Skip to main content
Log in

Low-level inotropic stimulation with type III phosphodiesterase inhibitors in patients with advanced symptomatic chronic heart failure receiving β-blocking agents

  • Published:
Current Cardiology Reports Aims and scope Submit manuscript

Abstract

β-blocking agents are now well established as a cornerstone therapy in mild to moderate heart failure. Patients with more advanced heart failure depend on adrenergic activation to maintain adequate myocardial function. This leads to significant difficulties in using β-blockers in advanced or severe heart failure. In addition, recent data indicate that adrenergic withdrawal might be detrimental in some of these patients. In higher doses, positive inotropic agents have been shown to increase mortality when used alone in subsets with advanced heart failure. Preliminary data suggest that the combination of low-dose phosphodiesterase inhibitors and a β-blocker may be better tolerated and does not appear to be associated with the adverse effects of either therapy used alone. We discuss the theoretic underpinning of this approach and the supportive clinical data.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

  1. Bristow MR: b-adrenergic receptor blockade in chronic heart failure. Circulation 2000, 101:558–569. A detailed discussion of the rationale behind using b-blockers in heart failure and of the results of trials using individual agents.

    PubMed  CAS  Google Scholar 

  2. Packer M, Bristow MR, Cohn JN, et al., for the US Carvedilol Heart Failure Study Group: The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996, 334:1349–1355.

    Article  PubMed  CAS  Google Scholar 

  3. MERIT-HF Study Group: Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). Lancet 1999, 353:2001–2007. This study using long-acting metoprolol reduced all-cause mortality by 34% in patients with class II-IV heart failure.

    Article  Google Scholar 

  4. CIBIS-II Investigators and Committees: The cardiac insufficiency bisoprolol study II (CIBIS-II). Lancet 1999, 353:9–13. This study showed that the b1-selective agent bisoprolol reduces all-cause mortality by 34% in mostly class III heart failure patients with an ejection fraction lower than 35%.

    Article  Google Scholar 

  5. Bristow MR: Mechanism of action of b-blocking agents in heart failure. Am J Cardiol 1997, 80:26L-40L.

    Article  PubMed  CAS  Google Scholar 

  6. Bristow MR, Gilbert EM, Abraham WT, et al., for the MOCHA Investigators: Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. Circulation 1996, 94:2807–2816.

    PubMed  CAS  Google Scholar 

  7. Krum H, Sackner-Bernstein JD, Goldsmith RL, et al.: Doubleblind, placebo-controlled study of the long-term efficacy of carvedilol in patients with severe chronic heart failure. Circulation 1995, 92:1499–1506.

    PubMed  CAS  Google Scholar 

  8. Macdonald PS, Keogh AM, Aboyoun CL, et al.: Tolerability and efficacy of carvedilol in patients with New York Heart Association class IV heart failure. J Am Coll Cardiol 1999, 33:924–931. In this paper 63 patients with class IV heart failure were treated with carvedilol. Nonfatal adverse effects occurred in 43% of the patients; 29% deteriorated or died.

    Article  PubMed  CAS  Google Scholar 

  9. CIBIS Investigators and Committees: A randomized trial of b-blockade in heart failure: the cardiac insufficiency bisoprolol study (CIBIS). Circulation 1994, 90:1765–1773.

    Google Scholar 

  10. Lechat P, Escolano S, Golmard JL, et al.: Prognostic value of bisoprolol-induced hemodynamic effects in heart failure during the Cardiac Insufficiency Bisoprolol Study (CIBIS). Circulation 1997, 96:2197–2205.

    PubMed  CAS  Google Scholar 

  11. The BEST Trial Investigators: The b-blocker evaluation of Survival Trial. N Engl J Med 2001, in press.

  12. Insel PA: Adrenergic receptors: evolving concepts and clinical implications. N Engl J Med 1996, 334:580–585.

    Article  PubMed  CAS  Google Scholar 

  13. Engelhardt S, Hein L, Wiesmann F, Lohse MJ: Progressive hypertrophy and heart failure in b 1-adrenergic receptor transgenic mice. Proc Natl Acad Sci U S A 1999, 96:7059–7064.

    Article  PubMed  CAS  Google Scholar 

  14. Bisognano JD, Weinberger HD, Bohlmeyer TJ, et al.: Myocardial- directed overexpression of the human b1-adrenergic receptor in transgenic mice. J Mol Cell Cardiol 2000, 32:817–830.

