Heart Failure Reviews

, 14:225 | Cite as

β-Adrenergic stimulation and myocardial function in the failing heart

Article

Abstract

The sympathetic nervous system provides the most powerful stimulation of cardiac function, brought about via norepinephrine and epinephrine and their postsynaptic β-adrenergic receptors. More than 30 years after the first use of practolol in patients with heart failure betablockers are now the mainstay of the pharmacological treatment of chronic heart failure. Many aspects of their mechanism of action are well understood, but others remain unresolved. This review focuses on a number of questions that are key to further developments in the field. What accounts for and what is the role of β-adrenergic desensitization, a hallmark of the failing heart? Is part of this adaptation predominantly beneficial and should therefore be reinforced, another part mainly maladaptive and therefore a target for antagonists? Which lessons can be drawn from studies in genetically engineered mice, which from (pharmaco) genetic studies? Finally, what are promising targets downstream of β-adrenergic receptors that go beyond the current neurohumoral blockade?

Keywords

Heart failure β-Adrenergic signaling Contractility Transgenic mice Inotropes Betablocker 

Notes

Acknowledgments

The work of the authors in this field is supported by the Deutsche Forschungsgemeinschaft (DFG-FOR-604 to AEA and TE) and by the European Union (EUGene Heart to AEA and TE) and by the German Heart Foundation (to AEA).

References

  1. 1.
    Waagstein F, Hjalmarson A, Varnauskas E, Wallentin I (1975) Effect of chronic beta-adrenergic receptor blockade in congestive cardiomyopathy. Br Heart J 37:1022–1036. doi: 10.1136/hrt.37.10.1022 PubMedCrossRefGoogle Scholar
  2. 2.
    Eschenhagen T (2008) Beta-adrenergic signaling in heart failure-adapt or die. Nat Med 14:485–487. doi: 10.1038/nm0508-485 PubMedCrossRefGoogle Scholar
  3. 3.
    Brodde OE, Michel MC (1999) Adrenergic and muscarinic receptors in the human heart. Pharmacol Rev 51:651–690PubMedGoogle Scholar
  4. 4.
    Rockman HA, Koch WJ, Lefkowitz RJ (2002) Seven-transmembrane-spanning receptors and heart function. Nature 415:206–212. doi: 10.1038/415206a PubMedCrossRefGoogle Scholar
  5. 5.
    Brodde OE, Bruck H, Leineweber K (2006) Cardiac adrenoceptors: physiological and pathophysiological relevance. J Pharmacol Sci 100:323–337. doi: 10.1254/jphs.CRJ06001X PubMedCrossRefGoogle Scholar
  6. 6.
    Kang M, Chung KY, Walker JW (2007) G-protein coupled receptor signaling in myocardium: not for the faint of heart. Physiology (Bethesda) 22:174–184. doi: 10.1152/physiol.00051.2006 Google Scholar
  7. 7.
    Xiang Y, Kobilka BK (2003) Myocyte adrenoceptor signaling pathways. Science 300:1530–1532. doi: 10.1126/science.1079206 PubMedCrossRefGoogle Scholar
  8. 8.
    Lohse MJ, Engelhardt S, Eschenhagen T (2003) What is the role of beta-adrenergic signaling in heart failure? Circ Res 93:896–906. doi: 10.1161/01.RES.0000102042.83024.CA PubMedCrossRefGoogle Scholar
  9. 9.
    Port JD, Bristow MR (2001) Beta-Adrenergic receptors, transgenic mice, and pharmacological model systems. Mol Pharmacol 60:629–631PubMedGoogle Scholar
  10. 10.
    Gauthier C, Leblais V, Kobzik L, Trochu JN, Khandoudi N, Bril A, Balligand JL, Le Marec H (1998) The negative inotropic effect of beta3-adrenoceptor stimulation is mediated by activation of a nitric oxide synthase pathway in human ventricle. J Clin Invest 102:1377–1384. doi: 10.1172/JCI2191 PubMedCrossRefGoogle Scholar
  11. 11.
    Strosberg AD (1997) Structure and function of the beta 3-adrenergic receptor. Annu Rev Pharmacol Toxicol 37:421–450. doi: 10.1146/annurev.pharmtox.37.1.421 PubMedCrossRefGoogle Scholar
  12. 12.
    Defer N, Best-Belpomme M, Hanoune J (2000) Tissue specificity and physiological relevance of various isoforms of adenylyl cyclase. Am J Physiol Renal Physiol 279:F400–F416PubMedGoogle Scholar
  13. 13.
    Xiao RP, Zhu W, Zheng M, Cao C, Zhang Y, Lakatta EG, Han Q (2006) Subtype-specific alpha1- and beta-adrenoceptor signaling in the heart. Trends Pharmacol Sci 27:330–337. doi: 10.1016/j.tips.2006.04.009 PubMedCrossRefGoogle Scholar
  14. 14.
    Zhu W, Zeng X, Zheng M, Xiao RP (2005) The enigma of beta2-adrenergic receptor Gi signaling in the heart: the good, the bad, and the ugly. Circ Res 97:507–509. doi: 10.1161/01.RES.0000184615.56822.bd PubMedCrossRefGoogle Scholar
  15. 15.
    Molenaar P, Savarimuthu SM, Sarsero D, Chen L, Semmler AB, Carle A, Yang I, Bartel S, Vetter D, Beyerdorfer I, Krause EG, Kaumann AJ (2007) (-)-Adrenaline elicits positive inotropic, lusitropic, and biochemical effects through beta2 -adrenoceptors in human atrial myocardium from nonfailing and failing hearts, consistent with Gs coupling but not with Gi coupling. Naunyn Schmiedebergs Arch Pharmacol 375:11–28. doi: 10.1007/s00210-007-0138-x PubMedCrossRefGoogle Scholar
  16. 16.
    Bers DM (2002) Cardiac excitation-contraction coupling. Nature 415:198–205. doi: 10.1038/415198a PubMedCrossRefGoogle Scholar
  17. 17.
    Bers DM (2008) Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol 70:23–49. doi: 10.1146/annurev.physiol.70.113006.100455 PubMedCrossRefGoogle Scholar
  18. 18.
    Rapundalo ST (1998) Cardiac protein phosphorylation: functional and pathophysiological correlates. Cardiovasc Res 38:559–588. doi: 10.1016/S0008-6363(98)00063-7 PubMedCrossRefGoogle Scholar
  19. 19.
    Simmerman HK, Jones LR (1998) Phospholamban: protein structure, mechanism of action, and role in cardiac function. Physiol Rev 78:921–947PubMedGoogle Scholar
  20. 20.
    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 75:401–409PubMedGoogle Scholar
  21. 21.
    MacLennan DH, Kranias EG (2003) Phospholamban: a crucial regulator of cardiac contractility. Nat Rev Mol Cell Biol 4:566–577. doi: 10.1038/nrm1151 PubMedCrossRefGoogle Scholar
  22. 22.
    Kobayashi T, Solaro RJ (2005) Calcium, thin filaments, and the integrative biology of cardiac contractility. Annu Rev Physiol 67:39–67. doi: 10.1146/annurev.physiol.67.040403.114025 PubMedCrossRefGoogle Scholar
  23. 23.
    Carrier L (2007) Cardiac myosin-binding protein C in the heart. Arch Mal Coeur Vaiss 100:238–243PubMedGoogle Scholar
  24. 24.
    Palmer CJ, Scott BT, Jones LR (1991) Purification and complete sequence determination of the major plasma membrane substrate for cAMP-dependent protein kinase and protein kinase C in myocardium. J Biol Chem 266:11126–11130PubMedGoogle Scholar
  25. 25.
    Despa S, Bossuyt J, Han F, Ginsburg KS, Jia LG, Kutchai H, Tucker AL, Bers DM (2005) Phospholemman-phosphorylation mediates the beta-adrenergic effects on Na/K pump function in cardiac myocytes. Circ Res 97:252–259. doi: 10.1161/01.RES.0000176532.97731.e5 PubMedCrossRefGoogle Scholar
  26. 26.
