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Myocardial energetics in heart failure

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Abstract

It has become common sense that the failing heart is an “engine out of fuel”. However, undisputable evidence that, indeed, the failing heart is limited by insufficient ATP supply is currently lacking. Over the last couple of years, an increasingly complex picture of mechanisms evolved that suggests that potentially metabolic intermediates and redox state could play the more dominant roles for signaling that eventually results in left ventricular remodeling and contractile dysfunction. In the pathophysiology of heart failure, mitochondria emerge in the crossfire of defective excitation–contraction coupling and increased energetic demand, which may provoke oxidative stress as an important upstream mediator of cardiac remodeling and cell death. Thus, future therapies may be guided towards restoring defective ion homeostasis and mitochondrial redox shifts rather than aiming solely at improving the generation of ATP.

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References

  1. Abel ED, Doenst T (2011) Mitochondrial adaptations to physiological vs. pathological cardiac hypertrophy. Cardiovasc Res 90:234–242. doi:10.1093/cvr/cvr015

    Article  CAS  PubMed  Google Scholar 

  2. Abozguia K, Elliott P, McKenna W, Phan TT, Nallur-Shivu G, Ahmed I, Maher AR, Kaur K, Taylor J, Henning A, Ashrafian H, Watkins H, Frenneaux M (2010) Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity in symptomatic hypertrophic cardiomyopathy. Circulation 122:1562–1569. doi:10.1161/CIRCULATIONAHA.109.934059

    Article  CAS  PubMed  Google Scholar 

  3. Abozguia K, Shivu GN, Ahmed I, Phan TT, Frenneaux MP (2009) The heart metabolism: pathophysiological aspects in ischaemia and heart failure. Curr Pharm Des 15:827–835. doi:10.2174/138161209787582101

    Article  CAS  PubMed  Google Scholar 

  4. Adlam VJ, Harrison JC, Porteous CM, James AM, Smith RA, Murphy MP, Sammut IA (2005) Targeting an antioxidant to mitochondria decreases cardiac ischemia-reperfusion injury. FASEB J 19:1088–1095. doi:10.1096/fj.05-3718com

    Article  CAS  PubMed  Google Scholar 

  5. Ago T, Liu T, Zhai P, Chen W, Li H, Molkentin JD, Vatner SF, Sadoshima J (2008) A redox-dependent pathway for regulating class II HDACs and cardiac hypertrophy. Cell 133:978–993. doi:10.1016/j.cell.2008.04.041

    Article  CAS  PubMed  Google Scholar 

  6. Akar FG, Aon MA, Tomaselli GF, O’Rourke B (2005) The mitochondrial origin of postischemic arrhythmias. J Clin Invest 115:3527–3535. doi:10.1172/JCI25371

    Article  CAS  PubMed  Google Scholar 

  7. Anker SD, Comin Colet J, Filippatos G, Willenheimer R, Dickstein K, Drexler H, Luscher TF, Bart B, Banasiak W, Niegowska J, Kirwan BA, Mori C, von Eisenhart Rothe B, Pocock SJ, Poole-Wilson PA, Ponikowski P, Investigators F-HT (2009) Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med 361:2436–2448. doi:10.1056/NEJMoa0908355

    Article  CAS  PubMed  Google Scholar 

  8. Aon MA, Cortassa S, Marban E, O’Rourke B (2003) Synchronized whole cell oscillations in mitochondrial metabolism triggered by a local release of reactive oxygen species in cardiac myocytes. J Biol Chem 278:44735–44744. doi:10.1074/jbc.M302673200

    Article  CAS  PubMed  Google Scholar 

  9. Aon MA, Cortassa S, O’Rourke B (2010) Redox-optimized ROS balance: a unifying hypothesis. Biochim Biophys Acta 1797:865–877. doi:10.1016/j.bbabio.2010.02.016

    Article  CAS  PubMed  Google Scholar 

  10. Armoundas AA, Hobai IA, Tomaselli GF, Winslow RL, O’Rourke B (2003) Role of sodium-calcium exchanger in modulating the action potential of ventricular myocytes from normal and failing hearts. Circ Res 93:46–53. doi:10.1161/01.RES.0000080932.98903.D8

    Article  CAS  PubMed  Google Scholar 

  11. Ashrafian H, McKenna WJ, Watkins H (2011) Disease pathways and novel therapeutic targets in hypertrophic cardiomyopathy. Circ Res 109:86–96. doi:10.1161/CIRCRESAHA.111.242974

    Article  CAS  PubMed  Google Scholar 

  12. Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H, Hambleton MA, Brunskill EW, Sayen MR, Gottlieb RA, Dorn GW, Robbins J, Molkentin JD (2005) Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434:658–662. doi:10.1038/nature03434

    Article  CAS  PubMed  Google Scholar 

  13. Balaban RS (2002) Cardiac energy metabolism homeostasis: role of cytosolic calcium. J Mol Cell Cardiol 34:1259–1271. doi:10.1006/jmcc.2002.2082

    Article  CAS  PubMed  Google Scholar 

  14. Balaban RS (2009) Domestication of the cardiac mitochondrion for energy conversion. J Mol Cell Cardiol 46:832–841. doi:10.1016/j.yjmcc.2009.02.018

    Article  CAS  PubMed  Google Scholar 

  15. Balaban RS, Nemoto S, Finkel T (2005) Mitochondria, oxidants, and aging. Cell 120:483–495. doi:10.1016/j.cell.2005.02.001

    Article  CAS  PubMed  Google Scholar 

  16. Bansal M, Chan J, Leano R, Pillans P, Horowitz J, Marwick TH (2010) Effects of perhexiline on myocardial deformation in patients with ischaemic left ventricular dysfunction. Int J Cardiol 139:107–112. doi:10.1016/j.ijcard.2009.08.007

    Article  PubMed  Google Scholar 

  17. Baudenbacher F, Schober T, Pinto JR, Sidorov VY, Hilliard F, Solaro RJ, Potter JD, Knollmann BC (2008) Myofilament Ca2+ sensitization causes susceptibility to cardiac arrhythmia in mice. J Clin Invest 118:3893–3903. doi:10.1172/JCI36642

    CAS  PubMed  Google Scholar 

  18. Baughman JM, Perocchi F, Girgis HS, Plovanich M, Belcher-Timme CA, Sancak Y, Bao XR, Strittmatter L, Goldberger O, Bogorad RL, Koteliansky V, Mootha VK (2011) Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476:341–345. doi:10.1038/nature10234

    Article  CAS  PubMed  Google Scholar 

  19. Belch JJ, Bridges AB, Scott N, Chopra M (1991) Oxygen free radicals and congestive heart failure. Br Heart J 65:245–248. doi:10.1136/hrt.65.5.245

    Article  CAS  PubMed  Google Scholar 

  20. Bendall JK, Cave AC, Heymes C, Gall N, Shah AM (2002) Pivotal role of a gp91(phox)-containing NADPH oxidase in angiotensin II-induced cardiac hypertrophy in mice. Circulation 105:293–296. doi:10.1161/hc0302.103712

    Article  CAS  PubMed  Google Scholar 

  21. Bers DM (2006) Altered cardiac myocyte Ca regulation in heart failure. Physiology (Bethesda) 21:380–387. doi:10.1152/physiol.00019.2006

    Article  CAS  Google Scholar 

  22. Blain JM, Schafer H, Siegel AL, Bing RJ (1956) Studies on myocardial metabolism. VI. Myocardial metabolism in congestive failure. Am J Med 20:820–833

    Article  CAS  PubMed  Google Scholar 

  23. Boengler K, Stahlhofen S, van de Sand A, Gres P, Ruiz-Meana M, Garcia-Dorado D, Heusch G, Schulz R (2009) Presence of connexin 43 in subsarcolemmal, but not in interfibrillar cardiomyocyte mitochondria. Basic Res Cardiol 104:141–147. doi:10.1007/s00395-009-0007-5

    Article  CAS  PubMed  Google Scholar 

  24. Bohles H (2004) Disturbances of the carnitine system as a cause of cardiomyopathy. In: Böhles HS, Sewell AC (eds) Metabolic Cardiomyopathy. Medpharm Scientific Publishers, Stuttgart, pp 17–24

  25. Böhm M, Maack C (2000) Treatment of heart failure with beta-blockers. Mechanisms and results. Basic Res Cardiol 95(Suppl 1):I15–I24

    PubMed  Google Scholar 

  26. Bolli R, Marban E (1999) Molecular and cellular mechanisms of myocardial stunning. Physiol Rev 79:609–634

    CAS  PubMed  Google Scholar 

  27. Bricker DK, Taylor EB, Schell JC, Orsak T, Boutron A, Chen YC, Cox JE, Cardon CM, Van Vranken JG, Dephoure N, Redin C, Boudina S, Gygi SP, Brivet M, Thummel CS, Rutter J (2012) A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans. Science 337:96–100. doi:10.1126/science.1218099

    Article  CAS  PubMed  Google Scholar 

  28. Bristow MR, Ginsburg R, Minobe W, Cubicciotti RS, Sageman WS, Lurie K, Billingham ME, Harrison DC, Stinson EB (1982) Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts. N Engl J Med 307:205–211. doi:10.1056/NEJM198207223070401

    Article  CAS  PubMed  Google Scholar 

  29. Brookes PS, Yoon Y, Robotham JL, Anders MW, Sheu SS (2004) Calcium, ATP, and ROS: a mitochondrial love-hate triangle. Am J Physiol Cell Physiol 287:C817–C833. doi:10.1152/ajpcell.00139.2004

