Highlights
- •A first integrative study using human and murine hearts on association of lipids in heart failure was investigated.
- •Lipid fingerprinting led to the identification of 273 species in clinical and mouse samples.
- •A decrease in cardiac phosphatidylethanolamines is associated with human ischemic heart disease.
- •Inter-organ (heart, spleen, and kidney) and systemic lipid signatures were profiled in acute and chronic HF post-MI mice.
Abstract
Background and aims
Myocardial infarction (MI) is a leading cause of heart failure (HF). After MI, lipids
undergo several phasic changes implicated in cardiac repair if inflammation resolves
on time. However, if inflammation continues, that leads to end stage HF progression
and development. Numerous studies have analyzed the traditional risk factors; however,
temporal lipidomics data for human and animal models are limited. Thus, we aimed to
obtain sequential lipid profiling from acute to chronic HF.
Methods
Here, we report the comprehensive lipidome of the hearts from diseased and healthy
subjects. To induce heart failure in mice, we used a non-reperfused model of coronary
ligation, and MI was confirmed by echocardiography and histology, then temporal kinetics
of lipids in different tissues (heart, spleen, kidney), and plasma was quantitated
from heart failure mice and compared with naïve controls. For lipid analysis in mouse
and human samples, untargeted liquid chromatography-linear trap quadrupole orbitrap
mass spectrometry (LC-LTQ-Orbitrap MS) was performed.
Results
In humans, multivariate analysis revealed distinct cardiac lipid profiles between
healthy and ischemic subjects, with 16 lipid species significantly downregulated by
5-fold, mainly phosphatidylethanolamines (PE), in the ischemic heart. In contrast,
PE levels were markedly increased in mouse tissues and plasma in chronic MI, indicating
possible cardiac remodeling. Further, fold change analysis revealed site-specific
lipid biomarkers for acute and chronic HF. A significant decrease in sulfatides (SHexCer
(34:1; 2O)) and sphingomyelins (SM (d18:1/16:0)) was observed in mouse tissues and
plasma in chronic HF.
Conclusions
Overall, a significant decreased lipidome in human ischemic LV and differential lipid
metabolites in the transition of acute to chronic HF with inter-organ communication
could provide novel insights into targeting integrative pathways for the early diagnosis
or development of novel therapeutics to delay/prevent HF.
Graphical abstract

Graphical Abstract
Keywords
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References
- Heart disease and stroke statistics-2020 update: a report from the American heart association.Circulation. 2020; 141: E139-E596https://doi.org/10.1161/CIR.0000000000000757
- Global public health burden of heart failure.Card. Fail. Rev. 2017; 3: 7https://doi.org/10.15420/CFR.2016:25:2
- Heart disease and stroke statistics-2021 update: a report from the American heart association.Circulation. 2021; 143: E254-E743https://doi.org/10.1161/CIR.0000000000000950
- Obesity treatment: weight loss versus increasing fitness and physical activity for reducing health risks.iScience. 2021; 24102995https://doi.org/10.1016/J.ISCI.2021.102995
- Risk prediction models for incident heart failure: a systematic Review of methodology and model performance.J. Card. Fail. 2017; 23: 680-687https://doi.org/10.1016/J.CARDFAIL.2017.03.005
- Heart failure after myocardial infarction: incidence and predictors.ESC Heart Fail. 2021; 8: 222-237https://doi.org/10.1002/EHF2.13144
- Obesity and cardiometabolic defects in heart failure pathology.Compr. Physiol. 2017; 7: 1463-1477https://doi.org/10.1002/CPHY.C170011
- Diagnostic and prognostic biomarkers for myocardial infarction.Front Cardiovasc Med. 2020; 7617277https://doi.org/10.3389/FCVM.2020.617277