    Mansuy IM, Shenolikar S (2006) Protein serine/threonine phosphatases in neuronal plasticity and disorders of learning and memory. Trends Neurosci 29:679–686. doi: 10.1016/j.tins.2006.10.004 PubMedCrossRefGoogle Scholar
  27. 27.
    Cohen PT (2002) Protein phosphatase 1–targeted in many directions. J Cell Sci 115:241–256PubMedGoogle Scholar
  28. 28.
    Ceulemans H, Bollen M (2004) Functional diversity of protein phosphatase-1, a cellular economizer and reset button. Physiol Rev 84:1–39. doi: 10.1152/physrev.00013.2003 PubMedCrossRefGoogle Scholar
  29. 29.
    Herzig S, Neumann J (2000) Effects of serine/threonine protein phosphatases on ion channels in excitable membranes. Physiol Rev 80:173–210PubMedGoogle Scholar
  30. 30.
    Marks AR, Marx SO, Reiken S (2002) Regulation of ryanodine receptors via macromolecular complexes: a novel role for leucine/isoleucine zippers. Trends Cardiovasc Med 12:166–170. doi: 10.1016/S1050-1738(02)00156-1 PubMedCrossRefGoogle Scholar
  31. 31.
    MacDougall LK, Jones LR, Cohen P (1991) Identification of the major protein phosphatases in mammalian cardiac muscle which dephosphorylate phospholamban. Eur J Biochem 196:725–734. doi: 10.1111/j.1432-1033.1991.tb15871.x PubMedCrossRefGoogle Scholar
  32. 32.
    Luss H, Klein-Wiele O, Boknik P, Herzig S, Knapp J, Linck B, Muller FU, Scheld HH, Schmid C, Schmitz W, Neumann J (2000) Regional expression of protein phosphatase type 1 and 2A catalytic subunit isoforms in the human heart. J Mol Cell Cardiol 32:2349–2359. doi: 10.1006/jmcc.2000.1265 PubMedCrossRefGoogle Scholar
  33. 33.
    Lygren B, Carlson CR, Santamaria K, Lissandron V, McSorley T, Litzenberg J, Lorenz D, Wiesner B, Rosenthal W, Zaccolo M, Tasken K, Klussmann E (2007) AKAP complex regulates Ca2 + re-uptake into heart sarcoplasmic reticulum. EMBO Rep 8:1061–1067. doi: 10.1038/sj.embor.7401081 PubMedCrossRefGoogle Scholar
  34. 34.
    Fink MA, Zakhary DR, Mackey JA, Desnoyer RW, Apperson-Hansen C, Damron DS, Bond M (2001) AKAP-mediated targeting of protein kinase a regulates contractility in cardiac myocytes. Circ Res 88:291–297PubMedGoogle Scholar
  35. 35.
    Dodge-Kafka KL, Langeberg L, Scott JD (2006) Compartmentation of cyclic nucleotide signaling in the heart: the role of A-kinase anchoring proteins. Circ Res 98:993–1001. doi: 10.1161/01.RES.0000218273.91741.30 PubMedCrossRefGoogle Scholar
  36. 36.
    El-Armouche A, Rau T, Zolk O, Ditz D, Pamminger T, Zimmermann WH, Jackel E, Harding SE, Boknik P, Neumann J, Eschenhagen T (2003) Evidence for protein phosphatase inhibitor-1 playing an amplifier role in beta-adrenergic signaling in cardiac myocytes. FASEB J 17:437–439PubMedGoogle Scholar
  37. 37.
    Carr AN, Schmidt AG, Suzuki Y, del Monte F, Sato Y, Lanner C, Breeden K, Jing SL, Allen PB, Greengard P, Yatani A, Hoit BD, Grupp IL, Hajjar RJ, DePaoli-Roach AA, Kranias EG (2002) Type 1 phosphatase, a negative regulator of cardiac function. Mol Cell Biol 22:4124–4135. doi: 10.1128/MCB.22.12.4124-4135.2002 PubMedCrossRefGoogle Scholar
  38. 38.
    Neumann J, Gupta RC, Schmitz W, Scholz H, Nairn AC, Watanabe AM (1991) Evidence for isoproterenol-induced phosphorylation of phosphatase inhibitor-1 in the intact heart. Circ Res 69:1450–1457PubMedGoogle Scholar
  39. 39.
    Mulkey RM, Endo S, Shenolikar S, Malenka RC (1994) Involvement of a calcineurin/inhibitor-1 phosphatase cascade in hippocampal long-term depression. Nature 369:486–488. doi: 10.1038/369486a0 PubMedCrossRefGoogle Scholar
  40. 40.
    El-Armouche A, Bednorz A, Pamminger T, Ditz D, Didie M, Dobrev D, Eschenhagen T (2006) Role of calcineurin and protein phosphatase-2A in the regulation of phosphatase inhibitor-1 in cardiac myocytes. Biochem Biophys Res Commun 346:700–706. doi: 10.1016/j.bbrc.2006.05.182 PubMedCrossRefGoogle Scholar
  41. 41.
    El-Armouche A, Wittkopper K, Degenhardt F, Weinberger F, Didie M, Melnychenko I, Grimm M, Peeck M, Zimmermann WH, Unsold B, Hasenfuss G, Dobrev D, Eschenhagen T (2008) Phosphatase inhibitor-1-deficient mice are protected from catecholamine-induced arrhythmias and myocardial hypertrophy. Cardiovasc Res 80:396–406PubMedCrossRefGoogle Scholar
  42. 42.
    Blitzer RD, Connor JH, Brown GP, Wong T, Shenolikar S, Iyengar R, Landau EM (1998) Gating of CaMKII by cAMP-regulated protein phosphatase activity during LTP. Science 280:1940–1942. doi: 10.1126/science.280.5371.1940 PubMedCrossRefGoogle Scholar
  43. 43.
    Fischmeister R, Castro LR, Abi-Gerges A, Rochais F, Jurevicius J, Leroy J, Vandecasteele G (2006) Compartmentation of cyclic nucleotide signaling in the heart: the role of cyclic nucleotide phosphodiesterases. Circ Res 99:816–828. doi: 10.1161/01.RES.0000246118.98832.04 PubMedCrossRefGoogle Scholar
  44. 44.
    Kaupp UB, Seifert R (2002) Cyclic nucleotide-gated ion channels. Physiol Rev 82:769–824PubMedGoogle Scholar
  45. 45.
    Biel M, Schneider A, Wahl C (2002) Cardiac HCN channels: structure, function, and modulation. Trends Cardiovasc Med 12:206–212. doi: 10.1016/S1050-1738(02)00162-7 PubMedCrossRefGoogle Scholar
  46. 46.
    Rehmann H, Schwede F, Doskeland SO, Wittinghofer A, Bos JL (2003) Ligand-mediated activation of the cAMP-responsive guanine nucleotide exchange factor Epac. J Biol Chem 278:38548–38556. doi: 10.1074/jbc.M306292200 PubMedCrossRefGoogle Scholar
  47. 47.
    Morel E, Marcantoni A, Gastineau M, Birkedal R, Rochais F, Garnier A, Lompre AM, Vandecasteele G, Lezoualc’h F (2005) cAMP-binding protein Epac induces cardiomyocyte hypertrophy. Circ Res 97:1296–1304PubMedCrossRefGoogle Scholar
  48. 48.
    Lezoualc’h F, Metrich M, Hmitou I, Duquesnes N, Morel E (2008) Small GTP-binding proteins and their regulators in cardiac hypertrophy. J Mol Cell Cardiol 44:623–632. doi: 10.1016/j.yjmcc.2008.01.011 PubMedCrossRefGoogle Scholar
  49. 49.
    Metrich M, Lucas A, Gastineau M, Samuel JL, Heymes C, Morel E, Lezoualc’h F (2008) Epac mediates beta-adrenergic receptor-induced cardiomyocyte hypertrophy. Circ Res 102:959–965. doi: 10.1161/CIRCRESAHA.107.164947 PubMedCrossRefGoogle Scholar
  50. 50.