    Article  CAS  PubMed  Google Scholar 

  30. Brown D, Hamlin RL, Yueyama Y, Kijtawornrat A, Yeh ST, Frasier CR, Stewart LM, Patel HD, Collins MC, Muller-Bohrer BJ, Shaikh SR, Harris M, Fisher-Wellman KH, Neufer PD, Kloner RA (2012) Bendavia, a mitochondria-targeting peptide, reduces reperfusion injury and reactive oxygen species levels through a mechanism independent of direct oxygen radical scavenging: a multicenter study. Circulation 126:A10740

    Google Scholar 

  31. Bugger H, Schwarzer M, Chen D, Schrepper A, Amorim PA, Schoepe M, Nguyen TD, Mohr FW, Khalimonchuk O, Weimer BC, Doenst T (2010) Proteomic remodelling of mitochondrial oxidative pathways in pressure overload-induced heart failure. Cardiovasc Res 85:376–384. doi:10.1093/cvr/cvp344

    Article  CAS  PubMed  Google Scholar 

  32. Canton M, Skyschally A, Menabo R, Boengler K, Gres P, Schulz R, Haude M, Erbel R, Di Lisa F, Heusch G (2006) Oxidative modification of tropomyosin and myocardial dysfunction following coronary microembolization. Eur Heart J 27:875–881. doi:10.1093/eurheartj/ehi751

    Article  CAS  PubMed  Google Scholar 

  33. Cappola TP, Kass DA, Nelson GS, Berger RD, Rosas GO, Kobeissi ZA, Marban E, Hare JM (2001) Allopurinol improves myocardial efficiency in patients with idiopathic dilated cardiomyopathy. Circulation 104:2407–2411. doi:10.1161/hc4501.098928

    Article  CAS  PubMed  Google Scholar 

  34. Chatham JC, Young ME (2012) Metabolic remodeling in the hypertrophic heart: fuel for thought. Circ Res 111:666–668. doi:10.1161/CIRCRESAHA.112.277392

    Article  CAS  PubMed  Google Scholar 

  35. Chen Y, Csordas G, Jowdy C, Schneider TG, Csordas N, Wang W, Liu Y, Kohlhaas M, Meiser M, Bergem S, Nerbonne JM, Dorn GW 2nd, Maack C (2012) Mitofusin 2-containing mitochondrial-reticular microdomains direct rapid cardiomyocyte bioenergetic responses via interorganelle Ca2+ crosstalk. Circ Res 111:863–875. doi:10.1161/CIRCRESAHA.112.266585

    Article  CAS  PubMed  Google Scholar 

  36. Chikando AC, Kettlewell S, Williams GS, Smith G, Lederer WJ (2011) Ca2+ dynamics in the mitochondria-state of the art. J Mol Cell Cardiol 51:627–631. doi:10.1016/j.yjmcc.2011.08.003

    Article  CAS  PubMed  Google Scholar 

  37. Clark RJ, McDonough PM, Swanson E, Trost SU, Suzuki M, Fukuda M, Dillmann WH (2003) Diabetes and the accompanying hyperglycemia impairs cardiomyocyte calcium cycling through increased nuclear O-GlcNAcylation. J Biol Chem 278:44230–44237. doi:10.1074/jbc.M303810200

    Article  CAS  PubMed  Google Scholar 

  38. Coppini R, Ferrantini C, Yao L, Fan P, Del Lungo M, Stillitano F, Sartiani L, Tosi B, Suffredini S, Tesi C, Yacoub M, Olivotto I, Belardinelli L, Poggesi C, Cerbai E, Mugelli A (2013) Late sodium current inhibition reverses electromechanical dysfunction in human hypertrophic cardiomyopathy. Circulation 127:575–584. doi:10.1161/CIRCULATIONAHA.112.134932

    Article  CAS  PubMed  Google Scholar 

  39. Cortassa S, O’Rourke B, Winslow RL, Aon MA (2009) Control and regulation of integrated mitochondrial function in metabolic and transport networks. Int J Mol Sci 10:1500–1513. doi:10.3390/ijms10041500

    Article  CAS  PubMed  Google Scholar 

  40. Csordas G, Renken C, Varnai P, Walter L, Weaver D, Buttle KF, Balla T, Mannella CA, Hajnoczky G (2006) Structural and functional features and significance of the physical linkage between ER and mitochondria. J Cell Biol 174:915–921. doi:10.1083/jcb.200604016

    Article  CAS  PubMed  Google Scholar 

  41. Dai DF, Chen T, Szeto H, Nieves-Cintron M, Kutyavin V, Santana LF, Rabinovitch PS (2011) Mitochondrial targeted antioxidant peptide ameliorates hypertensive cardiomyopathy. J Am Coll Cardiol 58:73–82. doi:10.1016/j.jacc.2010.12.044

    Article  CAS  PubMed  Google Scholar 

  42. Dai DF, Johnson SC, Villarin JJ, Chin MT, Nieves-Cintron M, Chen T, Marcinek DJ, Dorn GW 2nd, Kang YJ, Prolla TA, Santana LF, Rabinovitch PS (2011) Mitochondrial oxidative stress mediates angiotensin II-induced cardiac hypertrophy and Galphaq overexpression-induced heart failure. Circ Res 108:837–846. doi:10.1161/CIRCRESAHA.110.232306

    Article  CAS  PubMed  Google Scholar 

  43. De Stefani D, Raffaello A, Teardo E, Szabo I, Rizzuto R (2011) A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 476:336–340. doi:10.1038/nature10230

    Article  PubMed  CAS  Google Scholar 

  44. Dedkova EN, Blatter LA (2013) Calcium signaling in cardiac mitochondria. J Mol Cell Cardiol. doi:10.1016/j.yjmcc.2012.12.021

    Google Scholar 

  45. Des Rosiers C, Labarthe F, Lloyd SG, Chatham JC (2011) Cardiac anaplerosis in health and disease: food for thought. Cardiovasc Res 90:210–219. doi:10.1093/cvr/cvr055

    Article  CAS  PubMed  Google Scholar 

  46. Dixon LJ, Morgan DR, Hughes SM, McGrath LT, El-Sherbeeny NA, Plumb RD, Devine A, Leahey W, Johnston GD, McVeigh GE (2003) Functional consequences of endothelial nitric oxide synthase uncoupling in congestive cardiac failure. Circulation 107:1725–1728. doi:10.1161/01.CIR.0000066283.13253.78

    Article  CAS  PubMed  Google Scholar 

  47. Dorn GW 2nd, Maack C (2013) SR and mitochondria: calcium cross-talk between kissing cousins. J Mol Cell Cardiol 55:42–49. doi:10.1016/j.yjmcc.2012.07.015

    Article  CAS  PubMed  Google Scholar 

  48. 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 metabolomic markers of heart failure, including pseudouridine and 2-oxoglutarate. Metabolomics 3:413–426. doi:10.1007/s11306-007-0063-5

    Article  CAS  Google Scholar 

  49. Ekelund UE, Harrison RW, Shokek O, Thakkar RN, Tunin RS, Senzaki H, Kass DA, Marban E, Hare JM (1999) Intravenous allopurinol decreases myocardial oxygen consumption and increases mechanical efficiency in dogs with pacing-induced heart failure. Circ Res 85:437–445. doi:10.1161/01.RES.85.5.437

    Article  CAS  PubMed  Google Scholar 

  50. Erickson JR, Joiner ML, Guan X, Kutschke W, Yang J, Oddis CV, Bartlett RK, Lowe JS, O’Donnell SE, Aykin-Burns N, Zimmerman MC, Zimmerman K, Ham AJ, Weiss RM, Spitz DR, Shea MA, Colbran RJ, Mohler PJ, Anderson ME (2008) A dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation. Cell 133:462–474. doi:10.1016/j.cell.2008.02.048

    Article  CAS  PubMed  Google Scholar 

  51. Fiordaliso F, Leri A, Cesselli D, Limana F, Safai B, Nadal-Ginard B, Anversa P, Kajstura J (2001) Hyperglycemia activates p53 and p53-regulated genes leading to myocyte cell death. Diabetes 50:2363–2375. doi:10.2337/diabetes.50.10.2363

    Article  CAS  PubMed  Google Scholar 

  52. Flesch M, Maack C, Cremers B, Bäumer AT, Südkamp M, Böhm M (1999) Effect of beta-blockers on free radical-induced cardiac contractile dysfunction. Circulation 100:346–353. doi:10.1161/01.CIR.100.4.346

    Article  CAS  PubMed  Google Scholar 

  53. Fragasso G, Perseghin G, De Cobelli F, Esposito A, Palloshi A, Lattuada G, Scifo P, Calori G, Del Maschio A, Margonato A (2006) Effects of metabolic modulation by trimetazidine on left ventricular function and phosphocreatine/adenosine triphosphate ratio in patients with heart failure. Eur Heart J 27:942–948. doi:10.1093/eurheartj/ehi816

    Article  CAS  PubMed  Google Scholar 

  54. Fraysse B, Weinberger F, Bardswell SC, Cuello F, Vignier N, Geertz B, Starbatty J, Kramer E, Coirault C, Eschenhagen T, Kentish JC, Avkiran M, Carrier L (2012) Increased myofilament Ca2+ sensitivity and diastolic dysfunction as early consequences of Mybpc3 mutation in heterozygous knock-in mice. J Mol Cell Cardiol 52:1299–1307. doi:10.1016/j.yjmcc.2012.03.009

    Article  CAS  PubMed  Google Scholar 

  55. Funada J, Betts TR, Hodson L, Humphreys SM, Timperley J, Frayn KN, Karpe F (2009) Substrate utilization by the failing human heart by direct quantification using arterio-venous blood sampling. PLoS ONE 4:e7533. doi:10.1371/journal.pone.0007533

