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Evaluation of Docosahexaenoic Acid in a Dog Model of Hypertension Induced Left Ventricular Hypertrophy

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Abstract

Marine n-3 polyunsaturated fatty acids alter cardiac phospholipids and prevent cardiac pathology in rodents subjected to pressure overload. This approach has not been evaluated in humans or large animals with hypertension-induced pathological hypertrophy. We evaluated docosahexaenoic acid (DHA) in old female dogs with hypertension caused by 16 weeks of aldosterone infusion. Aldosterone-induced hypertension resulted in concentric left ventricular (LV) hypertrophy and impaired diastolic function in placebo-treated dogs. DHA supplementation increased DHA and depleted arachidonic acid in cardiac phospholipids, but did not improve LV parameters compared to placebo. Surprisingly, DHA significantly increased serum aldosterone concentration and blood pressure compared to placebo. Cardiac mitochondrial yield was decreased in placebo-treated hypertensive dogs compared to normal animals, which was prevented by DHA. Extensive analysis of mitochondrial function found no differences between DHA and placebo groups. In conclusion, DHA did not favorably impact mitochondrial or LV function in aldosterone hypertensive dogs.

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References

  1. Moertl, D., Hammer, A., Steiner, S., Hutuleac, R., Vonbank, K., & Berger, R. (2011). 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, 161, 915–919. doi:10.1016/j.ahj.2011.02.011.

    Article  PubMed  CAS  Google Scholar 

  2. Nodari, S., Triggiani, M., Campia, U., Manerba, A., Milesi, G., Cesana, B. M., et al. (2011). Effects of n-3 polyunsaturated fatty acids on left ventricular function and functional capacity in patients with dilated cardiomyopathy. J Am Coll Cardiol, 57, 870–879.

    Article  PubMed  CAS  Google Scholar 

  3. Gissi-Hf, I. (2008). 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, 372, 1223–1230.

    Article  Google Scholar 

  4. Duda, M. K., O’Shea, K. M., Lei, B., Barrows, B. R., Azimzadeh, A. M., McElfresh, T. E., et al. (2007). Dietary supplementation with omega-3 PUFA increases adiponectin and attenuates ventricular remodeling and dysfunction with pressure overload. Cardiovasc Res, 76, 303–310.

    Article  PubMed  CAS  Google Scholar 

  5. Duda, M. K., O’Shea, K. M., Tintinu, A., Xu, W., Khairallah, R. J., Barrows, B. R., et al. (2009). Fish oil, but not flaxseed oil, decreases inflammation and prevents pressure overload-induced cardiac dysfunction. Cardiovasc Res, 81, 319–327.

    Article  PubMed  CAS  Google Scholar 

  6. O’Shea, K. M., Chess, D. J., Khairallah, R. J., Hecker, P. A., Lei, B., Walsh, K., et al. (2010). omega-3 Polyunsaturated fatty acids prevent pressure overload-induced ventricular dilation and decrease in mitochondrial enzymes despite no change in adiponectin. Lipids Health Dis, 9, 95.

    Article  PubMed  Google Scholar 

  7. Chen, J., Shearer, G. C., Chen, Q., Healy, C. L., Beyer, A. J., Nareddy, V. B., et al. (2011). Omega-3 fatty acids prevent pressure overload-induced cardiac fibrosis through activation of cyclic GMP/protein kinase G signaling in cardiac fibroblasts. Circulation, 123, 584–593.

    Article  PubMed  CAS  Google Scholar 

  8. McLennan, P. L., Abeywardena, M. Y., Dallimore, J. A., & Raederstorff, D. (2011). Dietary fish oil preserves cardiac function in the hypertrophied rat heart. Br J Nutr, 108, 645–654.

    Article  PubMed  Google Scholar 

  9. Khairallah, R. J., O’Shea, K. M., Brown, B. H., Khanna, N., des Rosiers, C., & Stanley, W. C. (2010). Treatment with docosahexaenoic acid, but not eicosapentaenoic acid, delays Ca2+-induced mitochondria permeability transition in normal and hypertrophied myocardium. J Pharmacol Exp Ther, 335, 155–162.

    Article  PubMed  CAS  Google Scholar 

  10. O’Shea, K. M., Khairallah, R. J., Sparagna, G. C., Xu, W., Hecker, P. A., Robillard-Frayne, I., et al. (2009). Dietary omega-3 fatty acids alter cardiac mitochondrial phospholipid composition and delay Ca2+-induced permeability transition. J Mol Cell Cardiol, 47, 819–827.

    Article  PubMed  Google Scholar 

  11. Galvao, T. F., Khairallah, R. J., Dabkowski, E. R., Brown, B. H., Hecker, P. A., O’Connell, K. A., et al. (2013). 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, 73, H12–H21. doi:10.1152/ajpheart.00657.2012.

