Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Role of oxidative stress in heart failure

Michael M Givertz, MD
Section Editor
Wilson S Colucci, MD
Deputy Editor
Susan B Yeon, MD, JD, FACC


Oxidant byproducts, such as superoxide anion (O2-) and hydrogen peroxide, are produced in the body as a consequence of normal aerobic metabolism. These molecules are highly reactive with other biologic molecules, and are referred to as reactive oxygen species (ROS) [1]. Under normal physiologic conditions, the production of oxygen free radicals and peroxides is balanced by an efficient system of antioxidants, which are molecules capable of "scavenging" ROS, thereby preventing oxidative damage [2]. Naturally occurring antioxidants are of several types.

At the cellular level, enzymatic antioxidants, such as superoxide dismutase and catalase, play an important role in the conversion of ROS to oxygen and water.

Several nonenzymatic antioxidants are also important in scavenging free radicals. Included in this group are the lipid-soluble antioxidants alpha tocopherol (vitamin E) and beta-carotene, and the water-soluble antioxidants ascorbic acid (vitamin C) and glutathione. (See "Nutritional antioxidants in coronary heart disease".)

In pathologic states, free radicals may be present in relative excess. This shift of the balance in favor of oxidation, termed "oxidative stress," may have detrimental effects on cellular and tissue function, contributing to the pathogenesis of a wide variety of disease states, including HF, atherosclerosis, and cancer, and to the normal process of aging [3,4]. This topic will discuss the role of oxidative stress in HF [5,6].


A number of experimental observations have raised the possibility that oxidative stress may play a role in the development of myocardial failure.

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Jul 30, 2015.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Griendling KK, FitzGerald GA. Oxidative stress and cardiovascular injury: Part I: basic mechanisms and in vivo monitoring of ROS. Circulation 2003; 108:1912.
  2. Frei B. Reactive oxygen species and antioxidant vitamins: mechanisms of action. Am J Med 1994; 97:5S.
  3. Sies H. Oxidative stress: introductory remarks. In: Oxidative Stress, Sies H (Ed), Academic Press, Orlando 1985. p.1.
  4. Diaz MN, Frei B, Vita JA, Keaney JF Jr. Antioxidants and atherosclerotic heart disease. N Engl J Med 1997; 337:408.
  5. Sawyer DB, Siwik DA, Xiao L, et al. Role of oxidative stress in myocardial hypertrophy and failure. J Mol Cell Cardiol 2002; 34:379.
  6. Korantzopoulos P, Galaris D, Papaioannides D, Siogas K. The possible role of oxidative stress in heart failure and the potential of antioxidant intervention. Med Sci Monit 2003; 9:RA120.
  7. Cheng W, Li B, Kajstura J, et al. Stretch-induced programmed myocyte cell death. J Clin Invest 1995; 96:2247.
  8. Lopez BL, Liu GL, Christopher TA, Ma XL. Peroxynitrite, the product of nitric oxide and superoxide, causes myocardial injury in the isolated perfused rat heart. Coron Artery Dis 1997; 8:149.
  9. Pinsky DJ, Cai B, Yang X, et al. The lethal effects of cytokine-induced nitric oxide on cardiac myocytes are blocked by nitric oxide synthase antagonism or transforming growth factor beta. J Clin Invest 1995; 95:677.
  10. Möbert J, Becker BF. Cyclooxygenase inhibition aggravates ischemia-reperfusion injury in the perfused guinea pig heart: involvement of isoprostanes. J Am Coll Cardiol 1998; 31:1687.
  11. Gao WD, Liu Y, Marban E. Selective effects of oxygen free radicals on excitation-contraction coupling in ventricular muscle. Implications for the mechanism of stunned myocardium. Circulation 1996; 94:2597.
  12. Vaage J, Antonelli M, Bufi M, et al. Exogenous reactive oxygen species deplete the isolated rat heart of antioxidants. Free Radic Biol Med 1997; 22:85.
  13. Zweier JL, Rayburn BK, Flaherty JT, Weisfeldt ML. Recombinant superoxide dismutase reduces oxygen free radical concentrations in reperfused myocardium. J Clin Invest 1987; 80:1728.