    Article  PubMed  CAS  Google Scholar 

  56. Gadicherla AK, Stowe DF, Antholine WE, Yang M, Camara AK (2012) Damage to mitochondrial complex I during cardiac ischemia reperfusion injury is reduced indirectly by anti-anginal drug ranolazine. Biochim Biophys Acta 1817:419–429. doi:10.1016/j.bbabio.2011.11.021

    Article  CAS  PubMed  Google Scholar 

  57. Gao WD, Liu Y, Marban E (1996) Selective effects of oxygen free radicals on excitation-contraction coupling in ventricular muscle. Implications for the mechanism of stunned myocardium. Circulation 94:2597–2604. doi:10.1161/01.CIR.94.10.2597

    Article  CAS  PubMed  Google Scholar 

  58. Gardner PR, Raineri I, Epstein LB, White CW (1995) Superoxide radical and iron modulate aconitase activity in mammalian cells. J Biol Chem 270:13399–13405. doi:10.1074/jbc.270.22.13399

    Article  CAS  PubMed  Google Scholar 

  59. Gilbert EM, Abraham WT, Olsen S, Hattler B, White M, Mealy P, Larrabee P, Bristow MR (1996) Comparative hemodynamic, left ventricular functional, and antiadrenergic effects of chronic treatment with metoprolol versus carvedilol in the failing heart. Circulation 94:2817–2825. doi:10.1161/01.CIR.94.11.2817

    Article  CAS  PubMed  Google Scholar 

  60. Giordano FJ (2005) Oxygen, oxidative stress, hypoxia, and heart failure. J Clin Invest 115:500–508. doi:10.1172/JCI24408

    CAS  PubMed  Google Scholar 

  61. Graham D, Huynh NN, Hamilton CA, Beattie E, Smith RA, Cocheme HM, Murphy MP, Dominiczak AF (2009) Mitochondria-targeted antioxidant MitoQ10 improves endothelial function and attenuates cardiac hypertrophy. Hypertension 54:322–328. doi:10.1161/HYPERTENSIONAHA.109.130351

    Article  CAS  PubMed  Google Scholar 

  62. Hale SL, Leeka JA, Kloner RA (2006) Improved left ventricular function and reduced necrosis after myocardial ischemia/reperfusion in rabbits treated with ranolazine, an inhibitor of the late sodium channel. J Pharmacol Exp Ther 318:418–423. doi:10.1124/jpet.106.103242

    Article  CAS  PubMed  Google Scholar 

  63. Halestrap A (2005) Biochemistry: a pore way to die. Nature 434:578–579. doi:10.1038/434578a

    Article  CAS  PubMed  Google Scholar 

  64. Halestrap AP, Pasdois P (2009) The role of the mitochondrial permeability transition pore in heart disease. Biochim Biophys Acta 1787:1402–1415. doi:10.1016/j.bbabio.2008.12.017

    Article  CAS  PubMed  Google Scholar 

  65. Hash TW 2nd, Prisant LM (1997) Beta-blocker use in systolic heart failure and dilated cardiomyopathy. J Clin Pharmacol 37:7–19. doi:10.1177/009127009703700103

    Article  CAS  PubMed  Google Scholar 

  66. Hasin Y, Barry WH (1984) Myocardial metabolic inhibition and membrane potential, contraction, and potassium uptake. Am J Physiol 247:H322–H329. doi:10.1016/S0022-2828(84)80014-0

    CAS  PubMed  Google Scholar 

  67. Hermann HP, Arp J, Pieske B, Kogler H, Baron S, Janssen PM, Hasenfuss G (2004) Improved systolic and diastolic myocardial function with intracoronary pyruvate in patients with congestive heart failure. Eur J Heart Fail 6:213–218. doi:10.1016/j.ejheart.2003.10.001

    Article  CAS  PubMed  Google Scholar 

  68. Hermann HP, Pieske B, Schwarzmuller E, Keul J, Just H, Hasenfuss G (1999) Haemodynamic effects of intracoronary pyruvate in patients with congestive heart failure: an open study. Lancet 353:1321–1323. doi:10.1016/S0140-6736(98)06423-X

    Article  CAS  PubMed  Google Scholar 

  69. Herzig S, Raemy E, Montessuit S, Veuthey JL, Zamboni N, Westermann B, Kunji ER, Martinou JC (2012) Identification and functional expression of the mitochondrial pyruvate carrier. Science 337:93–96. doi:10.1126/science.1218530

    Article  CAS  PubMed  Google Scholar 

  70. Hesselink MK, Greenhaff PL, Constantin-Teodosiu D, Hultman E, Saris WH, Nieuwlaat R, Schaart G, Kornips E, Schrauwen P (2003) Increased uncoupling protein 3 content does not affect mitochondrial function in human skeletal muscle in vivo. J Clin Invest 111:479–486. doi:10.1172/JCI16653

    CAS  PubMed  Google Scholar 

  71. Hesselink MK, Schrauwen P (2005) Uncoupling proteins in the failing human heart: friend or foe? Lancet 365:385–386. doi:10.1016/S0140-6736(05)17823-4

    PubMed  Google Scholar 

  72. Heusch G, Boengler K, Schulz R (2008) Cardioprotection: nitric oxide, protein kinases, and mitochondria. Circulation 118:1915–1919. doi:10.1161/CIRCULATIONAHA.108.805242

    Article  PubMed  Google Scholar 

  73. Heusch G, Boengler K, Schulz R (2010) Inhibition of mitochondrial permeability transition pore opening: the Holy Grail of cardioprotection. Basic Res Cardiol 105:151–154. doi:10.1007/s00395-009-0080-9

    Article  PubMed  Google Scholar 

  74. Heusch G, Schulz R (2011) A radical view on the contractile machinery in human heart failure. J Am Coll Cardiol 57:310–312. doi:10.1016/j.jacc.2010.06.057

    Article  CAS  PubMed  Google Scholar 

  75. Heusch P, Canton M, Aker S, van de Sand A, Konietzka I, Rassaf T, Menazza S, Brodde OE, Di Lisa F, Heusch G, Schulz R (2010) The contribution of reactive oxygen species and p38 mitogen-activated protein kinase to myofilament oxidation and progression of heart failure in rabbits. Br J Pharmacol 160:1408–1416. doi:10.1111/j.1476-5381.2010.00793.x

    Article  CAS  PubMed  Google Scholar 

  76. Hohl M, Wagner M, Reil JC, Müller SA, Tauchnitz M, Zimmer AM, Lehmann LH, Thiel G, Böhm M, Backs J, Maack C (2013) HDAC4 controls histone methylation in response to elevated cardiac load. J Clin Invest 123:1359–1370. doi:10.1172/JCI61084

    Article  CAS  PubMed  Google Scholar 

  77. Horn M, Remkes H, Stromer H, Dienesch C, Neubauer S (2001) Chronic phosphocreatine depletion by the creatine analogue beta-guanidinopropionate is associated with increased mortality and loss of ATP in rats after myocardial infarction. Circulation 104:1844–1849. doi:10.1161/hc3901.095933

    Article  CAS  PubMed  Google Scholar 

  78. Houser SR, Margulies KB (2003) Is depressed myocyte contractility centrally involved in heart failure? Circ Res 92:350–358. doi:10.1161/01.RES.0000060027.40275.A6

    Article  CAS  PubMed  Google Scholar 

  79. Hu Y, Belke D, Suarez J, Swanson E, Clark R, Hoshijima M, Dillmann WH (2005) Adenovirus-mediated overexpression of O-GlcNAcase improves contractile function in the diabetic heart. Circ Res 96:1006–1013. doi:10.1161/01.RES.0000165478.06813.58

    Article  CAS  PubMed  Google Scholar 

  80. Ide T, Tsutsui H, Kinugawa S, Suematsu N, Hayashidani S, Ichikawa K, Utsumi H, Machida Y, Egashira K, Takeshita A (2000) Direct evidence for increased hydroxyl radicals originating from superoxide in the failing myocardium. Circ Res 86:152–157. doi:10.1161/01.RES.86.2.152

    Article  CAS  PubMed  Google Scholar 

  81. Ide T, Tsutsui H, Kinugawa S, Utsumi H, Kang D, Hattori N, Uchida K, Arimura K, Egashira K, Takeshita A (1999) Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium. Circ Res 85:357–363. doi:10.1161/01.RES.85.4.357

    Article  CAS  PubMed  Google Scholar 

  82. Ingwall JS (2009) Energy metabolism in heart failure and remodelling. Cardiovasc Res 81:412–419. doi:10.1093/cvr/cvn301

    Article  CAS  PubMed  Google Scholar 

  83. Ingwall JS, Weiss RG (2004) Is the failing heart energy starved? On using chemical energy to support cardiac function. Circ Res 95:135–145. doi:10.1161/01.RES.0000137170.41939.d9

    Article  CAS  PubMed  Google Scholar 

  84. Jacobshagen C, Belardinelli L, Hasenfuss G, Maier LS (2011) Ranolazine for the treatment of heart failure with preserved ejection fraction: background, aims, and design of the RALI-DHF study. Clin Cardiol 34:426–432. doi:10.1002/clc.20897

    Article  PubMed  Google Scholar 

  85. Jankowska EA, Rozentryt P, Witkowska A, Nowak J, Hartmann O, Ponikowska B, Borodulin-Nadzieja L, Banasiak W, Polonski L, Filippatos G, McMurray JJ, Anker SD, Ponikowski P (2010) Iron deficiency: an ominous sign in patients with systolic chronic heart failure. Eur Heart J 31:1872–1880. doi:10.1093/eurheartj/ehq158

