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Intropic agents in the treatment of heart failure: Despair or hope?

  • Congestive Heart Failure
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Summary

Depression of myocardial contractility plays an important role in the development of heart failure; therefore, intensive interest and passion have been generated to develop cardiotonic agents to improve the contractile function of the failing heart. Inotropic agents that increase cyclic AMP, either by increasing its synthesis or reducing its degradation, exert dramatic short-term hemodynamic benefits, but these acute effects cannot be extrapolated into long-term improvement of the clinical outcome in patients with advanced heart failure. Administration of these agents to an energy-starved failing heart would be expected to increase myocardial energy use and could accelerate disease progression. The role of digitalis in the management of heart failure has been controversial, but ironically the drug has now been proved to favorably affect the neurohormonal disorders and its reevaluation is now being intensively investigated. More recently, attention has been focused on other inotropic agents that have a complex and diversified mechanism. Recent clinical studies have demonstrated that they are potentially useful in the long-term treatment of heart failure patients. These agents have some phosphodiesterase-inhibitory action but also possess additional effects, including acting as cytokine inhibitors, immunomodulators, or calcium sensitizers. However, their therapeutic ratio is narrow and further studies are warranted to establish their optimal doses and their eventual status in the treatment of heart failure.

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References

  1. Ho, KKL, Pinsky, JL, Kannel, WB, Levy, D. The epidemiology of heart failure: The Framingham Study. J Am Coll Cardiol 1993;22(Suppl A):6A-13A.

    Google Scholar 

  2. Harigaya, S, Schwartz, A. Rate of calcium binding and uptake in normal animal and failing human cardiac muscle. Circ Res 1969;25:781–794.

    Google Scholar 

  3. Feldman, MD, Copelas, L, Gwathmey, JK, et al. Deficient production of cyclic AMP: Pharmacologic evidence of an important cause of contractile dysfunction in patients with end-stage heart failure. Circulation 1987;75:331–339.

    Google Scholar 

  4. Packer, M. The development of positive inotropic agents for chronic heart failure: How have we gone astray? J Am Coll Cardiol 1993;22(Suppl A):119A-126A.

    Google Scholar 

  5. Sasayama, S. What do the newer inotropic drugs have to offer? Cardiovasc Drugs Ther 1992;6:15–18.

    Google Scholar 

  6. Armstrong, PW, Moe, GW. Medical advances in the treatment of congestive heart failure. Circulation 1994;88: 2941–2952.

    Google Scholar 

  7. Bristow, MR, Ginsburg, R, Minobe, W, et al. Decreased catecholamine sensitivity and beta-adrenergic receptor density in failing human hearts. N Engl J Med 1982;307:205–211.

    Google Scholar 

  8. Lambertz, H, Meyer, J, Erbel, R. Long-term hemodynamic effects of prenalterol in patients with severe congestive heart failure. Circulation 1984;69:298–305.

    Google Scholar 

  9. Dies, F, Krell, MJ, Whitlow, P, Liang, CS, Goldenberg, I, Applefeld, MM, Gilbert, EM. Intermittent dobutamine in ambulatory outpatients with chronic heart failure. Circulation 1986;74(Suppl II):II38.

    Google Scholar 

  10. Sasayama, S, Yokawa, S, Akiyama, M, Mikawa, M, Sakai, O. Cardiovascular effects of ICI 118,587, a new beta-adrenoceptor partial agonist in man. Jpn Circ J 1986;50: 636–643.

    Google Scholar 

  11. Pouleur, H, van, Eyll, C, Hanet, C, Cheron, P, Charlier, AA, Rousseau, MF. Long-term effects of xamoterol on left ventricular diastolic function and late remodeling: A study in patients with anterior myocardial infarction and singlevessel disease. Circulation 1988;77:1081–1089.

    Google Scholar 

  12. The Xamoterol in Severe Heart Failure Study Group. Xamoterol in severe heart failure. Lancet 1990;336:1–6.

    Google Scholar 

  13. Benotti, JR, Grossman, W, Braunwald, E, Davolos, DD, Alousi, AA. Hemodynamic assessment of amrinone. N Engl J Med 1978;299:1373–1377.

    Google Scholar 

  14. Packer, M, Medina, N, Yushak, H. Hemodynamic and clinical limitation of long-term inotropic therapy with amrinone in patients with severe chronic heart failure. Circulation 1984; 70:1038–1047.

    Google Scholar 

  15. Petein, M, Levine, B, Chohn, JN. Persistent hemodynamic effects without long-term clinical benefits in response to oral piroximone (MDL 19,205) in patients with congestive heart failure. Circulation 1986;73(Suppl III):III230-III236.

