Metabolomic Profiling of Adults with Congenital Heart Disease.

Ari Cedars,Shelby Kutty,Angela Weingarten,Cedric Manlhiot,Alexander Opotowsky,Teodoro Bottiglieri,Erland Arning,Jong-Mi Ko

doi:10.3390/metabo11080525

Abstract

Metabolomic analysis may provide an integrated assessment in genetically and pathologically heterogeneous populations. We used metabolomic analysis to gain mechanistic insight into the small and diverse population of adults with congenital heart disease (ACHD). Consecutive ACHD patients seen at a single institution were enrolled. Clinical variables and whole blood were collected at regular clinical visits. Stored plasma samples were analyzed for the concentrations of 674 metabolites and metabolic markers using mass spectrometry with internal standards. These samples were compared to 28 simultaneously assessed healthy non-ACHD controls. Principal component analysis and multivariable regression modeling were used to identify metabolites associated with clinical outcomes in ACHD. Plasma from ACHD and healthy control patients differed in the concentrations of multiple metabolites. Differences between control and ACHD were greater in number and in degree than those between ACHD anatomic groups. A metabolite cluster containing amino acids and metabolites of amino acids correlated with negative clinical outcomes across all anatomic groups. Metabolites in the arginine metabolic pathway, betaine, dehydroepiandrosterone, cystine, 1-methylhistidine, serotonin and bile acids were associated with specific clinical outcomes. Metabolic markers of disease may both be useful as biomarkers for disease activity and suggest etiologically related pathways as possible targets for disease-modifying intervention.

Highlights

The field of metabolomics has the potential to dramatically impact research and progress in cardiology
By providing information on the substrates participating in a broad diversity of biological processes, metabolomic analysis can indicate changes in these processes which may be contributing to disease
We investigated the potential utility of metabolomic analysis to generate new hypotheses and provide new insights into the pathophysiology of adults with congenital heart disease (ACHD)

Summary

Introduction

The field of metabolomics has the potential to dramatically impact research and progress in cardiology. As metabolomic changes represent the integrated effects of genomic, proteomic and environmental or dietary influences, they may provide unique insights into disease pathobiology [1]. By providing information on the substrates participating in a broad diversity of biological processes, metabolomic analysis can indicate changes in these processes which may be contributing to disease. In the field of acquired heart disease, metabolomic studies have already led to significant new insights, revealing previously unrecognized biomarkers [3] and pathophysiological mechanisms [4,5,6]. In the field of congenital heart disease, metabolomic studies have revealed informative changes in the plasma concentrations of amino acids related to the nitric oxide signaling pathway [7] and in Fontan patients have revealed alterations in the concentrations of amino acids and lipid metabolites [8]. There is a comparative paucity of metabolomic data related to cardiac disease generally, in

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