Venkateswaran Vandana Revathi, She Ruicong, Gardell Stephen J, Luzum Jasmine A, Gupta Ramesh, Zhang Kefei, Williams L Keoki, Sabbah Hani N, Lanfear David E
Center for Individualized and Genomic Medicine Research (CIGMA), Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan, USA.
Department of Public Health Sciences, Henry Ford Hospital, Detroit, Michigan, USA.
ESC Heart Fail. 2025 Jun;12(3):2057-2065. doi: 10.1002/ehf2.15215. Epub 2025 Mar 10.
Plasma metabolites are prognostic in heart failure with reduced ejection fraction (HFrEF), with citric acid cycle metabolites linked to ejection fraction (EF) changes. We investigated these mechanisms in a canine chronic HFrEF model. We tested associations between changes in plasma metabolites, left ventricular (LV) end-diastolic volume and cardiomyocyte mitochondrial function.
Eighteen dogs underwent microembolization to induce moderate HFrEF (target LVEF 35%-40%). Plasma metabolites, LV size and mitochondrial function were assessed over 12 months.
Plasma metabolite heatmap showed acylcarnitine changes, with early alterations in organic acids and amino acids predicting later adverse LV remodelling. Using either baseline or change over time, 13 metabolites correlated with 12 month LV enlargement. This is mostly often at 3 months (11 of 13), notably C18:2 (r = -0.58, P = 0.003) and cardiac anaplerotic substrates like glutamine (r = -0.52, P = 0.009) and 3-HBA (r = -0.43, P = 0.035). Impaired cardiomyocyte mitochondrial function correlated with LV enlargement (max ATP synthesis 12.7 vs. 19.9 nmol/min/mg, P = 0.0036; ADP-stimulated respiration 224 vs. 308 nAtom O/min/mg protein; P = 0.0064). Plasma metabolites correlated with mitochondrial parameters at 12 month, particularly with MAX ATP: malate (r = -0.75, P < 0.001), fumarate (r = -0.6, P = 0.008) and glutamine (r = 0.51, P = 0.031).
In canine HFrEF, plasma acylcarnitines, citric acid cycle or anaplerotic metabolites predicted adverse LV remodelling. LV enlargement correlated with reduced cardiomyocyte mitochondrial function, which in turn was also associated with increased citric acid cycle metabolites. Together, these data suggest impaired cardiac energetic function drives plasma metabolite associations in HFrEF progression.
血浆代谢物对射血分数降低的心力衰竭（HFrEF）具有预后价值，柠檬酸循环代谢物与射血分数（EF）变化相关。我们在犬慢性HFrEF模型中研究了这些机制。我们测试了血浆代谢物变化、左心室（LV）舒张末期容积和心肌细胞线粒体功能之间的关联。
18只犬接受微栓塞以诱导中度HFrEF（目标左心室射血分数为35%-40%）。在12个月内评估血浆代谢物、左心室大小和线粒体功能。
血浆代谢物热图显示酰基肉碱变化，有机酸和氨基酸的早期改变可预测后期不良左心室重构。使用基线值或随时间的变化，13种代谢物与12个月时的左心室扩大相关。这种情况最常发生在3个月时（13种中的11种），特别是C18:2（r = -0.58，P = 0.003）以及心脏回补底物如谷氨酰胺（r = -0.52，P = 0.009）和3-羟基丁酸（r = -0.43，P = 0.035）。心肌细胞线粒体功能受损与左心室扩大相关（最大ATP合成量为12.7 vs. 19.9 nmol/min/mg，P = 0.0036；ADP刺激的呼吸为224 vs. 308 nAtom O/min/mg蛋白质；P = 0.0064）。血浆代谢物在12个月时与线粒体参数相关，特别是与最大ATP：苹果酸（r = -0.75，P < 0.001）、富马酸（r = -0.6，P = 0.008）和谷氨酰胺（r = 0.51，P = 0.031）相关。
在犬HFrEF中，血浆酰基肉碱、柠檬酸循环或回补代谢物可预测不良左心室重构。左心室扩大与心肌细胞线粒体功能降低相关，而这又与柠檬酸循环代谢物增加有关。总之，这些数据表明心脏能量功能受损驱动了HFrEF进展过程中血浆代谢物的关联。
