Excitation-contraction coupling and mitochondrial energetics

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Cardiac excitation-contraction (EC) coupling consumes vast amounts of cellular energy, most of which is produced in mitochondria by oxidative phosphorylation. In order to adapt the constantly varying workload of the heart to energy supply, tight coupling mechanisms are essential to maintain cellular pools of ATP, phosphocreatine and NADH. To our current knowledge, the most important regulators of oxidative phosphorylation are ADP, Pi, and Ca2+. However, the kinetics of mitochondrial Ca2+-uptake during EC coupling are currently a matter of intense debate. Recent experimental findings suggest the existence of a mitochondrial Ca2+ microdomain in cardiac myocytes, justified by the close proximity of mitochondria to the sites of cellular Ca2+ release, i. e., the ryanodine receptors of the sarcoplasmic reticulum. Such a Ca2+ microdomain could explain seemingly controversial results on mitochondrial Ca2+ uptake kinetics in isolated mitochondria versus whole cardiac myocytes. Another important consideration is that rapid mitochondrial Ca2+ uptake facilitated by microdomains may shape cytosolic Ca2+ signals in cardiac myocytes and have an impact on energy supply and demand matching. Defects in EC coupling in chronic heart failure may adversely affect mitochondrial Ca2+ uptake and energetics, initiating a vicious cycle of contractile dysfunction and energy depletion. Future therapeutic approaches in the treatment of heart failure could be aimed at interrupting this vicious cycle.

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  1. 1.

    Abozguia K,Clarke K, Lee L, Frenneaux M (2006) Modification of myocardial substrate use as a therapy for heart failure. Nat Clin Pract Cardiovasc Med 3:490–498

  2. 2.

    Aker S, Snabaitis AK, Konietzka I, Van De Sand A, Bongler K, Avkiran M, Heusch G, Schulz R (2004) Inhibition of the Na+/H+ exchanger attenuates the deterioration of ventricular function during pacing-induced heart failure in rabbits. Cardiovasc Res 63:273–282

  3. 3.

    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

  4. 4.

    Auffermann W, Wu ST, Parmley WW, Wikman-Coffelt J (1990) Glycolysis in heart failure: a 31P-NMR and surface fluorometry study. Basic Res Cardiol 85:342–357

  5. 5.

    Baartscheer A, Schumacher CA, van Borren MM, Belterman CN, Coronel R, Fiolet JW (2003) Increased Na+/H+-exchange activity is the cause of increased [Na+]i and underlies disturbed calcium handling in the rabbit pressure and volume overload heart failure model. Cardiovasc Res 57:1015–1024

  6. 6.

    Baartscheer A, Schumacher CA, van Borren MM, Belterman CN, Coronel R, Opthof T, Fiolet JW (2005) Chronic inhibition of Na+/H+-exchanger attenuates cardiac hypertrophy and prevents cellular remodeling in heart failure. Cardiovasc Res 65:83–92

  7. 7.

    Balaban RS (2002) Cardiac energy metabolism homeostasis: role of cytosolic calcium. J Mol Cell Cardiol 34:1259–1271

  8. 8.

    Balaban RS, Kantor HL, Katz LA, Briggs RW (1986) Relation between work and phosphate metabolite in the in vivo paced mammalian heart. Science 232:1121–1123

  9. 9.

    Bassani RA, Bassani JW, Bers DM (1992) Mitochondrial and sarcolemmal Ca2+ transport reduce [Ca2+]i during caffeine contractures in rabbit cardiac myocytes. J Physiol 453:591–608

  10. 10.

    Baysal K, Jung DW, Gunter KK, Gunter TE, Brierley GP (1994) Na(+)-dependent Ca2+ efflux mechanism of heart mitochondria is not a passive Ca2+/ 2Na+ exchanger. Am J Physiol 266:C800–808

  11. 11.

    Beer M, Seyfarth T, Sandstede J, Landschutz W, Lipke C, Kostler H, von Kienlin M, Harre K, Hahn D, Neubauer S (2002) Absolute concentrations of highenergy phosphate metabolites in normal, hypertrophied, and failing human myocardium measured noninvasively with (31)P-SLOOP magnetic resonance spectroscopy. J Am Coll Cardiol 40:1267–1274

  12. 12.

    Bell CJ, Bright NA, Rutter GA, Griffiths EJ (2006) ATP regulation in adult rat cardiomyocytes: Time resolved decoding of rapid mitochondrial calcium spiking imaged with targeted photoproteins. J Biol Chem 281:28058–28067

  13. 13.

    Bers DM (2006) Altered Cardiac Myocyte Ca Regulation In Heart Failure. Physiology (Bethesda) 21:380–387

  14. 14.

    Bers DM (2002) Cardiac excitationcontraction coupling. Nature 415:198–205

  15. 15.

    Bers DM (2001) Excitation-contraction coupling and cardiac contractile force. Kluwer Academic Publisher,Dordrecht, The Netherlands

  16. 16.

    Bers DM, Pogwizd SM, Schlotthauer K (2002) Upregulated Na/Ca exchange is involved in both contractile dysfunction and arrhythmogenesis in heart failure. Basic Res Cardiol 97 (Suppl 1):I36–42

  17. 17.

    Beuckelmann DJ, Näbauer M, Erdmann E (1992) Intracellular calcium handling in isolated ventricular myocytes from patients with terminal heart failure. Circulation 85:1046–1055

  18. 18.

    Beutner G, Sharma VK, Giovannucci DR, Yule DI, Sheu SS (2001) Identification of a ryanodine receptor in rat heart mitochondria. J Biol Chem 276:21482–21488

  19. 19.

    Beutner G, Sharma VK, Lin L, Ryu SY, Dirksen RT, Sheu SS (2005) Type 1 ryanodine receptor in cardiac mitochondria: transducer of excitation-metabolism coupling. Biochim Biophys Acta 1717:1–10

  20. 20.

    Bootman MD, Higazi DR, Coombes S, Roderick HL (2006) Calcium signalling during excitation-contraction coupling in mammalian atrial myocytes. J Cell Sci 119:3915–3925

  21. 21.

