Cardiovasc Res 81(3): 412-419

Energy metabolism in heart failure and remodelling

NMR Laboratory for Physiological Chemistry, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue, Room 247, Boston, MA 02115, USA

^{Corresponding author. Tel: +1 617 732 6994; fax: +1 617 732 6990.}E-mail address: ude.dravrah.hwb.scir@llawgnij

Received 2008 Aug 4; Revised 2008 Oct 9; Accepted 2008 Nov 2.

Abstract

Myocytes of the failing heart undergo impressive metabolic remodelling. The time line for changes in the pathways for ATP synthesis in compensated hypertrophy is: flux through the creatine kinase (CK) reaction falls as both creatine concentration ([Cr]) and CK activity fall; increases in [ADP] and [AMP] lead to increases in glucose uptake and utilization; fatty acid oxidation either remains the same or decreases. In uncompensated hypertrophy and in other forms of heart failure, CK flux and fatty acid oxidation are both lower; any increases in glucose uptake and utilization are not sufficient to compensate for overall decreases in the capacity for ATP supply and [ATP] falls. Metabolic remodelling is under transcriptional and post-transcriptional control. The lower metabolic reserve of the failing heart contributes to impaired contractile reserve.

Keywords: Energetics, Heart failure, Metabolic remodelling, Familial hypertrophic cardiomyopathy, Adenosine triphosphate

Abstract

Acknowledgement

The author wishes to thank Linda Johnson for her assistance.

Conflict of interest: none declared.

