Untargeted high-resolution plasma metabolomic profiling predicts outcomes in patients with coronary artery disease

• Authors: Anurag Mehta, Emory University; Chang Liu, Emory University; Aditi Nayak, Emory University; Ayman S. Tahhan, Emory University; Yi-An Ko, Emory University; Devinder S. Dhindsa, Emory University; Jeong Hwan Kim, Emory University; Salim S. Hayek, University of Michigan; Laurence Sperling, Emory University; Puja Kiran Mehta, Emory University; Yan Sun, Emory University; Karan Uppal, Emory University; Dean Jones, Emory University; Arshed Quyyumi, Emory University
• Journal Title: PLOS ONE
• Volume: Volume 15, Number 8
• Publisher: Public Library Science | 2020-08-18, Pages e0237579-e0237579
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1371/journal.pone.0237579
• Subjects: Health Sciences, Public Health; Health Sciences, Epidemiology; Biology, Biostatistics
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; ATHEROTHROMBOTIC RISK STRATIFICATION; ISCHEMIC-HEART-DISEASE; AMINO-ACID-METABOLISM; T-CELL PROLIFERATION; C-REACTIVE PROTEIN; MASS-SPECTROMETRY; MYOCARDIAL-INFARCTION; DENDRITIC CELLS; TRYPTOPHAN; INHIBITION

Abstract

Objective Patients with CAD have substantial residual risk of mortality, and whether hitherto unknown small-molecule metabolites and metabolic pathways contribute to this risk is unclear. We sought to determine the predictive value of plasma metabolomic profiling in patients with CAD. Approach and results Untargeted high-resolution plasma metabolomic profiling of subjects undergoing coronary angiography was performed using liquid chromatography/mass spectrometry. Metabolic features and pathways associated with mortality were identified in 454 subjects using metabolome-wide association studies and Mummichog, respectively, and validated in 322 subjects. A metabolomic risk score comprising of log-transformed HR estimates of metabolites that associated with mortality and passed LASSO regression was created and its performance validated. In 776 subjects (66.8 years, 64% male, 17% Black), 433 and 357 features associated with mortality (FDR-adjusted q<0.20); and clustered into 21 and 9 metabolic pathways in first and second cohorts, respectively. Six pathways (urea cycle/amino group, tryptophan, aspartate/asparagine, lysine, tyrosine, and carnitine shuttle) were common. A metabolomic risk score comprising of 7 metabolites independently predicted mortality in the second cohort (HR per 1-unit increase 2.14, 95%CI 1.62, 2.83). Adding the score to a model of clinical predictors improved risk discrimination (delta C-statistic 0.039, 95%CI -0.006, 0.086; and Integrated Discrimination Index 0.084, 95%CI 0.030, 0.151) and reclassification (continuous Net Reclassification Index 23.3%, 95%CI 7.9%, 38.2%). Conclusions Differential regulation of six metabolic pathways involved in myocardial energetics and systemic inflammation is independently associated with mortality in patients with CAD. A novel risk score consisting of representative metabolites is highly predictive of mortality.