Cardiovascular Drugs and Therapy

, Volume 27, Issue 6, pp 499–510 | Cite as

Docosahexaenoic Acid Supplementation Alters Key Properties of Cardiac Mitochondria and Modestly Attenuates Development of Left Ventricular Dysfunction in Pressure Overload-Induced Heart Failure

  • Erinne R. Dabkowski
  • Kelly A. O’Connell
  • Wenhong Xu
  • Rogerio F. RibeiroJr
  • Peter A. Hecker
  • Kadambari Chandra Shekar
  • Caroline Daneault
  • Christine Des Rosiers
  • William C. Stanley



Supplementation with the n3 polyunsaturated fatty acid docosahexaenoic acid (DHA) is beneficial in heart failure patients, however the mechanisms are unclear. DHA is incorporated into membrane phospholipids, which may prevent mitochondrial dysfunction. Thus we assessed the effects of DHA supplementation on cardiac mitochondria and the development of heart failure caused by aortic pressure overload.


Pathological cardiac hypertrophy was generated in rats by thoracic aortic constriction. Animals were fed either a standard diet or were supplemented with DHA (2.3 % of energy intake).


After 14 weeks, heart failure was evident by left ventricular hypertrophy and chamber enlargement compared to shams. Left ventricle fractional shortening was unaffected by DHA treatment in sham animals (44.1 ± 1.6 % vs. 43.5 ± 2.2 % for standard diet and DHA, respectively), and decreased with heart failure in both treatment groups, but to a lesser extent in DHA treated animals (34.9 ± 1.7 %) than with the standard diet (29.7 ± 1.5 %, P < 0.03). DHA supplementation increased DHA content in mitochondrial phospholipids and decreased membrane viscosity. Myocardial mitochondrial oxidative capacity was decreased by heart failure and unaffected by DHA. DHA treatment enhanced Ca2+ uptake by subsarcolemmal mitochondria in both sham and heart failure groups. Further, DHA lessened Ca2+-induced mitochondria swelling, an index of permeability transition, in heart failure animals. Heart failure increased hydrogen peroxide-induced mitochondrial permeability transition compared to sham, which was partially attenuated in interfibrillar mitochondria by treatment with DHA.


DHA decreased mitochondrial membrane viscosity and accelerated Ca2+ uptake, and attenuated susceptibility to mitochondrial permeability transition and development of left ventricular dysfunction.


Cardiac failure Metabolism Polyunsaturated fatty acids Reactive oxygen species 


Funding support

This work was supported by the National Institutes of Health, National Heart Lung and Blood Institute [Grant numbers HL074237, HL110731 and HL101434] .

Conflict of Interest

William Stanley is the inventor on a US patent application filed by the University of Maryland for the use of DHA for the treatment of heart failure. All other authors have no conflicts.