    Bose S, French S, Evans FJ, Joubert F, Balaban RS (2003) Metabolic network control of oxidative phosphorylation: multiple roles of inorganic phosphate. J Biol Chem 278:39155–39165

  22. 22.

    Bowditch HP (1871) Über die Eigenthümlichkeiten der Reizbarkeit, welche die Muskelfasern des Herzens zeigen. Ber Sächs Akad Wiss 23:652–689

  23. 23.

    Brandes R, Bers DM (1999) Analysis of the mechanisms of mitochondrial NADH regulation in cardiac trabeculae. Biophys J 77:1666–1682

  24. 24.

    Brandes R, Bers DM (1996) Increased work in cardiac trabeculae causes decreased mitochondrial NADH fluorescence followed by slow recovery. Biophys J 71:1024–1035

  25. 25.

    Brandes R, Bers DM (1997) Intracellular Ca2+ increases the mitochondrial NADH concentration during elevated work in intact cardiac muscle. Circ Res 80:82–87

  26. 26.

    Brandes R, Bers DM (2002) Simultaneous measurements of mitochondrial NADH and Ca(2+) during increased work in intact rat heart trabeculae. Biophys J 83:587–604

  27. 27.

    Brandes R, Maier LS, Bers DM (1998) Regulation of mitochondrial [NADH] by cytosolic [Ca2+] and work in trabeculae from hypertrophic and normal rat hearts. Circ Res 82:1189–1198

  28. 28.

    Brodde OE, Michel MC (1999) Adrenergic and muscarinic receptors in the human heart. Pharmacol Rev 51:651–690

  29. 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:C817–833

  30. 30.

    Buntinas L, Gunter KK, Sparagna GC, Gunter TE (2001) The rapid mode of calcium uptake into heart mitochondria (RaM): comparison to RaM in liver mitochondria. Biochim Biophys Acta 1504:248–261

  31. 31.

    Cannell MB, Cheng H, Lederer WJ (1994) Spatial non-uniformities in [Ca2+]i during excitation-contraction coupling in cardiac myocytes. Biophys J 67:1942–1956

  32. 32.

    Cannell MB, Crossman DJ, Soeller C (2006) Effect of changes in action potential spike configuration, junctional sarcoplasmic reticulum micro-architecture and altered t-tubule structure in human heart failure. J Muscle Res Cell Motil 27:297–306

  33. 33.

    Chacon E, Ohata H, Harper IS, Trollinger DR, Herman B, Lemasters JJ (1996) Mitochondrial free calcium transients during excitation-contraction coupling in rabbit cardiac myocytes. FEBS Lett 382:31–36

  34. 34.

    Chaitman BR (2006) Ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions. Circulation 113:2462–2472

  35. 35.

    Chamberlain BK, Volpe P, Fleischer S (1984) Inhibition of calcium-induced calcium release from purified cardiac sarcoplasmic reticulum vesicles. J Biol Chem 259:7547–7553

  36. 36.

    Chance B (1965) The Energy-Linked Reaction of Calcium with Mitochondria. J Biol Chem 240:2729–2748

  37. 37.

    Chance B, Williams GR (1955) A method for the localization of sites for oxidative phosphorylation. Nature 176:250–254

  38. 38.

    Chandler MP, Stanley WC, Morita H, Suzuki G, Roth BA, Blackburn B, Wolff A, Sabbah HN (2002) Short-term treatment with ranolazine improves mechanical efficiency in dogs with chronic heart failure. Circ Res 91:278–280

  39. 39.

    Chazov EI, Smirnov VN, Saks VA, Rosenshtraukh LV, Lipina NV, Levitsky DO (1980) Energy metabolism and ion fluxes across cardiac membranes. Adv Myocardiol 1:139–153

  40. 40.

    Chen L, Chen CX, Gan XT, Beier N, Scholz W, Karmazyn M (2004) Inhibition and reversal of myocardial infarction- induced hypertrophy and heart failure by NHE-1 inhibition. Am J Physiol Heart Circ Physiol 286:H381–387

  41. 41.

    Chen X, Piacentino V, 3rd, Furukawa S, Goldman B, Margulies KB, Houser SR (2002) L-type Ca2+ channel density and regulation are altered in failing human ventricular myocytes and recover after support with mechanical assist devices. Circ Res 91:517–524

  42. 42.

    Cheng H, Lederer WJ, Cannell MB (1993) Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle. Science 262:740–744

  43. 43.

    Chen-Izu Y, McCulle SL, Ward CW, Soeller C, Allen BM, Rabang C, Cannell MB, Balke CW, Izu LT (2006) Three-dimensional distribution of ryanodine receptor clusters in cardiac myocytes. Biophys J 91:1–13

  44. 44.

    Collins TJ, Lipp P, Berridge MJ, Bootman MD (2001) Mitochondrial Ca(2+) uptake depends on the spatial and temporal profile of cytosolic Ca(2+) signals. J Biol Chem 276:26411–26420

  45. 45.

    Cortassa S, Aon MA, Marban E, Winslow RL, O'Rourke B (2003) An integrated model of cardiac mitochondrial energy metabolism and calcium dynamics. Biophys J 84:2734–2755

  46. 46.

    Cortassa S, Aon MA, O'Rourke B, Jacques R, Tseng HJ, Marban E, Winslow RL (2006) A computational model integrating electrophysiology, contraction, and mitochondrial bioenergetics in the ventricular myocyte. Biophys J 91:1564–1589

  47. 47.

    Cox DA, Matlib MA (1993) A role for the mitochondrial Na(+)-Ca2+ exchanger in the regulation of oxidative phosphorylation in isolated heart mitochondria. J Biol Chem 268:938–947

  48. 48.

    Crompton M (1980) The sodium ion/calcium ion cycle of cardiac mitochondria. Biochem Soc Trans 8:261–262

  49. 49.

    Crompton M, Kunzi M, Carafoli E (1977) The calcium-induced and sodium-induced effluxes of calcium from heart mitochondria. Evidence for a sodium-calcium carrier. Eur J Biochem 79:549–558

  50. 50.