    Article  PubMed  CAS  Google Scholar 

  15. Liggett SB, Tepe NM, Lorenz JN, et al.: Early and delayed consequences of b2-adrenergic receptor overexpression in mouse hearts: critical role for expression level. Circulation 2000, 101:1707–1714.

    PubMed  CAS  Google Scholar 

  16. Rockman HA, Chien KR, Choi D-J, et al.: Expression of a b-adrenergic receptor kinase I inhibitor prevents the development of myocardial failure in gene-targeted mice. Proc Natl Acad Sci U S A 1998, 95:7000–7005.

    Article  PubMed  CAS  Google Scholar 

  17. Freeman K, Iaccarino G, Bohlmeyer T, Leinwand LA: Overexpression of the b2 adrenergic receptor accelerates heart failure in hypertrophic cardiomyopathy mice. Circulation 2000, 100(Suppl I):I493.

    Google Scholar 

  18. Mann DL, Kent RL, Parsons B, Cooper G IV: Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation 1992, 85:790–804.

    PubMed  CAS  Google Scholar 

  19. Communal C, Singh K, Sawyer DB, Colluci WS: Opposing effects of b1- and b2-adrenergic receptors on cardiac myocyte apoptosis: role of a pertussis-toxin sensitive G protein. Circulation 1999, 100:2210–2212.

    PubMed  CAS  Google Scholar 

  20. Ishikawa Y, Homcy CJ: The adenylyl cyclases as integrators of transmembrane signal transduction. Circ Res 1997, 80:297–304.

    PubMed  CAS  Google Scholar 

  21. Bristow MR, Hershberger RE, Port JD, et al.: b1- and b2- adrenergic receptor mediated adenylate cyclase stimulation in nonfailing and failing human ventricular myocardium. Mol Pharm 1989, 35:295–303.

    CAS  Google Scholar 

  22. Xiao RP, Cheng H, Zhou YY, Kuschel M, Lakatta EG: Recent advances in cardiac b2-adrenergic signal transduction. Circ Res 1999, 85:1092–1100.

    PubMed  CAS  Google Scholar 

  23. Rapundalo ST, Solaro RJ, Kranias EG: Inotropic responses to isoproterenol and phosphodiesterase inhibitors in intact guinea pig hearts: comparison of cyclic AMP levels and phosphorylation of sarcoplasmic reticulum and myofibrillar proteins. Circ Res 1989, 64:104–111.

    PubMed  CAS  Google Scholar 

  24. Goldspink PH, Russell B: The cAMP response element binding protein is expressed and phosphorylated in cardiac myocytes. Circ Res 1994, 74:1042–1049.

    PubMed  CAS  Google Scholar 

  25. Leroy M-J, Degerman E, Taira M, et al.: Characterization of two recombinant PDE3 (cGMP-inhibited cyclic nucleotide phosphodiesterase) isoforms, RcGIP1 and HcGIP2, expressed in NIH 3006 murine fibroblasts and Sf9 cells. Biochemistry 1996, 35:10194–10202.

    Article  PubMed  CAS  Google Scholar 

  26. Movsesian MA, Smith CJ, Krall J, et al.: Sarcoplasmic reticulum- associated cyclic adenosine 5'-monophosphate phosphodiesterase activity in normal and failing human hearts. J Clin Invest 1991, 88:15–19.

    PubMed  CAS  Google Scholar 

  27. Ludmer PL, Wright RF, Arnold JM, et al.: Separation of the direct myocardial and vasodilator actions of milrinone administered by an intracoronary infusion technique. Circulation 1986, 73:130–137.

    PubMed  CAS  Google Scholar 

  28. Herrmann HC, Ruddy TD, William G, et al.: Inotropic effect of enoximone in patients with severe heart failure: demonstration by left ventricular end-systolic pressure-volume analysis. J Am Coll Cardiol 1987, 9:1117–1123.

    Article  PubMed  CAS  Google Scholar 

  29. Monrad ES, McKay RG, Baim DS, et al.: Improvement in indexes of diastolic performance in patients with congestive heart failure treated with milrinone. Circulation 1984, 70:1030–1037.

    PubMed  CAS  Google Scholar 

  30. Binkley PF, Shaffer PB, Ryan JM, Leier CV: Augmentation of diastolic function with phosphodiesterase inhibition in congestive heart failure. J Lab Clin Med 1989, 114:266–271.