    Article  CAS  PubMed  Google Scholar 

  86. Jaswal JS, Keung W, Wang W, Ussher JR, Lopaschuk GD (2011) Targeting fatty acid and carbohydrate oxidation—a novel therapeutic intervention in the ischemic and failing heart. Biochim Biophys Acta 1813:1333–1350. doi:10.1016/j.bbamcr.2011.01.015

    Article  CAS  PubMed  Google Scholar 

  87. Jouaville LS, Pinton P, Bastianutto C, Rutter GA, Rizzuto R (1999) Regulation of mitochondrial ATP synthesis by calcium: evidence for a long-term metabolic priming. Proc Natl Acad Sci USA 96:13807–13812. doi:10.1073/pnas.96.24.13807

    Article  CAS  PubMed  Google Scholar 

  88. Juhaszova M, Zorov DB, Kim SH, Pepe S, Fu Q, Fishbein KW, Ziman BD, Wang S, Ytrehus K, Antos CL, Olson EN, Sollott SJ (2004) Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore. J Clin Invest 113:1535–1549. doi:10.1172/JCI19906

    CAS  PubMed  Google Scholar 

  89. Kimura S, Zhang GX, Nishiyama A, Shokoji T, Yao L, Fan YY, Rahman M, Abe Y (2005) Mitochondria-derived reactive oxygen species and vascular MAP kinases: comparison of angiotensin II and diazoxide. Hypertension 45:438–444. doi:10.1161/01.HYP.0000157169.27818.ae

    Article  CAS  PubMed  Google Scholar 

  90. Kimura S, Zhang GX, Nishiyama A, Shokoji T, Yao L, Fan YY, Rahman M, Suzuki T, Maeta H, Abe Y (2005) Role of NAD(P)H oxidase- and mitochondria-derived reactive oxygen species in cardioprotection of ischemic reperfusion injury by angiotensin II. Hypertension 45:860–866. doi:10.1161/01.HYP.0000163462.98381.7f

    Article  CAS  PubMed  Google Scholar 

  91. Kirchhefer U, Schmitz W, Scholz H, Neumann J (1999) Activity of cAMP-dependent protein kinase and Ca2+/calmodulin-dependent protein kinase in failing and nonfailing human hearts. Cardiovasc Res 42:254–261. doi:10.1016/S0008-6363(98)00296-X

    Article  CAS  PubMed  Google Scholar 

  92. Kloner RA, Hale SL, Dai W, Gorman RC, Shuto T, Koomalsingh KJ, Gorman JH 3rd, Sloan RC, Frasier CR, Watson CA, Bostian PA, Kypson AP, Brown DA (2012) Reduction of ischemia/reperfusion injury with bendavia, a mitochondria-targeting cytoprotective Peptide. J Am Heart Assoc 1:e001644. doi:10.1161/JAHA.112.001644

    Article  PubMed  CAS  Google Scholar 

  93. Kohlhaas M, Liu T, Knopp A, Zeller T, Ong MF, Böhm M, O’Rourke B, Maack C (2010) Elevated cytosolic Na+ increases mitochondrial formation of reactive oxygen species in failing cardiac myocytes. Circulation 121:1606–1613. doi:10.1161/CIRCULATIONAHA.109.914911

    Article  CAS  PubMed  Google Scholar 

  94. Kohlhaas M, Maack C (2010) Adverse bioenergetic consequences of Na+–Ca2+ exchanger-mediated Ca2+ influx in cardiac myocytes. Circulation 122:2273–2280. doi:10.1161/CIRCULATIONAHA.110.968057

    Article  CAS  PubMed  Google Scholar 

  95. Kohlhaas M, Maack C (2013) Calcium release microdomains and mitochondria. Cardiovasc Res. doi:10.1093/cvr/cvt1032 [Epub ahead of print]

  96. Kohlhaas M, Maack C (2011) Interplay of defective excitation-contraction coupling, energy starvation, and oxidative stress in heart failure. Trends Cardiovasc Med 21:69–73. doi:10.1016/j.tcm.2012.03.002

    Article  CAS  PubMed  Google Scholar 

  97. Kolobova E, Tuganova A, Boulatnikov I, Popov KM (2001) Regulation of pyruvate dehydrogenase activity through phosphorylation at multiple sites. Biochem J 358:69–77

    Article  CAS  PubMed  Google Scholar 

  98. Kolwicz SC Jr, Olson DP, Marney LC, Garcia-Menendez L, Synovec RE, Tian R (2012) Cardiac-specific deletion of acetyl CoA carboxylase 2 prevents metabolic remodeling during pressure-overload hypertrophy. Circ Res 111:728–738. doi:10.1161/CIRCRESAHA.112.268128

    Article  CAS  PubMed  Google Scholar 

  99. Kolwicz SC Jr, Tian R (2011) Glucose metabolism and cardiac hypertrophy. Cardiovasc Res 90:194–201. doi:10.1093/cvr/cvr071

    Article  CAS  PubMed  Google Scholar 

  100. Koonen DP, Glatz JF, Bonen A, Luiken JJ (2005) Long-chain fatty acid uptake and FAT/CD36 translocation in heart and skeletal muscle. Biochim Biophys Acta 1736:163–180. doi:10.1016/j.bbalip.2005.08.018

    Article  CAS  PubMed  Google Scholar 

  101. Korotchkina LG, Patel MS (2001) Site specificity of four pyruvate dehydrogenase kinase isoenzymes toward the three phosphorylation sites of human pyruvate dehydrogenase. J Biol Chem 276:37223–37229. doi:10.1074/jbc.M103069200

    Article  CAS  PubMed  Google Scholar 

  102. Kuroda J, Ago T, Matsushima S, Zhai P, Schneider MD, Sadoshima J (2010) NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart. Proc Natl Acad Sci USA 107:15565–15570. doi:10.1073/pnas.1002178107

    Article  CAS  PubMed  Google Scholar 

  103. Lee L, Campbell R, Scheuermann-Freestone M, Taylor R, Gunaruwan P, Williams L, Ashrafian H, Horowitz J, Fraser AG, Clarke K, Frenneaux M (2005) Metabolic modulation with perhexiline in chronic heart failure: a randomized, controlled trial of short-term use of a novel treatment. Circulation 112:3280–3288. doi:10.1161/CIRCULATIONAHA.105.551457

    Article  CAS  PubMed  Google Scholar 

  104. Li Y, Huang TT, Carlson EJ, Melov S, Ursell PC, Olson JL, Noble LJ, Yoshimura MP, Berger C, Chan PH, Wallace DC, Epstein CJ (1995) Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase. Nat Genet 11:376–381. doi:10.1038/ng1295-376

    Article  CAS  PubMed  Google Scholar 

  105. Liao R, Jain M, Cui L, D’Agostino J, Aiello F, Luptak I, Ngoy S, Mortensen RM, Tian R (2002) Cardiac-specific overexpression of GLUT1 prevents the development of heart failure attributable to pressure overload in mice. Circulation 106:2125–2131. doi:10.1161/01.CIR.0000034049.61181.F3

    Article  CAS  PubMed  Google Scholar 

  106. Lin CS, Sun YL, Liu CY (2003) Structural and biochemical evidence of mitochondrial depletion in pigs with hypertrophic cardiomyopathy. Res Vet Sci 74:219–226. doi:10.1016/S0034-5288(02)00189-3

    Google Scholar 

  107. Lin L, Sharma VK, Sheu SS (2007) Mechanisms of reduced mitochondrial Ca2+ accumulation in failing hamster heart. Pflugers Arch 454:395–402. doi:10.1007/s00424-007-0257-8

    Article  CAS  PubMed  Google Scholar 

  108. Lionetti V, Stanley WC, Recchia FA (2011) Modulating fatty acid oxidation in heart failure. Cardiovasc Res 90:202–209. doi:10.1093/cvr/cvr038

    Article  CAS  PubMed  Google Scholar 

  109. Liu T, O’Rourke B (2008) Enhancing mitochondrial Ca2+ uptake in myocytes from failing hearts restores energy supply and demand matching. Circ Res 103:279–288. doi:10.1161/CIRCRESAHA.108.175919

    Article  CAS  PubMed  Google Scholar 

  110. Lopaschuk GD, Barr R, Thomas PD, Dyck JR (2003) Beneficial effects of trimetazidine in ex vivo working ischemic hearts are due to a stimulation of glucose oxidation secondary to inhibition of long-chain 3-ketoacyl coenzyme a thiolase. Circ Res 93:e33–e37. doi:10.1161/01.RES.0000086964.07404.A5

    Article  CAS  PubMed  Google Scholar 

  111. Lovelock JD, Monasky MM, Jeong EM, Lardin HA, Liu H, Patel BG, Taglieri DM, Gu L, Kumar P, Pokhrel N, Zeng D, Belardinelli L, Sorescu D, Solaro RJ, Dudley SC Jr (2012) Ranolazine improves cardiac diastolic dysfunction through modulation of myofilament calcium sensitivity. Circ Res 110:841–850. doi:10.1161/CIRCRESAHA.111.258251

    Article  CAS  PubMed  Google Scholar 

  112. Lu X, Ginsburg KS, Kettlewell S, Bossuyt J, Smith GL, Bers DM (2013) Measuring local gradients of intramitochondrial [Ca(2+)] in cardiac myocytes during sarcoplasmic reticulum Ca(2+) release. Circ Res 112:424–431. doi:10.1161/CIRCRESAHA.111.300501

    Article  CAS  PubMed  Google Scholar 

  113. Lygate CA, Aksentijevic D, Dawson D, Ten Hove M, Phillips D, de Bono JP, Medway DJ, Sebag-Montefiore LM, Hunyor I, Channon K, Clarke K, Zervou S, Watkins H, Balaban R, Neubauer S (2013) Living without creatine: unchanged exercise capacity and response to chronic myocardial infarction in creatine-deficient mice. Circ Res 112:945–955. doi:10.1161/CIRCRESAHA.112.300725