    Article  Google Scholar 

  12. Billman, G. E., Nishijima, Y., Belevych, A. E., Terentyev, D., Xu, Y., Haizlip, K. M., et al. (2010). Effects of dietary omega-3 fatty acids on ventricular function in dogs with healed myocardial infarctions: in vivo and in vitro studies. Am J Physiol Heart Circ Physiol, 298, H1219–H1228.

    Article  PubMed  CAS  Google Scholar 

  13. Mozaffarian, D., & Wu, J. H. (2011). Omega-3 fatty acids and cardiovascular disease: Effects on risk factors, molecular pathways, and clinical events. J Am Coll Cardiol, 58, 2047–2067. doi:10.1016/j.jacc.2011.06.063.

    Article  PubMed  CAS  Google Scholar 

  14. Stanley, W. C., Khairallah, R. J., & Dabkowski, E. R. (2012). Update on lipids and mitochondrial function: impact of dietary n-3 polyunsaturated fatty acids. Curr Opin Clin Nutr Metab Care, 15, 122–126. doi:10.1097/MCO.0b013e32834fdaf7.

    Article  PubMed  CAS  Google Scholar 

  15. Sergiel, J. P., Martine, L., Raederstorff, D., Grynberg, A., & Demaison, L. (1998). Individual effects of dietary EPA and DHA on the functioning of the isolated working rat heart. Can J Physiol Pharmacol, 76, 728–736.

    Article  PubMed  CAS  Google Scholar 

  16. Mori, T. A., & Woodman, R. J. (2006). The independent effects of eicosapentaenoic acid and docosahexaenoic acid on cardiovascular risk factors in humans. Curr Opin Clin Nutr Metab Care, 9, 95–104.

    Article  PubMed  CAS  Google Scholar 

  17. Khairallah, R. J., Sparagna, G. C., Khanna, N., O’Shea, K. M., Hecker, P. A., Kristian, T., et al. (2010). Dietary supplementation with docosahexaenoic acid, but not eicosapentaenoic acid, dramatically alters cardiac mitochondrial phospholipid fatty acid composition and prevents permeability transition. Biochim Biophys Acta, 1797, 1555–1562.

    Article  PubMed  CAS  Google Scholar 

  18. Igarashi, M., Ma, K., Chang, L., Bell, J. M., & Rapoport, S. I. (2008). Rat heart cannot synthesize docosahexaenoic acid from circulating alpha-linolenic acid because it lacks elongase-2. J Lipid Res, 49, 1735–1745.

    Article  PubMed  CAS  Google Scholar 

  19. Harris, W. S., Sands, S. A., Windsor, S. L., Ali, H. A., Stevens, T. L., Magalski, A., et al. (2004). Omega-3 fatty acids in cardiac biopsies from heart transplantation patients: Correlation with erythrocytes and response to supplementation. Circulation, 110, 1645–1649.

    Article  PubMed  CAS  Google Scholar 

  20. Metcalf, R. G., James, M. J., Gibson, R. A., Edwards, J. R., Stubberfield, J., Stuklis, R., et al. (2007). Effects of fish-oil supplementation on myocardial fatty acids in humans. Am J Clin Nutr, 85, 1222–1228.

    PubMed  CAS  Google Scholar 

  21. Crawford, M. A. (1968). Fatty-acid ratios in free-living and domestic animals. Possible implications for atheroma. Lancet, 1, 1329–1333.

    Article  PubMed  CAS  Google Scholar 

  22. Asemu, G., O’Connell, K. A., Cox, J. W., Dabkowski, E. R., Xu, W., Ribeiro, R. F., Jr., et al. (2013). 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, 304, H514–H528. doi:10.1152/ajpheart.00674.2012.

    Article  PubMed  CAS  Google Scholar 

  23. Rainbird, A., & Kienzle, E. (1990). Studies on the energy requirement of dogs depending on breed and age. Kleintierpraxis, 35, 149–158.

    Google Scholar 

  24. Palmer, J. W., Tandler, B., & Hoppel, C. L. (1977). Biochemical properties of subsarcolemmal and interfibrillar mitochondria isolated from rat cardiac muscle. J Biol Chem, 252, 8731–8739.

    PubMed  CAS  Google Scholar 

  25. Rosca, M. G., Vazquez, E. C., Kerner, J., Parland, W., Chandler, M. P., Stanley, W. C., et al. (2008). Cardiac mitochondria in coronary microembolization-induced heart failure: Decrease in respirasomes and oxidative phosphorylation. Cardiovasc Res, 80, 30–39.

    Article  PubMed  CAS  Google Scholar 

  26. Khairallah, R. J., Kim, J., O’Shea, K. M., O’Connell KA, B. B. H., Galvao, T. D. R. C., Polster, B. M., et al. (2012). Improved mitochondrial function with diet-induced increase in either docosahexaenoic acid or arachidonic acid in membrane phospholipids. PLoS One, 7, e34402.

