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

Michel, Miriam; Dubowy, Karl-Otto; Zlamy, Manuela; Ádám, Márk; Entenmann, Andreas; Keller, Markus A.; Koch, Jakob; Komazec, Irena Odri; Geiger, Ralf; Salvador, Christina; Niederwanger, Christian; Müller, Udo; Scholl‐Bürgi, Sabine; Laser, Kai Thorsten

doi:10.1177/2040622320916031

Cited by 17 publications

(46 citation statements)

References 61 publications

(100 reference statements)

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“…1). The results of "traditional" examinations (patient and control clinical assessment, exercise capacity testing, routine laboratory analyses) are set out in our recent work on lipid metabolism 9 . Table 1 lists clinical and exercise capacity testing parameters, showing as major features that in Fontan patients, minimum (at exercise) and maximum (at rest) pulse-oximeter oxygen saturation as well as  VO 2 at the anaerobic threshold and at maximum were significantly lower than in controls.…”

Section: Resultsmentioning

confidence: 99%

“…its anti-oxidant and anti-inflammatory properties 37 , and by decreases in HDL-C 9,[38][39][40] . A direct interplay of lipoprotein metabolism and markers for oxidative stress exists: lipoprotein disorders are associated with increased ADMA 41 .…”

Section: Discussionmentioning

confidence: 99%

“…Like our recently published results on phospholipid and acylcarnitine metabolomic examinations, this work is a subwork of the main study protocol (Trial registration number: ClinicalTrials.gov Identifier NCT03886935) 9 .…”

Section: Methodsmentioning

confidence: 98%

“…Clinical and laboratory examinations were performed as described in detail elsewhere 9 . Age, sex, weight, medication, and cardiac risk factor assessment, with blood sampling for routine hematological and biochemical profiling, was conducted during an outpatient visit.…”

Section: Methodsmentioning

confidence: 99%

“…peptides and troponins, for congestive heart failure and vascular perturbations have been identified via metabolomics, the study of small organic molecules, their synthesis, and their breakdown 5,6 . Interest has grown recently in the metabolic status of Fontan patients: besides reported abnormalities in Fontan patients' glucose metabolism 7 , to date their handling of lipids has been best studied, with important changes shown, especially in the cholesterol, lipoprotein, and phospholipid pathways, hinting at chronic low-level inflammation and at altered cell signalling and energy metabolism as are found in biventricular patients with congestive heart failure 8,9 . In the biventricular patient with heart failure, alterations occur especially in the handling of amino acids important in both myocardium protein turnover and energy metabolism 10 .…”

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confidence: 99%

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Targeted metabolomic analysis of serum amino acids in the adult Fontan patient with a dominant left ventricle

Michel

Dubowy

Entenmann

et al. 2020

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Growing interest lies in the assessment of the metabolic status of patients with a univentricular circulation after Fontan operation, especially in changes of amino acid metabolism. Using targeted metabolomic examinations, we investigated amino acid metabolism in a homogeneous adult Fontanpatient group with a dominant left ventricle, seeking biomarker patterns that might permit better understanding of fontan pathophysiology and early detection of subtle ventricular or circulatory dysfunction. We compared serum amino acid levels (42 analytes; AbsoluteIDQ p180 kit, Biocrates Life Sciences, Innsbruck, Austria) in 20 adult Fontan patients with a dominant left ventricle and those in age-and sex-matched biventricular controls. Serum concentrations of asymmetric dimethylarginine, methionine sulfoxide, glutamic acid, and trans-4-hydroxyproline and the methionine sulfoxide/ methionine ratio (Met-SO/Met) were significantly higher and serum concentrations of asparagine, histidine, taurine, and threonine were significantly lower in patients than in controls. Met-SO/ Met values exhibited a significant negative correlation with oxygen uptake during exercise. The alterations in amino acid metabolome that we found in fontan patients suggest links between fontan pathophysiology, altered cell energy metabolism, oxidative stress, and endothelial dysfunction like those found in biventricular patients with congestive heart failure. Studies of extended amino acid metabolism may allow better understanding of fontan pathophysiology that will permit early detection of subtle ventricular or circulatory dysfunction in Fontan patients. Ventricular dysfunction and circulatory failure with progressing end-organ impairment like renal or liver dysfunction are an important cause of morbidity and mortality in adults with complex congenital heart disease (CHD), especially in patients with single-ventricle types of CHD and Fontan circulation 1,2. Besides limited cardiac output, alterations that mark Fontan hemodynamics are passive flow to the lungs, chronically elevated venous pressures, and congestion. Unfortunately, the clinical use of traditional markers such as N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels for non-invasive diagnostics and monitoring in such patients is limited 3,4. Thus, for early detection of cardiac and circulatory derangement and for evaluation and tailoring of treatment options, regular functional assessment of these patients is crucial, with complete clinical examination, electrocardiogram, imaging studies, determination of values for traditional laboratory markers, or exercise capacity testing.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Targeted metabolomic analysis of serum amino acids in the adult Fontan patient with a dominant left ventricle