    Article  CAS  PubMed  Google Scholar 

  114. Lygate CA, Medway DJ, Ostrowski PJ, Aksentijevic D, Sebag-Montefiore L, Hunyor I, Zervou S, Schneider JE, Neubauer S (2012) Chronic creatine kinase deficiency eventually leads to congestive heart failure, but severity is dependent on genetic background, gender and age. Basic Res Cardiol 107:276. doi:10.1007/s00395-012-0276-2

    Article  PubMed  CAS  Google Scholar 

  115. Lyon AR, MacLeod KT, Zhang Y, Garcia E, Kanda GK, Lab MJ, Korchev YE, Harding SE, Gorelik J (2009) Loss of T-tubules and other changes to surface topography in ventricular myocytes from failing human and rat heart. Proc Natl Acad Sci USA 106:6854–6859. doi:10.1073/pnas.0809777106

    Article  CAS  PubMed  Google Scholar 

  116. Maack C, Böhm M (2011) Targeting mitochondrial oxidative stress in heart failure throttling the afterburner. J Am Coll Cardiol 58:83–86. doi:10.1016/j.jacc.2011.01.032

    Article  CAS  PubMed  Google Scholar 

  117. Maack C, Cortassa S, Aon MA, Ganesan AN, Liu T, O’Rourke B (2006) Elevated cytosolic Na+ decreases mitochondrial Ca2+ uptake during excitation-contraction coupling and impairs energetic adaptation in cardiac myocytes. Circ Res 99:172–182. doi:10.1161/01.RES.0000232546.92777.05

    Article  CAS  PubMed  Google Scholar 

  118. Maack C, Dabew ER, Hohl M, Schäfers HJ, Böhm M (2009) Endogenous activation of mitochondrial KATP channels protects human failing myocardium from hydroxyl radical-induced stunning. Circ Res 105:811–817. doi:10.1161/CIRCRESAHA.109.206359

    Article  CAS  PubMed  Google Scholar 

  119. Maack C, Kartes T, Kilter H, Schäfers HJ, Nickenig G, Böhm M, Laufs U (2003) Oxygen free radical release in human failing myocardium is associated with increased activity of rac1-GTPase and represents a target for statin treatment. Circulation 108:1567–1574. doi:10.1161/01.CIR.0000091084.46500.BB

    Article  CAS  PubMed  Google Scholar 

  120. Maack C, O’Rourke B (2007) Excitation-contraction coupling and mitochondrial energetics. Basic Res Cardiol 102:369–392. doi:10.1007/s00395-007-0666-z

    Article  CAS  PubMed  Google Scholar 

  121. MacInnes A, Fairman DA, Binding P, Rhodes J, Wyatt MJ, Phelan A, Haddock PS, Karran EH (2003) The antianginal agent trimetazidine does not exert its functional benefit via inhibition of mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res 93:e26–e32. doi:10.1161/01.RES.0000086943.72932.71

    Article  CAS  PubMed  Google Scholar 

  122. Mackenzie L, Roderick HL, Berridge MJ, Conway SJ, Bootman MD (2004) The spatial pattern of atrial cardiomyocyte calcium signalling modulates contraction. J Cell Sci 117:6327–6337. doi:10.1242/jcs.01559

    Article  CAS  PubMed  Google Scholar 

  123. Mallat Z, Philip I, Lebret M, Chatel D, Maclouf J, Tedgui A (1998) 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 97:1536–1539. doi:10.1161/01.CIR.97.16.1536

    Article  CAS  PubMed  Google Scholar 

  124. Mallilankaraman K, Cardenas C, Doonan PJ, Chandramoorthy HC, Irrinki KM, Golenar T, Csordas G, Madireddi P, Yang J, Muller M, Miller R, Kolesar JE, Molgo J, Kaufman B, Hajnoczky G, Foskett JK, Madesh M (2012) MCUR1 is an essential component of mitochondrial Ca2+ uptake that regulates cellular metabolism. Nat Cell Biol 14:1336–1343. doi:10.1038/ncb2622

    Article  CAS  PubMed  Google Scholar 

  125. Maltsev VA, Silverman N, Sabbah HN, Undrovinas AI (2007) Chronic heart failure slows late sodium current in human and canine ventricular myocytes: implications for repolarization variability. Eur J Heart Fail 9:219–227. doi:10.1016/j.ejheart.2006.08.007

    Article  CAS  PubMed  Google Scholar 

  126. Matsushima S, Kuroda J, Ago T, Zhai P, Ikeda Y, Oka S, Fong GH, Tian R, Sadoshima J (2013) Broad suppression of NADPH oxidase activity exacerbates ischemia/reperfusion injury through inadvertent downregulation of hypoxia-inducible factor-1alpha and upregulation of peroxisome proliferator-activated receptor-alpha. Circ Res 112:1135–1149. doi:10.1161/CIRCRESAHA.111.300171

    Article  CAS  PubMed  Google Scholar 

  127. McCormack JG, Baracos VE, Barr R, Lopaschuk GD (1996) Effects of ranolazine on oxidative substrate preference in epitrochlearis muscle. J Appl Physiol 81:905–910

    CAS  PubMed  Google Scholar 

  128. McCormack JG, Barr RL, Wolff AA, Lopaschuk GD (1996) Ranolazine stimulates glucose oxidation in normoxic, ischemic, and reperfused ischemic rat hearts. Circulation 93:135–142. doi:10.1161/01.CIR.93.1.135

    Article  CAS  PubMed  Google Scholar 

  129. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, Falk V, Filippatos G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Kober L, Lip GY, Maggioni AP, Parkhomenko A, Pieske BM, Popescu BA, Ronnevik PK, Rutten FH, Schwitter J, Seferovic P, Stepinska J, Trindade PT, Voors AA, Zannad F, Zeiher A, Bax JJ, Baumgartner H, Ceconi C, Dean V, Deaton C, Fagard R, Funck-Brentano C, Hasdai D, Hoes A, Kirchhof P, Knuuti J, Kolh P, McDonagh T, Moulin C, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Torbicki A, Vahanian A, Windecker S, Bonet LA, Avraamides P, Ben Lamin HA, Brignole M, Coca A, Cowburn P, Dargie H, Elliott P, Flachskampf FA, Guida GF, Hardman S, Iung B, Merkely B, Mueller C, Nanas JN, Nielsen OW, Orn S, Parissis JT, Ponikowski P (2012) ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 14:803–869. doi:10.1093/eurjhf/hfs105

    Article  CAS  PubMed  Google Scholar 

  130. Metra M, Giubbini R, Nodari S, Boldi E, Modena MG, Dei Cas L (2000) Differential effects of beta-blockers in patients with heart failure: a prospective, randomized, double-blind comparison of the long-term effects of metoprolol versus carvedilol. Circulation 102:546–551. doi:10.1161/01.CIR.102.5.546

    Article  CAS  PubMed  Google Scholar 

  131. Meyer M, Keweloh B, Güth K, Holmes JW, Pieske B, Lehnart SE, Just H, Hasenfuss G (1998) Frequency-dependence of myocardial energetics in failing human myocardium as quantified by a new method for the measurement of oxygen consumption in muscle strip preparations. J Mol Cell Cardiol 30:1459–1470. doi:10.1006/jmcc.1998.0706

    Article  CAS  PubMed  Google Scholar 

  132. Michels G, Khan IF, Endres-Becker J, Rottlaender D, Herzig S, Ruhparwar A, Wahlers T, Hoppe UC (2009) Regulation of the human cardiac mitochondrial Ca2+ uptake by 2 different voltage-gated Ca2+ channels. Circulation 119:2435–2443. doi:10.1161/CIRCULATIONAHA.108.835389

    Article  CAS  PubMed  Google Scholar 

  133. Mootha VK, Arai AE, Balaban RS (1997) Maximum oxidative phosphorylation capacity of the mammalian heart. Am J Physiol 272:H769–H775

    CAS  PubMed  Google Scholar 

  134. Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, Murphy SA, Budaj A, Varshavsky S, Wolff AA, Skene A, McCabe CH, Braunwald E (2007) Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial. JAMA 297:1775–1783. doi:10.1001/jama.297.16.1775

    Article  CAS  PubMed  Google Scholar 

  135. Murphy E, Eisner DA (2009) Regulation of intracellular and mitochondrial sodium in health and disease. Circ Res 104:292–303. doi:10.1161/CIRCRESAHA.108.189050

    Article  CAS  PubMed  Google Scholar 

  136. Murray AJ, Anderson RE, Watson GC, Radda GK, Clarke K (2004) Uncoupling proteins in human heart. Lancet 364:1786–1788. doi:10.1016/S0140-6736(04)17402-3

    Article  CAS  PubMed  Google Scholar 

  137. Nakagawa T, Shimizu S, Watanabe T, Yamaguchi O, Otsu K, Yamagata H, Inohara H, Kubo T, Tsujimoto Y (2005) Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 434:652–658. doi:10.1038/nature03317

    Article  CAS  PubMed  Google Scholar 

  138. Nakamura K, Kusuoka H, Ambrosio G, Becker LC (1993) Glycolysis is necessary to preserve myocardial Ca2+ homeostasis during beta-adrenergic stimulation. Am J Physiol 264:H670–H678

    CAS  PubMed  Google Scholar 

  139. Nakamura R, Egashira K, Machida Y, Hayashidani S, Takeya M, Utsumi H, Tsutsui H, Takeshita A (2002) Probucol attenuates left ventricular dysfunction and remodeling in tachycardia-induced heart failure: roles of oxidative stress and inflammation. Circulation 106:362–367. doi:10.1161/01.CIR.0000021430.04195.51