  1. 1.
    Ghio S, Scelsi L, Latini R, Masson S, Eleuteri E, Palvarini M, et al. Effects of n-3 polyunsaturated fatty acids and of rosuvastatin on left ventricular function in chronic heart failure: a substudy of GISSI-HF trial. Eur J Heart Fail. 2010;12:1345–53.PubMedCrossRefGoogle Scholar
  2. 2.
    Gissi-Hf I. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:1223–30.CrossRefGoogle Scholar
  3. 3.
    Nodari S, Triggiani M, Campia U, Manerba A, Milesi G, Cesana BM, et al. Effects of n-3 polyunsaturated fatty acids on left ventricular function and functional capacity in patients with dilated cardiomyopathy. J Am Coll Cardiol. 2011;57:870–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Moertl D, Hammer A, Steiner S, Hutuleac R, Vonbank K, Berger R. Dose-dependent effects of omega-3-polyunsaturated fatty acids on systolic left ventricular function, endothelial function, and markers of inflammation in chronic heart failure of nonischemic origin: a double-blind, placebo-controlled, 3-arm study. Am Heart J. 2011;161:915–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Mozaffarian D, Wu JH. Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. J Am Coll Cardiol. 2011;58:2047–67.PubMedCrossRefGoogle Scholar
  6. 6.
    Duda MK, O’shea KM, Stanley WC. omega-3 polyunsaturated fatty acid supplementation for the treatment of heart failure: mechanisms and clinical potential. Cardiovasc Res. 2009;84:33–41.PubMedCrossRefGoogle Scholar
  7. 7.
    Khairallah RJ, Sparagna GC, Khanna N, O’shea KM, Hecker PA, Kristian T, et al. Dietary supplementation with docosahexaenoic acid, but not eicosapentaenoic acid, dramatically alters cardiac mitochondrial phospholipid fatty acid composition and prevents permeability transition. Biochim Biophys Acta. 2010;1797:1555–62.PubMedCrossRefGoogle Scholar
  8. 8.
    Khairallah RJ, O’shea KM, Brown BH, Khanna N, des Rosiers C, Stanley WC. Treatment with docosahexaenoic acid, but not eicosapentaenoic acid, delays Ca2+−induced mitochondria permeability transition in normal and hypertrophied myocardium. J Pharmacol Exp Ther. 2010;335:155–62.PubMedCrossRefGoogle Scholar
  9. 9.
    Khairallah RJ, Kim J, O’Shea KM, O’Connell KA, Brown BH, Galvao TDRC, et al. Improved mitochondrial function with diet-induced increase in either docosahexaenoic acid or arachidonic acid in membrane phospholipids. PLoS One. 2012;7:e34402.PubMedCrossRefGoogle Scholar
  10. 10.
    O’shea KM, Khairallah RJ, Sparagna GC, Xu W, Hecker PA, Robillard-Frayne I, et al. Dietary omega-3 fatty acids alter cardiac mitochondrial phospholipid composition and delay Ca2+−induced permeability transition. J Mol Cell Cardiol. 2009;47:819–27.PubMedCrossRefGoogle Scholar
  11. 11.
    Bugger H, Schwarzer M, Chen D, Schrepper A, Amorim PA, Schoepe M, et al. Proteomic remodelling of mitochondrial oxidative pathways in pressure overload-induced heart failure. Cardiovasc Res. 2010;85:376–84.PubMedCrossRefGoogle Scholar
  12. 12.
    Galvao TF, Khairallah RJ, Dabkowski ER, Brown BH, Hecker PA, O’Connell KA, et al. Marine n3 polyunsaturated fatty acids enhance resistance to mitochondrial permeability transition in heart failure, but do not improve survival. Am J Physiol Heart Circ Physiol. 2013;73:H12–21.CrossRefGoogle Scholar
  13. 13.
    Sharov VG, Todor A, Khanal S, Imai M, Sabbah HN. Cyclosporine A attenuates mitochondrial permeability transition and improves mitochondrial respiratory function in cardiomyocytes isolated from dogs with heart failure. J Mol Cell Cardiol. 2007;42:150–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Halestrap AP. A pore way to die: the role of mitochondria in reperfusion injury and cardioprotection. Biochem Soc Trans. 2010;38:841–60.PubMedCrossRefGoogle Scholar
  15. 15.
