Kaye David M, Wang Xiao Suo, Koay Yen Chin, Li Mengbo, McIntosh Bailey, Ng Yann Huey, Rahman Michael, Cao Yiyang, Marques Francine Z, Malecki Cassandra, Nanayakkara Shane, Mariani Justin, Wang Bing, Lal Sean, Guglielmi Giovanni, O'Sullivan John F
Heart Failure Research Group, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.
Department of Cardiology, Alfred Hospital, Melbourne, VIC, Australia.
Eur J Heart Fail. 2025 Jul;27(7):1342-1352. doi: 10.1002/ejhf.3704. Epub 2025 Jun 4.
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.
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.
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.
尽管使用左心室辅助装置（LVAD）减轻负荷后衰竭心脏的功能可得到恢复，但其潜在机制尚不清楚。我们旨在阐明LVAD支持在体内和体外对心肌生化作用的影响。
我们对从健康志愿者（n = 13）、射血分数降低的终末期心力衰竭患者（HFrEF，n = 20）和接受LVAD支持的HFrEF患者（n = 18）采集的经心脏（动脉和冠状窦）血样进行了靶向代谢组学和脂质组学分析。对来自健康供体、HFrEF和LVAD患者的心肌组织样本以及心肌母细胞进行了补充生化研究。HFrEF患者嘌呤、核苷酸和三羧酸（TCA）循环途径中中间产物的心肌摄取减少，LVAD患者则恢复。HFrEF患者葡萄糖摄取受到抑制，但在LVAD患者中恢复。HFrEF患者存在提示脂肪酸氧化受损的代谢物变化，而LVAD患者则没有。我们发现，与对照组相比，HFrEF心脏显著释放代谢物柠康酸，在另一组患者中也得到证实，HFrEF心肌中柠康酸水平升高，而LVAD心肌中则没有。虽然柠康酸增加了心肌母细胞中的琥珀酸脱氢酶（SDH）活性，但其异构体衣康酸抑制了SDH活性。SDH活性在HFrEF心肌中得以维持，但在LVAD心肌中降低。
我们首次报告了LVAD减轻负荷对人体心脏的体内生化作用。我们的数据确定柠康酸是衰竭心脏中TCA循环的潜在重要调节因子。