Acknowledgement

References

1. Ingwall JS ATP and the Heart. Norwell, MA: Kluwer Academic Publishers; 2002. ATP and the heart: an overview; pp. 3–6. [PubMed][Google Scholar]
2. Taegtmeyer H, Wilson CR, Razeghi P, Sharma SMetabolic energetics and genetics in the heart. Ann N Y Acad Sci. 2005;1047:208–218.[PubMed][Google Scholar]
3. Zhang J, Duncker DJ, Ya X, Zhang Y, Pavek T, Wei H, et al. Effect of left ventricular hypertrophy secondary to chronic pressure overload on transmural myocardial 2-deoxyglucose uptake. A ^{P NMR spectroscopic study.}Circulation. 1995;92:1274–1283.[PubMed]
4. Bittl JA, Ingwall JS. Reaction rates of creatine kinase and ATP synthesis in the isolated rat heart. A ^{P NMR magnetization transfer study.}J Biol Chem. 1985;260:3512–3517.[PubMed]
5. Ingwall JS. Boston: Kluwer Academic Publishers; 2002. ATP and the Heart. [PubMed]
6. De Sousa E, Veksler V, Minajeva A, Kaasik A, Mateo P, Mayoux E, et al. Subcellular creatine kinase alterations. Implications in heart failure. Circ Res. 1999;85:68–76.[PubMed]
7. Dzeja PP, Chung S, Terzic A. Integration of adenylate kinase, glycolytic and glycogenolytic circuits in cellular energetics. In: Saks V, editor. Molecular System Bioenergetics: Energy for Life. Weinheim: Wiley-VCH; 2007. [PubMed]
8. Ingwall JSTransgenesis and cardiac energetics: new insights into cardiac metabolism. J Mol Cell Cardiol. 2004;37:613–623.[PubMed][Google Scholar]
9. Dyck JRB, Lopaschuk GDAMPK alterations in cardiac physiology and pathology: enemy or ally? J Physiol. 2006;574:95–112.[Google Scholar]
10. Finck BN, Kelly DPPGC-1 coactivators: inducible regulators of energy metabolism in health and disease. J Clin Invest. 2006;116:615–622.[Google Scholar]
11. Sano M, Izumi Y, Helenius K, Asakura M, Rossi DJ, Xie M, et al Menage-a-trois 1 is critical for the transcriptional function of PPARγ coactivator 1. Cell Metab. 2007;5:129–142.[PubMed][Google Scholar]
12. Ventura-Clapier R, Garnier A, Veksler VTranscriptional control of mitochondrial biogenesis: the central role of PGC-1α Cardiovasc Res. 2008;79:208–217.[PubMed][Google Scholar]
13. Nascimben L, Ingwall JS, Pauletto P, Friedrich J, Gwathmey JK, Saks V, et al Creatine kinase system in failing and nonfailing human myocardium. Circulation. 1996;94:1894–1901.[PubMed][Google Scholar]
14. Weiss RG, Gerstenblith G, Bottomley PAATP flux through creatine kinase in the normal, stressed, and failing human heart. Proc Natl Acad Sci USA. 2005;102:808–813.[Google Scholar]
15. Nascimben L, Ingwall J, Lorell B, Pinz I, Schulta V, Tornheim K, et al Mechanisms for increased glycolysis in the hypertrophied rat heart. Hypertension. 2004;44:662–667.[PubMed][Google Scholar]
16. Degens H, de Brouwer KF, Gilde AJ, Lindhout M, Willemsen PH, Janssen BJ, et al Cardiac fatty acid metabolism is preserved in the compensated hypertrophic rat heart. Basic Res Cardiol. 2006;101:17–26.[PubMed][Google Scholar]
17. Lei B, Lionetti V, Young ME, Chandler MP, d'Agostino C, Kang E, et al Paradoxical downregulation of the glucose oxidation pathway despite enhanced flux in severe heart failure. J Mol Cell Cardiol. 2004;36:567–576.[PubMed][Google Scholar]
18. O'Donnell JM, Fields AD, Sorokina N, Lewandowski EDThe absence of endogenous lipid oxidation in early stage heart failure exposes limits in lipid storage and turnover. J Mol Cell Cardiol. 2008;44:315–322.[Google Scholar]
19. Sorokina N, O'Donnell JM, McKinney RD, Pound KM, Woldegiorgis G, LaNoue KF, et al Recruitment of compensatory pathways to sustain oxidative flux with reduced carnitine palmitoyltransferase I activity characterizes inefficiency in energy metabolism in hypertrophied hearts. Circulation. 2007;115:2033–2041.[PubMed][Google Scholar]
20. Osorio JC, Stanley WC, Linke A, Castellari M, Diep QN, Panchal AR, et al Impaired myocardial fatty acid oxidation and reduced protein expression of retinoid X receptor-alpha in pacing-induced heart failure. Circulation. 2002;106:606–612.[PubMed][Google Scholar]
21. Stanley WC, Recchia FA, Lopaschuk GDMyocardial substrate metabolism in the normal and failing heart. Physiol Rev. 2005;85:1093–1129.[PubMed][Google Scholar]
