Molecular Signature of HFpEF: Systems Biology in a Cardiac-Centric Large Animal Model

• Published in: JACC. Basic to translational science Vol. 6; no. 8; pp. 650 - 672
• Main Authors: Gibb, Andrew A, Murray, Emma K, Eaton, Deborah M, Huynh, Anh T, Tomar, Dhanendra, Garbincius, Joanne F, Kolmetzky, Devin W, Berretta, Remus M, Wallner, Markus, Houser, Steven R, Elrod, John W
• Format: Journal Article
• Language: English
• Published: United States Elsevier 01-08-2021
• Subjects: Preclinical Research; LV, left ventricle/ventricular; systems biology; m/z, mass to charge ratio; ECM, extracellular matrix; ESI, electrospray ionization; RI, retention index; preserved ejection fraction; LA, left atrial; metabolomics; HF, heart failure; transcriptomics; EF, ejection fraction; LAV, left atrial volume; ETC, electron transport chain; HFrEF, heart failure with reduced ejection fraction; UPLC, ultraperformance liquid chromatography; BCAA, branched chain amino acids; heart failure; GO, gene ontology; RCR, respiratory control ratio; mitochondria; DAG, diacylglycerol; MS/MS, tandem mass spectrometry; FC, fold change; HFpEF, heart failure with preserved ejection fraction; FDR, false discovery rate
• ISSN: 2452-302X
• DOI: 10.1016/j.jacbts.2021.07.004

In this study the authors used systems biology to define progressive changes in metabolism and transcription in a large animal model of heart failure with preserved ejection fraction (HFpEF). Transcriptomic analysis of cardiac tissue, 1-month post-banding, revealed loss of electron transport chain components, and this was supported by changes in metabolism and mitochondrial function, altogether signifying alterations in oxidative metabolism. Established HFpEF, 4 months post-banding, resulted in changes in intermediary metabolism with normalized mitochondrial function. Mitochondrial dysfunction and energetic deficiencies were noted in skeletal muscle at early and late phases of disease, suggesting cardiac-derived signaling contributes to peripheral tissue maladaptation in HFpEF. Collectively, these results provide insights into the cellular biology underlying HFpEF progression.