Skip to main content
SpringerLink
Log in

Comprehensive plasma metabolomic and lipidomic analyses reveal potential biomarkers for heart failure

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Heart failure is a syndrome with symptoms or signs caused by cardiac dysfunction. In clinic, four stages (A, B, C, and D) were used to describe heart failure progression. This study was aimed to explore plasma metabolomic and lipidomic profiles in different HF stages to identify potential biomarkers. Metabolomics and lipidomics were performed using plasma of heart failure patients at stages A (n = 49), B (n = 61), and C+D (n = 26). Analysis of Variance (ANOVA) was used for screening dysregulated molecules. Bioinformatics was used to retrieve perturbed metabolic pathways. Univariate and multivariate receiver operating characteristic curve (ROC) analyses were used for potential biomarker screening. Stage A showed significant difference to other stages, and 142 dysregulated lipids and 134 dysregulated metabolites were found belonging to several metabolic pathways. Several marker panels were proposed for the diagnosis of heart failure stage A versus stage B-D. Several molecules, including lysophosphatidylcholine 18:2, cholesteryl ester 18:1, alanine, choline, and Fructose, were found correlated with B-type natriuretic peptide or left ventricular ejection fractions. In summary, using untargeted metabolomic and lipidomic profiling, several dysregulated small molecules were successfully identified between HF stages A and B-D. These molecules would provide valuable information for further pathological researches and biomarker development.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Mosterd A, Hoes AW (2007) Clinical epidemiology of heart failure. Heart 93:1137–1146. https://doi.org/10.1136/hrt.2003.025270

    Article  PubMed  PubMed Central  Google Scholar 

  2. Mendez GF, Cowie MR (2001) The epidemiological features of heart failure in developing countries: a review of the literature. Int J Cardiol 80:213–219. https://doi.org/10.1016/s0167-5273(01)00497-1

    Article  CAS  PubMed  Google Scholar 

  3. McMurray JJ, Stewart S (2000) Epidemiology, aetiology, and prognosis of heart failure. Heart 83:596–602. https://doi.org/10.1136/heart.83.5.596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Redfield MM (2002) Heart failure–an epidemic of uncertain proportions. N Engl J Med 347:1442–1444. https://doi.org/10.1056/NEJMe020115

    Article  PubMed  Google Scholar 

  5. Aurigemma GP, Gottdiener JS, Shemanski L, Gardin J, Kitzman D (2001) Predictive value of systolic and diastolic function for incident congestive heart failure in the elderly: the cardiovascular health study. J Am Coll Cardiol 37:1042–1048. https://doi.org/10.1016/s0735-1097(01)01110-x

    Article  CAS  PubMed  Google Scholar 

  6. Aurigemma GP, Gaasch WH (2004) Clinical practice. Diastolic heart failure. N Engl J Med 351:1097–1105. https://doi.org/10.1056/NEJMcp022709

    Article  CAS  PubMed  Google Scholar 

  7. Hunt SA, Baker DW, Chin MH, Cinquegrani MP, Feldman AM, Francis GS, Ganiats TG, Goldstein S, Gregoratos G, Jessup ML, Noble RJ, Packer M, Silver MA, Stevenson LW, Gibbons RJ, Antman EM, Alpert JS, Faxon DP, Fuster V, Jacobs AK, Hiratzka LF, Russell RO, Smith SC Jr (2001) ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of Cardiology/American Heart Association task force on practice guidelines (committee to revise the 1995 guidelines for the evaluation and management of heart failure). J Am Coll Cardiol 38:2101–2113. https://doi.org/10.1016/s0735-1097(01)01683-7

    Article  CAS  PubMed  Google Scholar 

  8. Remes J, Miettinen H, Reunanen A, Pyörälä K (1991) Validity of clinical diagnosis of heart failure in primary health care. Eur Heart J 12:315–321. https://doi.org/10.1093/oxfordjournals.eurheartj.a059896

