Analytical and Bioanalytical Chemistry

, Volume 410, Issue 7, pp 1965–1976 | Cite as

Comprehensive targeted and non-targeted lipidomics analyses in failing and non-failing heart

  • Ganesh V. Halade
  • Anela Dorbane
  • Kevin A. Ingle
  • Vasundhara Kain
  • Jean-Marie Schmitter
  • Boutayna Rhourri-Frih
Research Paper


Myocardial infarction (MI) and subsequent progressive heart failure pathology is the major cause of death worldwide; however, the mechanism of this pathology remains unclear. The present work aimed at testing the hypothesis whether the inflammatory response is superimposed with the formation of bioactive lipid resolving molecules at the site of the injured myocardium in acute heart failure pathology post-MI. In this view, we used a robust permanent coronary ligation model to induce MI, leading to decreased contractility index with marked wall thinning and necrosis of the infarcted left ventricle. Then, we applied mass spectrometry imaging (MSI) in positive and negative ionization modes to characterize the spatial distribution of left ventricle lipids in the infarcted myocardium post-MI. After micro-extraction, liquid chromatography coupled to tandem mass spectrometry was used to confirm the structures of the imaged lipids. Statistical tools such as principal component analysis were used to establish a comprehensive visualization of lipid profile changes in MI and no-MI hearts. Resolving bioactive molecules such as resolvin (Rv) D1, RvD5, RvE3, 17-HDHA, LXA4, and 18-HEPE were detected in negative ion mode MSI, whereas phosphatidyl cholines (PC) and oxidized derivatives thereof were detected in positive ion mode. MSI-based analysis demonstrated a significant increase in resolvin bioactive lipids with comprehensive lipid remodeling at the site of infarction. These results clearly indicate that infarcted myocardium is the primary location of inflammation-resolution pathomechanics which is critical for resolution of inflammation and heart failure pathophysiology.

Graphical abstract

Applied scheme to determine comprehensive lipidomics in failing and non-failing heart.


Myocardial infarction Lipids Ischemic myocardium Resolution of inflammation Bioactive lipid molecules 



Arachidonic acid


Area under curve


Docosahexaenoic acid


Eicosapentaenoic acid


Fatty acids


Hydroxydocosahexaenoic acid


Hydroxyeicosapentaenoic acid


Hydroperoxyeicosatetraenoic acid


Liquid chromatography-mass spectrometry


Lipid mediators




Left ventricle




Matrix-assisted laser desorption ionization


Myocardial infarction


Multiple reaction monitoring


Molecular mass spectrometry imaging


Principal component analysis









We acknowledge the support from National Institutes of Health [AT006704 and HL132989] and The University of Alabama at Birmingham (UAB) Pittman scholar award to GVH, American Heart Association postdoctoral fellowship POST31000008 to VK, and Idex program from University of Bordeaux, France, to BF.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

216_2018_863_MOESM1_ESM.pdf (708 kb)
ESM 1 (PDF 707 kb)


