Mechanical unloading is accompanied by reverse metabolic remodelling in the failing heart: Identification of a novel citraconate-mediated pathway

Kaye, DM; Wang, XS; Koay, YC; Li, M; McIntosh, B; Ng, YH; Rahman, M; Cao, Y; Marques, FZ; Malecki, C; Nanayakkara, S; Mariani, J; Wang, B; Lal, S; Guglielmi, G; O&#39;Sullivan, JF

Author(s): Kaye, DM; Wang, XS; Koay, YC; Li, M; McIntosh, B; Ng, YH; Rahman, M; Cao, Y; Marques, FZ; Malecki, C; Nanayakkara, S; Mariani, J; Wang, B; Lal, S; Guglielmi, G; O'Sullivan, JF;
Details: Publication Year 2025-07,Volume 27,Issue #7,Page 1342-1352
Journal Title: European Heart Journal
Abstract: AIMS: Although functional recovery of the failing heart with left ventricular assist device (LVAD) unloading can occur, the underpinning mechanism is unclear. We aimed to characterize the effect of myocardial biochemical effect of LVAD support in vivo and in vitro. METHODS AND RESULTS: We performed targeted metabolomics and lipidomics on transcardiac (arterial and coronary sinus) blood samples collected from healthy volunteers (n = 13), patients with end-stage heart failure with reduced ejection fraction (HFrEF, n = 20), and LVAD-supported HFrEF patients (n = 18). Complementary biochemical studies in myocardial tissue samples from healthy donor, HFrEF and LVAD patients, and cardiomyoblasts were performed. Myocardial uptake of intermediates in purine, nucleotide, and tricarboxylic acid (TCA) cycle pathways was depressed in HFrEF patients, with recovery in LVAD patients. Glucose uptake was suppressed in HFrEF but restored in LVAD. Metabolite changes suggestive of impaired fatty acid oxidation were present in HFrEF but not in LVAD. We found that the metabolite citraconate was significantly released by HFrEF hearts compared to controls and this was corroborated, in separate patients, by increased levels of citraconate in HFrEF myocardium but not in LVAD. Whilst citraconate increased succinate deydrogenase (SDH) activity in cardiomyoblasts, its isomer itaconate suppressed SDH activity. SDH activity was maintained in HFrEF myocardium but was diminished in LVAD myocardium. CONCLUSIONS: We report, for the first time, the in-vivo biochemical effects of LVAD unloading in the human heart. Our data identify citraconate as a potentially important regulator of the TCA cycle in the failing heart.
Publisher: Wiley
Keywords: Humans; *Heart Failure/metabolism/physiopathology/therapy; Male; *Heart-Assist Devices; Female; *Myocardium/metabolism; Middle Aged; *Ventricular Remodeling/physiology; Metabolomics/methods; Citric Acid Cycle; Adult; Stroke Volume/physiology; *Succinates/metabolism; Lipidomics; HFrEF; Lvad; Metabolomics; Myocardial metabolism; Remodelling
Research Division(s): Bioinformatics and Computational Biology
PubMed ID: 40464107
Publisher's Version: https://doi.org/10.1002/ejhf.3704
Open Access at Publisher's Site: https://doi.org/10.1002/ejhf.3704
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-08-29 08:41:19

Last Modified: 2025-08-29 08:41:29