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

Andrew A Gibb; Emma K Murray; Deborah M Eaton; Anh T Huynh; Dhanendra Tomar; Joanne F Garbincius; Devin W Kolmetzky; Remus M Berretta; Markus Wallner; Steven R Houser; John W Elrod

doi:10.1016/j.jacbts.2021.07.004

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

JACC Basic Transl Sci. 2021 Aug 23;6(8):650-672. doi: 10.1016/j.jacbts.2021.07.004. eCollection 2021 Aug.

Authors

Affiliations

¹ Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA.
² Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA.
³ Division of Cardiology, Medical University of Graz, Graz, Austria.
⁴ Center for Biomarker Research in Medicine, CBmed GmbH, Graz, Austria.

Abstract

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.

Keywords: BCAA, branched chain amino acids; DAG, diacylglycerol; ECM, extracellular matrix; EF, ejection fraction; ESI, electrospray ionization; ETC, electron transport chain; FC, fold change; FDR, false discovery rate; GO, gene ontology; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LA, left atrial; LAV, left atrial volume; LV, left ventricle/ventricular; MS/MS, tandem mass spectrometry; RCR, respiratory control ratio; RI, retention index; UPLC, ultraperformance liquid chromatography; heart failure; m/z, mass to charge ratio; metabolomics; mitochondria; preserved ejection fraction; systems biology; transcriptomics.

Abstract

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