    Article  CAS  PubMed  Google Scholar 

  140. Neef S, Maier LS (2013) Novel aspects of excitation-contraction coupling in heart failure. Basic Res Cardiol (this issue)

  141. Neubauer S (2007) The failing heart—an engine out of fuel. N Engl J Med 356:1140–1151. doi:10.1056/NEJMra063052

    Article  PubMed  Google Scholar 

  142. Neubauer S, Horn M, Cramer M, Harre K, Newell JB, Peters W, Pabst T, Ertl G, Hahn D, Ingwall JS, Kochsiek K (1997) Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation 96:2190–2196. doi:10.1161/01.CIR.96.7.2190

    Article  CAS  PubMed  Google Scholar 

  143. Neubauer S, Horn M, Naumann A, Tian R, Hu K, Laser M, Friedrich J, Gaudron P, Schnackerz K, Ingwall JS et al (1995) Impairment of energy metabolism in intact residual myocardium of rat hearts with chronic myocardial infarction. J Clin Invest 95:1092–1100. doi:10.1172/JCI117756

    Article  CAS  PubMed  Google Scholar 

  144. Nulton-Persson AC, Szweda LI (2001) Modulation of mitochondrial function by hydrogen peroxide. J Biol Chem 276:23357–23361. doi:10.1074/jbc.M100320200

    Article  CAS  PubMed  Google Scholar 

  145. O’Rourke B, Blatter LA (2009) Mitochondrial Ca2+ uptake: tortoise or hare? J Mol Cell Cardiol 46:767–774. doi:10.1016/j.yjmcc.2008.12.011

    Article  PubMed  CAS  Google Scholar 

  146. O’Rourke B, Cortassa S, Aon MA (2005) Mitochondrial ion channels: gatekeepers of life and death. Physiology (Bethesda) 20:303–315. doi:10.1152/physiol.00020.2005

    Article  Google Scholar 

  147. O’Rourke B, Van Eyk JE, Foster DB (2011) Mitochondrial protein phosphorylation as a regulatory modality: implications for mitochondrial dysfunction in heart failure. Congest Heart Fail 17:269–282. doi:10.1111/j.1751-7133.2011.00266.x

    Article  PubMed  CAS  Google Scholar 

  148. Opie LH (2004) The metabolic vicious cycle in heart failure. Lancet 364:1733–1734. doi:10.1016/S0140-6736(04)17412-6

    Article  PubMed  Google Scholar 

  149. Opie LH, Knuuti J (2009) The adrenergic-fatty acid load in heart failure. J Am Coll Cardiol 54:1637–1646. doi:10.1016/j.jacc.2009.07.024

    Article  CAS  PubMed  Google Scholar 

  150. Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Castaigne A, Roecker EB, Schultz MK, DeMets DL (2001) Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 344:1651–1658. doi:10.1056/NEJM200105313442201

    Article  CAS  PubMed  Google Scholar 

  151. Pain T, Yang XM, Critz SD, Yue Y, Nakano A, Liu GS, Heusch G, Cohen MV, Downey JM (2000) Opening of mitochondrial K(ATP) channels triggers the preconditioned state by generating free radicals. Circ Res 87:460–466. doi:10.1161/01.RES.87.6.460

    Article  CAS  PubMed  Google Scholar 

  152. Palty R, Silverman WF, Hershfinkel M, Caporale T, Sensi SL, Parnis J, Nolte C, Fishman D, Shoshan-Barmatz V, Herrmann S, Khananshvili D, Sekler I (2010) NCLX is an essential component of mitochondrial Na+/Ca2+ exchange. Proc Natl Acad Sci USA 107:436–441. doi:10.1073/pnas.0908099107

    Article  CAS  PubMed  Google Scholar 

  153. Perocchi F, Gohil VM, Girgis HS, Bao XR, McCombs JE, Palmer AE, Mootha VK (2010) MICU1 encodes a mitochondrial EF hand protein required for Ca(2+) uptake. Nature 467:291–296. doi:10.1038/nature09358

    Article  CAS  PubMed  Google Scholar 

  154. Peskoff A, Langer GA (1998) Calcium concentration and movement in the ventricular cardiac cell during an excitation–contraction cycle. Biophys J 74:153–174. doi:10.1016/S0006-3495(98)77776-8

    Article  CAS  PubMed  Google Scholar 

  155. Phoon CK, Acehan D, Schlame M, Stokes DL, Edelman-Novemsky I, Yu D, Xu Y, Viswanathan N, Ren M (2012) Tafazzin knockdown in mice leads to a developmental cardiomyopathy with early diastolic dysfunction preceding myocardial noncompaction. J Am Heart Assoc. doi:10.1161/JAHA.111.000455

    PubMed  Google Scholar 

  156. Pieske B, Maier LS, Piacentino V 3rd, Weisser J, Hasenfuss G, Houser S (2002) Rate dependence of [Na+]i and contractility in nonfailing and failing human myocardium. Circulation 106:447–453. doi:10.1161/01.CIR.0000023042.50192.F4

    Article  CAS  PubMed  Google Scholar 

  157. Poole-Wilson PA, Swedberg K, Cleland JG, Di Lenarda A, Hanrath P, Komajda M, Lubsen J, Lutiger B, Metra M, Remme WJ, Torp-Pedersen C, Scherhag A, Skene A (2003) Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet 362:7–13. doi:10.1016/S0140-6736(03)13800-7

    Article  CAS  PubMed  Google Scholar 

  158. Randle PJ, Garland PB, Hales CN, Newsholme EA (1963) The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1:785–789

    Article  CAS  PubMed  Google Scholar 

  159. Rastogi S, Sharov VG, Mishra S, Gupta RC, Blackburn B, Belardinelli L, Stanley WC, Sabbah HN (2008) Ranolazine combined with enalapril or metoprolol prevents progressive LV dysfunction and remodeling in dogs with moderate heart failure. Am J Physiol Heart Circ Physiol 295:H2149–H2155. doi:10.1152/ajpheart.00728.2008

    Article  CAS  PubMed  Google Scholar 

  160. Ristow M, Zarse K (2010) How increased oxidative stress promotes longevity and metabolic health: the concept of mitochondrial hormesis (mitohormesis). Exp Gerontol 45:410–418. doi:10.1016/j.exger.2010.03.014

    Article  CAS  PubMed  Google Scholar 

  161. Rizzuto R, Pozzan T (2006) Microdomains of intracellular Ca2+: molecular determinants and functional consequences. Physiol Rev 86:369–408. doi:10.1152/physrev.00004.2005

    Article  CAS  PubMed  Google Scholar 

  162. Rosano GM, Fini M, Caminiti G, Barbaro G (2008) Cardiac metabolism in myocardial ischemia. Curr Pharm Des 14:2551–2562. doi:10.2174/138161208786071317

    Article  CAS  PubMed  Google Scholar 

  163. Rosca MG, Hoppel CL (2010) Mitochondria in heart failure. Cardiovasc Res 88:40–50. doi:10.1093/cvr/cvq240

    Article  CAS  PubMed  Google Scholar 

  164. Ruwald MH, Ruwald AC, Jons C, Alexis J, McNitt S, Zareba W, Moss AJ (2013) Effect of metoprolol versus carvedilol on outcomes in MADIT-CRT (multicenter automatic defibrillator implantation trial with cardiac resynchronization therapy). J Am Coll Cardiol 61:1518–1526. doi:10.1016/j.jacc.2013.01.020

    Article  CAS  PubMed  Google Scholar 

  165. Sabbah HN, Wang M, Zhang K, Gupta RC, Rastogi S (2012) Acute intravenous infusion of bendavia (MTP-131), a novel mitochondria-targeting peptide, improves left ventricular systolic function in dogs with advanced heart failure. Circulation 126:A15385

    Google Scholar 

  166. Saks V, Dzeja P, Schlattner U, Vendelin M, Terzic A, Wallimann T (2006) Cardiac system bioenergetics: metabolic basis of the Frank-Starling law. J Physiol 571:253–273. doi:10.1113/jphysiol.2005.101444

    Article  CAS  PubMed  Google Scholar 

  167. Santos CX, Anilkumar N, Zhang M, Brewer AC, Shah AM (2011) Redox signaling in cardiac myocytes. Free Radic Biol Med 50:777–793. doi:10.1016/j.freeradbiomed.2011.01.003

    Article  CAS  PubMed  Google Scholar 

  168. Schillinger W, Hunlich M, Sossalla S, Hermann HP, Hasenfuss G (2011) Intracoronary pyruvate in cardiogenic shock as an adjunctive therapy to catecholamines and intra-aortic balloon pump shows beneficial effects on hemodynamics. Clin Res Cardiol 100:433–438. doi:10.1007/s00392-010-0261-4

    Article  CAS  PubMed  Google Scholar 

  169. Schrauwen P, Saris WH, Hesselink MK (2001) An alternative function for human uncoupling protein 3: protection of mitochondria against accumulation of nonesterified fatty acids inside the mitochondrial matrix. FASEB J 15:2497–2502. doi:10.1096/fj.01-0400hyp

    Article  CAS  PubMed  Google Scholar 

  170. Schulz R, Kappeler C, Coenen H, Bockisch A, Heusch G (1998) Positron emission tomography analysis of [1-(11)C] acetate kinetics in short-term hibernating myocardium. Circulation 97:1009–1016. doi:10.1161/01.CIR.97.10.1009

    Article  CAS  PubMed  Google Scholar 

  171. Scirica BM, Morrow DA, Hod H, Murphy SA, Belardinelli L, Hedgepeth CM, Molhoek P, Verheugt FW, Gersh BJ, McCabe CH, Braunwald E (2007) Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non ST-segment elevation acute coronary syndrome: results from the Metabolic Efficiency With Ranolazine for Less Ischemia in Non ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) randomized controlled trial. Circulation 116:1647–1652. doi:10.1161/CIRCULATIONAHA.107.724880