    Article  CAS  PubMed  Google Scholar 

  9. Wang TJ, Larson MG, Levy D, Benjamin EJ, Leip EP, Omland T, Wolf PA, Vasan RS (2004) Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N Engl J Med 350:655–663. https://doi.org/10.1056/NEJMoa031994

    Article  CAS  PubMed  Google Scholar 

  10. Dunn WB, Bailey NJ, Johnson HE (2005) Measuring the metabolome: current analytical technologies. Analyst 130:606–625. https://doi.org/10.1039/b418288j

    Article  CAS  PubMed  Google Scholar 

  11. Ortmayr K, Dubuis S, Zampieri M (2019) Metabolic profiling of cancer cells reveals genome-wide crosstalk between transcriptional regulators and metabolism. Nat Commun 10:1841. https://doi.org/10.1038/s41467-019-09695-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Luo P, Yin P, Hua R, Tan Y, Li Z, Qiu G, Yin Z, Xie X, Wang X, Chen WJH (2018) A Large-scale, multicenter serum metabolite biomarker identification study for the early detection of hepatocellular carcinoma. Hepatology 67:662–675

    Article  CAS  Google Scholar 

  13. Calzada E, Avery E, Sam PN, Modak A, Wang C, McCaffery JM, Han X (2019) Phosphatidylethanolamine made in the inner mitochondrial membrane is essential for yeast cytochrome bc(1) complex function. Nat Commun 10:1432. https://doi.org/10.1038/s41467-019-09425-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chen W, Zeng J, Wang W, Yang B, Zhong L, Zhou J (2020) Comprehensive metabolomic and lipidomic analysis reveals metabolic changes after mindfulness training. Mindfulness 11:1390–1400. https://doi.org/10.1007/s12671-020-01359-w

    Article  Google Scholar 

  15. Zhou J, Sun L, Chen L, Liu S, Zhong L (2019) Comprehensive metabolomic and proteomic analyses reveal candidate biomarkers and related metabolic networks in atrial fibrillation. Metabolomics 15:96. https://doi.org/10.1007/s11306-019-1557-7

    Article  CAS  PubMed  Google Scholar 

  16. Zhou J, Li Q (2020) Plasma metabolomics and lipidomics reveal perturbed metabolites in different disease stages of chronic obstructive pulmonary disease. Int J Chron Obstr Pulm Dis 15:553–565. https://doi.org/10.2147/copd.s229505

    Article  CAS  Google Scholar 

  17. Xia J, Sinelnikov IV, Han B, Wishart DS (2015) Metaboanalyst 3.0–making metabolomics more meaningful. Nucleic Acids Res 43:W251–W257. https://doi.org/10.1093/nar/gkv380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. de Giuli F, Khaw KT, Cowie MR, Sutton GC, Ferrari R, Poole-Wilson PA (2005) Incidence and outcome of persons with a clinical diagnosis of heart failure in a general practice population of 696,884 in the United Kingdom. Eur J Heart Fail 7:295–302. https://doi.org/10.1016/j.ejheart.2004.10.017

    Article  PubMed  Google Scholar 

  19. Cowie MR, Wood DA, Coats AJ, Thompson SG, Suresh V, Poole-Wilson PA, Sutton GC (2000) Survival of patients with a new diagnosis of heart failure: a population based study. Heart 83:505–510. https://doi.org/10.1136/heart.83.5.505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hunter WG, Kelly JP, McGarrah RW 3rd, Kraus WE, Shah SH (2016) Metabolic dysfunction in heart failure: diagnostic, prognostic, and pathophysiologic insights from metabolomic profiling. Curr Heart Fail Rep 13:119–131. https://doi.org/10.1007/s11897-016-0289-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Cheng ML, Wang CH, Shiao MS, Liu MH, Huang YY, Huang CY, Mao CT, Lin JF, Ho HY, Yang NI (2015) Metabolic disturbances identified in plasma are associated with outcomes in patients with heart failure: diagnostic and prognostic value of metabolomics. J Am Coll Cardiol 65:1509–1520. https://doi.org/10.1016/j.jacc.2015.02.018