    Davidson SM, Duchen MR (2006) Calcium microdomains and oxidative stress. Cell Calcium 40:561–574

  51. 51.

    del Monte F, Harding SE, Dec GW, Gwathmey JK, Hajjar RJ (2002) Targeting phospholamban by gene transfer in human heart failure. Circulation 105:904–907

  52. 52.

    del Monte F, Williams E, Lebeche D, Schmidt U, Rosenzweig A, Gwathmey JK, Lewandowski ED, Hajjar RJ (2001) Improvement in survival and cardiac metabolism after gene transfer of sarcoplasmic reticulum Ca(2+)-ATPase in a rat model of heart failure. Circulation 104:1424–1429

  53. 53.

    Denton RM, McCormack JG (1990) Ca2+ as a second messenger within mitochondria of the heart and other tissues. Annual Review of Physiology 52:451–466

  54. 54.

    Denton RM, McCormack JG (1985) Ca2+ transport by mammalian mitochondria and its role in hormone action. Am J Physiol 249:E543–554

  55. 55.

    Denton RM, McCormack JG, Edgell NJ (1980) Role of calcium ions in the regulation of intramitochondrial metabolism. Effects of Na+ , Mg2+ and ruthenium red on the Ca2+ -stimulated oxidation of oxoglutarate and on pyruvate dehydrogenase activity in intact rat heart mitochondria. Biochem J 190:107–117

  56. 56.

    Denton RM, Randle PJ, Martin BR (1972) Stimulation by calcium ions of pyruvate dehydrogenase phosphate phosphatase. Biochem J 128:161–163

  57. 57.

    Denton RM, Richards DA, Chin JG (1978) Calcium ions and the regulation of NAD+-linked isocitrate dehydrogenase from the mitochondria of rat heart and other tissues. Biochem J 176:899–906

  58. 58.

    Despa S, Islam MA,Weber CR, Pogwizd SM, Bers DM (2002) Intracellular Na(+) concentration is elevated in heart failure but Na/K pump function is unchanged. Circulation 105:2543–2548

  59. 59.

    Di Lisa F, Fan CZ, Gambassi G, Hogue BA, Kudryashova I, Hansford RG (1993) Altered pyruvate dehydrogenase control and mitochondrial free Ca2+ in hearts of cardiomyopathic hamsters. Am J Physiol 264:H2188–2197

  60. 60.

    Di Lisa F, Gambassi G, Spurgeon H, Hansford RG (1993) Intramitochondrial free calcium in cardiac myocytes in relation to dehydrogenase activation. Cardiovasc Res 27:1840–1844

  61. 61.

    Duchen MR, Leyssens A, Crompton M (1998) Transient mitochondrial depolarizations reflect focal sarcoplasmic reticular calcium release in single rat cardiomyocytes. J Cell Biol 142:975–988

  62. 62.

    Engelhardt S, Hein L, Keller U, Klambt K, Lohse MJ (2002) Inhibition of Na(+)- H(+) exchange prevents hypertrophy, fibrosis, and heart failure in beta(1)- adrenergic receptor transgenic mice. Circ Res 90:814–819

  63. 63.

    Fabiato A (1985) Simulated calcium current can both cause calcium loading in and trigger calcium release from the sarcoplasmic reticulum of a skinned canine cardiac Purkinje cell. J Gen Physiol 85:291–320

  64. 64.

    Fabiato A (1985) Time and calcium dependence of activation and inactivation of calcium-induced release of calcium from the sarcoplasmic reticulum of a skinned canine cardiac Purkinje cell. J Gen Physiol 85:247–289

  65. 65.

    Flesch M, Schwinger RH, Schiffer F, Frank K, Sudkamp M, Kuhn-Regnier F, Arnold G, Bohm M (1996) Evidence for functional relevance of an enhanced expression of the Na(+)-Ca2+ exchanger in failing human myocardium. Circulation 94:992–1002

  66. 66.

    Frank O (1885) Zur Dynamik des Herzmuskels. Z Biologie 32:370–447

  67. 67.

    Fry CH, Powell T, Twist VW, Ward JP (1984) Net calcium exchange in adult rat ventricular myocytes: an assessment of mitochondrial calcium accumulating capacity. Proc R Soc Lond B Biol Sci 223:223–238

  68. 68.

    Gallitelli MF, Schultz M, Isenberg G, Rudolf F (1999) Twitch-potentiation increases calcium in peripheral more than in central mitochondria of guineapig ventricular myocytes. J Physiol 518 (Pt 2):433–447

  69. 69.

    Gavin CE,Gunter KK,Gunter TE (1990) Manganese and calcium efflux kinetics in brain mitochondria. Relevance to manganese toxicity. Biochem J 266: 329–334

  70. 70.

    Gavin CE, Gunter KK, Gunter TE (1992) Mn2+ sequestration by mitochondria and inhibition of oxidative phosphorylation. Toxicol Appl Pharmacol 115:1–5

  71. 71.

    Gomez AM, Valdivia HH, Cheng H, Lederer MR, Santana LF, Cannell MB, Mc- Cune SA, Altschuld RA, Lederer WJ (1997) Defective excitation-contraction coupling in experimental cardiac hypertrophy and heart failure. Science 276:800–806

  72. 72.

    Griffiths EJ (1999) Species dependence of mitochondrial calcium transients during excitation-contraction coupling in isolated cardiomyocytes. Biochem Biophys Res Commun 263:554–559

  73. 73.

    Griffiths EJ, Stern MD, Silverman HS (1997) Measurement of mitochondrial calcium in single living cardiomyocytes by selective removal of cytosolic indo 1. Am J Physiol 273:C37–44

  74. 74.

    Griffiths EJ, Wei SK, Haigney MC, Ocampo CJ, Stern MD, Silverman HS (1997) Inhibition of mitochondrial calcium efflux by clonazepam in intact single rat cardiomyocytes and effects on NADH production. Cell Calcium 21:321–329

  75. 75.

    Group TDI (1997) The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 336:525–533

  76. 76.

    Gunter TE, Gunter KK, Sheu SS, Gavin CE (1994) Mitochondrial calcium transport: physiological and pathological relevance. Am J Physiol 267: C313–339

  77. 77.