22. Luptak I, Balschi JA, Xing Y, Leone TC, Kelly DP, Tian RDecreased contractile and metabolic reserve in peroxisome proliferator-activated receptor-alpha-null hearts can be rescued by increasing glucose transport and utilization. Circulation. 2005;112:2339–2346.[PubMed][Google Scholar]
23. Neglia D, De Caterina A, Marraccini P, Natali A, Ciardetti M, Vecoli C, et al Impaired myocardial metabolic reserve and substrate selection flexibility during stress in patients with idiopathic dilated cardiomyopathy. Am J Physiol Heart Circ Physiol. 2007;293:H3270–H3278.[PubMed][Google Scholar]
24. deGoma EM, Vagelos RH, Fowler MB, Ashley EAEmerging therapies for the management of decompensated heart failure: from bench to bedside. J Am Coll Cardiol. 2006;48:2397–2409.[PubMed][Google Scholar]
25. Fragasso GInhibition of free fatty acids metabolism as a therapeutic target in patients with heart failure. Int J Clin Pract. 2007;61:603–610.[PubMed][Google Scholar]
26. Gustafsson AB, Gottlieb RAHeart mitochondria: gates of life and death. Cardiovasc Res. 2007;77:334–343.[PubMed][Google Scholar]
27. Ingwall JS, Weiss RGIs the failing heart energy starved? Circ Res. 2004;95:135–145.[PubMed][Google Scholar]
28. Kodde IF, van der Stok J, Smolenski RT, de Jong JWMetabolic and genetic regulation of cardiac energy substrate preference. Comp Biochem Physiol A. 2006;146:26–39.[PubMed][Google Scholar]
29. Marin-Garcia J, Goldenthal MJMitochondrial centrality in heart failure. Heart Fail Rev. 2008;13:137–150.[PubMed][Google Scholar]
30. Murray AJ, Edwards LM, Clarke KMitochondria and heart failure. Curr Opin Clin Nutr Metab Care. 2007;10:704–711.[PubMed][Google Scholar]
31. Neubauer SThe failing heart—an engine out of fuel. N Engl J Med. 2007;356:1140–1151.[PubMed][Google Scholar]
32. Schwenk RW, Luiken JJ, Bonen A, Glatz JFRegulation of sarcolemmal glucose and fatty acid transporters in cardiac disease. Cardiovasc Res. 2008;79:249–258.[PubMed][Google Scholar]
33. Taha M, Lopaschuk GDAlterations in energy metabolism in cardiomyopathies. Ann Med. 2007;39:594–607.[PubMed][Google Scholar]
34. Tsutsui HMitochondrial oxidative stress and heart failure. Intern Med. 2006;45:809–813.[PubMed][Google Scholar]
35. Ventura-Clapier RF, Garnier A, Veksler VEnergy metabolism in heart failure. J Physiol. 2004;555:1–15.[Google Scholar]
36. Crilley JG, Boehm EA, Blair E, Rajagopalan B, Blamire AM, Styles P, et al Hypertrophic cardiomyopathy due to sarcomeric gene mutations is characterized by impaired energy metabolism irrespective of the degree of hypertrophy. J Am Coll Cardiol. 2003;41:1776–1782.[PubMed][Google Scholar]
37. Jung W, Hoess T, Bunse M, Widmaier S, Sieverding L, Breuer J, et al Differences in cardiac energetics between patients with familial and nonfamilial hypertrophic cardiomyopathy. Circulation. 2000;101:E121.[PubMed][Google Scholar]
38. Jung WI, Sieverding L, Breuer J, Hoess T, Widmaier S, Schmidt O, et al ^{P NMR spectroscopy detects metabolic abnormalities in asymptomatic patients with hypertrophic cardiomyopathy.}Circulation. 1998;97:2536–2542.[PubMed][Google Scholar]
39. He ZH, Bottinelli R, Pellegrino MA, Ferenczi MA, Reggiani CATP consumption and efficiency of human single muscle fibers with different myosin isoform composition. Biophys J. 2000;79:945–961.[Google Scholar]
40. Javadpour MM, Tardiff JC, Pinz I, Ingwall JSDecreased energetics in murine hearts bearing the R92Q mutation in cardiac troponin T. J Clin Invest. 2003;112:768–775.[Google Scholar]
41. Spindler M, Saupe KW, Christe ME, Sweeney HL, Seidman CE, Seidman JG, et al Diastolic dysfunction and altered energetics in the alphaMHC403/+ mouse model of familial hypertrophic cardiomyopathy. J Clin Invest. 1998;101:1775–1783.[Google Scholar]
42. Keller DI, Coirault C, Rau T, Cheav T, Weyand M, Amann K, et al Human homozygous R403W mutant cardiac myosin presents disproportionate enhancement of mechanical and enzymatic properties. J Mol Cell Cardiol. 2004;36:355–362.[PubMed][Google Scholar]
43. Ertz-Berger BR, He H, Dowell C, Factor SM, Haim TE, Nunez S, et al Changes in the chemical and dynamic properties of cardiac troponin T cause discrete cardiomyopathies in transgenic mice. Proc Natl Acad Sci USA. 2005;102:18219–18224.[Google Scholar]