    Article  CAS  PubMed  Google Scholar 

  22. Wang J, Li Z, Chen J, Zhao H, Luo L, Chen C, Xu X, Zhang W, Gao K, Li B, Zhang J, Wang W (2013) Metabolomic identification of diagnostic plasma biomarkers in humans with chronic heart failure. Mol Biosyst 9:2618–2626. https://doi.org/10.1039/c3mb70227h

    Article  CAS  PubMed  Google Scholar 

  23. Deidda M, Piras C, Dessalvi CC, Locci E, Barberini L, Torri F, Ascedu F, Atzori L, Mercuro G (2015) Metabolomic approach to profile functional and metabolic changes in heart failure. J Transl Med 13:297. https://doi.org/10.1186/s12967-015-0661-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Dunn WB, Broadhurst DI, Deepak SM, Buch MH, McDowell G, Spasic I, Ellis DI, Brooks N, Kell DB, Neyses L (2007) Serum metabolomics reveals many novel metabolic markers of heart failure, including pseudouridine and 2-oxoglutarate. Metabolomics 3:413–426. https://doi.org/10.1007/s11306-007-0063-5

    Article  CAS  Google Scholar 

  25. Hunter WG, Kelly JP, McGarrah RW, Khouri MG, Craig D, Haynes C, Ilkayeva O, Stevens RD, Bain JR, Muehlbauer MJ, Newgard CB, Felker GM, Hernandez AF, Velazquez EJ, Kraus WE, Shah SH (2016) Metabolomic profiling identifies novel circulating biomarkers of mitochondrial dysfunction differentially elevated in heart failure with preserved versus reduced ejection fraction: evidence for shared metabolic impairments in clinical heart failure. J Am Heart Assoc. https://doi.org/10.1161/jaha.115.003190

    Article  PubMed  PubMed Central  Google Scholar 

  26. Zordoky BN, Sung MM, Ezekowitz J, Mandal R, Han B, Bjorndahl TC, Bouatra S, Anderson T, Oudit GY, Wishart DS, Dyck JR (2015) Metabolomic fingerprint of heart failure with preserved ejection fraction. PLoS ONE 10:e0124844. https://doi.org/10.1371/journal.pone.0124844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mahmod M, Pal N, Rayner J, Holloway C, Raman B, Dass S, Levelt E, Ariga R, Ferreira V, Banerjee R, Schneider JE, Rodgers C, Francis JM, Karamitsos TD, Frenneaux M, Ashrafian H, Neubauer S, Rider O (2018) The interplay between metabolic alterations, diastolic strain rate and exercise capacity in mild heart failure with preserved ejection fraction: a cardiovascular magnetic resonance study. J Cardiovasc Magn Reson 20:88. https://doi.org/10.1186/s12968-018-0511-6

    Article  PubMed  PubMed Central  Google Scholar 

  28. Shelp BJ, Bown AW, McLean MD (1999) Metabolism and functions of gamma-aminobutyric acid. Trends Plant Sci 4:446–452. https://doi.org/10.1016/s1360-1385(99)01486-7

    Article  CAS  PubMed  Google Scholar 

  29. Carillo BA, Oliveira-Sales EB, Andersen M, Tufik S, Hipolide D, Santos AA, Tucci PJ, Bergamaschi CT, Campos RR (2012) Changes in GABAergic inputs in the paraventricular nucleus maintain sympathetic vasomotor tone in chronic heart failure. Auton Neurosci 171:41–48. https://doi.org/10.1016/j.autneu.2012.10.005

    Article  CAS  PubMed  Google Scholar 

  30. Williams RB, Marchuk DA, Gadde KM, Barefoot JC, Grichnik K, Helms MJ, Kuhn CM, Lewis JG, Schanberg SM, Stafford-Smith M, Suarez EC, Clary GL, Svenson IK, Siegler IC (2001) Central nervous system serotonin function and cardiovascular responses to stress. Psychosom Med 63:300–305. https://doi.org/10.1097/00006842-200103000-00016