    Gunter TE, Pfeiffer DR (1990) Mechanisms by which mitochondria transport calcium. Am J Physiol 258:C755–786

  78. 78.

    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

  79. 79.

    Hansford RG (1985) Relation between mitochondrial calcium transport and control of energy metabolism. Rev Physiol Biochem Pharmacol 102:1–72

  80. 80.

    Harris DA, Das AM (1991) Control of mitochondrial ATP synthesis in the heart. Biochem J 280 (Pt 3):561–573

  81. 81.

    Harris DM,Mills GD, Chen X, Kubo H, Berretta RM, Votaw VS, Santana LF, Houser SR (2005) Alterations in early action potential repolarization causes localized failure of sarcoplasmic reticulum Ca2+ release. Circ Res 96:543–550

  82. 82.

    Hasenfuss G, Maier LS, Hermann HP, Luers C, Hunlich M, Zeitz O, Janssen PM, Pieske B (2002) Influence of pyruvate on contractile performance and Ca(2+) cycling in isolated failing human myocardium. Circulation 105:194–199

  83. 83.

    Hasenfuss G,Mulieri LA, Allen PD, Just H, Alpert NR (1996) Influence of isoproterenol and ouabain on excitationcontraction coupling, cross-bridge function, and energetics in failing human myocardium. Circulation 94:3155–3160

  84. 84.

    Hasenfuss G, Pieske B (2002) Calcium cycling in congestive heart failure. J Mol Cell Cardiol 34:951–969

  85. 85.

    Hasenfuss G, Schillinger W, Lehnart SE, Preuss M, Pieske B, Maier LS, Prestle J, Minami K, Just H (1999) Relationship between Na+-Ca2+-exchanger protein levels and diastolic function of failing human myocardium. Circulation 99: 641–648

  86. 86.

    He J, Conklin MW, Foell JD,Wolff MR, Haworth RA, Coronado R, Kamp TJ (2001) Reduction in density of transverse tubules and L-type Ca(2+) channels in canine tachycardia-induced heart failure. Cardiovasc Res 49:298–307

  87. 87.

    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

  88. 88.

    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

  89. 89.

    Hermann HP, Zeitz O, Lehnart SE, Keweloh B, Datz N, Hasenfuss G, Janssen PM (2002) Potentiation of betaadrenergic inotropic response by pyruvate in failing human myocardium. Cardiovasc Res 53:116–123

  90. 90.

    Hille B (2001) Ion Channels of Excitable Membranes. Sinauer Associates, Sunderland, Massachusetts

  91. 91.

    Hobai IA, Maack C, O'Rourke B (2004) Partial inhibition of sodium/calcium exchange restores cellular calcium handling in canine heart failure. Circ Res 95:292–299

  92. 92.

    Hobai IA, O'Rourke B (2001) Decreased sarcoplasmic reticulum calcium content is responsible for defective excitationcontraction coupling in canine heart failure. Circulation 103:1577–1584

  93. 93.

    Hobai IA, O'Rourke B (2000) Enhanced Ca(2+)-activated Na(+)-Ca(2+) exchange activity in canine pacing-induced heart failure. Circ Res 87:690–698

  94. 94.

    Houser SR, Margulies KB (2003) Is depressed myocyte contractility centrally involved in heart failure? Circ Res 92:350–358

  95. 95.

    Huser J, Blatter LA, Sheu SS (2000) Mitochondrial calcium in heart cells: beat-to-beat oscillations or slow integration of cytosolic transients? J Bioenerg Biomembr 32:27–33

  96. 96.

    Ide T, Tsutsui H, Hayashidani S, Kang D, Suematsu N, Nakamura K, Utsumi H, Hamasaki N, Takeshita A (2001) Mitochondrial DNA damage and dysfunction associated with oxidative stress in failing hearts after myocardial infarction. Circ Res 88:529–535

  97. 97.

    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

  98. 98.

    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

  99. 99.

    Ingwall JS,Weiss RG (2004) Is the failing heart energy starved? On using chemical energy to support cardiac function. Circ Res 95:135–145

  100. 100.

    Isenberg G, Han S, Schiefer A,Wendt- Gallitelli MF (1993) Changes in mitochondrial calcium concentration during the cardiac contraction cycle. Cardiovasc Res 27:1800–1809

  101. 101.

    Jo H,Noma A,Matsuoka S (2006) Calcium- mediated coupling between mitochondrial substrate dehydrogenation and cardiac workload in single guinea-pig ventricular myocytes. J Mol Cell Cardiol 40:394–404

  102. 102.

    Jones PP, Bazzazi H, Kargacin GJ, Colyer J (2006) Inhibition of cAMP-dependent protein kinase under conditions occurring in the cardiac dyad during a Ca2+ transient. Biophys J 91:433–443

  103. 103.

    Jung DW, Baysal K, Brierley GP (1995) The sodium-calcium antiport of heart mitochondria is not electroneutral. J Biol Chem 270:672–678

  104. 104.

    Kaasik A, Veksler V, Boehm E, Novotova M,Minajeva A,Ventura-Clapier R (2001) Energetic crosstalk between organelles: architectural integration of energy production and utilization. Circ Res 89:153–159

  105. 105.

    Kammermeier H (1987) High energy phosphate of the myocardium: concentration versus free energy change. Basic Res Cardiol 82 (Suppl 2):31–36

  106. 106.

    Katz LA, Koretsky AP, Balaban RS (1988) Activation of dehydrogenase activity and cardiac respiration: a 31P-NMR study. Am J Physiol 255: H185–188

  107. 107.

    Katz LA, Koretsky AP, Balaban RS (1987) Respiratory control in the glucose perfused heart. A 31P NMR and NADH fluorescence study. FEBS Lett 221:270–276

  108. 108.

    Katz LA, Swain JA, Portman MA, Balaban RS (1989) Relation between phosphate metabolites and oxygen consumption of heart in vivo. Am J Physiol 256:H265–274

  109. 109.