44. Maytum R, Geeves MA, Lehrer SSA modulatory role for the troponin T tail domain in thin filament regulation. J Biol Chem. 2002;277:29774–29780.[PubMed][Google Scholar]
45. Palm T, Graboski S, Hitchcock-DeGregori SE, Greenfield NJDisease-causing mutations in cardiac troponin T: identification of a critical tropomyosin-binding region. Biophys J. 2001;81:2827–2837.[Google Scholar]
46. Tobacman LS, Nihli M, Butters C, Heller M, Hatch V, Craig R, et al The troponin tail domain promotes a conformational state of the thin filament that suppresses myosin activity. J Biol Chem. 2002;277:27636–27642.[PubMed][Google Scholar]
47. Volkmann N, Lui H, Hazelwood L, Trybus KM, Lowey S, Hanein DThe R403Q myosin mutation implicated in familial hypertrophic cardiomyopathy causes disorder at the actomyosin interface. PLoS ONE. 2007;2:e1123.[Google Scholar]
48. Ho CY, Sweitzer NK, McDonough B, Maron BJ, Casey SA, Seidman JG, et al Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy. Circulation. 2002;105:2992–2997.[PubMed][Google Scholar]
49. Tian R, Christe ME, Spindler M, Hopkins JC, Halow JM, Camacho SA, et al Role of MgADP in the development of diastolic dysfunction in the intact beating rat heart. J Clin Invest. 1997;99:745–751.[Google Scholar]
50. Tian R, Nascimben L, Ingwall JS, Lorell BHFailure to maintain a low ADP concentration impairs diastolic function in hypertrophied rat hearts. Circulation. 1997;96:1313–1319.[PubMed][Google Scholar]
51. Ingwall JS. Energetic basis for heart failure—causes and consequences of decreased ATP and phosphocreatine. In: Mann D, editor. Heart Failure: A Companion to Braunwald's Heart Disease. Philadelphia: Saunders; 2004. pp. 91–108. [PubMed]
52. Shen W, Asai K, Uechi M, Mathier MA, Shannon RP, Vatner SF, et al Progressive loss of myocardial ATP due to a loss of total purines during the development of heart failure in dogs: a compensatory role for the parallel loss of creatine. Circulation. 1999;100:2113–2118.[PubMed][Google Scholar]
53. Herrmann G, Decherd MThe chemical nature of heart failure. Ann Intern Med. 1939;12:1233–1244.[PubMed][Google Scholar]
54. Ingwall JSThe hypertrophied myocardium accumulates the MB-creatine kinase isozyme. Eur Heart J. 1984;5:129–139.[PubMed][Google Scholar]
55. Ingwall JS, Kramer MF, Fifer MA, Lorell BH, Shemin R, Grossman W, et al The creatine kinase system in normal and diseased human myocardium. New Engl J Med. 1985;313:1050–1054.[PubMed][Google Scholar]
56. Boehm E, Chan S, Monfared M, Wallimann T, Clarke K, Neubauer SCreatine transporter activity and content in the rat heart supplemented by and depleted of creatine. Am J Physiol Endocrinol Metab. 2003;284:E399–E406.[PubMed][Google Scholar]
57. Neubauer S, Remkes H, Spindler M, Horn M, Weismann F, Prestle J, et al Down regulation of the Na(+)-creatine co-transporter in failing human myocardium and in experimental heart failure. Circulation. 1999;100:1847–1850.[PubMed][Google Scholar]
58. Ten Hove M, Chan S, Lygate C, Monfared M, Boehm E, Hulbert K, et al Mechanisms of creatine depletion in chronically failing rat heart. J Mol Cell Cardiol. 2005;38:309–313.[PubMed][Google Scholar]
59. Strutz-Seebohm N, Shojaiefard M, Christie D, Tavare J, Seebohm G, Lang FPIKfyve in the SGK1 mediated regulation of the creatine transporter SLC6A8. Cell Physiol Biochem. 2007;20:729–734.[PubMed][Google Scholar]
60. Shen W, Spindler M, Higgins M, Jin N, Gill R, Bloem L, et al The fall in creatine levels and creatine kinase isozyme changes in the failing heart are reversible: complex post-transcriptional regulation of the components of the CK system. J Mol Cell Cardiol. 2005;39:537–544.[PubMed][Google Scholar]
61. Park SJ, Zhang J, Ye Y, Ormaza S, Liang P, Bank AJ, et al Myocardial creatine kinase expression after left ventricular assist device support. J Am Coll Cardiol. 2002;39:1773–1779.[PubMed][Google Scholar]
62. Saupe KW, Spindler M, Hopkins JC, Shen W, Ingwall JS. Kinetic, thermodynamic, and developmental consequences of deleting creatine kinase isoenzymes from the heart. Reaction kinetics of the creatine kinase isoenzymes in the intact heart. J Biol Chem. 2000;275:19742–19746.[PubMed]