    PubMed  CAS  Google Scholar 

  31. Edes I, Kiss E, Kitada Y, et al.: Effects of levosimendan, a cardiotonic agent targeted to troponin C, on cardiac function and on phosphorylation and Ca2+ sensitivity of cardiac myofibrils and sarcoplasmic reticulum in guinea pig hearts. Circ Res 1995, 77:107–113.

    PubMed  CAS  Google Scholar 

  32. Gao MH, Lai NC, Roth DM, et al.: Adenylylcyclase increases responsiveness to catecholamine stimulation in transgenic mice. Circulation 1999, 99:1618–1622.

    PubMed  CAS  Google Scholar 

  33. Luo W, Grupp IL, Ponniah S, et al.: Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of b-agonist stimulation. Circ Res 1994, 75:401–409.

    PubMed  CAS  Google Scholar 

  34. Minamisawa S, Hoshijima M, Chu G, et al.: Chronic phospholamban- sarcoplasmic reticulum ATPase interaction is the critical calcium cycling defect in dilated cardiomyopathy. Cell 1999, 99:313–322.

    Article  PubMed  CAS  Google Scholar 

  35. Iwase M, Bishop SP, Uechi M, et al.: Adverse effects of chronic endogenous sympathetic drive induced by cardiac Gsa overexpression. Circ Res 1996, 78:517–524.

    PubMed  CAS  Google Scholar 

  36. Bristow MR, Port JD, Kelly RA: Treatment of heart failure. In Heart Disease: A Textbook of Cardiovascular Medicine, edn 6. Edited by Braunwald E. Philadelphia: WB Saunders; 2000.

    Google Scholar 

  37. Simpson P: Norepinephrine-stimulated hypertrophy of cultured rat myocardial cells is an alpha-1 adrenergic response. J Clin Invest 1983, 72:732–738.

    PubMed  CAS  Google Scholar 

  38. Pinson A, Schluter KD, Zhou XJ, et al.: Alpha- and b-adrenergic stimulation of protein synthesis in cultured adult ventricular cardiomyocytes. J Mol Cell Cardiol 1993, 25:477–490.

    Article  PubMed  CAS  Google Scholar 

  39. Milano CA, Dolber PC, Rockman HA, et al.: Myocardial expression of a constitutively active a1B-adrenergic receptor in transgenic mice induces cardiac hypertrophy. Proc Natl Acad Sci U S A 1994, 91:10109–10113.

    Article  PubMed  CAS  Google Scholar 

  40. Bristow MR: Changes in myocardial and vascular receptors in heart failure. J Am Coll Cardiol 1993, 22(Suppl A):61A-71A.

    Article  PubMed  CAS  Google Scholar 

  41. Ungerer M, Böhm M, Elce JS, et al.: Altered expression of b-adrenergic receptor kinase and b 1-adrenergic receptors in the failing human heart. Circulation 1993, 87:454–463.

    PubMed  CAS  Google Scholar 

  42. Fowler MB, Laser JA, Hopkins GL, et al.: Assessment of the b-adrenergic receptor pathway in the intact failing human heart: progressive receptor down-regulation and subsensitivity to agonist response. Circulation 1986, 74:1290–1302.

    PubMed  CAS  Google Scholar 

  43. Colucci WS, Denniss AR, Leatherman GF, et al.: Intracoronary infusion of dobutamine to patients with and without severe congestive heart failure. J Clin Invest 1988, 81:1103–1110.

    Article  PubMed  CAS  Google Scholar 

  44. White M, Yanowitz F, Gilbert EM, et al.: Role of b-adrenergic receptor downregulation in the peak exercise response in patients with heart failure due to idiopathic dilated cardiomyopathy. Am J Cardiol 1995, 76:1271–1276.

    Article  PubMed  CAS  Google Scholar 

  45. Bristow MR, Kantrowitz NE, Ginsburg R, Fowler MB: b-adrenergic function in heart muscle disease and heart failure. J Mol Cell Cardiol 1985, 17(Supp 2):41–52.

    Article  PubMed  CAS  Google Scholar 

  46. Cohn JN, Coats AJ: Heart failure 99 — the MOXCON story. Int J Cardiol 1999, 71:109–111.

    Article  Google Scholar 

  47. Cohn JN, Levine TB, Olivari MT, et al.: Plasma norepinephrine as a guide to prognosis in patients with chronic heart failure. N Engl J Med 1984, 311:819–823.

