Association of plasma metabolites and cardiac mitochondrial function with heart failure progression
Recommended Citation
Venkateswaran VR, She R, Gardell SJ, Luzum JA, Gupta R, Zhang K, Williams LK, Sabbah HN, and Lanfear DE. Association of plasma metabolites and cardiac mitochondrial function with heart failure progression. ESC Heart Fail 2025;12(3):2057-2065.
Document Type
Article
Publication Date
6-1-2025
Publication Title
ESC Heart Fail
Abstract
AIMS: 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.
METHODS: Eighteen dogs underwent microembolization to induce moderate HFrEF (target LVEF 35%-40%). Plasma metabolites, LV size and mitochondrial function were assessed over 12 months.
RESULTS: 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).
CONCLUSIONS: 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.
Medical Subject Headings
Animals; Dogs; Heart Failure; Disease Progression; Mitochondria, Heart; Ventricular Remodeling; Stroke Volume; Disease Models, Animal; Myocytes, Cardiac; Carnitine; Male; Biomarkers; Ventricular Function, Left; Female; Citric Acid Cycle
PubMed ID
40064034
ePublication
ePub ahead of print
Volume
12
Issue
3
First Page
2057
Last Page
2065