  14. Rajagopalan S, Politi PM, Sinha BK, Myers CE. Adriamycin-induced free radical formation in the perfused rat heart: implications for cardiotoxicity. Cancer Res 1988; 48:4766.
  15. Dhalla AK, Hill MF, Singal PK. Role of oxidative stress in transition of hypertrophy to heart failure. J Am Coll Cardiol 1996; 28:506.
  16. Dhalla AK, Singal PK. Antioxidant changes in hypertrophied and failing guinea pig hearts. Am J Physiol 1994; 266:H1280.
  17. Hill MF, Singal PK. Right and left myocardial antioxidant responses during heart failure subsequent to myocardial infarction. Circulation 1997; 96:2414.
  18. Lebovitz RM, Zhang H, Vogel H, et al. Neurodegeneration, myocardial injury, and perinatal death in mitochondrial superoxide dismutase-deficient mice. Proc Natl Acad Sci U S A 1996; 93:9782.
  19. Khaper N, Singal PK. Effects of afterload-reducing drugs on pathogenesis of antioxidant changes and congestive heart failure in rats. J Am Coll Cardiol 1997; 29:856.
  20. Dieterich S, Bieligk U, Beulich K, et al. Gene expression of antioxidative enzymes in the human heart: increased expression of catalase in the end-stage failing heart. Circulation 2000; 101:33.
  21. Shiomi T, Tsutsui H, Matsusaka H, et al. Overexpression of glutathione peroxidase prevents left ventricular remodeling and failure after myocardial infarction in mice. Circulation 2004; 109:544.
  22. Wang G, Hamid T, Keith RJ, et al. Cardioprotective and antiapoptotic effects of heme oxygenase-1 in the failing heart. Circulation 2010; 121:1912.
  23. Suematsu N, Tsutsui H, Wen J, et al. Oxidative stress mediates tumor necrosis factor-alpha-induced mitochondrial DNA damage and dysfunction in cardiac myocytes. Circulation 2003; 107:1418.
  24. Cox MJ, Hawkins UA, Hoit BD, Tyagi SC. Attenuation of oxidative stress and remodeling by cardiac inhibitor of metalloproteinase protein transfer. Circulation 2004; 109:2123.
  25. Shishido T, Nozaki N, Yamaguchi S, et al. Toll-like receptor-2 modulates ventricular remodeling after myocardial infarction. Circulation 2003; 108:2905.
  26. Qin F, Shite J, Liang CS. Antioxidants attenuate myocyte apoptosis and improve cardiac function in CHF: association with changes in MAPK pathways. Am J Physiol Heart Circ Physiol 2003; 285:H822.
  27. McMurray J, McLay J, Chopra M, et al. Evidence for enhanced free radical activity in chronic congestive heart failure secondary to coronary artery disease. Am J Cardiol 1990; 65:1261.
  28. McMurray J, Chopra M, Abdullah I, et al. Evidence of oxidative stress in chronic heart failure in humans. Eur Heart J 1993; 14:1493.
  29. Belch JJ, Bridges AB, Scott N, Chopra M. Oxygen free radicals and congestive heart failure. Br Heart J 1991; 65:245.
  30. Díaz-Vélez CR, García-Castiñeiras S, Mendoza-Ramos E, Hernández-López E. Increased malondialdehyde in peripheral blood of patients with congestive heart failure. Am Heart J 1996; 131:146.
  31. Keith M, Geranmayegan A, Sole MJ, et al. Increased oxidative stress in patients with congestive heart failure. J Am Coll Cardiol 1998; 31:1352.
  32. Nishiyama Y, Ikeda H, Haramaki N, et al. Oxidative stress is related to exercise intolerance in patients with heart failure. Am Heart J 1998; 135:115.
  33. Tsutsui T, Tsutamoto T, Wada A, et al. Plasma oxidized low-density lipoprotein as a prognostic predictor in patients with chronic congestive heart failure. J Am Coll Cardiol 2002; 39:957.