    Kirichok Y, Krapivinsky G, Clapham DE (2004) The mitochondrial calcium uniporter is a highly selective ion channel. Nature 427:360–364

  110. 110.

    Kockskamper J, Sheehan KA, Bare DJ, Lipsius SL, Mignery GA, Blatter LA (2001) Activation and propagation of Ca(2+) release during excitation-contraction coupling in atrial myocytes. Biophys J 81:2590–2605

  111. 111.

    Lee BH, Seo HW, Yi KY, Lee S, Yoo SE (2005) Effects of KR-32570, a new Na+/H+ exchanger inhibitor, on functional and metabolic impairments produced by global ischemia and reperfusion in the perfused rat heart. Eur J Pharmacol 511:175–182

  112. 112.

    Lehnart SE, Wehrens XH, Marks AR (2005) Defective ryanodine receptor interdomain interactions may contribute to intracellular Ca2+ leak: a novel therapeutic target in heart failure. Circulation 111:3342–3346

  113. 113.

    Litwin SE, Zhang D, Bridge JH (2000) Dyssynchronous Ca(2+) sparks in myocytes from infarcted hearts. Circ Res 87:1040–1047

  114. 114.

    Liu T, O'Rourke B (2007) Enhancing Mitochondrial Ca2+ Uptake Restores Energy Supply and Demand Matching at High Cytosolic Na+ in Cardiomyocytes. Biophys J 92:2198-Pos/B2414 (Abstract)

  115. 115.

    Louch WE, Bito V, Heinzel FR, Macianskiene R, Vanhaecke J, Flameng W, Mubagwa K, Sipido KR (2004) Reduced synchrony of Ca2+ release with loss of T-tubules – a comparison to Ca2+ release in human failing cardiomyocytes. Cardiovasc Res 62:63–73

  116. 116.

    Luo W, Grupp IL, Harrer J, Ponniah S, Grupp G, Duffy JJ, Doetschman T, Kranias EG (1994) Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of beta-agonist stimulation. Circ Res 75:401–409

  117. 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

  118. 118.

    Maack C, Ganesan A, Sidor A, O'Rourke B (2005) Cardiac sodiumcalcium exchanger is regulated by allosteric calcium and exchanger inhibitory peptide at distinct sites. Circ Res 96:91–99

  119. 119.

    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

  120. 120.

    Maier LS, Bers DM (2007) Role of Ca2+/calmodulin-dependent protein kinase (CaMK) in excitation-contraction coupling in the heart. Cardiovasc Res 73:631–640

  121. 121.

    Maltsev VA, Sabbah HN, Undrovinas AI (2001) Late sodium current is a novel target for amiodarone: studies in failing human myocardium. J Mol Cell Cardiol 33:923–932

  122. 122.

    Marx SO, Reiken S, Hisamatsu Y, Jayaraman T, Burkhoff D, Rosemblit N, Marks AR (2000) PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell 101:365–376

  123. 123.

    Masumiya H, Tsujikawa H, Hino N, Ochi R (2003) Modulation of manganese currents by 1:4-dihydropyridines, isoproterenol and forskolin in rabbit ventricular cells. Pflugers Arch 446:695–701

  124. 124.

    Matlib MA, Zhou Z, Knight S, Ahmed S, Choi KM, Krause-Bauer J, Phillips R, Altschuld R, Katsube Y, Sperelakis N, Bers DM (1998) Oxygen-bridged dinuclear ruthenium amine complex specifically inhibits Ca2+ uptake into mitochondria in vitro and in situ in single cardiac myocytes. J Biol Chem 273:10223–10231

  125. 125.

    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

  126. 126.

    McCormack JG, Browne HM, Dawes NJ (1989) Studies on mitochondrial Ca2+-transport and matrix Ca2+ using fura-2-loaded rat heart mitochondria. Biochim Biophys Acta 973:420–427

  127. 127.

    McCormack JG, Denton RM (1979) The effects of calcium ions and adenine nucleotides on the activity of pig heart 2-oxoglutarate dehydrogenase complex. Biochem J 180:533–544

  128. 128.

    McCormack JG, Denton RM (1984) Role of Ca2+ ions in the regulation of intramitochondrial metabolism in rat heart. Evidence from studies with isolated mitochondria that adrenaline activates the pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase complexes by increasing the intramitochondrial concentration of Ca2+. Biochem J 218:235–247

  129. 129.

    McCormack JG,Halestrap AP, Denton RM (1990) Role of calcium ions in regulation of mammalian intramitochondrial metabolism.Physiol Rev 70:391–425

  130. 130.

    McCutcheon LJ, Cory CR, Nowack L, Shen H, Mirsalami M, Lahucky R, Kovac L, O'Grady M, Horne R, O'Brien PJ (1992) Respiratory chain defect of myocardial mitochondria in idiopathic dilated cardiomyopathy of Doberman pinscher dogs. Can J Physiol Pharmacol 70:1529–1533

  131. 131.

    Mewes T, Ravens U (1994) L-type calcium currents of human myocytes from ventricle of non-failing and failing hearts and from atrium. J Mol Cell Cardiol 26:1307–1320

  132. 132.

    Meyer M, Keweloh B, Guth 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

  133. 133.

    Michailova A, McCulloch A (2001) Model study of ATP and ADP buffering, transport of Ca(2+) and Mg(2+), and regulation of ion pumps in ventricular myocyte. Biophys J 81:614–629

  134. 134.

    Minamisawa S, Hoshijima M, Chu G, Ward CA, Frank K,Gu Y,Martone ME, Wang Y, Ross J, Jr., Kranias EG, Giles WR, Chien KR (1999) Chronic phospholamban- sarcoplasmic reticulum calcium ATPase interaction is the critical calcium cycling defect in dilated cardiomyopathy. Cell 99:313–322

  135. 135.

    Miura T, Ogawa T, Suzuki K, Goto M, Shimamoto K (1997) Infarct size limitation by a new Na(+)-H+ exchange inhibitor, Hoe 642: difference from preconditioning in the role of protein kinase C. J Am Coll Cardiol 29:693–701

  136. 136.

