Application of Metabolic Profiling to Abdominal Aortic Aneurysm

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The application of metabolic profiling to abdominal aortic aneurysm research Mahim Irfan Qureshi, Michele Greco, Panagiotis Andrea Vorkas, Elaine Holmes, and Alun H. Davies J. Proteome Res., Just Accepted Manuscript • DOI: 10.1021/acs.jproteome.6b00894 • Publication Date (Web): 13 Mar 2017 Downloaded from http://pubs.acs.org on March 15, 2017

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Journal of Proteome Research

TITLE PAGE

Full title: The application of metabolic profiling to abdominal aortic aneurysm research

Short title: Metabolic Profiling of AAA

Authors:

Mahim I Qureshi1, Michele Greco1, Panagiotis A Vorkas2, Elaine Holmes2, Alun H Davies1 *

Affiliations 1. Section of Vascular Surgery Imperial College London 4 North Charing Cross Hospital Fulham Palace Road London W6 8RF UK

2. Computational & Systems Medicine Imperial College London 6th Floor Sir Alexander Fleming Building Imperial College London Exhibition Road South Kensington London SW7 2AZ UK

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Corresponding author: Professor Alun H Davies MA DM DSc FRCS FEBVS FACPh FHEA Head of Section of Vascular Surgery, Imperial College London 4 East Charing Cross Hospital Fulham Palace Road London W6 8RF UK

Telephone: +44 (0) 203 311 7309 Fax: +44 (0) 203 311 7362 Email: [email protected]

Author contribution: MIQ and MG performed the systematic review and drafted the manuscript. EH and PAV revised the manuscript to ensure accuracy with regard to scientific content. AHD revised the manuscript to ensure accuracy with regard to clinical and translational content. All authors approved the final draft for submission.

Key words: aneurysm, metabonomics, metabolomics, metabolic profiling, systems biology, arterial disease

Conflicts of interest: None to declare.


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The application of metabolic profiling to aneurysm research

Abstract

Rationale Abdominal aortic aneurysm (AAA) is a complex disease posing diagnostic and therapeutic challenges. Metabonomics may aid in the diagnosis of AAA, determination of individualised risk, discovery of therapeutic targets, and improve understanding of pathogenesis.

Objective To review the diversity and outcomes of existing AAA metabonomic research.

Methods and Results A systematic review has been performed. Original research studies applying metabonomics to human aneurysmal disease were included. Seven relevant articles were identified: four studies were based on plasma/serum metabolite profiling, and three studies examined aneurysmal tissue. Aminomalonic acid, guanidinosuccinic acid and glycerol emerge as potential plasma biomarkers of large aneurysm. Lipid profiling improves predictive models of aneurysm presence. Patterns of metabolite variation associated with AAA relate to carbohydrate and lipid metabolism. Perioperative perturbations in metabolites suggest differential systemic inflammatory responses to surgery, generating hypotheses for adjunctive perioperative therapy. Significant limitations include small study sizes, lack of correction for multiple testing false discovery rates, and single time-point sampling.

Conclusion Metabolic profiling carries the potential to identify biomarkers of AAA and elucidate pathways underlying aneurysmal disease. Statistically and methodologically robust studies are


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required for validation, addressing the hiatus in understanding mechanisms of aneurysm growth and developing effective treatment strategies.

Introduction

Abdominal aortic aneurysm (AAA) is a common disorder thought to occur in 8% of the western population over the age of 651. Death secondary to aortic aneurysm rupture occurs in 1-2% of males2, with other cardiovascular causes claiming responsibility for the majority of mortality in patients with AAA. Best medical therapy in aneurysmal disease is aimed at reducing cardiovascular mortality. Specific treatment to prevent aneurysm formation (primary prevention) or subsequent aortic dilation (secondary prevention) is not currently available.

Aneurysm development is a complex process, thought to involve inflammation, proteolytic extracellular matrix degradation, smooth muscle apoptosis, and oxidative stress3-4. The typical clinical risk factors for aneurysm formation (advancing age, male gender, smoking, hypertension, dyslipidaemia) are common to all atherosclerotic diseases, and it is uncertain why aneurysms may develop as opposed to, or in conjunction with, stenosing arterial disease 5. There is evidence of a strong genetic component; family history is, after smoking, the most significant risk factor for AAA6. Genetic studies indicate causality to be multifactorial, but aberrations relating to lipid and proteolytic pathways are frequently encountered7.

In the UK, men are offered a screening ultrasound scan at the age of 65 to determine the presence of an abdominal aortic aneurysm. While screening reduces rupture-related mortality in men (not women, though AAA prognosis is worse in women1), it does not decrease all-cause mortality at 3-5 years8. Ultrasound is an operator dependent modality,


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and abdominal views may be obscured by bowel gas, or challenging to obtain due to body habitus. Suprarenal aneurysms may be missed altogether. At present ultrasound is the only feasible option for screening, and there is no biomarker of adequate sensitivity or specificity to serve as a substitute.

Intervention is indicated for asymptomatic aneurysms when their diameter approaches 5.5cm, or if the aneurysm diameter increases by more than 1cm per year9. The decision to intervene at 5.5cm is based upon data from now aged clinical trials that demonstrated the risk of rupture to exceed the risk of operative repair beyond this size9. Although still adhered to, this data did not take into account current evidence-based medical prevention strategies for cardiovascular disease – statins10. Furthermore, sub-threshold aneurysms can rupture and larger aneurysms may remain intact11-12. Pathological factors increasing the risk of rupture are poorly defined, and rates of growth are non-uniform within and between individuals13. A meta-analysis published in 2013 has shown improved in-hospital or 30-day mortality following endovascular aneurysm repair (EVAR) and open surgery (1.3 % EVAR vs. 4.7% open repair; odds ratio (OR) 036, 95% confidence interval 021 – 061; P < 0 001), but clinical thresholds for intervention remain unchanged14.

Metabonomics offers a top-down systems biology approach15 involving the use of high resolution spectroscopic profiling of small (4.0cm) and 168 controls that were highly representative of patients with non-aneurysmal peripheral arterial disease (PAD). AAA patients were less likely to be diabetic (thus less likely to be prescribed Metformin) 22. Very small variations in age, HDL, CRP and Creatinine between the groups nonetheless produced highly significant differences (P

Application of Metabolic Profiling to Abdominal Aortic Aneurysm

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