  34. Wijeysundera HC, Hansen MS, Stanton E, et al. Neurohormones and oxidative stress in nonischemic cardiomyopathy: relationship to survival and the effect of treatment with amlodipine. Am Heart J 2003; 146:291.
  35. Morrow JD, Frei B, Longmire AW, et al. Increase in circulating products of lipid peroxidation (F2-isoprostanes) in smokers. Smoking as a cause of oxidative damage. N Engl J Med 1995; 332:1198.
  36. Morrow JD, Hill KE, Burk RF, et al. A series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical-catalyzed mechanism. Proc Natl Acad Sci U S A 1990; 87:9383.
  37. Mallat Z, Philip I, Lebret M, et al. Elevated levels of 8-iso-prostaglandin F2alpha in pericardial fluid of patients with heart failure: a potential role for in vivo oxidant stress in ventricular dilatation and progression to heart failure. Circulation 1998; 97:1536.
  38. Polidori MC, Praticó D, Savino K, et al. Increased F2 isoprostane plasma levels in patients with congestive heart failure are correlated with antioxidant status and disease severity. J Card Fail 2004; 10:334.
  39. LeLeiko RM, Vaccari CS, Sola S, et al. Usefulness of elevations in serum choline and free F2)-isoprostane to predict 30-day cardiovascular outcomes in patients with acute coronary syndrome. Am J Cardiol 2009; 104:638.
  40. Hokamaki J, Kawano H, Yoshimura M, et al. Urinary biopyrrins levels are elevated in relation to severity of heart failure. J Am Coll Cardiol 2004; 43:1880.
  41. Landmesser U, Spiekermann S, Dikalov S, et al. Vascular oxidative stress and endothelial dysfunction in patients with chronic heart failure: role of xanthine-oxidase and extracellular superoxide dismutase. Circulation 2002; 106:3073.
  42. Colombo PC, Banchs JE, Celaj S, et al. Endothelial cell activation in patients with decompensated heart failure. Circulation 2005; 111:58.
  43. Valgimigli M, Merli E, Malagutti P, et al. Hydroxyl radical generation, levels of tumor necrosis factor-alpha, and progression to heart failure after acute myocardial infarction. J Am Coll Cardiol 2004; 43:2000.
  44. Anker SD, Doehner W, Rauchhaus M, et al. Uric acid and survival in chronic heart failure: validation and application in metabolic, functional, and hemodynamic staging. Circulation 2003; 107:1991.
  45. Krishnan E. Hyperuricemia and incident heart failure. Circ Heart Fail 2009; 2:556.
  46. Doehner W, Schoene N, Rauchhaus M, et al. Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure: results from 2 placebo-controlled studies. Circulation 2002; 105:2619.
  47. Ahmed MI, Gladden JD, Litovsky SH, et al. Increased oxidative stress and cardiomyocyte myofibrillar degeneration in patients with chronic isolated mitral regurgitation and ejection fraction >60%. J Am Coll Cardiol 2010; 55:671.
  48. Heymes C, Bendall JK, Ratajczak P, et al. Increased myocardial NADPH oxidase activity in human heart failure. J Am Coll Cardiol 2003; 41:2164.
  49. Sam F, Kerstetter DL, Pimental DR, et al. Increased reactive oxygen species production and functional alterations in antioxidant enzymes in human failing myocardium. J Card Fail 2005; 11:473.
  50. Nakamura K, Kusano KF, Matsubara H, et al. Relationship between oxidative stress and systolic dysfunction in patients with hypertrophic cardiomyopathy. J Card Fail 2005; 11:117.
  51. Lu Z, Xu X, Hu X, et al. Oxidative stress regulates left ventricular PDE5 expression in the failing heart. Circulation 2010; 121:1474.
  52. Halliwell B, Gatteridge JM. Free Radicals in Biology and Medicine, Oxford University Press, Oxford 1989.
  53. McCord JM. Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med 1985; 312:159.
  54. Hare JM, Johnson RJ. Uric acid predicts clinical outcomes in heart failure: insights regarding the role of xanthine oxidase and uric acid in disease pathophysiology. Circulation 2003; 107:1951.