    Sharov VG, Todor AV, Imai M, Sabbah HN. Inhibition of mitochondrial permeability transition pores by cyclosporine A improves cytochrome C oxidase function and increases rate of ATP synthesis in failing cardiomyocytes. Heart Fail Rev. 2005;10:305–10.PubMedCrossRefGoogle Scholar
  16. 16.
    Stanley WC, Khairallah RJ, Dabkowski ER. Update on lipids and mitochondrial function: impact of dietary n-3 polyunsaturated fatty acids. Curr Opin Clin Nutr Metab Care. 2012;15:122–6.PubMedCrossRefGoogle Scholar
  17. 17.
    Pepe S, Tsuchiya N, Lakatta EG, Hansford RG. PUFA and aging modulate cardiac mitochondrial membrane lipid composition and Ca2+ activation of PDH. Am J Physiol. 1999;276:H149–58.PubMedGoogle Scholar
  18. 18.
    Elrod JW, Wong R, Mishra S, Vagnozzi RJ, Sakthievel B, Goonasekera SA, et al. Cyclophilin D controls mitochondrial pore-dependent Ca(2+) exchange, metabolic flexibility, and propensity for heart failure in mice. J Clin Invest. 2010;120:3680–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Elrod JW, Molkentin JD. Physiologic functions of cyclophilin d and the mitochondrial permeability transition pore. Circ J. 2013;77:1111–22.PubMedCrossRefGoogle Scholar
  20. 20.
    O’shea KM, Chess DJ, Khairallah RJ, Hecker PA, Lei B, Walsh K, et al. omega-3 Polyunsaturated fatty acids prevent pressure overload-induced ventricular dilation and decrease in mitochondrial enzymes despite no change in adiponectin. Lipids Health Dis. 2010;9:95.PubMedCrossRefGoogle Scholar
  21. 21.
    Duda MK, O’shea KM, Tintinu A, Xu W, Khairallah RJ, Barrows BR, et al. Fish oil, but not flaxseed oil, decreases inflammation and prevents pressure overload-induced cardiac dysfunction. Cardiovasc Res. 2009;81:319–27.PubMedCrossRefGoogle Scholar
  22. 22.
    Duda MK, O’shea KM, Lei B, Barrows BR, Azimzadeh AM, McElfresh TE, et al. Dietary supplementation with omega-3 PUFA increases adiponectin and attenuates ventricular remodeling and dysfunction with pressure overload. Cardiovasc Res. 2007;76:303–10.PubMedCrossRefGoogle Scholar
  23. 23.
    Shah KB, Duda MK, O’shea KM, Sparagna GC, Chess DJ, Khairallah RJ, et al. The cardioprotective effects of fish oil during pressure overload are blocked by high fat intake: role of cardiac phospholipid remodeling. Hypertension. 2009;54:605–11.PubMedCrossRefGoogle Scholar
  24. 24.
    Chen J, Shearer GC, Chen Q, Healy CL, Beyer AJ, Nareddy VB, et al. Omega-3 fatty acids prevent pressure overload-induced cardiac fibrosis through activation of cyclic GMP/protein kinase G signaling in cardiac fibroblasts. Circulation. 2011;123:584–93.PubMedCrossRefGoogle Scholar
  25. 25.
    McLennan PL, Abeywardena MY, Dallimore JA, Raederstorff D. Dietary fish oil preserves cardiac function in the hypertrophied rat heart. Br J Nutr. 2011;108:645–54.PubMedCrossRefGoogle Scholar
  26. 26.
    Gong G, Liu J, Liang P, Guo T, Hu Q, Ochiai K, et al. Oxidative capacity in failing hearts. Am J Physiol Heart Circ Physiol. 2003;285:H541–8.PubMedGoogle Scholar
  27. 27.
    Garnier A, Fortin D, Delomenie C, Momken I, Veksler V, Ventura-Clapier R. Depressed mitochondrial transcription factors and oxidative capacity in rat failing cardiac and skeletal muscles. J Physiol. 2003;551:491–501.PubMedCrossRefGoogle Scholar
  28. 28.
    Javadov S, Choi A, Rajapurohitam V, Zeidan A, Basnakian AG, Karmazyn M. NHE-1 inhibition-induced cardioprotection against ischaemia/reperfusion is associated with attenuation of the mitochondrial permeability transition. Cardiovasc Res. 2008;77:416–24.PubMedCrossRefGoogle Scholar
  29. 29.
    Javadov S, Huang C, Kirshenbaum L, Karmazyn M. NHE-1 inhibition improves impaired mitochondrial permeability transition and respiratory function during postinfarction remodelling in the rat. J Mol Cell Cardiol. 2005;38:135–43.PubMedCrossRefGoogle Scholar
  30. 30.