  1. 1.
    Ponikowski P, Anker SD, AlHabib KF, Cowie MR, Force TL, Hu S, et al. Heart failure: preventing disease and death worldwide. ESC Heart Failure. 2014;1(1):4–25.CrossRefGoogle Scholar
  2. 2.
    Ziaeian B, Fonarow GC. Epidemiology and aetiology of heart failure. Nat Rev Cardiol. 2016;13(6):368–78.CrossRefGoogle Scholar
  3. 3.
    Ertl G, Frantz S. Healing after myocardial infarction. Cardiovasc Res. 2005;66(1):22–32.CrossRefGoogle Scholar
  4. 4.
    Grey AC, Gelasco AK, Section J, Moreno-Rodriguez RA, Krug EL, Schey KL. Molecular morphology of the chick heart visualized by MALDI imaging mass spectrometry. Anat Rec (Hoboken, NJ : 2007). 2010;293(5):821–8.CrossRefGoogle Scholar
  5. 5.
    Trim PJ, Henson CM, Avery JL, McEwen A, Snel MF, Claude E, et al. Matrix-assisted laser desorption/ionization-ion mobility separation-mass spectrometry imaging of vinblastine in whole body tissue sections. Anal Chem. 2008;80(22):8628–34.CrossRefGoogle Scholar
  6. 6.
    Gessel MM, Norris JL, Caprioli RM. MALDI imaging mass spectrometry: spatial molecular analysis to enable a new age of discovery. J Proteome. 2014;107:71–82.CrossRefGoogle Scholar
  7. 7.
    Jones EE, Powers TW, Neely BA, Cazares LH, Troyer DA, Parker AS, et al. MALDI imaging mass spectrometry profiling of proteins and lipids in clear cell renal cell carcinoma. Proteomics. 2014;14(7–8):924–35.CrossRefGoogle Scholar
  8. 8.
    De Sio G, Smith AJ, Galli M, Garancini M, Chinello C, Bono F, et al. A MALDI-mass spectrometry imaging method applicable to different formalin-fixed paraffin-embedded human tissues. Mol BioSyst. 2015;11(6):1507–14.CrossRefGoogle Scholar
  9. 9.
    Diehl HC, Beine B, Elm J, Trede D, Ahrens M, Eisenacher M, et al. The challenge of on-tissue digestion for MALDI MSI—a comparison of different protocols to improve imaging experiments. Anal Bioanal Chem. 2015;407(8):2223–43.CrossRefGoogle Scholar
  10. 10.
    Angel PM, Spraggins JM, Baldwin HS, Caprioli R. Enhanced sensitivity for high spatial resolution lipid analysis by negative ion mode matrix assisted laser desorption ionization imaging mass spectrometry. Anal Chem. 2012;84(3):1557–64.CrossRefGoogle Scholar
  11. 11.
    Angel PM, Bayoumi AS, Hinton RB, Ru Su Y, Bichell D, Mayer JE, et al. MALDI imaging mass spectrometry as a lipidomic approach to heart valve research. J Heart Valve Dis. 2016;25(2):240–52.Google Scholar
  12. 12.
    Steurer S, Singer JM, Rink M, Chun F, Dahlem R, Simon R, et al. MALDI imaging-based identification of prognostically relevant signals in bladder cancer using large-scale tissue microarrays. Urol Oncol. 2014;32(8):1225–33.CrossRefGoogle Scholar
  13. 13.
    Kofeler HC, Fauland A, Rechberger GN, Trotzmuller M. Mass spectrometry based lipidomics: an overview of technological platforms. Meta. 2012;2(1):19–38.Google Scholar
  14. 14.
    Bure C, Ayciriex S, Testet E, Schmitter JM. A single run LC-MS/MS method for phospholipidomics. Anal Bioanal Chem. 2013;405(1):203–13.CrossRefGoogle Scholar
  15. 15.
    Ma Y, Halade GV, Zhang J, Ramirez TA, Levin D, Voorhees A, et al. Matrix metalloproteinase-28 deletion exacerbates cardiac dysfunction and rupture after myocardial infarction in mice by inhibiting M2 macrophage activation. Cir Res. 2013;112(4):675–88.CrossRefGoogle Scholar
  16. 16.