  55. Gioda CR, de Oliveira Barreto T, Prímola-Gomes TN, et al. Cardiac oxidative stress is involved in heart failure induced by thiamine deprivation in rats. Am J Physiol Heart Circ Physiol 2010; 298:H2039.
  56. Predmore JM, Wang P, Davis F, et al. Ubiquitin proteasome dysfunction in human hypertrophic and dilated cardiomyopathies. Circulation 2010; 121:997.
  57. Venardos KM, Zatta AJ, Marshall T, et al. Reduced L-arginine transport contributes to the pathogenesis of myocardial ischemia-reperfusion injury. J Cell Biochem 2009; 108:156.
  58. Griendling KK, Alexander RW. Oxidative stress and cardiovascular disease. Circulation 1997; 96:3264.
  59. Taniyama Y, Griendling KK. Reactive oxygen species in the vasculature: molecular and cellular mechanisms. Hypertension 2003; 42:1075.
  60. Keaney JF Jr, Larson MG, Vasan RS, et al. Obesity and systemic oxidative stress: clinical correlates of oxidative stress in the Framingham Study. Arterioscler Thromb Vasc Biol 2003; 23:434.
  61. Li T, Singal PK. Adriamycin-induced early changes in myocardial antioxidant enzymes and their modulation by probucol. Circulation 2000; 102:2105.
  62. Bolli R, Jeroudi MO, Patel BS, et al. Marked reduction of free radical generation and contractile dysfunction by antioxidant therapy begun at the time of reperfusion. Evidence that myocardial "stunning" is a manifestation of reperfusion injury. Circ Res 1989; 65:607.
  63. Gross GJ, O'Rourke ST, Pelc LR, Warltier DC. Myocardial and endothelial dysfunction after multiple, brief coronary occlusions: role of oxygen radicals. Am J Physiol 1992; 263:H1703.
  64. Nakamura R, Egashira K, Machida Y, et al. Probucol attenuates left ventricular dysfunction and remodeling in tachycardia-induced heart failure: roles of oxidative stress and inflammation. Circulation 2002; 106:362.
  65. Sia YT, Parker TG, Liu P, et al. Improved post-myocardial infarction survival with probucol in rats: effects on left ventricular function, morphology, cardiac oxidative stress and cytokine expression. J Am Coll Cardiol 2002; 39:148.
  66. Redout EM, van der Toorn A, Zuidwijk MJ, et al. Antioxidant treatment attenuates pulmonary arterial hypertension-induced heart failure. Am J Physiol Heart Circ Physiol 2010; 298:H1038.
  67. Hamblin M, Smith HM, Hill MF. Dietary supplementation with vitamin E ameliorates cardiac failure in type I diabetic cardiomyopathy by suppressing myocardial generation of 8-iso-prostaglandin F2alpha and oxidized glutathione. J Card Fail 2007; 13:884.
  68. WRITING COMMITTEE MEMBERS, Yancy CW, Jessup M, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013; 128:e240.
  69. Ye Y, Li J, Yuan Z. Effect of antioxidant vitamin supplementation on cardiovascular outcomes: a meta-analysis of randomized controlled trials. PLoS One 2013; 8:e56803.
  70. Alameddine FM, Zafari AM. Genetic polymorphisms and oxidative stress in heart failure. Congest Heart Fail 2002; 8:157.
  71. Iida S, Chu Y, Francis J, et al. Gene transfer of extracellular superoxide dismutase improves endothelial function in rats with heart failure. Am J Physiol Heart Circ Physiol 2005; 289:H525.
  72. Rautiainen S, Levitan EB, Mittleman MA, Wolk A. Total antioxidant capacity of diet and risk of heart failure: a population-based prospective cohort of women. Am J Med 2013; 126:494.
  73. Frei B, England L, Ames BN. Ascorbate is an outstanding antioxidant in human blood plasma. Proc Natl Acad Sci U S A 1989; 86:6377.
  74. Blanchard J, Tozer TN, Rowland M. Pharmacokinetic perspectives on megadoses of ascorbic acid. Am J Clin Nutr 1997; 66:1165.