    Google Scholar 

  16. Uretsky, BF, for the Enoximone Multicenter Trial Group. Multicenter trial of oral enoximone in patients with moderate to moderately severe congestive heart failure. Lack of benefit compared with placebo. Circulation 1990;82:774–780.

    Google Scholar 

  17. Massie, B, Bourassa, M, DiBianco, R, Hess, M, Konstam, M, Likoff, M, Packer, M, for the Amrinone Multicenter Trial Group. Long-term oral administration of amrinone for congestive heart failure: Lack of efficacy in a multicenter controlled trial. Circulation 1985;71:963–971.

    Google Scholar 

  18. DiBianco, R, for the Amrinone Multicenter Study Investigators. Oral amrinone for the treatment of chronic congestive heart failure: Results of a multicenter randomized doubleblind and placebo-controlled withdrawal study. J Am Coll Cardiol 1984;4:855–866.

    Google Scholar 

  19. Packer, M, for the PROMISE Study Research Group. Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med 1991;325:1468–1475.

    Google Scholar 

  20. Colucci, WS, for the Milrinone Multicenter Trials Investigators. Efficacy of phosphodiesterase inhibition with milrinone in combination with converting enzyme inhibitors in patients with heart failure. J Am Coll Cardiol 1993; 22(Suppl A):113A-118A.

    Google Scholar 

  21. Anversa, P, Olivetti, G, Melissari, M, Loud, VA. Stereological measurement of cellular and subcellular hypertrophy and hyperplasia in the papillary muscle of adult rat. J Mol Cell Cardiol 1980;12:781–795.

    Google Scholar 

  22. Bashore, TM, Magorien, DJ, Letterio, J, Shaffer, P, Unverferth, DV. Histologic and biochemical correlates of left ventricular chamber dynamics in man. J Am Coll Cardiol 1987; 9:734–742.

    Google Scholar 

  23. Ingwall, JS. Is cardiac failure a consequence of decreased energy reserve? Circulation 1993;87(Suppl VII):VII58-VII62.

    Google Scholar 

  24. Schultheiss, HP, Schulze, K, Schauer, R, et al. Antibody-mediated imbalance of myocardial energy metabolism. A causal factor of cardiac failure? Circ Res 1995;76:64–72.

    Google Scholar 

  25. Katz, AM. Potential deleterious effects of inotropic agents in the therapy of chronic heart failure. Circulation 1986; 73(Suppl III):III184-III190.

    Google Scholar 

  26. Katz, AM. Scientific insights from clinical studies of converting-enzyme inhibitors in the failing heart. Trends Cardiovasc Med 1995;5:37–44.

    Google Scholar 

  27. Lubbe, WF, Podzuweit, T, Opie, LH. Potential arrhythmogenic role of cyclic adenosine monophosphate (AMP) and cytosolic calcium overload: Implications for prophylactic effects of beta-blockers in myocardial infarction and proarrhythmic effects of phosphodiesterase inhibitors. J Am Coll Cardiol 1992;19:1622–1633.

    Google Scholar 

  28. Matsuda, H, Noma, A, Kurachi, Y, Irisawa, H. Transient depolarizations and spontaneous voltage fluctuations in isolated single cells from guinea pig ventricles. Circ Res 1982; 51:142–151.

    Google Scholar 

  29. Gheorghiade, M, Beller, GA. Effects of discontinuing maintenance digoxin therapy in patients with ischemic heart disease and congestive heart failure in sinus rhythm. Am J Cardiol 1983;51:1243–1250.

    Google Scholar 

  30. Fleg, JL, Gottlieb, SH, Lakatta, EG. Is digoxin really important in treatment of compensated heart failure? A placebo-controlled crossover study in patients with sinus rhythm. Am J Med 1982;73:244–250.

    Google Scholar 

  31. Poole-Wilson, PA, Robinson, K. Digoxin—A redundant drug in congestive cardiac failure. Cardiovasc Drugs Ther 1989; 2:733–741.

    Google Scholar 

  32. Feguson, DW, Berg, WJ, Sanders, JS, Roach, PJ, Kempf, JS, Kienzle, ME. Sympathoinhibitory responses to digitalis glycosides in heart failure patients: Direct evidence from sympathetic neural recordings. Circulation 1989;80:65–77.

    Google Scholar 

  33. Covit, AB, Schaer, GL, Sealey, JE, Laragh, JH, Cody, RJ. Suppression of the renin-angiotensin system by intravenous digoxin in chronic congestive heart failure. Am J Med 1983; 73;445–447.

