Key result
LVAD unloading in HFrEF linked to restored myocardial TCA and glucose uptake vs unsupported failing hearts.
Why the study?
Although functional recovery of the failing heart can occur with LVAD unloading, the underpinning mechanism is unclear.
Does LVAD support improve myocardial metabolic remodeling in patients with end-stage HFrEF?
Observational (n=51)
Does LVAD support improve myocardial metabolic remodeling in patients with end-stage HFrEF?
Mechanical unloading with LVAD in failing hearts is accompanied by reverse metabolic remodeling, potentially regulated by a novel citraconate-mediated pathway.
LVAD unloading was associated with restored myocardial metabolism in HFrEF; hypothesis-generating for citraconate pathway and requires prospective validation.
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.
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Kaye et al. (2025) conducted an observational in Heart failure with reduced ejection fraction (HFrEF) (n=51). Left ventricular assist device (LVAD) support vs. Healthy volunteers and unsupported HFrEF patients was evaluated on Myocardial biochemical and metabolic changes (metabolomics and lipidomics). LVAD unloading in patients with HFrEF restored myocardial uptake of TCA cycle intermediates and glucose, and normalized citraconate levels compared to unsupported failing hearts.
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