  75. Keaney JF JR, Frei B. Antioxidant protection of low-density lipoprotein and its role in the prevention of atherosclerotic vascular disease. In: Natural antioxidants in human health and disease, Frei B (Ed), Academic Press, San Diego 1994. p.303.
  76. Erbs S, Gielen S, Linke A, et al. Improvement of peripheral endothelial dysfunction by acute vitamin C application: different effects in patients with coronary artery disease, ischemic, and dilated cardiomyopathy. Am Heart J 2003; 146:280.
  77. Tomiyama H, Watanabe G, Yoshida H, et al. Reduction of oxidative stress augments natriuretic effect of furosemide in moderate heart failure. Am Heart J 2003; 145:E2.
  78. Shinke T, Shite J, Takaoka H, et al. Vitamin C restores the contractile response to dobutamine and improves myocardial efficiency in patients with heart failure after anterior myocardial infarction. Am Heart J 2007; 154:645.e1.
  79. Mak S, Newton GE. Redox modulation of the inotropic response to dobutamine is impaired in patients with heart failure. Am J Physiol Heart Circ Physiol 2004; 286:H789.
  80. Hornig B, Arakawa N, Kohler C, Drexler H. Vitamin C improves endothelial function of conduit arteries in patients with chronic heart failure. Circulation 1998; 97:363.
  81. Ashor AW, Lara J, Mathers JC, Siervo M. Effect of vitamin C on endothelial function in health and disease: a systematic review and meta-analysis of randomised controlled trials. Atherosclerosis 2014; 235:9.
  82. Ellis GR, Anderson RA, Lang D, et al. Neutrophil superoxide anion--generating capacity, endothelial function and oxidative stress in chronic heart failure: effects of short- and long-term vitamin C therapy. J Am Coll Cardiol 2000; 36:1474.
  83. Wannamethee SG, Bruckdorfer KR, Shaper AG, et al. Plasma vitamin C, but not vitamin E, is associated with reduced risk of heart failure in older men. Circ Heart Fail 2013; 6:647.
  84. Nightingale AK, Crilley JG, Pegge NC, et al. Chronic oral ascorbic acid therapy worsens skeletal muscle metabolism in patients with chronic heart failure. Eur J Heart Fail 2007; 9:287.
  85. Gomes ME, El Messaoudi S, Lenders JW, et al. High dose ascorbic acid does not reverse central sympathetic overactivity in chronic heart failure. J Clin Pharm Ther 2011; 36:546.
  86. Steiner M. Influence of vitamin E on platelet function in humans. J Am Coll Nutr 1991; 10:466.
  87. Rifici VA, Khachadurian AK. Dietary supplementation with vitamins C and E inhibits in vitro oxidation of lipoproteins. J Am Coll Nutr 1993; 12:631.
  88. Keith ME, Jeejeebhoy KN, Langer A, et al. A controlled clinical trial of vitamin E supplementation in patients with congestive heart failure. Am J Clin Nutr 2001; 73:219.
  89. Lonn E, Bosch J, Yusuf S, et al. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA 2005; 293:1338.
  90. Tousoulis D, Antoniades C, Vassiliadou C, et al. Effects of combined administration of low dose atorvastatin and vitamin E on inflammatory markers and endothelial function in patients with heart failure. Eur J Heart Fail 2005; 7:1126.
  91. Keaney JF Jr, Xu A, Cunningham D, et al. Dietary probucol preserves endothelial function in cholesterol-fed rabbits by limiting vascular oxidative stress and superoxide generation. J Clin Invest 1995; 95:2520.
  92. Tardif JC, Grégoire J, Schwartz L, et al. Effects of AGI-1067 and probucol after percutaneous coronary interventions. Circulation 2003; 107:552.
  93. Mortensen SA, Rosenfeldt F, Kumar A, et al. The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: results from Q-SYMBIO: a randomized double-blind trial. JACC Heart Fail 2014; 2:641.
  94. Farquharson CA, Butler R, Hill A, et al. Allopurinol improves endothelial dysfunction in chronic heart failure. Circulation 2002; 106:221.