Michel

Dubowy

Entenmann

et al. 2020

Sci Rep

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Method comparison of HPLC-ninhydrin-photometry and UHPLC-PITC-tandem mass spectrometry for serum amino acid analyses in patients with complex congenital heart disease and controls

et al. 2020

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Introduction Metabolomics studies are not routine when quantifying amino acids (AA) in congenital heart disease (CHD). Objectives Comparative analysis of 24 AA in serum by traditional high-performance liquid chromatography (HPLC) based on ion exchange and ninhydrin derivatisation followed by photometry (PM) with ultra-high-performance liquid chromatography and phenylisothiocyanate derivatisation followed by tandem mass spectrometry (TMS); interpretation of findings in CHD patients and controls. Methods PM: Sample analysis as above (total run time, ~ 119 min). TMS: Sample analysis by AbsoluteIDQ® p180 kit assay (BIOCRATES Life Sciences AG, Innsbruck, Austria), which employs PITC derivatisation; separation of analytes on a Waters Acquity UHPLC BEH18 C18 reversed-phase column, using water and acetonitrile with 0.1% formic acid as the mobile phases; and quantification on a Triple-Stage Quadrupole tandem mass spectrometer (Thermo Fisher Scientific, Waltham, MA) with electrospray ionisation in the presence of internal standards (total run time, ~ 8 min). Calculation of coefficients of variation (CV) (for precision), intra- and interday accuracies, limits of detection (LOD), limits of quantification (LOQ), and mean concentrations. Results Both methods yielded acceptable results with regard to precision (CV < 10% PM, < 20% TMS), accuracies (< 10% PM, < 34% TMS), LOD, and LOQ. For both Fontan patients and controls AA concentrations differed significantly between methods, but patterns yielded overall were parallel. Conclusion Serum AA concentrations differ with analytical methods but both methods are suitable for AA pattern recognition. TMS is a time-saving alternative to traditional PM under physiological conditions as well as in patients with CHD. Trial registration number ClinicalTrials.gov Identifier NCT03886935, date of registration March 27th, 2019 (retrospectively registered).

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Metabolic profiles identify circulating biomarkers associated with heart failure in young single ventricle patients

et al. 2021

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Background Children and young adults with single ventricle (SV) heart disease frequently develop heart failure (HF) that is intractable and difficult to treat. Our understanding of the molecular and biochemical reasons underlying this is imperfect. Thus, there is an urgent need for biomarkers that predict outcome and provide a rational basis for treatment, and advance our understanding of the basis of HF. Objective We sought to determine if a metabolomic approach would provide biochemical signatures of HF in SV children and young adults. If significant, these analytes might serve as biomarkers to predict outcome and inform on the biological mechanism(s) of HF. Methods We applied a multi-platform metabolomics approach composed of mass spectrometry (MS) and nuclear magnetic resonance (NMR) which yielded 495 and 26 metabolite measurements respectively. The plasma samples came from a cross-sectional set of young SV subjects, ages 2–19 years with ten control (Con) subjects and 16 SV subjects. Of the SV subjects, nine were diagnosed as congestive HF (SVHF), and 7 were not in HF. Metabolomic data were correlated with clinical status to determine if there was a signature associated with HF. Results There were no differences in age, height, weight or sex between the 3 cohorts. However, statistical analysis of the metabolomic profiles using ANOVA revealed 44 metabolites with significant differences between cohorts including 41 profiled by MS and 3 by NMR. These metabolites included acylcarnitines, amino acids, and bile acids, which distinguished Con from all SV subjects. Furthermore, metabolite profiles could distinguish between SV and SVHF subjects. Conclusion These are the first data to demonstrate a clear metabolomic signature associated with HF in children and young adults with SV. Larger studies are warranted to determine if these findings are predictive of progression to HF in time to provide intervention.

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

Cited by 17 publications

References 61 publications

Targeted metabolomic analysis of serum amino acids in the adult Fontan patient with a dominant left ventricle

Targeted metabolomic analysis of serum amino acids in the adult Fontan patient with a dominant left ventricle

Method comparison of HPLC-ninhydrin-photometry and UHPLC-PITC-tandem mass spectrometry for serum amino acid analyses in patients with complex congenital heart disease and controls

Metabolic profiles identify circulating biomarkers associated with heart failure in young single ventricle patients

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