    Movsesian MA, Bristow MR (2005) Alterations in cAMP-mediated signaling and their role in the pathophysiology of dilated cardiomyopathy. Curr Top Dev Biol 68:25–48. doi: 10.1016/S0070-2153(05)68002-7 PubMedCrossRefGoogle Scholar
  51. 51.
    El-Armouche A, Zolk O, Rau T, Eschenhagen T (2003) Inhibitory G-proteins and their role in desensitization of the adenylyl cyclase pathway in heart failure. Cardiovasc Res 60:478–487. doi: 10.1016/j.cardiores.2003.09.014 PubMedCrossRefGoogle Scholar
  52. 52.
    Vatner SF, Vatner DE, Homcy CJ (2000) Beta-adrenergic receptor signaling: an acute compensatory adjustment-inappropriate for the chronic stress of heart failure? Insights from Gsalpha overexpression and other genetically engineered animal models. Circ Res 86:502–506PubMedGoogle Scholar
  53. 53.
    Dorn GW II, Molkentin JD (2004) Manipulating cardiac contractility in heart failure: data from mice and men. Circulation 109:150–158. doi: 10.1161/01.CIR.0000111581.15521.F5 PubMedCrossRefGoogle Scholar
  54. 54.
    Mudd JO, Kass DA (2008) Tackling heart failure in the twenty-first century. Nature 451:919–928. doi: 10.1038/nature06798 PubMedCrossRefGoogle Scholar
  55. 55.
    Mann DL, Bristow MR (2005) Mechanisms and models in heart failure: the biomechanical model and beyond. Circulation 111:2837–2849. doi: 10.1161/CIRCULATIONAHA.104.500546 PubMedCrossRefGoogle Scholar
  56. 56.
    Colucci WS, Denniss AR, Leatherman GF, Quigg RJ, Ludmer PL, Marsh JD, Gauthier DF (1988) Intracoronary infusion of dobutamine to patients with and without severe congestive heart failure. Dose-response relationships, correlation with circulating catecholamines, and effect of phosphodiesterase inhibition. J Clin Invest 81:1103–1110. doi: 10.1172/JCI113423 PubMedCrossRefGoogle Scholar
  57. 57.
    Feldman MD, Copelas L, Gwathmey JK, Phillips P, Warren SE, Schoen FJ, Grossman W, Morgan JP (1987) Deficient production of cyclic AMP: pharmacologic evidence of an important cause of contractile dysfunction in patients with end-stage heart failure. Circulation 75:331–339PubMedGoogle Scholar
  58. 58.
    Bohm M, Beuckelmann D, Brown L, Feiler G, Lorenz B, Nabauer M, Kemkes B, Erdmann E (1988) Reduction of beta-adrenoceptor density and evaluation of positive inotropic responses in isolated, diseased human myocardium. Eur Heart J 9:844–852PubMedGoogle Scholar
  59. 59.
    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 PubMedCrossRefGoogle Scholar
  60. 60.
    Hasenfuss G (1998) Alterations of calcium-regulatory proteins in heart failure. Cardiovasc Res 37:279–289. doi: 10.1016/S0008-6363(97)00277-0 PubMedCrossRefGoogle Scholar
  61. 61.
    Hasenfuss G, Pieske B (2002) Calcium cycling in congestive heart failure. J Mol Cell Cardiol 34:951–969. doi: 10.1006/jmcc.2002.2037 PubMedCrossRefGoogle Scholar
  62. 62.
    Eschenhagen T (1993) G proteins and the heart. Cell Biol Int 17:723–749. doi: 10.1006/cbir.1993.1135 PubMedCrossRefGoogle Scholar
  63. 63.
    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 307:205–211PubMedGoogle Scholar
  64. 64.
    Engelhardt S, Bohm M, Erdmann E, Lohse MJ (1996) Analysis of beta-adrenergic receptor mRNA levels in human ventricular biopsy specimens by quantitative polymerase chain reactions: progressive reduction of beta 1-adrenergic receptor mRNA in heart failure. J Am Coll Cardiol 27:146–154. doi: 10.1016/0735-1097(95)00425-4 PubMedCrossRefGoogle Scholar
  65. 65.
    Ungerer M, Bohm M, Elce JS, Erdmann E, Lohse MJ (1993) Altered expression of beta-adrenergic receptor kinase and beta 1-adrenergic receptors in the failing human heart. Circulation 87:454–463PubMedGoogle Scholar
  66. 66.
    Feldman AM, Cates AE, Veazey WB, Hershberger RE, Bristow MR, Baughman KL, Baumgartner WA, Van Dop C (1988) Increase of the 40, 000-mol wt pertussis toxin substrate (G protein) in the failing human heart. J Clin Invest 82:189–197. doi: 10.1172/JCI113569 PubMedCrossRefGoogle Scholar
  67. 67.
    Neumann J, Schmitz W, Scholz H, von Meyerinck L, Doring V, Kalmar P (1988) Increase in myocardial Gi-proteins in heart failure. Lancet 2:936–937. doi: 10.1016/S0140-6736(88)92601-3 PubMedCrossRefGoogle Scholar
  68. 68.
    Böhm M, Gierschik P, Jakobs KH, Pieske B, Schnabel P, Ungerer M, Erdmann E (1990) Increase of Gi alpha in human hearts with dilated but not ischemic cardiomyopathy. Circulation 82:1249–1265PubMedGoogle Scholar
  69. 69.
    Eschenhagen T, Mende U, Nose M, Schmitz W, Scholz H, Haverich A, Hirt S, Doring V, Kalmar P, Hoppner W et al (1992) Increased messenger RNA level of the inhibitory G protein alpha subunit Gi alpha-2 in human end-stage heart failure. Circ Res 70:688–696PubMedGoogle Scholar
  70. 70.
    El-Armouche A, Pamminger T, Ditz D, Zolk O, Eschenhagen T (2004) Decreased protein and phosphorylation level of the protein phosphatase inhibitor-1 in failing human hearts. Cardiovasc Res 61:87–93. doi: 10.1016/j.cardiores.2003.11.005 PubMedCrossRefGoogle Scholar
  71. 71.
    Neumann J, Eschenhagen T, Jones LR, Linck B, Schmitz W, Scholz H, Zimmermann N (1997) Increased expression of cardiac phosphatases in patients with end-stage heart failure. J Mol Cell Cardiol 29:265–272. doi: 10.1006/jmcc.1996.0271 PubMedCrossRefGoogle Scholar
  72. 72.
    Diviani D (2008) Modulation of cardiac function by A-kinase anchoring proteins. Curr Opin Pharmacol 8:166–173. doi: 10.1016/j.coph.2007.11.001 PubMedCrossRefGoogle Scholar
  73. 73.
    Zakhary DR, Moravec CS, Bond M (2000) Regulation of PKA binding to AKAPs in the heart: alterations in human heart failure. Circulation 101:1459–1464PubMedGoogle Scholar
  74. 74.
    Bartel S, Stein B, Eschenhagen T, Mende U, Neumann J, Schmitz W, Krause EG, Karczewski P, Scholz H (1996) Protein phosphorylation in isolated trabeculae from nonfailing and failing human hearts. Mol Cell Biochem 157:171–179. doi: 10.1007/BF00227896 PubMedCrossRefGoogle Scholar
  75. 75.
    El-Armouche A, Pohlmann L, Schlossarek S, Starbatty J, Yeh YH, Nattel S, Dobrev D, Eschenhagen T, Carrier L (2007) Decreased phosphorylation levels of cardiac myosin-binding protein-C in human and experimental heart failure. J Mol Cell Cardiol 43:223–229. doi: 10.1016/j.yjmcc.2007.05.003 PubMedCrossRefGoogle Scholar
  76. 76.
    Bodor GS, Oakeley AE, Allen PD, Crimmins DL, Ladenson JH, Anderson PA (1997) Troponin I phosphorylation in the normal and failing adult human heart. Circulation 96:1495–1500PubMedGoogle Scholar
  77. 77.