    Miyata H, Lakatta EG, Stern MD, Silverman HS (1992) Relation of mitochondrial and cytosolic free calcium to cardiac myocyte recovery after exposure to anoxia. Circ Res 71:605–613

  137. 137.

    Miyata H, Silverman HS, Sollott SJ, Lakatta EG, Stern MD, Hansford RG (1991) Measurement of mitochondrial free Ca2+ concentration in living single rat cardiac myocytes. Am J Physiol 261:H1123–1134

  138. 138.

    Moore CL (1971) Specific inhibition of mitochondrial Ca++ transport by ruthenium red. Biochem Biophys Res Commun 42:298–305

  139. 139.

    Mootha VK, Arai AE, Balaban RS (1997) Maximum oxidative phosphorylation capacity of the mammalian heart. Am J Physiol 272:H769–775

  140. 140.

    Moravec CS, Bond M (1991) Calcium is released from the junctional sarcoplasmic reticulum during cardiac muscle contraction. Am J Physiol 260:H989–997

  141. 141.

    Moravec CS, Bond M (1992) Effect of inotropic stimulation on mitochondrial calcium in cardiac muscle. J Biol Chem 267:5310–5316

  142. 142.

    Morris K (2002) Targeting the myocardial sodium-hydrogen exchange for treatment of heart failure. Expert Opin Ther Targets 6:291–298

  143. 143.

    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

  144. 144.

    Ohata H, Chacon E, Tesfai SA, Harper IS,Herman B, Lemasters JJ (1998) Mitochondrial Ca2+ transients in cardiac myocytes during the excitation-contraction cycle: effects of pacing and hormonal stimulation. J Bioenerg Biomembr 30:207–222

  145. 145.

    Ohler A, Houser S, Tomaselli GF, O'Rourke B (2001) Transverse tubules are unchanged in myocytes from failing human hearts. Biophys J 80:590e (abstract)

  146. 146.

    O'Rourke B, Kass DA, Tomaselli GF, Kaab S, Tunin R, Marban E (1999) Mechanisms of altered excitationcontraction coupling in canine tachycardia- induced heart failure, I: experimental studies. Circ Res 84:562–570

  147. 147.

    Pacher P, Csordas P, Schneider T, Hajnoczky G (2000) Quantification of calcium signal transmission from sarco-endoplasmic reticulum to the mitochondria. J Physiol 529 Pt 3: 553–564

  148. 148.

    Pacher P, Thomas AP, Hajnoczky G (2002) Ca2+ marks: miniature calcium signals in single mitochondria driven by ryanodine receptors. Proc Natl Acad Sci U S A 99:2380–2385

  149. 149.

    Patterson SW, Piper H, Starling EH (1914) The regulation of the heartbeat. J Physiol 48:357–379

  150. 150.

    Paucek P, Jaburek M (2004) Kinetics and ion specificity of Na(+)/Ca(2+) exchange mediated by the reconstituted beef heart mitochondrial Na(+)/Ca(2+) antiporter. Biochim Biophys Acta 1659:83–9148

  151. 151.

    Peskoff A, Langer GA (1998) Calcium concentration and movement in the ventricular cardiac cell during an excitation- contraction cycle. Biophys J 74:153–174

  152. 152.

    Peskoff A, Post JA, Langer GA (1992) Sarcolemmal calcium binding sites in heart: II.Mathematical model for diffusion of calcium released from the sarcoplasmic reticulum into the diadic region. J Membr Biol 129:59–69

  153. 153.

    Piacentino V, 3rd, Weber CR, Chen X, Weisser-Thomas J,Margulies KB, Bers DM,Houser SR (2003) Cellular basis of abnormal calcium transients of failing human ventricular myocytes.Circ Res 92:651–658

  154. 154.

    Pieske B,Houser SR (2003) [Na+]i handling in the failing human heart. Cardiovasc Res 57:874–886

  155. 155.

    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

  156. 156.

    Pogwizd SM, Sipido KR, Verdonck F, Bers DM (2003) Intracellular Na in animal models of hypertrophy and heart failure: contractile function and arrhythmogenesis. Cardiovasc Res 57:887–896

  157. 157.

    Reed KC, Bygrave FL (1974) A low molecular weight ruthenium complex inhibitory to mitochondrial Ca2+ transport. FEBS Lett 46:109–114

  158. 158.

    Rice JJ, Jafri MS, Winslow RL (1999) Modeling gain and gradedness of Ca2+ release in the functional unit of the cardiac diadic space. Biophys J 77:1871–1884

  159. 159.

    Rizzuto R, Duchen MR, Pozzan T (2004) Flirting in little space: the ER/mitochondria Ca2+ liaison. Sci STKE 2004:re1

  160. 160.

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

  161. 161.

    Robert V, Gurlini P, Tosello V, Nagai T, Miyawaki A,Di Lisa F,Pozzan T (2001) Beat-to-beat oscillations of mitochondrial [Ca2+] in cardiac cells. Embo J 20:4998–5007

  162. 162.

    Ruiz-Meana M,Garcia-Dorado D,Pina P, Inserte J, Agullo L, Soler-Soler J (2003) Cariporide preserves mitochondrial proton gradient and delays ATP depletion in cardiomyocytes during ischemic conditions. Am J Physiol Heart Circ Physiol 285:H999–1006

  163. 163.

    Sabbah HN, Chandler MP,Mishima T, Suzuki G, Chaudhry P, Nass O, Biesiadecki BJ, Blackburn B,Wolff A, Stanley WC (2002) Ranolazine, a partial fatty acid oxidation (pFOX) inhibitor, improves left ventricular function in dogs with chronic heart failure. J Card Fail 8:416–422

  164. 164.

    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

  165. 165.

    Saks VA, Kuznetsov AV, Vendelin M, Guerrero K, Kay L, Seppet EK (2004) Functional coupling as a basic mechanism of feedback regulation of cardiac energy metabolism. Mol Cell Biochem 256–257:185–199

  166. 166.

    Saupe KW, Spindler M,Tian R, Ingwall JS (1998) Impaired cardiac energetics in mice lacking muscle-specific isoenzymes of creatine kinase. Circ Res 82:898–907

  167. 167.