    Lopez EF, Kabarowski JH, Ingle KA, Kain V, Barnes S, Crossman DK, et al. Obesity superimposed on aging magnifies inflammation and delays the resolving response after myocardial infarction. Am J Physiol Heart Circ Physiol. 2015;308(4):H269–80.CrossRefGoogle Scholar
  17. 17.
    Halade GV, Kain V, Ingle KA (2017) Heart functional and structural compendium of cardiosplenic and cardiorenal networks in acute and chronic heart failure pathology. Am J Physiol Heart Circ Physiol. :ajpheart 00528 02017.Google Scholar
  18. 18.
    Halade GV, Kain V, Black LM, Prabhu SD, Ingle KA. Aging dysregulates D- and E-series resolvins to modulate cardiosplenic and cardiorenal network following myocardial infarction. Aging. 2016;8(11):2611–34.CrossRefGoogle Scholar
  19. 19.
    Halade GV, Ma Y, Ramirez TA, Zhang J, Dai Q, Hensler JG, et al. Reduced BDNF attenuates inflammation and angiogenesis to improve survival and cardiac function following myocardial infarction in mice. Am J Physiol Heart Circ Physiol. 2013;305(12):H1830–42.CrossRefGoogle Scholar
  20. 20.
    Heaberlin JR, Ma Y, Zhang J, Ahuja SS, Lindsey ML, Halade GV. Obese and diabetic KKAy mice show increased mortality but improved cardiac function following myocardial infarction. Cardiovasc Pathol : the official journal of the Society for Cardiovascular Pathology. 2013;22(6):481–7.CrossRefGoogle Scholar
  21. 21.
    Ejsing CS, Sampaio JL, Surendranath V, Duchoslav E, Ekroos K, Klemm RW, et al. Global analysis of the yeast lipidome by quantitative shotgun mass spectrometry. Proc Natl Acad Sci U S A. 2009;106(7):2136–41.CrossRefGoogle Scholar
  22. 22.
    Colas RA, Shinohara M, Dalli J, Chiang N, Serhan CN. Identification and signature profiles for pro-resolving and inflammatory lipid mediators in human tissue. Am J Physiol Cell Physiol. 2014;307(1):C39–54.CrossRefGoogle Scholar
  23. 23.
    Thiele H, Heldmann S, Trede D, Strehlow J, Wirtz S, Dreher W, et al. 2D and 3D MALDI-imaging: conceptual strategies for visualization and data mining. Biochim Biophys Acta. 2014;1844(1 Pt A):117–37.CrossRefGoogle Scholar
  24. 24.
    Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol. 2008;8(5):349–61.CrossRefGoogle Scholar
  25. 25.
    Patterson NH, Doonan RJ, Daskalopoulou SS, Dufresne M, Lenglet S, Montecucco F, et al. Three-dimensional imaging MS of lipids in atherosclerotic plaques: open-source methods for reconstruction and analysis. Proteomics. 2016;16(11–12):1642–51.CrossRefGoogle Scholar
  26. 26.
    Halade GV, Kain V, Ingle KA, Prabhu SD. Interaction of 12/15-lipoxygenase with fatty acids alters the leukocyte kinetics leading to improved postmyocardial infarction healing. Am J Physiol Heart Circ Physiol. 2017;313(1):H89–H102.CrossRefGoogle Scholar
  27. 27.
    Halade GV, Kain V. Obesity and cardiometabolic defects in heart failure pathology. Compr Physiol. 2017;7(4):1463–77.CrossRefGoogle Scholar
  28. 28.
    Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature. 2014;510(7503):92–101.CrossRefGoogle Scholar
  29. 29.
    Halade GV, Rahman MM, Bhattacharya A, Barnes JL, Chandrasekar B, Fernandes G. Docosahexaenoic acid-enriched fish oil attenuates kidney disease and prolongs median and maximal life span of autoimmune lupus-prone mice. J Immunol. 2010;184(9):5280–6.CrossRefGoogle Scholar
  30. 30.
    Halade GV, Jin YF, Lindsey ML. Roles of saturated vs. polyunsaturated fat in heart failure survival: not all fats are created equal. Cardiovasc Res. 2012;93(1):4–5. Scholar
  31. 31.