    Messer AE, Jacques AM, Marston SB (2007) Troponin phosphorylation and regulatory function in human heart muscle: dephosphorylation of Ser23/24 on troponin I could account for the contractile defect in end-stage heart failure. J Mol Cell Cardiol 42:247–259. doi: 10.1016/j.yjmcc.2006.08.017 PubMedCrossRefGoogle Scholar
  78. 78.
    Schroder F, Handrock R, Beuckelmann DJ, Hirt S, Hullin R, Priebe L, Schwinger RH, Weil J, Herzig S (1998) Increased availability and open probability of single L-type calcium channels from failing compared with nonfailing human ventricle. Circulation 98:969–976PubMedGoogle Scholar
  79. 79.
    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. doi: 10.1016/S0092-8674(00)80847-8 PubMedCrossRefGoogle Scholar
  80. 80.
    Benkusky NA, Weber CS, Scherman JA, Farrell EF, Hacker TA, John MC, Powers PA, Valdivia HH (2007) Intact beta-adrenergic response and unmodified progression toward heart failure in mice with genetic ablation of a major protein kinase A phosphorylation site in the cardiac ryanodine receptor. Circ Res 101:819–829. doi: 10.1161/CIRCRESAHA.107.153007 PubMedCrossRefGoogle Scholar
  81. 81.
    Lehnart S, Marks AR (2007) Regulation of ryanodine receptors in the heart. Circ Res 101:746–749. doi: 10.1161/CIRCRESAHA.107.162479 PubMedCrossRefGoogle Scholar
  82. 82.
    Osadchii OE (2007) Cardiac hypertrophy induced by sustained beta-adrenoreceptor activation: pathophysiological aspects. Heart Fail Rev 12:66–86. doi: 10.1007/s10741-007-9007-4 PubMedCrossRefGoogle Scholar
  83. 83.
    El-Armouche A, Gocht F, Jaeckel E, Wittkopper K, Peeck M, Eschenhagen T (2007) Long-term beta-adrenergic stimulation leads to downregulation of protein phosphatase inhibitor-1 in the heart. Eur J Heart Fail 9:1077–1080. doi: 10.1016/j.ejheart.2007.09.006 PubMedCrossRefGoogle Scholar
  84. 84.
    Boknik P, Fockenbrock M, Herzig S, Knapp J, Linck B, Luss H, Muller FU, Muller T, Schmitz W, Schroder F, Neumann J (2000) Protein phosphatase activity is increased in a rat model of long-term beta-adrenergic stimulation. Naunyn Schmiedebergs Arch Pharmacol 362:222–231. doi: 10.1007/s002100000283 PubMedCrossRefGoogle Scholar
  85. 85.
    Eschenhagen T, Mende U, Diederich M, Nose M, Schmitz W, Scholz H, Schulte am Esch J, Warnholtz A, Schafer H (1992) Long term beta-adrenoceptor-mediated up-regulation of Gi alpha and G(o) alpha mRNA levels and pertussis toxin-sensitive guanine nucleotide-binding proteins in rat heart. Mol Pharmacol 42:773–783PubMedGoogle Scholar
  86. 86.
    Mende U, Eschenhagen T, Geertz B, Schmitz W, Scholz H, Schulte am Esch J, Sempell R, Steinfath M (1992) Isoprenaline-induced increase in the 40/41 kDa pertussis toxin substrates and functional consequences on contractile response in rat heart. Naunyn Schmiedebergs Arch Pharmacol 345:44–50. doi: 10.1007/BF00175468 PubMedCrossRefGoogle Scholar
  87. 87.
    Cohn JN, Levine TB, Olivari MT, Garberg V, Lura D, Francis GS, Simon AB, Rector T (1984) Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 311:819–823PubMedGoogle Scholar
  88. 88.
    Faulx MD, Ernsberger P, Vatner D, Hoffman RD, Lewis W, Strachan R, Hoit BD (2005) Strain-dependent beta-adrenergic receptor function influences myocardial responses to isoproterenol stimulation in mice. Am J Physiol Heart Circ Physiol 289:H30–H36. doi: 10.1152/ajpheart.00636.2004 PubMedCrossRefGoogle Scholar
  89. 89.
    Liggett SB, Cresci S, Kelly RJ, Syed FM, Matkovich SJ, Hahn HS, Diwan A, Martini JS, Sparks L, Parekh RR, Spertus JA, Koch WJ, Kardia SL, Dorn GW II (2008) A GRK5 polymorphism that inhibits beta-adrenergic receptor signaling is protective in heart failure. Nat Med 14:510–517. doi: 10.1038/nm1750 PubMedCrossRefGoogle Scholar
  90. 90.
    O’Connor CM, Gattis WA, Uretsky BF, Adams KF Jr, McNulty SE, Grossman SH, McKenna WJ, Zannad F, Swedberg K, Gheorghiade M, Califf RM (1999) Continuous intravenous dobutamine is associated with an increased risk of death in patients with advanced heart failure: insights from the Flolan International Randomized Survival Trial (FIRST). Am Heart J 138:78–86. doi: 10.1016/S0002-8703(99)70250-4 PubMedCrossRefGoogle Scholar
  91. 91.
    Feldman AM, Bristow MR, Parmley WW, Carson PE, Pepine CJ, Gilbert EM, Strobeck JE, Hendrix GH, Powers ER, Bain RP et al (1993) Effects of vesnarinone on morbidity and mortality in patients with heart failure. Vesnarinone Study Group. The New England Journal of Medicine 329:149–155. doi: 10.1056/NEJM199307153290301 PubMedCrossRefGoogle Scholar
  92. 92.
    Stevenson LW (2003) Clinical use of inotropic therapy for heart failure: looking backward or forward? Part II: chronic inotropic therapy. Circulation 108:492–497. doi: 10.1161/01.CIR.0000078349.43742.8A PubMedCrossRefGoogle Scholar
  93. 93.
    Satwani S, Dec GW, Narula J (2004) Beta-adrenergic blockers in heart failure: review of mechanisms of action and clinical outcomes. J Cardiovasc Pharmacol Ther 9:243–255. doi: 10.1177/107424840400900404 PubMedCrossRefGoogle Scholar
  94. 94.
    Bristow MR (2000) Beta-adrenergic receptor blockade in chronic heart failure. Circulation 101:558–569PubMedGoogle Scholar
  95. 95.
    Packer M (2001) Current role of beta-adrenergic blockers in the management of chronic heart failure. Am J Med 110(Suppl 7A):81S–94S. doi: 10.1016/S0002-9343(01)00676-3 PubMedCrossRefGoogle Scholar
  96. 96.
    Mudd JO, Kass DA (2007) Reversing chronic remodeling in heart failure. Expert Rev Cardiovasc Ther 5:585–598. doi: 10.1586/14779072.5.3.585 PubMedCrossRefGoogle Scholar
  97. 97.
    Lowes BD, Gilbert EM, Abraham WT, Minobe WA, Larrabee P, Ferguson D, Wolfel EE, Lindenfeld J, Tsvetkova T, Robertson AD, Quaife RA, Bristow MR (2002) Myocardial gene expression in dilated cardiomyopathy treated with beta-blocking agents. N Engl J Med 346:1357–1365. doi: 10.1056/NEJMoa012630 PubMedCrossRefGoogle Scholar
  98. 98.
    Hall SA, Cigarroa CG, Marcoux L, Risser RC, Grayburn PA, Eichhorn EJ (1995) Time course of improvement in left ventricular function, mass and geometry in patients with congestive heart failure treated with beta-adrenergic blockade. J Am Coll Cardiol 25:1154–1161. doi: 10.1016/0735-1097(94)00543-Y PubMedCrossRefGoogle Scholar
  99. 99.
    Hadcock JR, Port JD, Malbon CC (1991) Cross-regulation between G-protein-mediated pathways. Activation of the inhibitory pathway of adenylylcylclase increases the expression of beta 2-adrenergic receptors. J Biol Chem 266:11915–11922PubMedGoogle Scholar
  100. 100.