    Google Scholar 

  34. Captopril-Digoxin Multicenter Research Group. Comparative effects of therapy with captopril and digoxin in patients with mild to moderate heart failure. JAMA 1988;259: 539–544.

    Google Scholar 

  35. The German and Austrian Xamoterol Study Group. Double blind placebo-controlled comparison of digoxin and xamoterol in chronic heart failure. Lancet 1988;1:489–493.

    Google Scholar 

  36. DiBianco, R, for the Milrinone Multicenter Trial Group. A comparison of oral milrinone, digoxin, and their combination in the treatment of patients with chronic heart failure. N Engl J Med 1989;320:677–683.

    Google Scholar 

  37. Packer, M, for the RADIANCE Study. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. N Engl J Med 1993;329:1–7.

    Google Scholar 

  38. Krum, H, Bigger, JT, Goldsmith, RL, Packer, M. Effect of long-term digoxin therapy on autonomic function in patients with chronic heart failure. J Am Coll Cardiol 1995;25: 289–294.

    Google Scholar 

  39. Yusuf, S, Garg, R, Held, P, Gorlin, R. Need for a large randomized trial to evaluate the effects of digitalis on morbidity and mortality in congestive heart failure. Am J Cardiol 1992;69:64G-70G.

    Google Scholar 

  40. Gorlin R. The effect of digitalis on mortality and hospitalations in patients with heart failure. Presentation of the 45th Annual Scientific Session of the American College of Cardiology, Orlando, Florida, 1996.

  41. Sasayama, S, Inoue, M, Asanoi, H, Kodama, K, Hori, M, Sakurai, T, Kawai, C. Acute hemodynamic effects of a new intropic agent, OPC-8212, on severe congestive heart failure. Heart Vessels 1986;2:23–28.

    Google Scholar 

  42. Iijima, T, Taira, N. Membrane current changes responsible for the positive inotropic effect of OPC-8212, a new positive inotropic agent, in single ventricular cells of the guinea pig heart. J Pharmacol Exp Ther 1987;240:657–662.

    Google Scholar 

  43. Sasayama, S, for OPC-8212 Multicenter Research Group. A placebo-controlled, randomized, double-blind study of OPC-8212 in patients with mild chronic heart failure. Cardiovasc Drugs Ther 1990;4:19–25.

    Google Scholar 

  44. Feldman, AM, for the Vesnarinone Study Group. Effects of vesnarinone of morbidity and mortality in patients with heart failure. N Engl J Med 1993;329:149–155.

    Google Scholar 

  45. Matsui, S, Matsumori, A, Matoba, Y, Uchida, A, Sasayama, S. Treatment of virus-induced myocardial injury with a novel immunomodulating agent, vesnarinone. J Clin Invest 1994; 94:1212–1217.

    Google Scholar 

  46. Lin, CS, Boltz, RC, Blake, JT, et al. Voltage-gated potassium channels regulate calcium-dependent pathways involved in human T lymphocyte activation. J Exp Med 1993;177: 637–645.

    Google Scholar 

  47. Felzen, B, Lavy, R, Garcia, M, Berke, G, Gardner, P, Binah, O. Interaction of cytotoxic T lymphocytes and guinea pig ventricular myocytes. Pharmacological modulation by blocking K+ currents in cytotoxic T lymphocytes. Circ Res 1996;78:253–261.

    Google Scholar 

  48. Levine, B, Kalman, J, Mayer, L, Fillit, HM, Packer, M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 1990;323:236–241.

    Google Scholar 

  49. Barry, WH. Mechanisms of immune-mediated myocyte injury. Circulation 1994;89:2421–2432.

    Google Scholar 

  50. Matsumori, A, Yamada, T, Suzuki, H, Matoba, Y, Sasayama, S. Increased circulating cytokines in patients with myocarditis and cardiomyopathy. Br Heart J 1994;72:561–566.

    Google Scholar 

  51. Doyama, K, Fujiwara, H, Fukumoto, M, et al. Tumor necrosis factor is expressed in cardiac tissues of patients with heart failure. Int J Cardiol 1996;54:217–225.

    Google Scholar 

  52. Yamada, T, Matsumori, A, Sasayama, S. Therapeutic effect of anti-tumor necrosis factor-α antibody on the murine model of viral myocarditis induced by encephalomyocarditis virus. Circulation 1994;89:846–851.

    Google Scholar 

  53. Shioi, T, Matsumori, A, Matsui, S, Sasayama, S. Inhibition of cytokine production by a new inotropic agent, vesnarinone, in human lymphocytes, T cell line, and monocytic cell line. Life Sci 1994;54:PL11–16.

