scholarly journals Identifying functional metabolic shifts in heart failure with the integration of omics data and a cardiomyocyte-specific, genome-scale model

2020 ◽  
Author(s):  
Bonnie V. Dougherty ◽  
Kristopher D. Rawls ◽  
Glynis L. Kolling ◽  
Kalyan C. Vinnakota ◽  
Anders Wallqvist ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Specific Model ◽  
Metabolic Phenotype ◽  
Scale Model ◽  
Metabolic Markers ◽  
Metabolic Functions ◽  
Carbon Substrates ◽  
End Stage ◽  
Genome Scale

SummaryThe heart is a metabolic omnivore, known to consume many different carbon substrates in order to maintain function. In diseased states, the heart’s metabolism can shift between different carbon substrates; however, there is some disagreement in the field as to the metabolic shifts seen in end-stage heart failure and whether all heart failure converges to a common metabolic phenotype. Here, we present a new, validated cardiomyocyte-specific GEnome-scale metabolic Network REconstruction (GENRE), iCardio, and use the model to identify common shifts in metabolic functions across heart failure omics datasets. We demonstrate the utility of iCardio in interpreting heart failure gene expression data by identifying Tasks Inferred from Differential Expression (TIDEs) which represent metabolic functions associated with changes in gene expression. We identify decreased NO and Neu5Ac synthesis as common metabolic markers of heart failure across datasets. Further, we highlight the differences in metabolic functions seen across studies, further highlighting the complexity of heart failure. The methods presented for constructing a tissue-specific model and identifying TIDEs can be extended to multiple tissue and diseases of interest.

scholarly journals Troponin I gene expression during human cardiac development and in end-stage heart failure.

1993 ◽  
Vol 72 (5) ◽  
pp. 932-938 ◽  
Author(s):  
S Sasse ◽  
N J Brand ◽  
P Kyprianou ◽  
G K Dhoot ◽  
R Wade ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Troponin I ◽  
Cardiac Development ◽  
End Stage Heart Failure ◽  
End Stage ◽  
I Gene

scholarly journals Fibroblast-specific genome-scale modelling predicts an imbalance in amino acid metabolism in Refsum disease

2019 ◽  
Author(s):  
Agnieszka B. Wegrzyn ◽  
Katharina Herzog ◽  
Albert Gerding ◽  
Marcel Kwiatkowski ◽  
Justina C. Wolters ◽  
...  
Keyword(s):  
Amino Acid ◽  
Phytanic Acid ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Disease Patient ◽  
Metabolic Phenotype ◽  
Scale Model ◽  
Refsum Disease ◽  
Model Based ◽  
Genome Scale

ABSTRACTRefsum disease is an inborn error of metabolism that is characterised by a defect in peroxisomal α-oxidation of the branched-chain fatty acid phytanic acid. The disorder presents with late-onset progressive retinitis pigmentosa and polyneuropathy and can be diagnosed biochemically by elevated levels of phytanic acid in plasma and tissues of patients. To date, no cure exists for Refsum disease, but phytanic acid levels in patients can be reduced by plasmapheresis and a strict diet.In this study, we reconstructed a fibroblast-specific genome-scale model based on the recently published, FAD-curated model, based on Recon3D reconstruction. We used transcriptomics (available via GEO database with identifier GSE138379), metabolomics, and proteomics data (available via ProteomeXchange with identifier PXD015518), which we obtained from healthy controls and Refsum disease patient fibroblasts incubated with phytol, a precursor of phytanic acid.Our model correctly represents the metabolism of phytanic acid and displays fibroblast-specific metabolic functions. Using this model, we investigated the metabolic phenotype of Refsum disease at the genome-scale, and we studied the effect of phytanic acid on cell metabolism. We identified 53 metabolites that were predicted to discriminate between Healthy and Refsum disease patients, several of which with a link to amino acid metabolism. Ultimately, these insights in metabolic changes may provide leads for pathophysiology and therapy.