- Novel biomarkers of heart failure.Adv. Clin. Chem. 2017; 79: 93-152https://doi.org/10.1016/BS.ACC.2016.09.002
- Lipid metabolism and toxicity in the heart.Cell Metabol. 2012; 15: 805-812https://doi.org/10.1016/J.CMET.2012.04.006
- Serum untargeted lipidomic profiling reveals dysfunction of phospholipid metabolism in subclinical coronary artery disease.Vasc. Health Risk Manag. 2019; 15: 123-135https://doi.org/10.2147/VHRM.S202344
- Lipoxygenase drives lipidomic and metabolic reprogramming in ischemic heart failure.Metabolism. 2019; 96: 22-32https://doi.org/10.1016/J.METABOL.2019.04.011
- Serum lipids profiling perturbances in patients with ischemic heart disease and ischemic cardiomyopathy.Lipids Health Dis. 2020; 19https://doi.org/10.1186/S12944-020-01269-9
- Serum lipids profiling perturbances in patients with ischemic heart disease and ischemic cardiomyopathy.Lipids Health Dis. 2020; 19https://doi.org/10.1186/S12944-020-01269-9
- Untargeted lipidomics reveals a specific enrichment in plasmalogens in epicardial adipose tissue and a specific signature in coronary artery disease.Arterioscler. Thromb. Vasc. Biol. 2020; 40: 986-1000https://doi.org/10.1161/ATVBAHA.120.313955
- Metabolic disturbances identified in plasma are associated with outcomes in patients with heart failure: diagnostic and prognostic value of metabolomics.J. Am. Coll. Cardiol. 2015; 65: 1509-1520https://doi.org/10.1016/J.JACC.2015.02.018
- Guidelines for in vivo mouse models of myocardial infarction.Am. J. Physiol. Heart Circ. Physiol. 2021; https://doi.org/10.1152/AJPHEART.00459.2021
- Heart functional and structural compendium of cardiosplenic and cardiorenal networks in acute and chronic heart failure pathology.Am. J. Physiol. Heart Circ. Physiol. 2018; 314: H255-H267https://doi.org/10.1152/ajpheart.00528.2017
- Sphingosine-1-phosphate interactions in the spleen and heart reflect extent of cardiac repair in mice and failing human hearts.Am. J. Physiol. Heart Circ. Physiol. 2021; 321: H599-H611https://doi.org/10.1152/AJPHEART.00314.2021
- Subacute treatment of carprofen facilitate splenocardiac resolution deficit in cardiac injury.J. Leukoc. Biol. 2018; 104: 1173-1186https://doi.org/10.1002/JLB.3A0618-223R
- Untargeted lipidomic analysis of plasma from high fat diet-induced obese rats using UHPLC- linear trap quadrupole -Orbitrap MS.Anal. Sci. 2020; : 1-20https://doi.org/10.2116/analsci.19p442
- Lipid fingerprinting of yellow mealworm Tenebrio molitor by untargeted liquid chromatography-mass spectrometry.J Insects Food Feed. 2022; 8: 157-168https://doi.org/10.3920/JIFF2020.0119/ASSET/IMAGES/SMALL/GA_JIFF2020.0119.GIF
- Biophysical and lipidomic biomarkers of cardiac remodeling post-myocardial infarction in humans.Biomolecules. 2020; 10: 1-20https://doi.org/10.3390/BIOM10111471
- Acute heart failure.Nat. Rev. Dis. Prim. 2020; 6https://doi.org/10.1038/S41572-020-0151-7
- Lipid profiles and heart failure risk: results from two prospective studies.Circ. Res. 2021; 128: 309-320https://doi.org/10.1161/CIRCRESAHA.120.317883
- Altered myocardial calcium cycling and energetics in heart failure--a rational approach for disease treatment.Cell Metabol. 2015; 21: 183-194https://doi.org/10.1016/J.CMET.2015.01.005
- Mitochondrial dysfunction and oxidative stress in heart disease.Exp. Mol. Med. 2019; 51https://doi.org/10.1038/S12276-019-0355-7
- Metabolism and chronic inflammation: the links between chronic heart failure and comorbidities.Front Cardiovasc Med. 2021; 8https://doi.org/10.3389/FCVM.2021.650278
- Investigation of the presence of ischemic heart disease by the 1H NMR-based lipidomics of red blood cell membranes.Atherosclerosis. 2015; 241: e124-e125https://doi.org/10.1016/j.atherosclerosis.2015.04.432