    Eschenhagen T, Friedrichsen M, Gsell S, Hollmann A, Mittmann C, Schmitz W, Scholz H, Weil J, Weinstein LS (1996) Regulation of the human Gi alpha-2 gene promotor activity in embryonic chicken cardiomyocytes. Basic Res Cardiol 91(Suppl 2):41–46. doi: 10.1007/BF00795361 PubMedCrossRefGoogle Scholar
  101. 101.
    Regitz-Zagrosek V, Hertrampf R, Steffen C, Hildebrandt A, Fleck E (1994) Myocardial cyclic AMP and norepinephrine content in human heart failure. Eur Heart J 15(Suppl D):7–13PubMedGoogle Scholar
  102. 102.
    Lee S, Schwinger RH, Brixius K (2008) Genetically changed mice with chronic deficiency or overexpression of the beta-adrenoceptors—what can we learn for the therapy of heart failure? Pflugers Arch 455:767–774. doi: 10.1007/s00424-007-0324-1 PubMedCrossRefGoogle Scholar
  103. 103.
    Gaudin C, Ishikawa Y, Wight DC, Mahdavi V, Nadal-Ginard B, Wagner TE, Vatner DE, Homcy CJ (1995) Overexpression of Gs alpha protein in the hearts of transgenic mice. J Clin Invest 95:1676–1683. doi: 10.1172/JCI117843 PubMedCrossRefGoogle Scholar
  104. 104.
    Antos CL, Frey N, Marx SO, Reiken S, Gaburjakova M, Richardson JA, Marks AR, Olson EN (2001) Dilated cardiomyopathy and sudden death resulting from constitutive activation of protein kinase a. Circ Res 89:997–1004. doi: 10.1161/hh2301.100003 PubMedCrossRefGoogle Scholar
  105. 105.
    Engelhardt S, Hein L, Wiesmann F, Lohse MJ (1999) Progressive hypertrophy and heart failure in beta1-adrenergic receptor transgenic mice. Proc Natl Acad Sci USA 96:7059–7064. doi: 10.1073/pnas.96.12.7059 PubMedCrossRefGoogle Scholar
  106. 106.
    Iwase M, Uechi M, Vatner DE, Asai K, Shannon RP, Kudej RK, Wagner TE, Wight DC, Patrick TA, Ishikawa Y, Homcy CJ, Vatner SF (1997) Cardiomyopathy induced by cardiac Gs alpha overexpression. Am J Physiol 272:H585–H589PubMedGoogle Scholar
  107. 107.
    Liggett SB, Tepe NM, Lorenz JN, Canning AM, Jantz TD, Mitarai S, Yatani A, Dorn GW II (2000) Early and delayed consequences of beta(2)-adrenergic receptor overexpression in mouse hearts: critical role for expression level. Circulation 101:1707–1714PubMedGoogle Scholar
  108. 108.
    Cross HR, Steenbergen C, Lefkowitz RJ, Koch WJ, Murphy E (1999) Overexpression of the cardiac beta(2)-adrenergic receptor and expression of a beta-adrenergic receptor kinase-1 (betaARK1) inhibitor both increase myocardial contractility but have differential effects on susceptibility to ischemic injury. Circ Res 85:1077–1084PubMedGoogle Scholar
  109. 109.
    Du XJ, Autelitano DJ, Dilley RJ, Wang B, Dart AM, Woodcock EA (2000) Beta(2)-adrenergic receptor overexpression exacerbates development of heart failure after aortic stenosis. Circulation 101:71–77PubMedGoogle Scholar
  110. 110.
    DeGeorge BR, Koch WJ (2008) Gi/o signaling and its potential role in cardioprotection. Expert Rev Cardiovasc Ther 6:785–787. doi: 10.1586/14779072.6.6.785 PubMedCrossRefGoogle Scholar
  111. 111.
    Foerster K, Groner F, Matthes J, Koch WJ, Birnbaumer L, Herzig S (2003) Cardioprotection specific for the G protein Gi2 in chronic adrenergic signaling through beta 2-adrenoceptors. Proc Natl Acad Sci USA 100:14475–14480. doi: 10.1073/pnas.1936026100 PubMedCrossRefGoogle Scholar
  112. 112.
    Lehnart SE, Wehrens XH, Reiken S, Warrier S, Belevych AE, Harvey RD, Richter W, Jin SL, Conti M, Marks AR (2005) Phosphodiesterase 4D deficiency in the ryanodine-receptor complex promotes heart failure and arrhythmias. Cell 123:25–35. doi: 10.1016/j.cell.2005.07.030 PubMedCrossRefGoogle Scholar
  113. 113.
    Brede M, Wiesmann F, Jahns R, Hadamek K, Arnolt C, Neubauer S, Lohse MJ, Hein L (2002) Feedback inhibition of catecholamine release by two different alpha2-adrenoceptor subtypes prevents progression of heart failure. Circulation 106:2491–2496. doi: 10.1161/01.CIR.0000036600.39600.66 PubMedCrossRefGoogle Scholar
  114. 114.
    Asai K, Yang GP, Geng YJ, Takagi G, Bishop S, Ishikawa Y, Shannon RP, Wagner TE, Vatner DE, Homcy CJ, Vatner SF (1999) Beta-adrenergic receptor blockade arrests myocyte damage and preserves cardiac function in the transgenic G(salpha) mouse. J Clin Invest 104:551–558. doi: 10.1172/JCI7418 PubMedCrossRefGoogle Scholar
  115. 115.
    Lai NC, Tang T, Gao MH, Saito M, Takahashi T, Roth DM, Hammond HK (2008) Activation of cardiac adenylyl cyclase expression increases function of the failing ischemic heart in mice. J Am Coll Cardiol 51:1490–1497. doi: 10.1016/j.jacc.2008.01.015 PubMedCrossRefGoogle Scholar
  116. 116.
    Roth DM, Bayat H, Drumm JD, Gao MH, Swaney JS, Ander A, Hammond HK (2002) Adenylyl cyclase increases survival in cardiomyopathy. Circulation 105:1989–1994. doi: 10.1161/01.CIR.0000014968.54967.D3 PubMedCrossRefGoogle Scholar
  117. 117.
    Harding VB, Jones LR, Lefkowitz RJ, Koch WJ, Rockman HA (2001) Cardiac beta ARK1 inhibition prolongs survival and augments beta blocker therapy in a mouse model of severe heart failure. Proc Natl Acad Sci USA 98:5809–5814. doi: 10.1073/pnas.091102398 PubMedCrossRefGoogle Scholar
  118. 118.
    Raake PW, Vinge LE, Gao E, Boucher M, Rengo G, Chen X, DeGeorge BR Jr, Matkovich S, Houser SR, Most P, Eckhart AD, Dorn GW II, Koch WJ (2008) G protein-coupled receptor kinase 2 ablation in cardiac myocytes before or after myocardial infarction prevents heart failure. Circ Res 103:413–422. doi: 10.1161/CIRCRESAHA.107.168336 PubMedCrossRefGoogle Scholar
  119. 119.
    Gao MH, Lai NC, Roth DM, Zhou J, Zhu J, Anzai T, Dalton N, Hammond HK (1999) Adenylylcyclase increases responsiveness to catecholamine stimulation in transgenic mice. Circulation 99:1618–1622PubMedGoogle Scholar
  120. 120.
    Phan HM, Gao MH, Lai NC, Tang T, Hammond HK (2007) New signaling pathways associated with increased cardiac adenylyl cyclase 6 expression: implications for possible congestive heart failure therapy. Trends Cardiovasc Med 17:215–221. doi: 10.1016/j.tcm.2007.07.001 PubMedCrossRefGoogle Scholar
  121. 121.
    Okumura S, Kawabe J, Yatani A, Takagi G, Lee MC, Hong C, Liu J, Takagi I, Sadoshima J, Vatner DE, Vatner SF, Ishikawa Y (2003) Type 5 adenylyl cyclase disruption alters not only sympathetic but also parasympathetic and calcium-mediated cardiac regulation. Circ Res 93:364–371. doi: 10.1161/01.RES.0000086986.35568.63 PubMedCrossRefGoogle Scholar
  122. 122.