FGF21 (Fibroblast Growth Factor 21) Defines a Potential Cardiohepatic Signaling Circuit in End-Stage Heart Failure

2021 ◽  
Author(s):  
Salah Sommakia ◽  
Naredos H. Almaw ◽  
Sandra H. Lee ◽  
Dinesh K.A. Ramadurai ◽  
Iosif Taleb ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Growth Factor ◽  
Ejection Fraction ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Reduced Ejection Fraction ◽  
End Stage ◽  
Signaling Circuit

Background: Extrinsic control of cardiomyocyte metabolism is poorly understood in heart failure (HF). FGF21 (Fibroblast growth factor 21), a hormonal regulator of metabolism produced mainly in the liver and adipose tissue, is a prime candidate for such signaling. Methods: To investigate this further, we examined blood and tissue obtained from human subjects with end-stage HF with reduced ejection fraction at the time of left ventricular assist device implantation and correlated serum FGF21 levels with cardiac gene expression, immunohistochemistry, and clinical parameters. Results: Circulating FGF21 levels were substantially elevated in HF with reduced ejection fraction, compared with healthy subjects (HF with reduced ejection fraction: 834.4 [95% CI, 628.4–1040.3] pg/mL, n=40; controls: 146.0 [86.3–205.7] pg/mL, n=20, P =1.9×10 −5 ). There was clear FGF21 staining in diseased cardiomyocytes, and circulating FGF21 levels negatively correlated with the expression of cardiac genes involved in ketone metabolism, consistent with cardiac FGF21 signaling. FGF21 gene expression was very low in failing and nonfailing hearts, suggesting extracardiac production of the circulating hormone. Circulating FGF21 levels were correlated with BNP (B-type natriuretic peptide) and total bilirubin, markers of chronic cardiac and hepatic congestion. Conclusions: Circulating FGF21 levels are elevated in HF with reduced ejection fraction and appear to bind to the heart. The liver is likely the main extracardiac source. This supports a model of hepatic FGF21 communication to diseased cardiomyocytes, defining a potential cardiohepatic signaling circuit in human HF.

Myocardial Gene Expression of Regulators of Myocyte Apoptosis and Myocyte Calcium Homeostasis During Hemodynamic Unloading by Ventricular Assist Devices in Patients With End-Stage Heart Failure

Circulation ◽  
1999 ◽  
Vol 100 (suppl_2) ◽  
Author(s):  
Babett Bartling ◽  
Hendrik Milting ◽  
Heike Schumann ◽  
Dorothea Darmer ◽  
Lativ Arusoglu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Sarcoplasmic Reticulum ◽  
Calcium Homeostasis ◽  
Cardiac Transplantation ◽  
Left Ventricular ◽  
Ventricular Assist ◽  
End Stage Heart Failure ◽  
End Stage ◽  
Myocardial Gene Expression

Background —In patients with end-stage heart failure, characterized by an increased susceptibility to cardiomyocyte apoptosis and a labile cardiomyocyte calcium homeostasis, a ventricular assist device (VAD) is implanted for bridging to cardiac transplantation and results in myocardial unloading. Although phenotype changes in the failing heart are assumed to result from hemodynamic overload, the reversibility of these changes under unloading is unknown. Methods and Results —By use of quantitative reverse-transcription polymerase chain reaction, mRNA expression analyses were performed on left ventricular specimens obtained from 10 nonfailing donor hearts (from 8 patients with dilated cardiomyopathy and 2 patients with coronary heart disease) at the time of VAD implantation and 36 to 169 days later during VAD removal with subsequent cardiac transplantation. In terminally failing hearts before VAD support, left ventricular mRNA analyses revealed increased Pro-ANP, reduced antiapoptotic Bcl-x L and antiapoptotic Fas isoform FasExo6Del, and a decreased ratio of sarcoplasmic reticulum Ca 2+ -ATPase per sarcolemmal Na + -Ca 2+ exchanger in comparison with nonfailing ventricles. After VAD unloading, ventricular transcription of Pro-ANP was immediately normalized, and apoptotic DNA fragmentation was attenuated. In patients with dilated cardiomyopathy, mRNAs of Bcl-x L and FasExo6Del/Fas were enhanced depending on time on VAD. The Bcl-x L mRNA level correlated positively with that of the Bcl-x L protein. Transcription of sarcoplasmic reticulum Ca 2+ -ATPase/Na + -Ca 2+ exchanger demonstrated recovery in only 4 of 10 patients. Conclusions —Mechanical support of the failing heart induces a time-dependent change in myocardial gene expression compatible with a decreased susceptibility to apoptosis.

Gene expression profiling in peripheral blood nuclear cells in patients with refractory ischaemic end-stage heart failure

2010 ◽  
Vol 51 (3) ◽  
pp. 353-368 ◽  
Author(s):  
S. Szmit ◽  
M. Jank ◽  
H. Maciejewski ◽  
M. Grabowski ◽  
R. Glowczynska ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Gene Expression Profiling ◽  
Peripheral Blood ◽  
Expression Profiling ◽  
End Stage Heart Failure ◽  
End Stage
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