    Article  PubMed  CAS  Google Scholar 

  48. Kaye DM, Lefkovits J, Jennings GL, et al.: Adverse consequences of high sympathetic nervous activity in the failing human heart. J Am Coll Cardiol 1995, 26:1257–1263.

    Article  PubMed  CAS  Google Scholar 

  49. Bristow MR, Zelis R, Nuzzo R, et al.: Baseline and three month changes in systemic venous norepinephrine as predictors of clinical outcomes of the BEST trial. J Am Coll Cardiol 2001, 37:218A.

    Google Scholar 

  50. Heilbrunn SM, Shah P, Bristow MR, et al.: Baseline and threemonth changes in systemic venous norepinephrine as predictors of clinical outcomes of the best trial. J Am Coll Cardiol 2001, 37:218A.

    Google Scholar 

  51. Böhm M, Deutsch HJ, Hartmann D, et al.: Improvement of postreceptor events by metoprolol treatment in patients with chronic heart failure. J Am Coll Cardiol 1997, 30:992–996.

    Article  PubMed  Google Scholar 

  52. Yamada S, Ohkura T, Uchida S, et al.: A sustained increase in b-adrenoceptors bdduring long-term therapy with metoprolol and bisoprolol in patients with heart failure from idiopathic dilated cardiomyopathy. Life Sci 1996, 58:1737–1744.

    Article  PubMed  CAS  Google Scholar 

  53. Gilbert EM, Abraham WT, Olsen S, et al.: Comparative hemodynamic, left ventricular functional, and antiadrenergic effects of chronic treatment with metoprolol versus carvedilol in the failing heart. Circulation 1996, 94:2817–2825.

    PubMed  CAS  Google Scholar 

  54. Böhm M, Ettelbruck S, Flesch M, et al.: b-adrenergic signal transduction following carvedilol treatment in hypertensive cardiac hypertrophy. Cardiovasc Res 1998, 40:146–155.

    Article  PubMed  Google Scholar 

  55. Iaccarino G, Tomhave ED, Lefkowitz RJ, Koch WJ: Reciprocal in vivo regulation of myocardial G protein-coupled receptor kinase expression by b-adrenergic receptor stimulation and blockade. Circulation 1998, 98:1783–1789.

    PubMed  CAS  Google Scholar 

  56. Newton GE, Parker JD: Acute effects of b1-selective and nonselective b-adrenergic receptor blockade on cardiac sympathetic activity in congestive heart failure. Circulation 1996, 94:353–358.

    PubMed  CAS  Google Scholar 

  57. Travill CM, Pugh S, Noble M: The inotropic and hemodynamic effects of intravenous milrinone when reflex adrenergic stimulation is suppressed by b-adrenergic blockade. Clinical Therapeutics 1994, 16:783–792.

    PubMed  CAS  Google Scholar 

  58. Galie N, Branzi A, Magnani G, et al.: Effects of enoximone alone and in combination with metoprolol on myocardial function and energetics in severe congestive heart failure: improvement in hemodynamic and metabolic profile. Cardiovasc Drugs Ther 1993, 7:337–347.

    Article  PubMed  CAS  Google Scholar 

  59. Tsvetkova TO, Farber DJ, Abraham WT, et al.: Comparative hemodynamic effects of milrinone and dobutamine in heart failure patients treated chronically with carvedilol [abstract 135]. J Card Fail 1998, 4:36.

    Article  Google Scholar 

  60. Dage RC, Okerholm RA: Pharmacology and pharmacokinetics of enoximone. Cardiology 1990, 77(Suppl 3):2–13.

    Article  PubMed  Google Scholar 

  61. Edes I, Kiss E, Kitada Y: et al: Effects of levosimendan, a cardiac agent targeted to troponin C, on cardiac function and on phosphorylation and CA2+ sensitivity of cardiac myofibrils and sarcoplasmic reticulum in guinea pig heart. Circ Res 1995, 77:107–113.

    PubMed  CAS  Google Scholar 

  62. Francis SH, Noblett BD, Todd BW, et al.: Relaxation of vascular and tracheal smooth muscle by cyclic nucleotide analogs that preferentially activate purified cGMP-dependent protein kinase. Mol Pharmacol 1988, 34:506–517.

