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

Abstract

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.

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

“…Among the 398 Fontan patients seen in our outpatient clinic, only those with a dominant left ventricle were included (n = 176). After exclusion of all patients < 18 years of age (n = 105) and after applying all further exclusion criteria, 20 patients and their matched controls were left for analysis (Michel et al 2020a , b ). Serum concentrations of 24 AA were compared.…”

“…Details of differences in AA concentrations between control and Fontan patients as determined by TMS are reported elsewhere (Michel et al 2020a , b ). In both control and Fontan patients, mean analyte concentrations determined by PM versus TMS differed (p-values, Table 1 ).…”

“…At the Center of Pediatric Cardiology and Congenital Heart Disease, Heart and Diabetes Center North Rhine-Westphalia, Ruhr-University of Bochum, Germany, we prospectively examined both adult Fontan patients with a dominant left ventricle and age- and sex-matched healthy biventricular controls. Inclusion and exclusion criteria are described elsewhere (Michel et al 2020a , b ). Age, sex, weight, body mass index, vital parameters, cardiac risk factors, history of cardiac disease, and cardiac medication were assessed and blood was drawn for biochemical profiling during an outpatient-clinic visit (Michel et al 2020a , b ).…”

“…Inclusion and exclusion criteria are described elsewhere (Michel et al 2020a , b ). Age, sex, weight, body mass index, vital parameters, cardiac risk factors, history of cardiac disease, and cardiac medication were assessed and blood was drawn for biochemical profiling during an outpatient-clinic visit (Michel et al 2020a , b ). The fasting patients underwent phlebotomy while recumbent.…”

“…TMS might be an interesting alternative for AA measurements in patients with complex CHD. Measurement of serum AA is not now routinely performed in such patients, but initial metabolomic results are promising, as in the observation that altered serum concentrations of AA point towards inflammation and oxidative stress (Michel et al 2020a , b ).…”