    Article  PubMed  CAS  Google Scholar 

  27. Papanicolaou, K. N., Ngoh, G. A., Dabkowski, E. R., O’Connell, K. A., Ribeiro, R. F., Stanley, W. C., et al. (2012). 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, 302, H167–H179. doi:10.1152/ajpheart.00833.2011.

    Article  PubMed  CAS  Google Scholar 

  28. Dabkowski, E. R., Baseler, W. A., Williamson, C. L., Powell, M., Razunguzwa, T. T., Frisbee, J. C., et al. (2010). Mitochondrial dysfunction in the type 2 diabetic heart is associated with alterations in spatially distinct mitochondrial proteomes. Am J Physiol Heart Circ Physiol, 299, H529–H540. doi:10.1152/ajpheart.00267.2010.

    Article  PubMed  CAS  Google Scholar 

  29. Gelinas, R., Thompson-Legault, J., Bouchard, B., Daneault, C., Mansour, A., Gillis, M. A., et al. (2011). 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, 301, H813–H823. doi:10.1152/ajpheart.01275.2010.

    Article  PubMed  CAS  Google Scholar 

  30. Sabbah, H. N., Stanley, W. C., Sharov, V. G., Mishima, T., Tanimura, M., Benedict, C. R., et al. (2000). Effects of dopamine beta-hydroxylase inhibition with nepicastat on the progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure. Circulation, 102, 1990–1995.

    Article  PubMed  CAS  Google Scholar 

  31. Xin, W., Wei, W., & Li, X. (2012). Effects of fish oil supplementation on cardiac function in chronic heart failure: A meta-analysis of randomised controlled trials. Heart, 98, 1620–1625. doi:10.1136/heartjnl-2012-302119.

    Article  PubMed  Google Scholar 

  32. Melenovsky, V., Borlaug, B. A., Rosen, B., Hay, I., Ferruci, L., Morell, C. H., et al. (2007). Cardiovascular features of heart failure with preserved ejection fraction versus nonfailing hypertensive left ventricular hypertrophy in the urban Baltimore community: The role of atrial remodeling/dysfunction. J Am Coll Cardiol, 49, 198–207.

    Article  PubMed  Google Scholar 

  33. Owan, T. E., Hodge, D. O., Herges, R. M., Jacobsen, S. J., Roger, V. L., & Redfield, M. M. (2006). Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med, 355, 251–259.

    Article  PubMed  CAS  Google Scholar 

  34. Bhatia, R. S., Tu, J. V., Lee, D. S., Austin, P. C., Fang, J., Haouzi, A., et al. (2006). Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med, 355, 260–269.

    Article  PubMed  CAS  Google Scholar 

  35. Mori, T. A., Bao, D. Q., Burke, V., Puddey, I. B., & Beilin, L. J. (1999). Docosahexaenoic acid but not eicosapentaenoic acid lowers ambulatory blood pressure and heart rate in humans. Hypertension, 34, 253–260.

    Article  PubMed  CAS  Google Scholar 

  36. Elrod, J. W., Wong, R., Mishra, S., Vagnozzi, R. J., Sakthievel, B., Goonasekera, S. A., et al. (2010). Cyclophilin D controls mitochondrial pore-dependent Ca(2+) exchange, metabolic flexibility, and propensity for heart failure in mice. J Clin Invest, 120, 3680–3687. doi:10.1172/JCI43171.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the National Institutes of Health grant numbers HL074237 and HL110731. The authors wish to thank Ramesh Dandu and Seon Hepburn for assistance with the capsule manufacturing and analysis.

Disclosures

William Stanley is the inventor on a pending US patent application filed by the University of Maryland for the use of DHA for the treatment of heart failure.

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Authors and Affiliations

  1. Discipline of Physiology, University of Sydney, Anderson Stuart Building (F13), Sydney, NSW, 2006, Australia

    William C. Stanley

  2. Division of Cardiology, Department of Medicine, University of Maryland, Baltimore, MD, USA

    James W. Cox, Girma Asemu, Kelly A. O’Connell, Erinne R. Dabkowski, Wenhong Xu, Rogerio F. Ribeiro Jr & Kadambari C. Shekar

  3. Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, USA

    Stephen W. Hoag

  4. Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Health System, Detroit, MI, USA

    Sharad Rastogi & Hani N. Sabbah

  5. Department of Nutrition and Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada

    Caroline Daneault & Christine des Rosiers

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  1. William C. Stanley
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  2. James W. Cox
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  3. Girma Asemu
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Correspondence to William C. Stanley.

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Associate Editor Jennifer L. Hall oversaw the review of this article

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Stanley, W.C., Cox, J.W., Asemu, G. et al. Evaluation of Docosahexaenoic Acid in a Dog Model of Hypertension Induced Left Ventricular Hypertrophy. J. of Cardiovasc. Trans. Res. 6, 1000–1010 (2013). https://doi.org/10.1007/s12265-013-9511-y

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  • DOI: https://doi.org/10.1007/s12265-013-9511-y

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