Abnormal glucose metabolism in patients with Fontan circulation: Unique characteristics and associations with Fontan pathophysiology

Ohuchi, Hideo; Negishi, Jun; Hayama, Yosuke; Miike, Hikari; Suzuki, Daiki; Nakajima, Kimiko; Konagai, Nao; Iwasa, Takeshi; Sakaguchi, Heima; Kurosaki, Kenichi; Nakai, Michikazu

doi:10.1016/j.ahj.2019.07.013

Cited by 12 publications

(21 citation statements)

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“…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%

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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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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confidence: 99%

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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“…However, HbA1c -a marker of long term glycemic status- and C-peptide—a marker of endogenous insulin production- are both increased ( 29 ). The results from an oral glucose tolerance test are more unfavorable for Fontan patients compared to healthy controls ( 29 , 85 ). A large study of 275 patients found thirty-four percent of patients had impaired glucose tolerance and five percent had diabetes mellitus ( 85 ).…”

Section: Resultsmentioning

confidence: 99%

“…The results from an oral glucose tolerance test are more unfavorable for Fontan patients compared to healthy controls ( 29 , 85 ). A large study of 275 patients found thirty-four percent of patients had impaired glucose tolerance and five percent had diabetes mellitus ( 85 ). Furthermore, oral glucose tolerance decreased over a follow-up of 6.5 ± 2.7 years for a subset of 175 patients aged 20 ± 7 years ( 85 ).…”

Section: Resultsmentioning

confidence: 99%

“…A large study of 275 patients found thirty-four percent of patients had impaired glucose tolerance and five percent had diabetes mellitus ( 85 ). Furthermore, oral glucose tolerance decreased over a follow-up of 6.5 ± 2.7 years for a subset of 175 patients aged 20 ± 7 years ( 85 ). Remarkably, HbA1c decreased during this time frame ( 85 ).…”

Section: Resultsmentioning

confidence: 99%

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Fontan Circulation Associated Organ Abnormalities Beyond the Heart, Lungs, Liver, and Gut: A Systematic Review

Ritmeester

Veger

Ven

et al. 2022

Front. Cardiovasc. Med.

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IntroductionPatients with a Fontan circulation are at risk for sequelae of Fontan physiology during follow-up. Fontan physiology affects all organ systems and an overview of end-organ damage is needed.MethodsWe performed a systematic review of abnormalities in multiple organ systems for patients with a longstanding Fontan circulation. We searched online databases for articles describing abnormalities in multiple organ systems. Cardio-pulmonary abnormalities, protein losing enteropathy, and Fontan associated liver disease have already extensively been described and were excluded from this systematic review.ResultsOur search returned 5,704 unique articles. After screening, we found 111 articles relating to multiple organ systems. We found abnormalities in, among others, the nervous system, pituitary, kidneys, and musculoskeletal system. Pituitary edema—relating to the unique pituitary vasculature- may affect the thyroid axis. Renal dysfunction is common. Creatinine based renal function estimates may be inappropriate due to myopenia. Both lean muscle mass and bone mineral density are decreased. These abnormalities in multiple organ systems may be related to Fontan physiology, cyanosis, iatrogenic factors, or lifestyle.ConclusionsHealth care providers should be vigilant for hypothyroidism, visual or hearing deficits, and sleep disordered breathing in Fontan patients. We recommend including cystatin C for assessment of renal function. This review may aid health care providers and guide future research.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021232461, PROSPERO, identifier: CRD42021232461.

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“…After the Fontan operation, the palliative nature of the procedure is associated with various non-cardiac comorbidities, including renal and liver dysfunctions, which can have an adverse effect on survival [5] , [6] , [7] . Glucose and lipid metabolism disorders have also been described in patients with Fontan circulation [8] , [9] . Metabolic disorders are important pathophysiologies that are related to asymptomatic multiple organ dysfunction and may diminish prognosis [10] .…”

Section: Introductionmentioning

confidence: 99%

Identification of metabolomic profile related to adult Fontan pathophysiology

Motoki

Utsumi

et al. 2021

IJC Heart & Vasculature

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Background Metabolic disorders are important pathophysiologies that can cause multiple organ dysfunction and worsen prognosis in Fontan patients. This study aimed to comprehensively evaluate the metabolomic profile of adult Fontan patients and characterize its pathophysiology in relation to 2 control groups. Methods and Results We performed metabolomic analysis of 31 plasma samples using capillary electrophoresis time-of-flight mass spectrometry. This observational cross-sectional study compared plasma metabolites of 14 heterogeneous adult Fontan patients with those of control groups, including 9 patients with congenital heart disease after biventricular repair and 8 normal healthy controls. Fontan patients exhibited significant differences in intermediate metabolite concentrations related to glycolysis, the tricarboxylic acid (TCA) cycle, and the urea cycle. The plasma concentrations of lactic acid, 2-oxoglutarate, isocitric acid, malic acid, cis -aconitic acid, arginine, citrulline, and the ratio of ornithine/citrulline showed significantly differences among the groups. Multiple logistic regression analysis with a stepwise selection-elimination method identified 2-oxoglutaric acid (odds ratio [OR] 1.98, 95% confidence interval [CI] 1.05–3.76) and cis -aconitic acid (OR 2.69, 95% CI 1.04–6.99) as independently associated with Fontan patients. After adjustment for the covariates of age and gender, 2-oxoglutaric acid (OR 1.97, 95% CI 0.98–3.93) and cis -aconitic acid (OR 3.88, 95% CI 0.99–15.2) showed remarkable relationships with Fontan patients. Conclusions The present findings suggest that abnormalities in the TCA cycle and amino acid metabolism are distinguishing features in the pathophysiology of Fontan patients. Future metabolomic studies will assist in developing biomarkers for the early prediction of “silent” Fontan pathophysiologies.

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Abnormal glucose metabolism in patients with Fontan circulation: Unique characteristics and associations with Fontan pathophysiology

Cited by 12 publications

References 30 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

Fontan Circulation Associated Organ Abnormalities Beyond the Heart, Lungs, Liver, and Gut: A Systematic Review

Identification of metabolomic profile related to adult Fontan pathophysiology

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