    Scaduto RC, Jr.,Grotyohann LW (2000) 2,3-butanedione monoxime unmasks Ca(2+)-induced NADH formation and inhibits electron transport in rat hearts. Am J Physiol Heart Circ Physiol 279:H1839–18

  168. 168.

    Scholz W, Albus U, Counillon L, Gogelein H, Lang HJ, Linz W,Weichert A, Scholkens BA (1995) Protective effects of HOE642, a selective sodiumhydrogen exchange subtype 1 inhibitor, on cardiac ischaemia and reperfusion. Cardiovasc Res 29:260–268

  169. 169.

    Schwinger RH, Bundgaard H, Muller- Ehmsen J, Kjeldsen K (2003) The Na, K-ATPase in the failing human heart. Cardiovasc Res 57:913–920

  170. 170.

    Sedova M, Dedkova EN, Blatter LA (2006) Integration of rapid cytosolic Ca2+ signals by mitochondria in cat ventricular myocytes. Am J Physiol Cell Physiol 291:C840–850

  171. 171.

    Seguchi H, Ritter M, Shizukuishi M, Ishida H, Chokoh G, Nakazawa H, Spitzer KW, Barry WH (2005) Propagation of Ca2+ release in cardiac myocytes: role of mitochondria. Cell Calcium 38:1–9

  172. 172.

    Semb SO,Lunde PK,Holt E,Tonnessen T, Christensen G, Sejersted OM (1998) Reduced myocardial Na+ , K(+)-pump capacity in congestive heart failure following myocardial infarction in rats. J Mol Cell Cardiol 30:1311–1328

  173. 173.

    Sham JS, Song LS, Chen Y, Deng LH, Stern MD,Lakatta EG, Cheng H (1998) Termination of Ca2+ release by a local inactivation of ryanodine receptors in cardiac myocytes. Proc Natl Acad Sci U S A 95:15096–15101

  174. 174.

    Shannon TR,Wang F, Puglisi J,Weber C, Bers DM (2004) A mathematical treatment of integrated Ca dynamics within the ventricular myocyte. Biophys J 87:3351–3371

  175. 175.

    Shao Q, Ren B, Elimban V, Tappia PS, Takeda N, Dhalla NS (2005) Modification of sarcolemmal Na+-K+-ATPase and Na+/Ca2+ exchanger expression in heart failure by blockade of renin-angiotensin system. Am J Physiol Heart Circ Physiol 288:H2637–2646

  176. 176.

    Sharma VK, Ramesh V, Franzini-Armstrong C, Sheu SS (2000) Transport of Ca2+ from sarcoplasmic reticulum to mitochondria in rat ventricular myocytes. J Bioenerg Biomembr 32:97–104

  177. 177.

    Shen JX, Wang S, Song LS, Han T, Cheng H (2004) Polymorphism of Ca2+ sparks evoked from in-focus Ca2+ release units in cardiac myocytes. Biophys J 86:182–190

  178. 178.

    Sipido KR, Volders PG, Vos MA, Verdonck F (2002) Altered Na/Ca exchange activity in cardiac hypertrophy and heart failure: a new target for therapy? Cardiovasc Res 53:782–805

  179. 179.

    Sipido KR, Wier WG (1991) Flux of Ca2+ across the sarcoplasmic reticulum of guinea-pig cardiac cells during excitation-contraction coupling. J Physiol 435:605–630

  180. 180.

    Smets I, Caplanusi A, Despa S,Molnar Z, Radu M, VandeVen M, Ameloot M, Steels P (2004) Ca2+ uptake in mitochondria occurs via the reverse action of the Na+/Ca2+ exchanger in metabolically inhibited MDCK cells. Am J Physiol Renal Physiol 286:F784–794

  181. 181.

    Soeller C, Cannell MB (2002) Estimation of the sarcoplasmic reticulum Ca2+ release flux underlying Ca2+ sparks. Biophys J 82:2396–2414

  182. 182.

    Song LS, Guatimosim S, Gomez- Viquez L, Sobie EA, Ziman A, Hartmann H, Lederer WJ (2005) Calcium biology of the transverse tubules in heart. Ann N Y Acad Sci 1047:99–111

  183. 183.

    Song LS, Sham JS, Stern MD, Lakatta EG, Cheng H (1998) Direct measurement of SR release flux by tracking ‘Ca2+ spikes' in rat cardiac myocytes. J Physiol 512 (Pt 3):677–691

  184. 184.

    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

  185. 185.

    Song Q, Schmidt AG, Hahn HS, Carr AN, Frank B, Pater L, Gerst M, Young K, Hoit BD, McConnell BK, Haghighi K, Seidman CE, Seidman JG, Dorn GW, 2nd, Kranias EG (2003) Rescue of cardiomyocyte dysfunction by phospholamban ablation does not prevent ventricular failure in genetic hypertrophy. J Clin Invest 111:859–867

  186. 186.

    Sparagna GC, Gunter KK, Sheu SS, Gunter TE (1995) Mitochondrial calcium uptake from physiological-type pulses of calcium. A description of the rapid uptake mode. J Biol Chem 270:27510–27515

  187. 187.

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

  188. 188.

    Starling RC, Hammer DF, Altschuld RA (1998) Human myocardial ATP content and in vivo contractile function. Mol Cell Biochem 180:171–177

  189. 189.

    Stromer H, de Groot MC, Horn M, Faul C, Leupold A, Morgan JP, Scholz W, Neubauer S (2000) Na(+)/H(+) exchange inhibition with HOE642 improves postischemic recovery due to attenuation of Ca(2+) overload and prolonged acidosis on reperfusion. Circulation 101:2749–2755

  190. 190.

    Studer R, Reinecke H, Bilger J, Eschenhagen T, Bohm M, Hasenfuss G, Just H, Holtz J, Drexler H (1994) Gene expression of the cardiac Na(+)-Ca2+ exchanger in end-stage human heart failure. Circ Res 75:443–453

  191. 191.

    Szalai G, Csordas G, Hantash BM, Thomas AP, Hajnoczky G (2000) Calcium signal transmission between ryanodine receptors and mitochondria. J Biol Chem 275:15305–15313

  192. 192.