  95. George J, Carr E, Davies J, et al. High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid. Circulation 2006; 114:2508.
  96. Cappola TP, Kass DA, Nelson GS, et al. Allopurinol improves myocardial efficiency in patients with idiopathic dilated cardiomyopathy. Circulation 2001; 104:2407.
  97. Minhas KM, Saraiva RM, Schuleri KH, et al. Xanthine oxidoreductase inhibition causes reverse remodeling in rats with dilated cardiomyopathy. Circ Res 2006; 98:271.
  98. Hirsch GA, Bottomley PA, Gerstenblith G, Weiss RG. Allopurinol acutely increases adenosine triphospate energy delivery in failing human hearts. J Am Coll Cardiol 2012; 59:802.
  99. Hare JM, Mangal B, Brown J, et al. Impact of oxypurinol in patients with symptomatic heart failure. Results of the OPT-CHF study. J Am Coll Cardiol 2008; 51:2301.
  100. Givertz MM, Mann DL, Lee KL, et al. Xanthine oxidase inhibition for hyperuricemic heart failure patients: design and rationale of the EXACT-HF study. Circ Heart Fail 2013; 6:862.
  101. Givertz MM, Anstrom KJ, Redfield MM, et al. Effects of Xanthine Oxidase Inhibition in Hyperuricemic Heart Failure Patients: The Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure Patients (EXACT-HF) Study. Circulation 2015; 131:1763.
  102. Liu C, Cao F, Tang QZ, et al. Allicin protects against cardiac hypertrophy and fibrosis via attenuating reactive oxygen species-dependent signaling pathways. J Nutr Biochem 2010; 21:1238.
  103. Yue TL, Cheng HY, Lysko PG, et al. Carvedilol, a new vasodilator and beta adrenoceptor antagonist, is an antioxidant and free radical scavenger. J Pharmacol Exp Ther 1992; 263:92.
  104. Kukin ML, Kalman J, Charney RH, et al. Prospective, randomized comparison of effect of long-term treatment with metoprolol or carvedilol on symptoms, exercise, ejection fraction, and oxidative stress in heart failure. Circulation 1999; 99:2645.
  105. Nakamura K, Kusano K, Nakamura Y, et al. Carvedilol decreases elevated oxidative stress in human failing myocardium. Circulation 2002; 105:2867.
  106. Cohen-Solal A, Rouzet F, Berdeaux A, et al. Effects of carvedilol on myocardial sympathetic innervation in patients with chronic heart failure. J Nucl Med 2005; 46:1796.
  107. Sun Y, Zhang J, Lu L, et al. Aldosterone-induced inflammation in the rat heart : role of oxidative stress. Am J Pathol 2002; 161:1773.
  108. Keidar S, Hayek T, Kaplan M, et al. Effect of eplerenone, a selective aldosterone blocker, on blood pressure, serum and macrophage oxidative stress, and atherosclerosis in apolipoprotein E-deficient mice. J Cardiovasc Pharmacol 2003; 41:955.
  109. Linke A, Adams V, Schulze PC, et al. Antioxidative effects of exercise training in patients with chronic heart failure: increase in radical scavenger enzyme activity in skeletal muscle. Circulation 2005; 111:1763.
  110. Yamanaka S, Tatsumi T, Shiraishi J, et al. Amlodipine inhibits doxorubicin-induced apoptosis in neonatal rat cardiac myocytes. J Am Coll Cardiol 2003; 41:870.
  111. Daiber A, Oelze M, Coldewey M, et al. Hydralazine is a powerful inhibitor of peroxynitrite formation as a possible explanation for its beneficial effects on prognosis in patients with congestive heart failure. Biochem Biophys Res Commun 2005; 338:1865.
  112. Münzel T, Kurz S, Rajagopalan S, et al. Hydralazine prevents nitroglycerin tolerance by inhibiting activation of a membrane-bound NADH oxidase. A new action for an old drug. J Clin Invest 1996; 98:1465.
  113. Sasaki H, Asanuma H, Fujita M, et al. Metformin prevents progression of heart failure in dogs: role of AMP-activated protein kinase. Circulation 2009; 119:2568.