood vessel that comes out of the heart and it rapidly distributes blood to the whole body. In some people, the aorta becomes swollen (an aneurysm) and bursts, especially as it passes through the abdomen. These 'abdominal aortic aneurysms' often occur without symptoms and can burst or rupture without warning. This usually leads to death and represents the thirteenth commonest cause of death in the United Kingdom. In this proposal, we wish to study a new technique that can look at the aortic aneurysm using magnetic resonance imaging; a technique that does not require x-rays or radiation. We have recently shown that, using magnetic resonance combined with a new imaging agent, we can detect 'hotspots' of activity in these aneurysms that seem to predict which aneurysms grow rapidly, and are therefore potentially at risk of rupture. We here propose to conduct a study in Edinburgh that will invite all patients who are under surveillance because of an aneurysm. We will image these patients using this novel technique and see if we can identify in which patients the aneursyms grow the fastest. This may help identify those patients who are most likely to burst their aneurysm or have an aneurysm that grows so large it needs to have surgery. This will be important to establish as it will potentially lead to a new way of managing people that could ultimately save lives. This is particularly timely as national screening and surveillance programmes are currently being launched, and many pharmaceutical industries are exploring new treatments to delay the progression of the disease. The research team have already conducted a pilot 'proof-of-concept' study that has demonstrated the power of this technique, having been able to pick out the aneurysms that grow three times as fast as other aneurysms. Our multidisciplinary team has expertise in the appropriate areas needed to deliver this trial including experts in blood vessel surgery, blood vessel imaging, image analysis, computer modeling and statistics. In Edinburgh, we are the national Scottish referral centre for aneurysms of the chest and abdomen, and have an establish history of conducting research in this area. We request support to provide the personnel, scanning, modeling and image analysis to deliver this important and highly innovative study.

Technical Summary

Background: Ruptured aortic aneurysms are the thirteenth commonest cause of death in the United Kingdom. Surgical intervention to prevent rupture is considered when the risk of rupture outweighs the risk of procedural complications. There is a major unmet clinical need to develop a better method of identifying patients at risk of rupture and death that goes beyond simple ultrasound measurement of aneurysm. In a preliminary proof-of-concept study, we have recently demonstrated that magnetic resonance detection of mural uptake of ultrasmall superparamagnetic particles of iron oxide (USPIOs) identifies abdominal aortic aneurysms with a 3-fold higher growth rate. Research Design: Prospective observational cohort study. Study Population: Patients with abdominal aortic aneurysms with anteroposterior diameter >40 mm. Planned Interventions: 3T magnetic resonance scan before and after administration of 4.0 mg/kg of USPIOs. Outcome Measures: The abdominal aortic aneurysm of each subject will be imaged with an ultrasound scanner and a 320-multidetector computed tomography scanner with contrast enhancement. Subjects will be followed up every 6 months with clinical and ultrasound scanning as part of the clinical surveillance programme. At 2 years, a repeat computed tomography scan will be performed to assess three-dimensional growth of the aneurysm. Biomechanical stresses of the aneurysm will be assessed by finite element analysis and computational modeling. Assessment and Follow-up: The primary end-point of the study will be the composite of aneurysm rupture or need for surgical repair. Secondary end-points will include aneurysm growth rate as well as the individual rates of aneurysm rupture, aortic aneurysm repair and aneurysm-related mortality. Growth rate will be assessed by both ultrasound and computed tomography. Reproducibility will be assessed in a subgroup of randomly selected patients (n=40). Sample Size: At 80% power and 2-sided P<0.05, 228 patients with abdominal aortic aneurysms will be needed to detect a 20% absolute difference in the primary end-point assuming a 2-year event rate of 50% in those with mural USPIO uptake and 30% in those without. Statistical Analysis: Differences in event rates will be assessed using a binomial test for proportions. Growth rates will be compared using 2-sample t-test or non-parametric equivalent as appropriate. Using an appropriate regression model, we will investigate whether mural uptake of USPIOs is an independent predictor of aneurysm growth. Project Timetables: Following the initial 6-month set up phase, patients will be recruited from our ongoing surveillance programme (>500 suitable patients) over an 18-month period and followed up for up to 36 months. Data analysis, presentation and publication will be undertaken in the final 6 months.