- Using metabolomics to assess myocardial metabolism and energetics in heart failure.J. Mol. Cell. Cardiol. 2013; 55: 12-18https://doi.org/10.1016/J.YJMCC.2012.08.025
- Activation of a membrane-associated phospholipase A2 during rabbit myocardial ischemia which is highly selective for plasmalogen substrate - PubMed.(n.d.)https://pubmed.ncbi.nlm.nih.gov/2005103/Date accessed: October 27, 2021
- Phosphatidylglycerol incorporates into cardiolipin to improve mitochondrial activity and inhibits inflammation.Sci. Rep. 2018; 8https://doi.org/10.1038/S41598-018-23190-Z
- Specific degradation of phosphatidylglycerol is necessary for proper mitochondrial morphology and function.Biochim. Biophys. Acta Bioenerg. 2016; 1857: 34-45https://doi.org/10.1016/J.BBABIO.2015.10.004
- Depletion of cardiac cardiolipin synthase alters systolic and diastolic function.iScience. 2021; https://doi.org/10.1016/j.isci.2021.103314
- Lipids of mitochondria.Biochim. Biophys. Acta. 1985; 822: 1-42https://doi.org/10.1016/0304-4157(85)90002-4
- Phosphatidylethanolamine positively regulates autophagy and longevity.Cell Death Differ. 2015; 22: 499-508https://doi.org/10.1038/CDD.2014.219
- Phospholipid homeostasis regulates lipid metabolism and cardiac function through SREBP signaling in Drosophila.Genes Dev. 2011; 25: 189-200https://doi.org/10.1101/GAD.1992411
- Biophysical and lipidomic biomarkers of cardiac remodeling post-myocardial infarction in humans.Biomolecules. 2020; 10: 1-20https://doi.org/10.3390/BIOM10111471
- Lipidomics revealed alteration of sphingolipid metabolism during the reparative phase After myocardial infarction injury.Front. Physiol. 2021; 12663480https://doi.org/10.3389/FPHYS.2021.663480
- Arachidonic acid and ischemic heart disease.J. Nutr. 2005; 135: 2271-2273https://doi.org/10.1093/JN/135.9.2271
- Lipid profiles and heart failure risk: results from two prospective studies.Circ. Res. 2021; 128: 309-320https://doi.org/10.1161/CIRCRESAHA.120.317883
- Free fatty acids during acute myocardial infarction.Prog. Cardiovasc. Dis. 1971; 13: 361-373https://doi.org/10.1016/S0033-0620(71)80012-9
- Cholesteryl esters accumulate in the heart in a porcine model of ischemia and reperfusion.PLoS One. 2013; 8e61942https://doi.org/10.1371/JOURNAL.PONE.0061942
- Altering sphingolipid metabolism attenuates cell death and inflammatory response after myocardial infarction.Circulation. 2020; 141: 916-930https://doi.org/10.1161/CIRCULATIONAHA.119.041882
- Increased de novo ceramide synthesis and accumulation in failing myocardium.JCI Insight. 2017; 2https://doi.org/10.1172/JCI.INSIGHT.82922
- Sphingolipids in the heart: from cradle to grave.Front. Endocrinol. 2020; 11https://doi.org/10.3389/FENDO.2020.00652
- Circulating sulfatide, A novel biomarker for ST-segment elevation myocardial infarction.J. Atherosclerosis Thromb. 2019; 26: 84https://doi.org/10.5551/JAT.43976
- Impaired renal function in acute myocardial infarction - PubMed.(n.d.)https://pubmed.ncbi.nlm.nih.gov/19753517/Date accessed: October 27, 2021
- Doxorubicin triggers splenic contraction and irreversible dysregulation of COX and LOX that alters the inflammation-resolution program in the myocardium.Am. J. Physiol. Heart Circ. Physiol. 2018; 315: H1091-H1100https://doi.org/10.1152/AJPHEART.00290.2018
- Postmortem lipid levels for the analysis of risk factors of sudden death: usefulness of the Ektachem and Monarch analyzers.Am. J. Forensic Med. Pathol. 1997; 18: 354-359https://doi.org/10.1097/00000433-199712000-00008
- Effect of post-mortem time on the biochemical composition of coronary arteries.Atherosclerosis. 1985; 56: 1-10https://doi.org/10.1016/0021-9150(85)90079-6
Article info
Publication history
Published online: November 09, 2022
Accepted:
November 3,
2022
Received in revised form:
October 18,
2022
Received:
June 30,
2022
Identification
Copyright
© 2022 Elsevier B.V. All rights reserved.