    Taegtmeyer H (2004) Cardiac metabolism as a target for the treatment of heart failure. Circulation 110:894–896

  193. 193.

    Territo PR, French SA, Balaban RS (2001) Simulation of cardiac work transitions, in vitro: effects of simultaneous Ca2+ and ATPase additions on isolated porcine heart mitochondria. Cell Calcium 30:19–27

  194. 194.

    Territo PR, French SA, Dunleavy MC, Evans FJ, Balaban RS (2001) Calcium activation of heart mitochondrial oxidative phosphorylation: rapid kinetics of mVO2, NADH, AND light scattering. J Biol Chem 276:2586–2599

  195. 195.

    Territo PR, Mootha VK, French SA, Balaban RS (2000) Ca(2+) activation of heart mitochondrial oxidative phosphorylation: role of the F(0)/F(1)-ATPase. Am J Physiol Cell Physiol 278:C423–435

  196. 196.

    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:H2064–2071

  197. 197.

    Tian R, Ingwall JS (1996) Energetic basis for reduced contractile reserve in isolated rat hearts. Am J Physiol 270:H1207–1216

  198. 198.

    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

  199. 199.

    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

  200. 200.

    Trollinger DR, Cascio WE, Lemasters JJ (2000) Mitochondrial calcium transients in adult rabbit cardiac myocytes: inhibition by ruthenium red and artifacts caused by lysosomal loading of Ca(2+)-indicating fluorophores. Biophys J 79:39–50

  201. 201.

    Trollinger DR, Cascio WE, Lemasters JJ (1997) Selective loading of Rhod 2 into mitochondria shows mitochondrial Ca2+ transients during the contractile cycle in adult rabbit cardiac myocytes. Biochem Biophys Res Commun 236:738–742

  202. 202.

    Undrovinas AI, Belardinelli L, Undrovinas NA, Sabbah HN (2006) Ranolazine improves abnormal repolarization and contraction in left ventricular myocytes of dogs with heart failure by inhibiting late sodium current. J Cardiovasc Electrophysiol 17 (Suppl 1):S169-S177

  203. 203.

    Undrovinas AI, Maltsev VA, Kyle JW, Silverman N, Sabbah HN (2002) Gating of the late Na+ channel in normal and failing human myocardium. J Mol Cell Cardiol 34:1477–1489

  204. 204.

    Undrovinas AI, Maltsev VA, Sabbah HN (1999) Repolarization abnormalities in cardiomyocytes of dogs with chronic heart failure: role of sustained inward current. Cell Mol Life Sci 55:494–505

  205. 205.

    Valdivia CR, Chu WW, Pu J, Foell JD, Haworth RA, Wolff MR, Kamp TJ, Makielski JC (2005) Increased late sodium current in myocytes from a canine heart failure model and from failing human heart. J Mol Cell Cardiol 38:475–483

  206. 206.

    Verdonck F, Volders PG, Vos MA, Sipido KR (2003) Increased Na+ concentration and altered Na/K pump activity in hypertrophied canine ventricular cells. Cardiovasc Res 57:1035–1043

  207. 207.

    Verdonck F, Volders PG, Vos MA, Sipido KR (2003) Intracellular Na+ and altered Na+ transport mechanisms in cardiac hypertrophy and failure. J Mol Cell Cardiol 35:5–25

  208. 208.

    Weber CR, Ginsburg KS, Philipson KD, Shannon TR, Bers DM (2001) Allosteric regulation of Na/Ca exchange current by cytosolic Ca in intact cardiac myocytes. J Gen Physiol 117:119–131

  209. 209.

    Weber CR, Piacentino V, 3rd, Ginsburg KS,Houser SR, Bers DM (2002) Na(+)- Ca(2+) exchange current and submembrane [Ca(2+)] during the cardiac action potential. Circ Res 90:182–189

  210. 210.

    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

  211. 211.

    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

  212. 212.

    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

  213. 213.

    Wendt-Gallitelli MF, Isenberg G (1991) Total and free myoplasmic calcium during a contraction cycle: x-ray microanalysis in guinea-pig ventricular myocytes. J Physiol 435:349–372

  214. 214.

    White RL, Wittenberg BA (1995) Effects of calcium on mitochondrial NAD(P)H in paced rat ventricular myocytes. Biophys J 69:2790–2799

  215. 215.

    White RL, Wittenberg BA (1993) NADH fluorescence of isolated ventricular myocytes: effects of pacing, myoglobin, and oxygen supply. Biophys J 65:196–204

  216. 216.

    Williamson JR, Ford C, Illingworth J, Safer B (1976) Coordination of citric acid cycle activity with electron transport flux. Circ Res 38:I39–51

  217. 217.

    Winslow RL, Rice J, Jafri S,Marban E, O'Rourke B (1999) Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart failure, II: model studies. Circ Res 84:571–586

  218. 218.

    Xie Z (2003) Molecular mechanisms of Na/K-ATPase-mediated signal transduction. Ann N Y Acad Sci 986:497–503

  219. 219.

    Xu KY, Zweier JL, Becker LC (1995) Functional coupling between glycolysis and sarcoplasmic reticulum Ca2+ transport. Circ Res 77:88–97

  220. 220.

    Yoshikane H, Nihei T, Moriyama K (1986) Three-dimensional observation of intracellular membranous structures in dog heart muscle cells by scanning electron microscopy. J Submicrosc Cytol 18:629–636

  221. 221.

    Zhou Z, Bers DM (2002) Time course of action of antagonists of mitochondrial Ca uptake in intact ventricular myocytes. Pflugers Arch 445:132–138

  222. 222.

    Zhou Z, Matlib MA, Bers DM (1998) Cytosolic and mitochondrial Ca2+ signals in patch clamped mammalian ventricular myocytes. J Physiol 507 (Pt 2):379–403

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

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Key words

  • calcium
  • sodium
  • microdomain
  • heart failure
  • adenosine triphosphate
  • adenosine diphosphate
  • respiration
  • tricarboxylic acid cycle