Publications

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Akerele MI (2019) Iterative reconstruction incorporating background correction improves quantification of [F]-NaF PET/CT images of patients with abdominal aortic aneurysm. in Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology

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Doyle BJ (2016) Commentary: Computational Biomechanics-Based Rupture Prediction of Abdominal Aortic Aneurysms. in Journal of endovascular therapy : an official journal of the International Society of Endovascular Specialists

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Forsythe RO (2016) Monitoring the biological activity of abdominal aortic aneurysms Beyond Ultrasound. in Heart (British Cardiac Society)

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Forsythe RO (2018) F-Sodium Fluoride Uptake in Abdominal Aortic Aneurysms: The SoFIA Study. in Journal of the American College of Cardiology

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Forsythe RO (2019) Imaging Biomarkers for Abdominal Aortic Aneurysms. in Circulation. Cardiovascular imaging

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Hardman D (2013) On the prediction of monocyte deposition in abdominal aortic aneurysms using computational fluid dynamics. in Proceedings of the Institution of Mechanical Engineers. Part H, Journal of engineering in medicine

 
Description Engineering better clinical outcomes: computer guided aneurysm risk assessment
Amount £242,708 (GBP)
Organisation National Health and Medical Research Council 
Sector Public
Country Australia
Start  
 
Description Experimental and Translation Medicine
Amount £205,747 (GBP)
Funding ID ETM/365 
Organisation Chief Scientist Office 
Sector Public
Country United Kingdom
Start 01/2015 
End 07/2016
 
Description Experimental and Translational Medicine Research Committee
Amount £205,747 (GBP)
Funding ID ETM/365 
Organisation Chief Scientist Office 
Sector Public
Country United Kingdom
Start 08/2014 
End 08/2016
 
Title A patent (US 9275432 B2) held by the University of Edinburgh has been filed relating to the registration of medical images which were generated as part of the MA3RS study.  
Description A patent (US 9275432 B2) held by the University of Edinburgh has been filed relating to the registration of medical images which were generated as part of this study.  
IP Reference US9275432 
Protection Patent granted
Year Protection Granted 2016
Licensed No
Impact None to date
 
Title Magnetic Resonance Imaging with Ultrasmall Superparamagnetic Particles of Iron Oxide 
Description In a multicentre prospective observational cohort study, we have demonstrated that USPIO-enhanced MRI predicts the rate of aneurysm expansion, and the risk of abdominal aortic aneurysm rupture and repair. Although it does not provide independent prediction of aneurysm expansion or clinical outcomes in a model incorporating known clinical risk factors, this is the first demonstration of a cellular imaging technique that can predict clinical events in patients with abdominal aortic aneurysm. Whether clinical outcomes can be improved by treatment decisions based on this novel imaging approach remains to be established. 
Type Diagnostic Tool - Imaging
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2017
Development Status Closed
Clinical Trial? Yes
Impact Publications and further grants arose from this work. A patent (US 9275432 B2) held by the University of Edinburgh has been filed relating to the registration of medical images which were generated as part of this study.  
URL http://www.isrctn.com/ISRCTN76413758
 
Title Image Registration software 
Description A patent (US 9275432 B2) held by the University of Edinburgh has been filed relating to the registration of medical images which were generated as part of the MA3RS study.  
Type Of Technology Software 
Year Produced 2016 
Impact None to date 
 
Description CSANZ Annual Scientific Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact presentations - What interventionists need to know about PET/MRI/CTA for prediction of ACS. Prediction and prevention of ACS: Hot and Cold plaques. - Magnetic Resonance Imaging using ultra-small superparamagnetic particles of iron oxide in patients under surveillance for abdominal aortic aneurysms to predict rupture or surgical repair: The MA3RS Study
Year(s) Of Engagement Activity 2017
 
Description SCCT 2018 - London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation to the Society of Cardiovascular Computed Tomography
Year(s) Of Engagement Activity 2018