    Allen PB, Hvalby O, Jensen V, Errington ML, Ramsay M, Chaudhry FA, Bliss TV, Storm-Mathisen J, Morris RG, Andersen P, Greengard P (2000) Protein phosphatase-1 regulation in the induction of long-term potentiation: heterogeneous molecular mechanisms. J Neurosci 20:3537–3543PubMedGoogle Scholar
  123. 123.
    Okumura S, Takagi G, Kawabe J, Yang G, Lee MC, Hong C, Liu J, Vatner DE, Sadoshima J, Vatner SF, Ishikawa Y (2003) Disruption of type 5 adenylyl cyclase gene preserves cardiac function against pressure overload. Proc Natl Acad Sci USA 100:9986–9990. doi: 10.1073/pnas.1733772100 PubMedCrossRefGoogle Scholar
  124. 124.
    Okumura S, Vatner DE, Kurotani R, Bai Y, Gao S, Yuan Z, Iwatsubo K, Ulucan C, Kawabe J, Ghosh K, Vatner SF, Ishikawa Y (2007) Disruption of type 5 adenylyl cyclase enhances desensitization of cyclic adenosine monophosphate signal and increases Akt signal with chronic catecholamine stress. Circulation 116:1776–1783. doi: 10.1161/CIRCULATIONAHA.107.698662 PubMedCrossRefGoogle Scholar
  125. 125.
    Yan L, Vatner DE, O’Connor JP, Ivessa A, Ge H, Chen W, Hirotani S, Ishikawa Y, Sadoshima J, Vatner SF (2007) Type 5 adenylyl cyclase disruption increases longevity and protects against stress. Cell 130:247–258. doi: 10.1016/j.cell.2007.05.038 PubMedCrossRefGoogle Scholar
  126. 126.
    Iwatsubo K, Minamisawa S, Tsunematsu T, Nakagome M, Toya Y, Tomlinson JE, Umemura S, Scarborough RM, Levy DE, Ishikawa Y (2004) Direct inhibition of type 5 adenylyl cyclase prevents myocardial apoptosis without functional deterioration. J Biol Chem 279:40938–40945. doi: 10.1074/jbc.M314238200 PubMedCrossRefGoogle Scholar
  127. 127.
    Pathak A, del Monte F, Zhao W, Schultz JE, Lorenz JN, Bodi I, Weiser D, Hahn H, Carr AN, Syed F, Mavila N, Jha L, Qian J, Marreez Y, Chen G, McGraw DW, Heist EK, Guerrero JL, DePaoli-Roach AA, Hajjar RJ, Kranias EG (2005) Enhancement of cardiac function and suppression of heart failure progression by inhibition of protein phosphatase 1. Circ Res 96:756–766. doi: 10.1161/01.RES.0000161256.85833.fa PubMedCrossRefGoogle Scholar
  128. 128.
    Chen ZM, Pan HC, Chen YP, Peto R, Collins R, Jiang LX, Xie JX, Liu LS (2005) Early intravenous then oral metoprolol in 45, 852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 366:1622–1632. doi: 10.1016/S0140-6736(05)67661-1 PubMedCrossRefGoogle Scholar
  129. 129.
    Brodde OE (2008) Beta-1 and beta-2 adrenoceptor polymorphisms: functional importance, impact on cardiovascular diseases and drug responses. Pharmacol Ther 117:1–29. doi: 10.1016/j.pharmthera.2007.07.002 PubMedCrossRefGoogle Scholar
  130. 130.
    Mason DA, Moore JD, Green SA, Liggett SB (1999) A gain-of-function polymorphism in a G-protein coupling domain of the human beta1-adrenergic receptor. J Biol Chem 274:12670–12674. doi: 10.1074/jbc.274.18.12670 PubMedCrossRefGoogle Scholar
  131. 131.
    Small KM, Forbes SL, Rahman FF, Bridges KM, Liggett SB (2000) A four amino acid deletion polymorphism in the third intracellular loop of the human alpha 2C-adrenergic receptor confers impaired coupling to multiple effectors. J Biol Chem 275:23059–23064. doi: 10.1074/jbc.M000796200 PubMedCrossRefGoogle Scholar
  132. 132.
    Small KM, Wagoner LE, Levin AM, Kardia SL, Liggett SB (2002) Synergistic polymorphisms of beta1- and alpha2C-adrenergic receptors and the risk of congestive heart failure. N Engl J Med 347:1135–1142. doi: 10.1056/NEJMoa020803 PubMedCrossRefGoogle Scholar
  133. 133.
    Liggett SB, Mialet-Perez J, Thaneemit-Chen S, Weber SA, Greene SM, Hodne D, Nelson B, Morrison J, Domanski MJ, Wagoner LE, Abraham WT, Anderson JL, Carlquist JF, Krause-Steinrauf HJ, Lazzeroni LC, Port JD, Lavori PW, Bristow MR (2006) A polymorphism within a conserved beta(1)-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure. Proc Natl Acad Sci USA 103:11288–11293. doi: 10.1073/pnas.0509937103 PubMedCrossRefGoogle Scholar
  134. 134.
    Sehnert AJ, Daniels SE, Elashoff M, Wingrove JA, Burrow CR, Horne B, Muhlestein JB, Donahue M, Liggett SB, Anderson JL, Kraus WE (2008) Lack of association between adrenergic receptor genotypes and survival in heart failure patients treated with carvedilol or metoprolol. J Am Coll Cardiol 52:644–651. doi: 10.1016/j.jacc.2008.05.022 PubMedCrossRefGoogle Scholar
  135. 135.
    Teerlink JR (2002) Recent heart failure trials of neurohormonal modulation (OVERTURE and ENABLE): approaching the asymptote of efficacy? J Card Fail 8:124–127. doi: 10.1054/jcaf.2002.126486 PubMedCrossRefGoogle Scholar
  136. 136.
    Cohn JN, Pfeffer MA, Rouleau J, Sharpe N, Swedberg K, Straub M, Wiltse C, Wright TJ (2003) Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON). Eur J Heart Fail 5:659–667. doi: 10.1016/S1388-9842(03)00163-6 PubMedCrossRefGoogle Scholar
  137. 137.
    Anker SD, Coats AJ (2002) How to RECOVER from RENAISSANCE? The significance of the results of RECOVER, RENAISSANCE, RENEWAL and ATTACH. Int J Cardiol 86:123–130. doi: 10.1016/S0167-5273(02)00470-9 PubMedCrossRefGoogle Scholar
  138. 138.
    Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Kober L, Maggioni AP, Solomon SD, Swedberg K, Van de Werf F, White H, Leimberger JD, Henis M, Edwards S, Zelenkofske S, Sellers MA, Califf RM (2003) Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 349:1893–1906. doi: 10.1056/NEJMoa032292 PubMedCrossRefGoogle Scholar
  139. 139.
    Cleland JG, Coletta AP, Abdellah AT, Cullington D, Clark AL, Rigby AS (2008) Clinical trials update from the American Heart Association 2007: CORONA, RethinQ, MASCOT, AF-CHF, HART, MASTER, POISE and stem cell therapy. Eur J Heart Fail 10:102–108. doi: 10.1016/j.ejheart.2007.12.004 PubMedCrossRefGoogle Scholar
  140. 140.
    Komajda M, Follath F, Swedberg K, Cleland J, Aguilar JC, Cohen-Solal A, Dietz R, Gavazzi A, Van Gilst WH, Hobbs R, Korewicki J, Madeira HC, Moiseyev VS, Preda I, Widimsky J, Freemantle N, Eastaugh J, Mason J (2003) The EuroHeart Failure Survey programme—a survey on the quality of care among patients with heart failure in Europe Part. 2: treatment. Eur Heart J 24:464–474. doi: 10.1016/S0195-668X(02)00700-5 PubMedCrossRefGoogle Scholar
  141. 141.