    PubMed  CAS  Google Scholar 

  63. Baim DS, McDowell AV, Cherniles J, et al.: Evaluation of a new bipyridine inotropic agent, milrinoe, in patients with severe congestive heart failure. N Engl J Med 1983, 309:748–756.

    Article  PubMed  CAS  Google Scholar 

  64. Heiss HW, Hasenfuss G, Holubarsch C, et al.: Cardiac energetics after intravenous enoximone in idiopathic dilated cardiomyopathy. Am J Cardiol 1987, 60:53C.

    Article  PubMed  CAS  Google Scholar 

  65. Szabo BM, van Vedhuisen DJ, van Dijk RB, et al.: Hemodynamic and autonomic effects of intravenous saterinone in patients with chronic heart failure. J Cardiovasc Pharmacol 1997, 29:618–623.

    Article  PubMed  CAS  Google Scholar 

  66. Silke B, Hanratty CG, Riddell JG: Heart-rate variability effects of b-adrenoceptor agonists (xamoterol, prenalterol, and salbutamol) assessed nonlinearly with scatterplots and sequence methods. J Cardiovasc Pharmacol 1999, 33:859–867.

    Article  PubMed  CAS  Google Scholar 

  67. Lowes BD, Higginbotham M, Petrovich L, et al.: Low-dose enoximone improves exercise capacity in chronic heart failure. J Am Coll Cardiol 2000, 36:501–508.

    Article  PubMed  CAS  Google Scholar 

  68. Herrmann HC, Ruddy TD, Dec GW, et al.: Diastolic function in patients with severe heart failure: comparison of the effects of enoximone and nitroprusside. Circulation 1987, 75:1214–1221.

    PubMed  CAS  Google Scholar 

  69. Haber HL, Simek CL, Gimple LW, et al.: Why do patients with congestive heart failure tolerate the initiation of b-blocker therapy? Circulation 1993, 88:1610–1619.

    PubMed  CAS  Google Scholar 

  70. Newton GE, Parker JD: Acute effects of b 1-selective and nonselective b-adrenergic receptor blockade on cardiac sympathetic activity in congestive heart failure. Circulation 1996, 94:353–358.

    PubMed  CAS  Google Scholar 

  71. Shakar SF, Abraham WT, Gilbert EM, et al.: Combined oral positive inotropic and b-blocker therapy for treatment of refractory class IV heart failure. J Am Coll Cardiol 1998, 31:1336–1340. This is the first publication regarding a novel approach to the treatment of class IV heart failure, using a combination of a PDEI and metoprolol. The patients had a significant increase in their ejection fraction, NYHA class, and an improved mortality when compared with comparable historic controls.

    Article  PubMed  CAS  Google Scholar 

  72. Lowes BD, Simon MA, Tsvetkova TO, Bristow MR: Inotropes in the b-blocker era. Clin Cardiol 2000, 23(Suppl III):III11-III16. This review discusses the underpinnings behind the use of inotropes in patients treated with b-blockers. It has some original data from a series of patients treated by our group.

    Article  PubMed  CAS  Google Scholar 

  73. Hall JA, Ferro A, Dickerson JE, Brown MJ: b adrenoreceptor subtype cross regulation in the human heart. Br Heart J 1993, 69:332–337.

    PubMed  CAS  Google Scholar 

  74. Gilbert EM, Hershberger RE, Wiechmann RJ, et al.: Pharmacologic and hemodynamic effects of combined b-agonist stimulation and phosphodiesterase inhibition in the failing human heart. Chest 1995, 108:1524–1532.

    PubMed  CAS  Google Scholar 

  75. Böhm M, Diet F, Kemkes B, Erdmann E: Enhancement of the effectiveness of milrinone to increase force of contraction by stimulation of cardiac b-adrenoceptors in the failing human heart. Klin Wochenschr 1988, 66:957–962.

    Article  PubMed  Google Scholar 

  76. Sigmund M, Jakob H, Becker H, et al.: Effects of metoprolol on myocardial b-adrenoceptors and Gia-proteins in patients with congestive heart failure. Eur J Clin Pharmacol 1996, 51:127–132.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shakar, S.F., Bristow, M.R. Low-level inotropic stimulation with type III phosphodiesterase inhibitors in patients with advanced symptomatic chronic heart failure receiving β-blocking agents. Curr Cardiol Rep 3, 224–231 (2001). https://doi.org/10.1007/s11886-001-0027-8

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11886-001-0027-8

Keywords

Navigation