    Article  CAS  PubMed  Google Scholar 

  172. Shah SH, Kraus WE, Newgard CB (2012) Metabolomic profiling for the identification of novel biomarkers and mechanisms related to common cardiovascular diseases: form and function. Circulation 126:1110–1120. doi:10.1161/CIRCULATIONAHA.111.060368

    Article  PubMed  Google Scholar 

  173. Sharma S, Adrogue JV, Golfman L, Uray I, Lemm J, Youker K, Noon GP, Frazier OH, Taegtmeyer H (2004) Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart. FASEB J 18:1692–1700. doi:10.1096/fj.04-2263com

    Article  CAS  PubMed  Google Scholar 

  174. Sheu SS, Nauduri D, Anders MW (2006) Targeting antioxidants to mitochondria: a new therapeutic direction. Biochim Biophys Acta 1762:256–265. doi:10.1016/j.bbadis.2005.10.007

    Article  CAS  PubMed  Google Scholar 

  175. Smith RA, Murphy MP (2010) Animal and human studies with the mitochondria-targeted antioxidant MitoQ. Ann N Y Acad Sci 1201:96–103. doi:10.1111/j.1749-6632.2010.05627.x

    Article  CAS  PubMed  Google Scholar 

  176. Song LS, Sobie EA, McCulle S, Lederer WJ, Balke CW, Cheng H (2006) Orphaned ryanodine receptors in the failing heart. Proc Natl Acad Sci USA 103:4305–4310. doi:10.1073/pnas.0509324103

    Article  CAS  PubMed  Google Scholar 

  177. Song Y, Shryock JC, Wagner S, Maier LS, Belardinelli L (2006) Blocking late sodium current reduces hydrogen peroxide-induced arrhythmogenic activity and contractile dysfunction. J Pharmacol Exp Ther 318:214–222. doi:10.1124/jpet.106.101832

    Article  CAS  PubMed  Google Scholar 

  178. Sorokina N, O’Donnell JM, McKinney RD, Pound KM, Woldegiorgis G, LaNoue KF, Ballal K, Taegtmeyer H, Buttrick PM, Lewandowski ED (2007) Recruitment of compensatory pathways to sustain oxidative flux with reduced carnitine palmitoyltransferase I activity characterizes inefficiency in energy metabolism in hypertrophied hearts. Circulation 115:2033–2041. doi:10.1161/CIRCULATIONAHA.106.668665

    Article  CAS  PubMed  Google Scholar 

  179. Sossalla S, Maurer U, Schotola H, Hartmann N, Didie M, Zimmermann WH, Jacobshagen C, Wagner S, Maier LS (2011) Diastolic dysfunction and arrhythmias caused by overexpression of CaMKIIdelta(C) can be reversed by inhibition of late Na(+) current. Basic Res Cardiol 106:263–272. doi:10.1007/s00395-010-0136-x

    Article  CAS  PubMed  Google Scholar 

  180. Sossalla S, Wagner S, Rasenack EC, Ruff H, Weber SL, Schondube FA, Tirilomis T, Tenderich G, Hasenfuss G, Belardinelli L, Maier LS (2008) Ranolazine improves diastolic dysfunction in isolated myocardium from failing human hearts—role of late sodium current and intracellular ion accumulation. J Mol Cell Cardiol 45:32–43. doi:10.1016/j.yjmcc.2008.03.006

    Article  CAS  PubMed  Google Scholar 

  181. Spindler M, Meyer K, Stromer H, Leupold A, Boehm E, Wagner H, Neubauer S (2004) Creatine kinase-deficient hearts exhibit increased susceptibility to ischemia-reperfusion injury and impaired calcium homeostasis. Am J Physiol Heart Circ Physiol 287:H1039–H1045. doi:10.1152/ajpheart.01016.2003

    Article  CAS  PubMed  Google Scholar 

  182. Stanley WC, Recchia FA, Lopaschuk GD (2005) Myocardial substrate metabolism in the normal and failing heart. Physiol Rev 85:1093–1129. doi:10.1152/physrev.00006.2004

    Article  CAS  PubMed  Google Scholar 

  183. Sugden MC, Holness MJ (2003) Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs. Am J Physiol Endocrinol Metab 284:E855–E862. doi:10.1152/ajpendo.00526.2002

    CAS  PubMed  Google Scholar 

  184. Supinski GS, Murphy MP, Callahan LA (2009) MitoQ administration prevents endotoxin-induced cardiac dysfunction. Am J Physiol Regul Integr Comp Physiol 297:R1095–R1102. doi:10.1152/ajpregu.90902.2008

    Article  CAS  PubMed  Google Scholar 

  185. Taegtmeyer H, Ingwall JS (2013) Creatine—a dispensable metabolite? Circ Res 112:878–880. doi:10.1161/CIRCRESAHA.113.300974

    Article  CAS  PubMed  Google Scholar 

  186. Takimoto E, Champion HC, Li M, Ren S, Rodriguez ER, Tavazzi B, Lazzarino G, Paolocci N, Gabrielson KL, Wang Y, Kass DA (2005) Oxidant stress from nitric oxide synthase-3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure load. J Clin Invest 115:1221–1231. doi:10.1172/JCI21968

    CAS  PubMed  Google Scholar 

  187. ten Hove M, Lygate CA, Fischer A, Schneider JE, Sang AE, Hulbert K, Sebag-Montefiore L, Watkins H, Clarke K, Isbrandt D, Wallis J, Neubauer S (2005) Reduced inotropic reserve and increased susceptibility to cardiac ischemia/reperfusion injury in phosphocreatine-deficient guanidinoacetate-N-methyltransferase-knockout mice. Circulation 111:2477–2485. doi:10.1161/01.CIR.0000165147.99592.01

    Article  PubMed  CAS  Google Scholar 

  188. Teshima Y, Akao M, Jones SP, Marban E (2003) Uncoupling protein-2 overexpression inhibits mitochondrial death pathway in cardiomyocytes. Circ Res 93:192–200. doi:10.1161/01.RES.0000085581.60197.4D

    Article  CAS  PubMed  Google Scholar 

  189. Tian R, Halow JM, Meyer M, Dillmann WH, Figueredo VM, Ingwall JS, Camacho SA (1998) Thermodynamic limitation for Ca2+ handling contributes to decreased contractile reserve in rat hearts. Am J Physiol 275:H2064–H2071

    CAS  PubMed  Google Scholar 

  190. Tian R, Ingwall JS (1996) Energetic basis for reduced contractile reserve in isolated rat hearts. Am J Physiol 270:H1207–H1216

    CAS  PubMed  Google Scholar 

  191. Tian R, Nascimben L, Ingwall JS, Lorell BH (1997) Failure to maintain a low ADP concentration impairs diastolic function in hypertrophied rat hearts. Circulation 96:1313–1319. doi:10.1161/01.CIR.96.4.1313

    Article  CAS  PubMed  Google Scholar 

  192. Tian R, Nascimben L, Kaddurah-Daouk R, Ingwall JS (1996) Depletion of energy reserve via the creatine kinase reaction during the evolution of heart failure in cardiomyopathic hamsters. J Mol Cell Cardiol 28:755–765. doi:10.1006/jmcc.1996.0070

    Article  CAS  PubMed  Google Scholar 

  193. Tritto I, D’Andrea D, Eramo N, Scognamiglio A, De Simone C, Violante A, Esposito A, Chiariello M, Ambrosio G (1997) Oxygen radicals can induce preconditioning in rabbit hearts. Circ Res 80:743–748. doi:10.1161/01.RES.80.5.743

    Article  CAS  PubMed  Google Scholar 

  194. Tsukada Y, Fang J, Erdjument-Bromage H, Warren ME, Borchers CH, Tempst P, Zhang Y (2006) Histone demethylation by a family of JmjC domain-containing proteins. Nature 439:811–816. doi:10.1038/nature04433

    Article  CAS  PubMed  Google Scholar 

  195. Turer AT (2013) Using metabolomics to assess myocardial metabolism and energetics in heart failure. J Mol Cell Cardiol 55:12–18. doi:10.1016/j.yjmcc.2012.08.025

    Article  CAS  PubMed  Google Scholar 

  196. Turner JD, Gaspers LD, Wang G, Thomas AP (2010) Uncoupling protein-2 modulates myocardial excitation–contraction coupling. Circ Res 106:730–738. doi:10.1161/CIRCRESAHA.109.206631

    Article  CAS  PubMed  Google Scholar 

  197. Tuunanen H, Engblom E, Naum A, Nagren K, Hesse B, Airaksinen KE, Nuutila P, Iozzo P, Ukkonen H, Opie LH, Knuuti J (2006) Free fatty acid depletion acutely decreases cardiac work and efficiency in cardiomyopathic heart failure. Circulation 114:2130–2137. doi:10.1161/CIRCULATIONAHA.106.645184

    Article  CAS  PubMed  Google Scholar 

  198. Tuunanen H, Engblom E, Naum A, Nagren K, Scheinin M, Hesse B, Juhani Airaksinen KE, Nuutila P, Iozzo P, Ukkonen H, Opie LH, Knuuti J (2008) Trimetazidine, a metabolic modulator, has cardiac and extracardiac benefits in idiopathic dilated cardiomyopathy. Circulation 118:1250–1258. doi:10.1161/CIRCULATIONAHA.108.778019

    Article  CAS  PubMed  Google Scholar 

  199. Tuunanen H, Knuuti J (2011) Metabolic remodelling in human heart failure. Cardiovasc Res 90:251–257. doi:10.1093/cvr/cvr052