    Wikstrand J, Hjalmarson A, Waagstein F, Fagerberg B, Goldstein S, Kjekshus J, Wedel H (2002) Dose of metoprolol CR/XL and clinical outcomes in patients with heart failure: analysis of the experience in metoprolol CR/XL randomized intervention trial in chronic heart failure (MERIT-HF). J Am Coll Cardiol 40:491–498. doi: 10.1016/S0735-1097(02)01970-8 PubMedCrossRefGoogle Scholar
  142. 142.
    Rau T, Heide R, Bergmann K, Wuttke H, Werner U, Feifel N, Eschenhagen T (2002) Effect of the CYP2D6 genotype on metoprolol metabolism persists during long-term treatment. Pharmacogenetics 12:465–472. doi: 10.1097/00008571-200208000-00007 PubMedCrossRefGoogle Scholar
  143. 143.
    Giessmann T, Modess C, Hecker U, Zschiesche M, Dazert P, Kunert-Keil C, Warzok R, Engel G, Weitschies W, Cascorbi I, Kroemer HK, Siegmund W (2004) CYP2D6 genotype and induction of intestinal drug transporters by rifampin predict presystemic clearance of carvedilol in healthy subjects. Clin Pharmacol Ther 75:213–222. doi: 10.1016/j.clpt.2003.10.004 PubMedCrossRefGoogle Scholar
  144. 144.
    Jahns R, Boivin V, Schwarzbach V, Ertl G, Lohse MJ (2008) Pathological autoantibodies in cardiomyopathy. Autoimmunity 41:454–461. doi: 10.1080/08916930802031603 PubMedCrossRefGoogle Scholar
  145. 145.
    Fox K, Ford I, Steg PG, Tendera M, Ferrari R (2008) Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet 372:807–816. doi: 10.1016/S0140-6736(08)61170-8 PubMedCrossRefGoogle Scholar
  146. 146.
    Onda T, Hashimoto Y, Nagai M, Kuramochi H, Saito S, Yamazaki H, Toya Y, Sakai I, Homcy CJ, Nishikawa K, Ishikawa Y (2001) Type-specific regulation of adenylyl cyclase. Selective pharmacological stimulation and inhibition of adenylyl cyclase isoforms. J Biol Chem 276:47785–47793PubMedGoogle Scholar
  147. 147.
    Lai NC, Roth DM, Gao MH, Tang T, Dalton N, Lai YY, Spellman M, Clopton P, Hammond HK (2004) Intracoronary adenovirus encoding adenylyl cyclase VI increases left ventricular function in heart failure. Circulation 110:330–336. doi: 10.1161/01.CIR.0000136033.21777.4D PubMedCrossRefGoogle Scholar
  148. 148.
    Shah AS, White DC, Emani S, Kypson AP, Lilly RE, Wilson K, Glower DD, Lefkowitz RJ, Koch WJ (2001) In vivo ventricular gene delivery of a beta-adrenergic receptor kinase inhibitor to the failing heart reverses cardiac dysfunction. Circulation 103:1311–1316. doi: 10.1161/hc2501.092494 PubMedCrossRefGoogle Scholar
  149. 149.
    Bers DM (2006) Altered cardiac myocyte Ca regulation in heart failure. Physiology (Bethesda) 21:380–387. doi: 10.1152/physiol.00019.2006 Google Scholar
  150. 150.
    Sato Y, Kiriazis H, Yatani A, Schmidt AG, Hahn H, Ferguson DG, Sako H, Mitarai S, Honda R, Mesnard-Rouiller L, Frank KF, Beyermann B, Wu G, Fujimori K, Dorn GW II, Kranias EG (2001) Rescue of contractile parameters and myocyte hypertrophy in calsequestrin overexpressing myocardium by phospholamban ablation. J Biol Chem 276:9392–9399. doi: 10.1074/jbc.M006889200 PubMedCrossRefGoogle Scholar
  151. 151.
    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. doi: 10.1016/S0092-8674(00)81662-1 PubMedCrossRefGoogle Scholar
  152. 152.
    Engelhardt S, Hein L, Dyachenkow V, Kranias EG, Isenberg G, Lohse MJ (2004) Altered calcium handling is critically involved in the cardiotoxic effects of chronic beta-adrenergic stimulation. Circulation 109:1154–1160. doi: 10.1161/01.CIR.0000117254.68497.39 PubMedCrossRefGoogle Scholar
  153. 153.
    Kiriazis H, Sato Y, Kadambi VJ, Schmidt AG, Gerst MJ, Hoit BD, Kranias EG (2002) Hypertrophy and functional alterations in hyperdynamic phospholamban-knockout mouse hearts under chronic aortic stenosis. Cardiovasc Res 53:372–381. doi: 10.1016/S0008-6363(01)00487-4 PubMedCrossRefGoogle Scholar
  154. 154.
    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 II, Kranias EG (2003) Rescue of cardiomyocyte dysfunction by phospholamban ablation does not prevent ventricular failure in genetic hypertrophy. J Clin Invest 111:859–867PubMedGoogle Scholar
  155. 155.
    Delling U, Sussman MA, Molkentin JD (2000) Re-evaluating sarcoplasmic reticulum function in heart failure. Nat Med 6:942–943. doi: 10.1038/79592 PubMedCrossRefGoogle Scholar
  156. 156.
    Hoshijima M, Ikeda Y, Iwanaga Y, Minamisawa S, Date MO, Gu Y, Iwatate M, Li M, Wang L, Wilson JM, Wang Y, Ross J Jr, Chien KR (2002) Chronic suppression of heart-failure progression by a pseudophosphorylated mutant of phospholamban via in vivo cardiac rAAV gene delivery. Nat Med 8:864–871PubMedGoogle Scholar
  157. 157.
    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. doi: 10.1161/hc0802.105564 PubMedCrossRefGoogle Scholar
  158. 158.
    Iwanaga Y, Hoshijima M, Gu Y, Iwatate M, Dieterle T, Ikeda Y, Date MO, Chrast J, Matsuzaki M, Peterson KL, Chien KR, Ross J Jr (2004) Chronic phospholamban inhibition prevents progressive cardiac dysfunction and pathological remodeling after infarction in rats. J Clin Invest 113:727–736PubMedGoogle Scholar
  159. 159.
    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. doi: 10.1161/hc3601.095574 PubMedCrossRefGoogle Scholar
  160. 160.
    Kawase Y, Ly HQ, Prunier F, Lebeche D, Shi Y, Jin H, Hadri L, Yoneyama R, Hoshino K, Takewa Y, Sakata S, Peluso R, Zsebo K, Gwathmey JK, Tardif JC, Tanguay JF, Hajjar RJ (2008) Reversal of cardiac dysfunction after long-term expression of SERCA2a by gene transfer in a pre-clinical model of heart failure. J Am Coll Cardiol 51:1112–1119. doi: 10.1016/j.jacc.2007.12.014 PubMedCrossRefGoogle Scholar
  161. 161.
    Chen Y, Escoubet B, Prunier F, Amour J, Simonides WS, Vivien B, Lenoir C, Heimburger M, Choqueux C, Gellen B, Riou B, Michel JB, Franz WM, Mercadier JJ (2004) Constitutive cardiac overexpression of sarcoplasmic/endoplasmic reticulum Ca2+–ATPase delays myocardial failure after myocardial infarction in rats at a cost of increased acute arrhythmias. Circulation 109:1898–1903. doi: 10.1161/01.CIR.0000124230.60028.42 PubMedCrossRefGoogle Scholar
  162. 162.
    Haghighi K, Kolokathis F, Pater L, Lynch RA, Asahi M, Gramolini AO, Fan GC, Tsiapras D, Hahn HS, Adamopoulos S, Liggett SB, Dorn GW II, MacLennan DH, Kremastinos DT, Kranias EG (2003) Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human. J Clin Invest 111:869–876PubMedGoogle Scholar
  163. 163.
    Hajjar RJ, Zsebo K, Deckelbaum L, Thompson C, Rudy J, Yaroshinsky A, Ly H, Kawase Y, Wagner K, Borow K, Jaski B, London B, Greenberg B, Pauly DF, Patten R, Starling R, Mancini D, Jessup M (2008) Design of a phase 1/2 trial of intracoronary administration of AAV1/SERCA2a in patients with heart failure. J Card Fail 14:355–367. doi: 10.1016/j.cardfail.2008.02.005 PubMedCrossRefGoogle Scholar
  164. 164.