    Faerber G, Barreto-Perreia F, Schoepe M, Gilsbach R, Schrepper A, Schwarzer M, et al. Induction of heart failure by minimally invasive aortic constriction in mice: reduced peroxisome proliferator-activated receptor gamma coactivator levels and mitochondrial dysfunction. J Thorac Cardiovasc Surg. 2011;141(492–500):500.Google Scholar
  31. 31.
    Zaha V, Grohmann J, Gobel H, Geibel A, Beyersdorf F, Doenst T. Experimental model for heart failure in rats–induction and diagnosis. Thorac Cardiovasc Surg. 2003;51:211–5.PubMedGoogle Scholar
  32. 32.
    Doenst T, Pytel G, Schrepper A, Amorim P, Farber G, Shingu Y, et al. Decreased rates of substrate oxidation ex vivo predict the onset of heart failure and contractile dysfunction in rats with pressure overload. Cardiovasc Res. 2010;86:461–70.PubMedCrossRefGoogle Scholar
  33. 33.
    Palmer JW, Tandler B, Hoppel CL. Biochemical properties of subsarcolemmal and interfibrillar mitochondria isolated from rat cardiac muscle. J Biol Chem. 1977;252:8731–9.PubMedGoogle Scholar
  34. 34.
    Papanicolaou KN, Ngoh GA, Dabkowski ER, O’Connell KA, Ribeiro RF, Stanley WC, et al. Cardiomyocyte deletion of mitofusin-1 leads to mitochondrial fragmentation and improves tolerance to ROS-induced mitochondrial dysfunction and cell death. Am J Physiol Heart Circ Physiol. 2012;302:H167–79.PubMedCrossRefGoogle Scholar
  35. 35.
    Lee J, Yu BP, Herlihy JT. Modulation of cardiac mitochondrial membrane fluidity by age and calorie intake. Free Radic Biol Med. 1999;26:260–5.PubMedCrossRefGoogle Scholar
  36. 36.
    Dabkowski ER, Baseler WA, Williamson CL, Powell M, Razunguzwa TT, Frisbee JC, et al. Mitochondrial dysfunction in the type 2 diabetic heart is associated with alterations in spatially distinct mitochondrial proteomes. Am J Physiol Heart Circ Physiol. 2010;299:H529–40.PubMedCrossRefGoogle Scholar
  37. 37.
    Chess DJ, Xu W, Khairallah R, O’shea KM, Kop WJ, Azimzadeh AM, et al. The antioxidant tempol attenuates pressure overload-Induced cardiac hypertrophy and contractile dysfunction in mice fed a high-fructose diet. Am J Physiol Heart Circ Physiol. 2008;295:H2223–30.PubMedCrossRefGoogle Scholar
  38. 38.
    Gelinas R, Thompson-Legault J, Bouchard B, Daneault C, Mansour A, Gillis MA, et al. Prolonged QT interval and lipid alterations beyond {beta}-oxidation in very long-chain acyl-CoA dehydrogenase null mouse hearts. Am J Physiol Heart Circ Physiol. 2011;301:H813–23.PubMedCrossRefGoogle Scholar
  39. 39.
    Asemu G, O’Connell KA, Cox JW, Dabkowski ER, Xu W, Ribeiro Jr RF, et al. Enhanced resistance to permeability transition in interfibrillar cardiac mitochondria in dogs: effects of aging and long-term aldosterone infusion. Am J Physiol Heart Circ Physiol. 2013;304:H514–28.PubMedCrossRefGoogle Scholar
  40. 40.
    Galvao TF, Brown BH, Hecker PA, O’Connell KA, O’shea KM, Sabbah HN, et al. High intake of saturated fat, but not polyunsaturated fat, improves survival in heart failure despite persistent mitochondrial defects. Cardiovasc Res. 2012;93:24–32.PubMedCrossRefGoogle Scholar
  41. 41.
    Stanley WC, Dabkowski ER, Ribeiro Jr RF, O’Connell KA. Dietary fat and heart failure: moving from lipotoxicity to lipoprotection. Circ Res. 2012;110:764–76.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Erinne R. Dabkowski
    • 1
  • Kelly A. O’Connell
    • 1
  • Wenhong Xu
    • 1
  • Rogerio F. RibeiroJr
    • 1
  • Peter A. Hecker
    • 1
  • Kadambari Chandra Shekar
    • 1
  • Caroline Daneault
    • 2
  • Christine Des Rosiers
    • 2
  • William C. Stanley
    • 1
    • 3
  1. 1.Division of Cardiology, Department of MedicineUniversity of MarylandBaltimoreUSA
  2. 2.Department of Nutrition and Montreal Heart InstituteUniversité de MontréalMontrealCanada
  3. 3.Discipline of PhysiologyUniversity of SydneySydneyAustralia

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