Targeted metabolomic analysis of serum phospholipid and acylcarnitine in the adult Fontan patient with a dominant left ventricle

Miriam Michel, Karl-Otto Dubowy, Manuela Zlamy, Daniela Karall, Mark Gordian Adam, Andreas Entenmann, Markus Andreas Keller, Jakob Koch, Irena Odri Komazec, Ralf Geiger, Christina Salvador, Christian Niederwanger, Udo Müller, Sabine Scholl-Bürgi, Kai Thorsten Laser, Miriam Michel, Karl-Otto Dubowy, Manuela Zlamy, Daniela Karall, Mark Gordian Adam, Andreas Entenmann, Markus Andreas Keller, Jakob Koch, Irena Odri Komazec, Ralf Geiger, Christina Salvador, Christian Niederwanger, Udo Müller, Sabine Scholl-Bürgi, Kai Thorsten Laser

Abstract

Background: Patients with a Fontan circulation have altered cholesterol and lipoprotein values. We analysed small organic molecules in extended phopsholipid and acylcarnitine metabolic pathways ('metabolomes') in adult Fontan patients with a dominant left ventricle, seeking differences between profiles in baseline and Fontan circulations.

Methods: In an observational matched cross-sectional study, we compared phosphatidylcholine (PC), sphingomyelin (SM), and acylcarnitine metabolomes (105 analytes; AbsoluteIDQ® p180 kit (Biocrates Life Sciences AG, Innsbruck, Austria) in 20 adult Fontan patients having a dominant left ventricle with those in 20 age- and sex-matched healthy controls.

Results: Serum levels of total PC (q-value 0.01), total SM (q-value 0.0002) were significantly lower, and total acylcarnitines (q-value 0.02) were significantly higher in patients than in controls. After normalisation of data, serum levels of 12 PC and 1 SM Fontan patients were significantly lower (q-values <0.05), and concentrations of 3 acylcarnitines were significantly higher than those in controls (q-values <0.05).

Conclusion: Metabolomic profiling can use small specimens to identify biomarker patterns that track derangement in multiple metabolic pathways. The striking alterations in the phospholipid and acylcarnitine metabolome that we found in Fontan patients may reflect altered cell signalling and metabolism as found in heart failure in biventricular patients, chronic low-level inflammation, and alteration of functional or structural properties of lymphatic or blood vessels.

Trial registration number: ClinicalTrials.gov Identifier NCT03886935.

Keywords: Fontan; acylcarnitine; angiogenesis; congenital heart disease; heart failure; inflammation; lipid; lymphatic vessel; metabolism; metabolomics; phosphatidylcholine; phospholipid; sphingomyelin; vascular stiffening.

Conflict of interest statement

Conflict of interest statement: MM, KOD, MZ, DK, MGA, AE, MK, JK, IOK, RG, CS, CN, UM, SS-B, and KTL declare that they have no financial or non-financial competing interests with respect to the research, authorship, and/or publication of this article.

© The Author(s), 2020.

Figures

Figure 1.
Figure 1.
Patient flow chart according to STROBE. The study population. AT, anaerobic threshold; h, hour; V̇O2, oxygen uptake.
Figure 2.
Figure 2.
Heat map of phospholipid serum concentrations. Heat map of serum concentrations of all phospholipids that were significantly different between Fontan patients (green boxes) and matched healthy biventricular controls (red boxes). The colours in the heat map represent the fold changes (Fontan patients versus controls) of the univariate statistic: negative values represent a decrease in concentration. PC, phosphatidylcholine; SM, sphingomyelin.
Figure 3.
Figure 3.
Serum concentrations of phospholipid subgroups. Box-and-whisker-plots of serum concentrations of phospholipid subgroups that were significantly lower in Fontan patients (grey boxes) than in matched healthy biventricular controls (white boxes). The boxes show the 25th and the 75th percentile, the whiskers the minimum and the maximum. PC, phosphatidylcholine; SM, sphingomyelin.

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