    Rocchetti M, Besana A, Mostacciuolo G, Micheletti R, Ferrari P, Sarkozi S, Szegedi C, Jona I, Zaza A (2005) Modulation of sarcoplasmic reticulum function by Na+/K+pump inhibitors with different toxicity: digoxin and PST2744 [(E, Z)-3-((2-aminoethoxy)imino)androstane-6, 17-dione hydrochloride]. J Pharmacol Exp Ther 313:207–215. doi: 10.1124/jpet.104.077933 PubMedCrossRefGoogle Scholar
  165. 165.
    Gheorghiade M, Blair JE, Filippatos GS, Macarie C, Ruzyllo W, Korewicki J, Bubenek-Turconi SI, Ceracchi M, Bianchetti M, Carminati P, Kremastinos D, Valentini G, Sabbah HN (2008) Hemodynamic, echocardiographic, and neurohormonal effects of istaroxime, a novel intravenous inotropic and lusitropic agent: a randomized controlled trial in patients hospitalized with heart failure. J Am Coll Cardiol 51:2276–2285. doi: 10.1016/j.jacc.2008.03.015 PubMedCrossRefGoogle Scholar
  166. 166.
    Priori SG, Napolitano C, Tiso N, Memmi M, Vignati G, Bloise R, Sorrentino V, Danieli GA (2001) Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation 103:196–200PubMedGoogle Scholar
  167. 167.
    Lehnart SE, Mongillo M, Bellinger A, Lindegger N, Chen BX, Hsueh W, Reiken S, Wronska A, Drew LJ, Ward CW, Lederer WJ, Kass RS, Morley G, Marks AR (2008) Leaky Ca2+release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice. J Clin Invest 118:2230–2245PubMedGoogle Scholar
  168. 168.
    Lehnart SE, Wehrens XH, Laitinen PJ, Reiken SR, Deng SX, Cheng Z, Landry DW, Kontula K, Swan H, Marks AR (2004) Sudden death in familial polymorphic ventricular tachycardia associated with calcium release channel (ryanodine receptor) leak. Circulation 109:3208–3214. doi: 10.1161/01.CIR.0000132472.98675.EC PubMedCrossRefGoogle Scholar
  169. 169.
    Laitinen PJ, Brown KM, Piippo K, Swan H, Devaney JM, Brahmbhatt B, Donarum EA, Marino M, Tiso N, Viitasalo M, Toivonen L, Stephan DA, Kontula K (2001) Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia. Circulation 103:485–490PubMedGoogle Scholar
  170. 170.
    Venetucci LA, Trafford AW, O’Neill SC, Eisner DA (2007) Na/Ca exchange: regulator of intracellular calcium and source of arrhythmias in the heart. Ann N Y Acad Sci 1099:315–325. doi: 10.1196/annals.1387.033 PubMedCrossRefGoogle Scholar
  171. 171.
    Lehnart SE, Terrenoire C, Reiken S, Wehrens XH, Song LS, Tillman EJ, Mancarella S, Coromilas J, Lederer WJ, Kass RS, Marks AR (2006) Stabilization of cardiac ryanodine receptor prevents intracellular calcium leak and arrhythmias. Proc Natl Acad Sci USA 103:7906–7910. doi: 10.1073/pnas.0602133103 PubMedCrossRefGoogle Scholar
  172. 172.
    Taylor AL, Ziesche S, Yancy C, Carson P, D’Agostino R Jr, Ferdinand K, Taylor M, Adams K, Sabolinski M, Worcel M, Cohn JN (2004) Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 351:2049–2057. doi: 10.1056/NEJMoa042934 PubMedCrossRefGoogle Scholar
  173. 173.
    Milano CA, Allen LF, Rockman HA, Dolber PC, McMinn TR, Chien KR, Johnson TD, Bond RA, Lefkowitz RJ (1994) Enhanced myocardial function in transgenic mice overexpressing the beta 2-adrenergic receptor. Science 264:582–586. doi: 10.1126/science.8160017 PubMedCrossRefGoogle Scholar
  174. 174.
    Dorn GW II, Tepe NM, Lorenz JN, Koch WJ, Liggett SB (1999) Low- and high-level transgenic expression of beta2-adrenergic receptors differentially affect cardiac hypertrophy and function in Galphaq-overexpressing mice. Proc Natl Acad Sci USA 96:6400–6405. doi: 10.1073/pnas.96.11.6400 PubMedCrossRefGoogle Scholar
  175. 175.
    Du XJ, Gao XM, Jennings GL, Dart AM, Woodcock EA (2000) Preserved ventricular contractility in infarcted mouse heart overexpressing beta(2)-adrenergic receptors. Am J Physiol Heart Circ Physiol 279:H2456–H2463PubMedGoogle Scholar
  176. 176.
    Kohout TA, Takaoka H, McDonald PH, Perry SJ, Mao L, Lefkowitz RJ, Rockman HA (2001) Augmentation of cardiac contractility mediated by the human beta(3)-adrenergic receptor overexpressed in the hearts of transgenic mice. Circulation 104:2485–2491. doi: 10.1161/hc4501.098933 PubMedCrossRefGoogle Scholar
  177. 177.
    Koch WJ, Rockman HA, Samama P, Hamilton RA, Bond RA, Milano CA, Lefkowitz RJ (1995) Cardiac function in mice overexpressing the beta-adrenergic receptor kinase or a beta ARK inhibitor. Science 268:1350–1353. doi: 10.1126/science.7761854 PubMedCrossRefGoogle Scholar
  178. 178.
    Rockman HA, Chien KR, Choi DJ, Iaccarino G, Hunter JJ, Ross J Jr, Lefkowitz RJ, Koch WJ (1998) Expression of a beta-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice. Proc Natl Acad Sci USA 95:7000–7005. doi: 10.1073/pnas.95.12.7000 PubMedCrossRefGoogle Scholar
  179. 179.
    Matkovich SJ, Diwan A, Klanke JL, Hammer DJ, Marreez Y, Odley AM, Brunskill EW, Koch WJ, Schwartz RJ, Dorn GW II (2006) Cardiac-specific ablation of G-protein receptor kinase 2 redefines its roles in heart development and beta-adrenergic signaling. Circ Res 99:996–1003. doi: 10.1161/01.RES.0000247932.71270.2c PubMedCrossRefGoogle Scholar
  180. 180.
    Crackower MA, Oudit GY, Kozieradzki I, Sarao R, Sun H, Sasaki T, Hirsch E, Suzuki A, Shioi T, Irie-Sasaki J, Sah R, Cheng HY, Rybin VO, Lembo G, Fratta L, Oliveira-dos-Santos AJ, Benovic JL, Kahn CR, Izumo S, Steinberg SF, Wymann MP, Backx PH, Penninger JM (2002) Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell 110:737–749. doi: 10.1016/S0092-8674(02)00969-8 PubMedCrossRefGoogle Scholar
  181. 181.
    Patrucco E, Notte A, Barberis L, Selvetella G, Maffei A, Brancaccio M, Marengo S, Russo G, Azzolino O, Rybalkin SD, Silengo L, Altruda F, Wetzker R, Wymann MP, Lembo G, Hirsch E (2004) PI3Kgamma modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and -independent effects. Cell 118:375–387. doi: 10.1016/j.cell.2004.07.017 PubMedCrossRefGoogle Scholar
  182. 182.
    Gilsbach R, Brede M, Beetz N, Moura E, Muthig V, Gerstner C, Barreto F, Neubauer S, Vieira-Coelho MA, Hein L (2007) Heterozygous alpha 2C-adrenoceptor-deficient mice develop heart failure after transverse aortic constriction. Cardiovasc Res 75:728–737. doi: 10.1016/j.cardiores.2007.05.017 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Department of Experimental and Clinical Pharmacology and ToxicologyUniversity Medical Center Hamburg-EppendorfHamburgGermany

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