    Article  CAS  PubMed  Google Scholar 

  200. Vanden Hoek TL, Becker LB, Shao Z, Li C, Schumacker PT (1998) Reactive oxygen species released from mitochondria during brief hypoxia induce preconditioning in cardiomyocytes. J Biol Chem 273:18092–18098. doi:10.1074/jbc.273.29.18092

    Article  CAS  PubMed  Google Scholar 

  201. Ventura-Clapier R, Garnier A, Veksler V (2008) Transcriptional control of mitochondrial biogenesis: the central role of PGC-1alpha. Cardiovasc Res 79:208–217. doi:10.1093/cvr/cvn098

    Article  CAS  PubMed  Google Scholar 

  202. Ventura-Clapier R, Kuznetsov AV, d’Albis A, van Deursen J, Wieringa B, Veksler VI (1995) Muscle creatine kinase-deficient mice. I. Alterations in myofibrillar function. J Biol Chem 270:19914–19920. doi:10.1074/jbc.270.34.19914

    Article  CAS  PubMed  Google Scholar 

  203. Vergeade A, Mulder P, Vendeville-Dehaudt C, Estour F, Fortin D, Ventura-Clapier R, Thuillez C, Monteil C (2010) Mitochondrial impairment contributes to cocaine-induced cardiac dysfunction: prevention by the targeted antioxidant MitoQ. Free Radic Biol Med 49:748–756. doi:10.1016/j.freeradbiomed.2010.05.024

    Article  CAS  PubMed  Google Scholar 

  204. Viatchenko-Karpinski S, Kornyeyev D, Fan P, Jiang Z, Shryock J, Anderson ME, Belardinelli L, Yao L (2013) Intracellular Na+overload of cardiomyocytes causes ROS induced CaMKII activation, leading to RyR dysfunction and diastolic Ca2+ mishandling Biophys J:2260-Pos (Abstract)

  205. Wagner S, Dybkova N, Rasenack EC, Jacobshagen C, Fabritz L, Kirchhof P, Maier SK, Zhang T, Hasenfuss G, Brown JH, Bers DM, Maier LS (2006) Ca2+/calmodulin-dependent protein kinase II regulates cardiac Na+ channels. J Clin Invest 116:3127–3138. doi:10.1172/JCI26620

    Article  CAS  PubMed  Google Scholar 

  206. Wagner S, Ruff HM, Weber SL, Bellmann S, Sowa T, Schulte T, Anderson ME, Grandi E, Bers DM, Backs J, Belardinelli L, Maier LS (2011) Reactive oxygen species-activated Ca/calmodulin kinase IIdelta is required for late I(Na) augmentation leading to cellular Na and Ca overload. Circ Res 108:555–565. doi:10.1161/CIRCRESAHA.110.221911

    Article  CAS  PubMed  Google Scholar 

  207. Watkins H, Ashrafian H, Redwood C (2011) Inherited cardiomyopathies. N Engl J Med 364:1643–1656. doi:10.1056/NEJMra0902923

    Article  CAS  PubMed  Google Scholar 

  208. Watson LJ, Facundo HT, Ngoh GA, Ameen M, Brainard RE, Lemma KM, Long BW, Prabhu SD, Xuan YT, Jones SP (2010) O-linked beta-N-acetylglucosamine transferase is indispensable in the failing heart. Proc Natl Acad Sci USA 107:17797–17802. doi:10.1073/pnas.1001907107

    Article  CAS  PubMed  Google Scholar 

  209. Weber CR, Piacentino V 3rd, Houser SR, Bers DM (2003) Dynamic regulation of sodium/calcium exchange function in human heart failure. Circulation 108:2224–2229. doi:10.1161/01.CIR.0000095274.72486.94

    Article  CAS  PubMed  Google Scholar 

  210. Weiss RG, Gerstenblith G, Bottomley PA (2005) ATP flux through creatine kinase in the normal, stressed, and failing human heart. Proc Natl Acad Sci USA 102:808–813. doi:10.1073/pnas.0408962102

    Article  CAS  PubMed  Google Scholar 

  211. Weisser-Thomas J, Piacentino V 3rd, Gaughan JP, Margulies K, Houser SR (2003) Calcium entry via Na/Ca exchange during the action potential directly contributes to contraction of failing human ventricular myocytes. Cardiovasc Res 57:974–985. doi:10.1016/S0008-6363(02)00732-0

    Article  CAS  PubMed  Google Scholar 

  212. Wende AR, Abel ED (2010) Lipotoxicity in the heart. Biochim Biophys Acta 1801:311–319. doi:10.1016/j.bbalip.2009.09.023

    Article  CAS  PubMed  Google Scholar 

  213. White M, Yanowitz F, Gilbert EM, Larrabee P, O’Connell JB, Anderson JL, Renlund D, Mealey P, Abraham WT, Bristow MR (1995) Role of beta-adrenergic receptor downregulation in the peak exercise response in patients with heart failure due to idiopathic dilated cardiomyopathy. Am J Cardiol 76:1271–1276. doi:10.1016/S0002-9149(99)80355-5

    Article  CAS  PubMed  Google Scholar 

  214. Wilson SR, Scirica BM, Braunwald E, Murphy SA, Karwatowska-Prokopczuk E, Buros JL, Chaitman BR, Morrow DA (2009) Efficacy of ranolazine in patients with chronic angina observations from the randomized, double-blind, placebo-controlled MERLIN-TIMI (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Segment Elevation Acute Coronary Syndromes) 36 Trial. J Am Coll Cardiol 53:1510–1516. doi:10.1016/j.jacc.2009.01.037

    Article  CAS  PubMed  Google Scholar 

  215. Wyatt KM, Skene C, Veitch K, Hue L, McCormack JG (1995) The antianginal agent ranolazine is a weak inhibitor of the respiratory complex I, but with greater potency in broken or uncoupled than in coupled mitochondria. Biochem Pharmacol 50:1599–1606. doi:0006-2952(95)02042-X

    Article  CAS  PubMed  Google Scholar 

  216. Xu KY, Zweier JL, Becker LC (1997) Hydroxyl radical inhibits sarcoplasmic reticulum Ca(2+)-ATPase function by direct attack on the ATP binding site. Circ Res 80:76–81. doi:10.1161/01.RES.80.1.76

    Article  CAS  PubMed  Google Scholar 

  217. Yin X, Dwyer J, Langley SR, Mayr U, Xing Q, Drozdov I, Nabeebaccus A, Shah AM, Madhu B, Griffiths J, Edwards LM, Mayr M (2013) Effects of perhexiline-induced fuel switch on the cardiac proteome and metabolome. J Mol Cell Cardiol 55:27–30. doi:10.1016/j.yjmcc.2012.12.014

    Article  CAS  PubMed  Google Scholar 

  218. Ying W (2008) NAD+/NADH and NADP+/NADPH in cellular functions and cell death: regulation and biological consequences. Antioxid Redox Signal 10:179–206. doi:10.1089/ars.2007.1672

    Article  CAS  PubMed  Google Scholar 

  219. Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P (2000) Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 342:154–160. doi:10.1056/NEJM200001203420302

    Article  CAS  PubMed  Google Scholar 

  220. Zhang M, Brewer AC, Schroder K, Santos CX, Grieve DJ, Wang M, Anilkumar N, Yu B, Dong X, Walker SJ, Brandes RP, Shah AM (2010) NADPH oxidase-4 mediates protection against chronic load-induced stress in mouse hearts by enhancing angiogenesis. Proc Natl Acad Sci USA 107:18121–18126. doi:10.1073/pnas.1009700107

    Article  CAS  PubMed  Google Scholar 

  221. Zhang QJ, Chen HZ, Wang L, Liu DP, Hill JA, Liu ZP (2011) The histone trimethyllysine demethylase JMJD2A promotes cardiac hypertrophy in response to hypertrophic stimuli in mice. J Clin Invest 121:2447–2456. doi:10.1172/JCI46277

    Article  CAS  PubMed  Google Scholar 

  222. Zhao K, Zhao GM, Wu D, Soong Y, Birk AV, Schiller PW, Szeto HH (2004) Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury. J Biol Chem 279:34682–34690. doi:10.1074/jbc.M402999200

    Article  CAS  PubMed  Google Scholar 

  223. Zhou L, Huang H, Yuan CL, Keung W, Lopaschuk GD, Stanley WC (2008) Metabolic response to an acute jump in cardiac workload: effects on malonyl-CoA, mechanical efficiency, and fatty acid oxidation. Am J Physiol Heart Circ Physiol 294:H954–H960. doi:10.1152/ajpheart.00557.2007

    Article  CAS  PubMed  Google Scholar 

  224. Zorov DB, Filburn CR, Klotz LO, Zweier JL, Sollott SJ (2000) Reactive oxygen species (ROS)-induced ROS release: a new phenomenon accompanying induction of the mitochondrial permeability transition in cardiac myocytes. J Exp Med 192:1001–1014. doi:10.1084/jem.192.7.1001

    Article  CAS  PubMed  Google Scholar 

  225. Zweier JL, Talukder MA (2006) The role of oxidants and free radicals in reperfusion injury. Cardiovasc Res 70:181–190. doi:10.1016/j.cardiores.2006.02.025

    Article  CAS  PubMed  Google Scholar 

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  1. Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, 66421, Homburg, Germany

    Alexander Nickel, Joachim Löffler & Christoph Maack

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  1. Alexander Nickel
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This article is part of the Topical Collection Novel Perspectives on Heart Failure.

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Nickel, A., Löffler, J. & Maack, C. Myocardial energetics in heart failure. Basic Res Cardiol 108, 358 (2013). https://doi.org/10.1007/s00395-013-0358-9

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