    Menger RF, Stutts WL, Anbukumar DS, Bowden JA, Ford DA, Yost RA. MALDI mass spectrometric imaging of cardiac tissue following myocardial infarction in a rat coronary artery ligation model. Anal Chem. 2012;84(2):1117–25.CrossRefGoogle Scholar
  32. 32.
    Fruhwirth GO, Loidl A, Hermetter A. Oxidized phospholipids: from molecular properties to disease. Biochim Biophys Acta. 2007;1772(7):718–36.CrossRefGoogle Scholar
  33. 33.
    Leitinger N. Oxidized phospholipids as triggers of inflammation in atherosclerosis. Mol Nutr Food Res. 2005;49(11):1063–71.CrossRefGoogle Scholar
  34. 34.
    Niki E, Yoshida Y, Saito Y, Noguchi N. Lipid peroxidation: mechanisms, inhibition, and biological effects. Biochem Biophys Res Commun. 2005;338(1):668–76.CrossRefGoogle Scholar
  35. 35.
    Spickett CM, Dever G. Studies of phospholipid oxidation by electrospray mass spectrometry: from analysis in cells to biological effects. BioFactors (Oxford, England). 2005;24(1–4):17–31.CrossRefGoogle Scholar
  36. 36.
    Subbanagounder G, Deng Y, Borromeo C, Dooley AN, Berliner JA, Salomon RG. Hydroxy alkenal phospholipids regulate inflammatory functions of endothelial cells. Vasc Pharmacol. 2002;38(4):201–9.CrossRefGoogle Scholar
  37. 37.
    Erridge C, Spickett CM. Oxidised phospholipid regulation of Toll-like receptor signalling. Redox Rep : Communications in Free Radical Research. 2007;12(1):76–80.CrossRefGoogle Scholar
  38. 38.
    Bochkov VN, Leitinger N. Anti-inflammatory properties of lipid oxidation products. J Mol Med (Berlin, Germany). 2003;81(10):613–26.CrossRefGoogle Scholar
  39. 39.
    Spiteller G. Peroxyl radicals: inductors of neurodegenerative and other inflammatory diseases. Their origin and how they transform cholesterol, phospholipids, plasmalogens, polyunsaturated fatty acids, sugars, and proteins into deleterious products. Free Radic Biol Med. 2006;41(3):362–87.CrossRefGoogle Scholar
  40. 40.
    Rysman E, Brusselmans K, Scheys K, Timmermans L, Derua R, Munck S, et al. De novo lipogenesis protects cancer cells from free radicals and chemotherapeutics by promoting membrane lipid saturation. Cancer Res. 2010;70(20):8117–26.CrossRefGoogle Scholar
  41. 41.
    Deigner HP, Hermetter A. Oxidized phospholipids: emerging lipid mediators in pathophysiology. Curr Opin Lipidol. 2008;19(3):289–94.CrossRefGoogle Scholar
  42. 42.
    Schneider C, Porter NA, Brash AR. Routes to 4-hydroxynonenal: fundamental issues in the mechanisms of lipid peroxidation. J Biol Chem. 2008;283(23):15539–43.CrossRefGoogle Scholar
  43. 43.
    Tourki B, Halade G. Leukocyte diversity in resolving and nonresolving mechanisms of cardiac remodeling. FASEB J : official publication of the Federation of American Societies for Experimental Biology. 2017;31(10):4226–39.CrossRefGoogle Scholar
  44. 44.
    Kain V, Prabhu SD, Halade GV. Inflammation revisited: inflammation versus resolution of inflammation following myocardial infarction. Basic Res Cardiol. 2014;109(6):444.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Ganesh V. Halade
    • 1
  • Anela Dorbane
    • 2
  • Kevin A. Ingle
    • 1
  • Vasundhara Kain
    • 1
  • Jean-Marie Schmitter
    • 2
  • Boutayna Rhourri-Frih
    • 2
  1. 1.Division of Cardiovascular Disease, Department of MedicineThe University of Alabama at BirminghamBirminghamUSA
  2. 2.Chimie et Biologie des Membranes et NanoobjetsUniversity of BordeauxBordeauxFrance

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