    Google Scholar 

  54. Matsumori, A, Shioi, T, Yamada, T, Matsui, S, Sasayama, S. Vesnarinone, a new inotropic agent, inhibits cytokine production by stimulated human blood from patients with heart failure. Circulation 1994;89:955–958.

    Google Scholar 

  55. Matsui, S, Matsumori, A, Sasayama, S. Vesnarinone prolongs survival and reduces lethality in a murine model of lethal endotoxemia. Life Sci 1994;55:1735–1741.

    Google Scholar 

  56. Sato, Y, Matsumori, A, Sasayama, S. Inotropic agent vesnarinone inhibits cytokine production and E-selectin expression in human umbilical vein endothelial cells. J Mol Cell Cardiol 1995;27:2265–2273.

    Google Scholar 

  57. Hattori, Y, So, S, Hattori, S, Kasai, K, Shimoda, S. Vesnarinone inhibits induction of nitric oxide synthase in J774 macrophages and rat cardiac myocytes in culture. Cardiovasc Res 1995;30:187–192.

    Google Scholar 

  58. Sasayama, S. Immune modulation of cardiac function: A new frontier. J Card Failure 1995;1:331–335.

    Google Scholar 

  59. Sasayama, S, Matsumori, A. Role of cytokines in the syndrome of heart failure. Intern Med 1996;35:60–63.

    Google Scholar 

  60. Ruegg, JC, Morano, I. Calcium-sensitivity modulation of cardiac myofibrillar proteins. J Cardiovasc Pharmacol 1989; 14(Suppl III):S20-S23.

    Google Scholar 

  61. Fujino, K, Sperelakis, N, Solaro, RJ. Sensitization of dog and guinea pig heart myofilaments to Ca2+ activation and the inotropic effect of pimobendan: Comparison with milrinone. Circ Res 1988;63:911–922.

    Google Scholar 

  62. Solaro, RJ, Fujino, K, Sperelakis, N. The positive inotropic effect of pimobendan involves stereospecific increases in the calcium sensitivity of cardiac myofilaments. J Cardiovasc Pharmacol 1989;14(Suppl 2):S7-S12.

    Google Scholar 

  63. Holubarsch, C, Hasenfuss, G, Just, H, Blanchard, E, Mulieri, LA, Alpert, NR. Influence of the positive inotropic substance pimobendan (UD-CG 115 BS) on contractile economy of guinea pig papillary muscles. J Cardiovasc Pharmacol 1989;14(Suppl II):S13-S17.

    Google Scholar 

  64. Hasenfuss, G, Holubarsch, C, Heiss, HW, Rattert, B, Just, H. Influence of the calcium-sensitizer UDCG-115 on hemodynamics and myocardial energetics in patients with idiopathic dilated cardiomyopathy. Comparison with nitroprusside. Basic Res Cardiol 1989;84(Suppl I):225–233.

    Google Scholar 

  65. Kubo, SH, for the Pimobendan Multicenter Research Group. Beneficial effects of pimobendan on exercise tolerance and quality of life in patients with heart failure: Results of a multicenter trial. Circulation 1992;85:942–949.

    Google Scholar 

  66. Sasayama, S, Asanoi, H, Kihara, Y, et al. Clinical effects of long-term administration of pimobendan in patients with moderate congestive heart failure. Heart Vessels 1994;9: 113–120.

    Google Scholar 

  67. van, Meel, JCA, Mauz, ABM, Wienen, W, Diederen, W. Pimobendan increases survival of cardiomyopathic hamsters. J Cardiovasc Pharmacol 1989;13:508–509.

    Google Scholar 

  68. Verdouw, PD, Hartog, JM, Duncker, DJ, Roth, W, Saxena, PR. Cardiovascular profile of pimobendan, a benzimidazolepyridazinone derivative with vasodilating and inotropic properties. Eur J Pharmacol 1986;126:21–30.

    Google Scholar 

  69. Arnout, J, Deckmyn, H, Huybrechts, E, Verstraete, M. UDCG 115 and 212, two benzimidazo-pyridazinones with broad spectrum antiplatelet activity. Thromb Haemost 1986;54:134.

    Google Scholar 

  70. Just, H. For the Pimobendan in Congestive Heart Failure (PICO) Investigators: Effect of pimobendan on exercise capacity in patients with heart failure: main results from the PICO trial. Heart 1996;76:223–231.

    Google Scholar 

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Sasayama, S. Intropic agents in the treatment of heart failure: Despair or hope?. Cardiovasc Drug Ther 10, 703–709 (1997). https://doi.org/10.1007/BF00053027

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