    Article  CAS  PubMed  Google Scholar 

  31. Saxena PR, Villalón CM (1990) Cardiovascular effects of serotonin agonists and antagonists. J Cardiovasc Pharmacol 15(Suppl 7):S17-34

    Article  CAS  Google Scholar 

  32. Turski WA, Nakamura M, Todd WP, Carpenter BK, Whetsell WO Jr, Schwarcz R (1988) Identification and quantification of kynurenic acid in human brain tissue. Brain Res 454:164–169. https://doi.org/10.1016/0006-8993(88)90815-3

    Article  CAS  PubMed  Google Scholar 

  33. Swartz KJ, During MJ, Freese A, Beal MF (1990) Cerebral synthesis and release of kynurenic acid: an endogenous antagonist of excitatory amino acid receptors. J Neurosci 10:2965–2973. https://doi.org/10.1523/jneurosci.10-09-02965.1990

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Boldyrev AA, Severin SE (1990) The histidine-containing dipeptides, carnosine and anserine: distribution, properties and biological significance. Adv Enzyme Regul 30:175–194. https://doi.org/10.1016/0065-2571(90)90017-v

    Article  CAS  PubMed  Google Scholar 

  35. Troughton RW, Frampton CM, Yandle TG, Espiner EA, Nicholls MG, Richards AM (2000) Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations. Lancet 355:1126–1130. https://doi.org/10.1016/s0140-6736(00)02060-2

    Article  CAS  PubMed  Google Scholar 

  36. Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J (2003) Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-preserved trial. Lancet 362:777–781. https://doi.org/10.1016/s0140-6736(03)14285-7

    Article  CAS  PubMed  Google Scholar 

  37. Schymanski EL, Jeon J, Gulde R, Fenner K, Ruff M, Singer HP, Hollender J (2014) Identifying small molecules via high resolution mass spectrometry: communicating confidence. Environ Sci Technol 48:2097–2098. https://doi.org/10.1021/es5002105

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This study was funded by the Fund for Fostering Young Scholars of Peking University Health Science Center (Grant No. BMU2018PY006), the National Natural Science Foundation of China (82070272) and Beijing Municipal Natural Science Foundation (7202225).

Author information

Author notes

  1. Juntuo Zhou and Xi Chen contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, No. 49, Hua Yuan North Rd, Hai Dian District, Beijing, 100191, China

    Juntuo Zhou & Ming Cui

  2. Department of Pathology, School of Basic Medical Science, Peking University Health Science Center, Beijing, 100191, China

    Xi Chen

  3. Center of Medical and Health Analysis, Peking University Health Science Center, Beijing, 100191, China

    Juntuo Zhou, Wei Chen & Lijun Zhong

  4. Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Beijing, 100191, China

    Ming Cui

  5. Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, China

    Ming Cui

  6. Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China

    Ming Cui

Authors
  1. Juntuo Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xi Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wei Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lijun Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ming Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JZ, XC, LZ, and MC designed this study. XC and WC collected the clinical samples. JZ and LZ performed the metabolomic and lipidomic experiments. JZ analyzed the omics data. XC and MC reviewed the statistical results. JZ and MC wrote the manuscript. All the authors read and approved the final manuscript.

Corresponding authors

Correspondence to Lijun Zhong or Ming Cui.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

All procedures performed in these studies involving human participants were in accordance with the ethical standards of the institutional and national research committee of Peking University Third Hospital (ethical approval number M2017293), and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Consent to participate

Written informed consent was provided for all participants before enrollment.

Consent for publication

Written informed consent for publication was obtained from all participants.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhou, J., Chen, X., Chen, W. et al. Comprehensive plasma metabolomic and lipidomic analyses reveal potential biomarkers for heart failure. Mol Cell Biochem 476, 3449–3460 (2021). https://doi.org/10.1007/s11010-021-04159-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-021-04159-5

Keywords

Search

Navigation