63. Saupe KW, Spindler M, Tian R, Ingwall JSImpaired cardiac energetics in mice lacking muscle-specific isoenzymes of creatine kinase. Circ Res. 1998;82:898–907.[PubMed][Google Scholar]
64. ten Hove M, Lygate CA, Fischer A, Schneider JE, Sang AE, Hulbert K, et al Reduced inotropic reserve and increased susceptibility to cardiac ischemia/reperfusion injury in phosphocreatine-deficient guanidinoacetate-N-methyltransferase-knockout mice. Circulation. 2005;111:2477–2485.[PubMed][Google Scholar]
65. Tian R, Ingwall JSEnergetic basis for reduced contractile reserve in isolated rat hearts. Am J Physiol. 1996;270:H1207–H1216.[PubMed][Google Scholar]
66. Zweier JL, Jacobus WE, Korecky B, Brandejs-Barry YBioenergetic consequences of cardiac phosphocreatine depletion induced by creatine analogue feeding. J Biol Chem. 1991;266:20296–20304.[PubMed][Google Scholar]
67. Hopkins J, Miao W, Ingwall JParadoxical effects of creatine kinase deletion on systolic and diastolic function in ischemia. Circulation. 1998;98:I–758.[PubMed][Google Scholar]
68. Horn M, Remkes H, Stromer H, Dienesch C, Neubauer SChronic phosphocreatine depletion by the creatine analogue beta-guanidinopropionate is associated with increased mortality and loss of ATP in rats after myocardial infarction. Circulation. 2001;104:1844–1849.[PubMed][Google Scholar]
69. Abraham MR, Selivanov VA, Hodgson DM, Pucar D, Zingman LV, Wieringa B, et al. Coupling of cell energetics with membrane metabolic sensing. Integrative signaling through creatine kinase phosphotransfer disrupted by M-CK gene knock-out. J Biol Chem. 2002;277:24427–24434.[PubMed]
70. Janssen E, Dzeja PP, Oerlemans F, Simonetti AW, Heerschap A, de Haan A, et al Adenylate kinase 1 gene deletion disrupts muscle energetic economy despite metabolic rearrangement. EMBO J. 2000;19:6371–6381.[Google Scholar]
71. Wallis J, Lygate CA, Fischer A, ten Hove M, Schneider JE, Sebag-Montefiore L, et al Supranormal myocardial creatine and phosphocreatine concentrations lead to cardiac hypertrophy and heart failure: insights from creatine transporter-overexpressing transgenic mice. Circulation. 2005;112:3131–3139.[PubMed][Google Scholar]
72. Bak MI, Ingwall JS. Acidosis during ischemia promotes adenosine triphosphate resynthesis in postischemic rat heart. In vivo regulation of 5′-nucleotidase. J Clin Invest. 1994;93:40–49.
73. Tian R, Musi N, D'Agostino J, Hirshman MF, Goodyear LJIncreased adenosine monophosphate-activated protein kinase activity in rat hearts with pressure-overload hypertrophy. Circulation. 2001;104:1664–1669.[PubMed][Google Scholar]
74. Allard MF, Parsons HL, Saeedi R, Wamboldt RB, Brownsey RAMPK and metabolic adaptation by the heart to pressure overload. Am J Physiol Heart Circ Physiol. 2007;292:140–148.[PubMed][Google Scholar]
75. Allard MF, Schonekess BO, Henning SL, English DR, Lopaschuk GDContribution of oxidative metabolism and glycolysis to ATP production in hypertrophied hearts. Am J Physiol. 1994;267:H742–H750.[PubMed][Google Scholar]
76. Liao R, Jain M, Cui L, D'Agostino J, Aiello F, Luptak I, et al Cardiac-specific overexpression of GLUT1 prevents the development of heart failure due to pressure-overload in mice. Circulation. 2002;106:2125–2131.[PubMed][Google Scholar]
77. Gong G, Liu J, Liang P, Guo T, Hu Q, Ochiai K, et al Oxidative capacity in failing hearts. Am J Physiol Heart Circ Physiol. 2003;285:541–548.[PubMed][Google Scholar]
78. Murakami Y, Zhang Y, Cho YK, Mansoor AM, Chung JK, Chu C, et al Myocardial oxygenation during high work states in hearts with postinfarction remodeling. Circulation. 1999;99:942–948.[PubMed][Google Scholar]
79. Kong SW, Bodyak N, Yue P, Liu Z, Brown J, Izumo S, et al Genetic expression profiles during physiological and pathological cardiac hypertrophy and heart failure in rats. Physiol Genomics. 2005;21:31–42.[PubMed][Google Scholar]
80. Arany Z, Wagner BK, Ma Y, Chinsomboon J, Laznik D, Spiegelman BMGene expression-based screening identifies microtubule inhibitors as inducers of PGC-1alpha and oxidative phosphorylation. Proc Natl Acad Sci USA. 2008;105:4721–4726.[Google Scholar]
