MSACL 2019 EU Abstract

Metabolomics Applied to Coronary Clinical Burden: Use of Mass Spectrometry to Re-Stratify Asymptomatic Subjects of Intermediate Cardiovascular Risk

Mariana Ubaldo Barbosa Paiva(1), Diego Viana Neves Paiva(1), Henrique Louzan Machado(2), Leonardo Jadyr Silva Rodrigues Alves(2), Raphaela Meneses Oliveira(1),Fabio Neves dos Santos(3), Marcos Nogueira Eberlin(3), Carolina Raíssa Costa Picossi(4), Guilherme Urpia Monte(5), Fernando Antibas Atik(1,5), Javier Ruperez(6), Coral Barbas(6), Aline Maria Araújo Martins(1,2,6)
(1)Faculty of Medicine, University of Brasilia, DF, Brazil (2) Medicine College, University Center of Brasilia, Brasilia, DF, Brazil (3)Chemistry Institute, University of Campinas, Campinas, SP, Brazil(4)Chemistry Institute, University of Sao Paulo, Sao Paulo, SP, Brazil(5)Imaging Unit, Cardiologic Institute of Distrito Federal, Brasilia, DF, Brazil(6)CEMBIO, Universidad CEU San Pablo, Madrid, Spain

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Aline Martins (Presenter) Universidad CEU San Pablo Madrid

Presenter Bio: Graduated in Biological Sciences with PhD in Biotechnology in Functional Cancer Proteomics. The doctoral thesis was developed at the Liver Transplantation Center of university hospital) and the experimental work at the University of Siena, Italy. Currently, works with Translational Medicine, in experimental problems translated from the clinic to the benchside (from downstream services to upstream technologies), using MS to answer clinical questions, especially on non-invasive markers on Hepatology and Cardiology. Also develops experiments on the area of MSI with human biopsies in Chaga’s Disease Cardiology and zika experimental models. Nowadays is a researcher at CEMBIO, Universidad CEU San Pablo Madrid on the area of Translational Cardiology, Visiting Professor at Medicine College and Collaborator researcher at Department of Surgery of the Federal University of Ceara.

Relevant Financial Disclosures (within past 24 months) Committee/Board/Advisory Board Brazilian Mass Spectrometry Society Salary Universidad CEU San Pablo Discussing Products? NO, presenter will NOT present educational content related to products/services of the ineligible company(ies) listed above. Conflict mitigation NOT REQUIRED.

Introduction
Early detection of subclinical atherosclerosis has a major impact on the prevention actions of manifest coronary disease. The management of asymptomatic patients with intermediate Framingham risk is considered uncertain and additional tests are recommended to personalize the risk estimates. Prospection of metabolic markers and the evaluation of the detailed characteristics of the plaque with atherosclerotic burden score can be used as a complementary technique for re-stratification of the risk. Purpose: Compare the overall metabolic profile among patients with coronary plaques classified by modified Leaman score (CT-LeSc) versus control subjects (without plaques), using mass spectrometry (MS), correlating patient’s clinical data with possible molecular discriminants, for re-stratification of cardiovascular risk.

Methods
20 asymptomatic subjects classified as intermediate coronary artery disease risk according to the Framingham risk score, and with myocardial perfusion scintigraphy negative for ischemia and normal left ventricular fraction on transthoracic echocardiography, were recruited into four groups according to coronary computed tomography angiography (CCTA) and CT – LeSc: T1 (0,3 - 3,7); T2 (3,8 - 8,2); T3 (8,3 – 24,1) terciles. Plasma non-targeted metabolomics approach with UPLC-QTOF/MS was applied. Raw data was pre-processed in XCMS to extract chemical entities. Non-parametric univariate analysis and non-supervised (PCA), as well as supervised (PLS-DA) multivariate analysis were used to obtain the significant molecular features (p<0.05, VIP>1). CEU Mass Mediator was used to putatively identify the significant metabolites. The metabolic profile was compared with calcium score, carotid intima-media thickness, high sensitivity C-reactive protein and a family history of atherosclerotic disease regarding the capacity to reclassify cardiovascular risk.

Results
More than 2000 molecular features were extracted from the raw data. PLS-DA of the lipid profiles based on CT-LeSc showed good classification power (Q2=0.8960). No lipid profile showed discriminatory power when patients were classified based under calcified plaques (CP) and non-calcified and mixed plaques (NCMP), which is the current method on clinics to plaque characterization. 53 molecular features (MF) had significance both in uni- and multivariate analysis. 17 MF could be annotated. Phosphatidylethanolamine, phosphatidylcoline and cardiolipins were more abundant in the highest Leaman score groups (T2/T3).

Conclusions & Discussion
The global lipid profile of asymptomatic subjects at Framingham intermediate risk of coronary artery disease may be useful as a complementary molecular marker presenting valuable discriminant power between the different tomographic Leaman phenotypes. Unlike the classification based only on the presence of plaque calcification, the Leaman score discriminated with greater accuracy. The implementation of this high-performance analysis by MS forecasts an important future impact in the prevention of clinical events focusing on patients whose traditional risk markers fail to correctly stratify subjects. Application of new biomarkers with clinical utility may transform cardiovascular care, improving new diagnostic approach to subclinical atherosclerosis and enabling a more personalized medicine.

We acknowledge Dr. Francisco Laurindo for valuable discussion on cardiolipins role in atherosclerosis. To Carolina Gonzáles-Riaño and Dra. Joanna Godzien from CEMBIO for valuable tips on metabolites identification. To LBBQ/UnB, especially to Dr. Wagner Fontes.