81. Murray AJ, Cole MA, Lygate CA, Carr CA, Stuckey DJ, Little SE, et al Increased mitochondrial uncoupling proteins, respiratory uncoupling and decreased efficiency in the chronically infarcted rat heart. J Mol Cell Cardiol. 2008;44:694–700.[PubMed][Google Scholar]
82. Sheeran FL, Pepe SEnergy deficiency in the failing heart: linking increased reactive oxygen species and disruption of oxidative phosphorylation rate. Biochem Biophys Acta. 2006;1757:543–552.[PubMed][Google Scholar]
83. Garnier A, Fortin D, Delomenie C, Momken I, Veksler V, Ventura-Clapier RDepressed mitochondrial transcription factors and oxidative capacity in rat failing cardiac and skeletal muscles. J Physiol. 2003;551:491–501.[Google Scholar]
84. Arany Z, He H, Lin J, Hoyer K, Handschin C, Toka O, et al Transcriptional coactivator PGC-1α controls the energy state and contractile function of cardiac muscle. Cell Metab. 2005;1:259–271.[PubMed][Google Scholar]
85. Lehman JJ, Boudina S, Banke NH, Sambandam N, Han X, Young DM, et al The transcriptional coactivator PGC-1α is essential for maximal and efficient cardiac mitochondrial fatty acid oxidation and lipid homeostasis. Am J Physiol Heart Circ Physiol. 2008;295:H185–H196.[Google Scholar]
86. Arany Z, Novikov M, Chin S, Ma Y, Rosenzweig A, Spiegelman BMTransverse aortic constriction leads to accelerated heart failure in mice lacking PPARγ coactivator 1α Proc Natl Acad Sci USA. 2006;103:10086–10091.[Google Scholar]
87. Lehman JJ, Barger PM, Kovacs A, Saffitz JE, Medeiros DM, Kelly DPPeroxisome proliferator-activated receptor gamma coactivator-1 promotes cardiac mitochondrial biogenesis. J Clin Invest. 2000;106:847–856.[Google Scholar]
88. Russell LK, Mansfield CM, Lehman JJ, Kovacs A, Courtois M, Saffitz JE, et al Cardiac-specific induction of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1α promotes mitochondrial biogenesis and reversible cardiomyopathy in a developmental stage-dependent manner. Circ Res. 2004;94:525–533.[PubMed][Google Scholar]
89. Hansson A, Hance N, Dufour E, Rantanen A, Hultenby K, Clayton DA, et al A switch in metabolism precedes increased mitochondrial biogenesis in respiratory chain-deficient mouse hearts. Proc Natl Acad Sci USA. 2004;101:3136–3141.[Google Scholar]
90. van den Bosch BJ, van den Burg CM, Schoonderwoerd K, Lindsey PJ, Scholte HR, de Coo RF, et al Regional absence of mitochondria causing energy depletion in the myocardium of muscle LIM protein knockout mice. Cardiovasc Res. 2005;65:411–418.[PubMed][Google Scholar]
91. Huss JM, Imahashi K-i, Dufour CR, Weinheimer CJ, Courtois M, Kovacs A, et al The nuclear receptor ERRα is required for the bioenergetic and functional adaptation to cardiac pressure overload. Cell Metab. 2007;6:25–37.[PubMed][Google Scholar]
92. Sano M, Wang SC, Shirai M, Scaglia F, Xie M, Sakai S, et al Activation of cardiac Cdk9 represses PGC-1 and confers a predisposition to heart failure. EMBO J. 2004;23:3559–3569.[Google Scholar]
93. Brixius K, Lu R, Boelck B, Grafweg S, Hoyer F, Pott C, et al Chronic treatment with carvedilol improves Ca(2+)-dependent ATP consumption in triton X-skinned fiber preparations of human myocardium. J Pharmacol Exp Ther. 2007;322:222–227.[PubMed][Google Scholar]
94. Lamberts RR, Caldenhoven E, Lansink M, Witte G, Vaessen RJ, St Cyr JA, et al Preservation of diastolic function in monocrotaline-induced right ventricular hypertrophy in rats. Am J Physiol Heart Circ Physiol. 2007;293:H1869–H1876.[PubMed][Google Scholar]
95. Tuunanen H, Engblom E, Naum A, Nagren K, Hesse B, Airaksinen KE, et al Free fatty acid depletion acutely decreases cardiac work and efficiency in cardiomyopathic heart failure. Circulation. 2006;114:2130–2137.[PubMed][Google Scholar]
96. Neubauer S, Horn M, Cramer M, Harre K, Newell JB, Peters W, et al Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation. 1997;96:2190–2196.[PubMed][Google Scholar]
97. Tian R, Nascimben L, Kaddurah-Daouk R, Ingwall JSDepletion of energy reserve via the creatine kinase reaction during the evolution of heart failure in cardiomyopathic hamsters. J Mol Cell Cardiol. 1996;28:755–765.[PubMed][Google Scholar]