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Effect of Ramipril on Heart Rate Variability in Digitalis-Treated Patients with Chronic Heart Failure

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Abstract

The aim of this study was to evaluate the effect of an angiotensin-converting enzyme (ACE) inhibitor, ramipril, on heart rate variability in patients with heart failure simultaneously treated with digitalis. This study was a multicentric, randomized, double-blind, placebo-controlled study including 50 patients with chronic heart failure (CHF). All patients were in NYHA functional class II and III. The etiology of CHF was mainly idiopathic dilated cardiomyopathy and ischemic heart disease. After a 4-week placebo run-in period with digoxin and diuretics, patients were randomized to receive additional ramipril or placebo. To assess heart rate variability (HRV) and arrhythmias, 24-hour ECGs were recorded at the end of the placebo run-in period, 8 and 24 weeks after randomization. Spectral analysis of HRV was performed during one diurnal and one nocturnal 5-minute time period. No statistically significant differences in HRV within low-, high-, and total-frequency bands were induced by ramipril in either the diurnal or nocturnal periods, both at 8 and 24 weeks after randomization. Ramipril produced a significant decrease in nonsustained ventricular tachycardia at 24 weeks of treatment (p = 0.01). These results run against previous observations showing an increase in parasympathetic tone with ACE inhibitors in heart failure. The present study thus suggests that the effects of ACE inhibitors in CHF are variable and depend on the patient and concomitant treatment that might influence HRV such as digoxin treatment.

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References

  1. Eckberg DL, Drabinsky M, Braunwald E. Defective cardiac parasympathetic control in patients with heart disease. N Engl J Med 1971;285:877–883.

    Article  PubMed  CAS  Google Scholar 

  2. Hasking GL, Esler MD, Jennings G, et al. Norepinephrine spillover to plasma in patients with congestive heart failure: Evidence of increased overall and cardiorenal sympathetic nervous activity. Circulation 1986;73:615–621.

    PubMed  CAS  Google Scholar 

  3. Vallbo AB, Hagbarth KE, Torebjork HE, et al. Somatosensory proprioceptive and sympathetic activity in human peripheral nerve. Physiol Rev 1979;59:919–957.

    PubMed  CAS  Google Scholar 

  4. Leimbach WN, Wallin BG, Victor RG, et al. Direct evidence from intraneural recording for increased central sympathetic outflow in patients with heart failure. Circulation 1986;73:913–919.

    PubMed  Google Scholar 

  5. Ferguson DW, Berg WJ, Sanders JS, et al. Clinical and hemodynamic correlates of sympathetic nerve activity in normal humans and patients with heart failure: Evidence from direct microneurographic recordings. J Am Coll Cardiol 1990;16:1125–1134.

    PubMed  CAS  Google Scholar 

  6. Cohn JN. Abnormalities of peripheral sympathetic nervous system control in congestive heart failure. Circulation 1990;82(Suppl. I):I59–67.

    PubMed  CAS  Google Scholar 

  7. Malliani A, Pagani M. The role of the sympathetic nervous system in congestive heart failure. Eur Heart J 1983;4(Suppl. a):49–54.

    PubMed  Google Scholar 

  8. Mancia G. Neurohormonal activation in congestive heart failure. Am Heart J 1990;120:1532–1537.

    Article  PubMed  CAS  Google Scholar 

  9. Genest J, Granger P, De Champlain J, et al. Endocrine factors in congestive heart failure. Am J Cardiol 1968;22:35–42.

    Article  PubMed  CAS  Google Scholar 

  10. Laragh JH. Endocrine mechanisms in congestive cardiac failure: Renin, aldosteron and atrial natruretic hormone. Drugs 1986;32(Suppl. 5):1–12.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  12. Dzau VJ, Colucci WS, Hollenberg NK, et al. Relation of the renin-angiotensin-aldosterone system to clinical state in congestive heart failure. Circulation 1981;63:645–651.

    PubMed  CAS  Google Scholar 

  13. Thomas JA, Marks BH. Plasma norepinephrine in congestive heart failure. Am J Cardiol 1978;41:233–243.

    Article  PubMed  CAS  Google Scholar 

  14. Higgins CB, Vatner SF, Eckberg DL, et al. Alteration in the baroreceptor reflex in conscious dogs with heart failure. J Clin Invest 1972;51:715–724.

    PubMed  CAS  Google Scholar 

  15. Levine TB, Francis GS, Goldsmith SR, et al. The neurohumoral and hemodynamic response to orthostatic tilt in patients with congestive heart failure. Circulation 1983;67:1070–1075.

    PubMed  CAS  Google Scholar 

  16. Ferguson DW, Abboud FM, Mark AL. Selective impairment of baroreflex-mediated vasoconstrictor responses in patients with ventricular dysfunction. Circulation 1984;69:451–460.

    PubMed  CAS  Google Scholar 

  17. Goldsmith SR. Impaired suppression of plasma norepinephrine during headdown tilt in patients with congestive heart failure. Am Heart J 1991;122:1252–1258.

    Article  Google Scholar 

  18. Kassis E. Cardiovascular response to orthostatic tilt in patients with severe congestive heart failure. Cardiovasc Res 1987;21:362–368.

    PubMed  CAS  Google Scholar 

  19. Ellenbogen KA, Mohanty PK, Szentpetery S, et al. Arterial baroreflex abnormalities in heart failure: Reversal after orthotopic cardiac transplantation. Circulation 1989;79:51–58.

    PubMed  CAS  Google Scholar 

  20. Ferguson DW, Berg WJ, Roach PJ, et al. Effects of heart failure on baroreflex control of sympathetic neural activity. Am J Cardiol 1992;69:523–531.

    Article  PubMed  CAS  Google Scholar 

  21. Sopher SM, Smith ML, Eckberg DL, et al. Autonomic pathophysiology in heart failure: Carotid baroreceptor-cardiac reflexes. Am J Physiol 1990;259:H689–696.

    PubMed  CAS  Google Scholar 

  22. Hughes J, Roth RH. Evidence that angiotensin enhances transmmiter release during sympathetic nerve stimulation. Br J Pharmacol 1971;41:239–255.

    PubMed  CAS  Google Scholar 

  23. Potter EK. Angiotensin inhibits the action of the vagus nerve at the heart. Br J Pharmacol 1982;75:9–11.

    PubMed  CAS  Google Scholar 

  24. Lumbers ER, Mc Cluskey DI, Potter EK. Inhibition by angiotensin II of baroreceptor-evoked activity in cardiac vagal efferent nerves in the dog. J Physiol 1979;294:69–80.

    PubMed  CAS  Google Scholar 

  25. Scroop GC, Lowe RD. Efferent pathways of the cardiovascular response to vertebral artery infusions of angiotensin in the dog. Clin Sci 1969;37:605–619.

    PubMed  CAS  Google Scholar 

  26. Goldsmith SR, Hasking GJ. Effect of a pressor infusion of angiotensin II on sympathetic activity and heart rate in normals humans. Circ Res 1991;68:263–268.

    PubMed  CAS  Google Scholar 

  27. Saul JP, Arai Y, Berger RD, et al. Assessment of autonomic regulation in chronic congestive heart failure by heart rate spectral analysis. Am J Cardiol 1988;61:1292–1299.

    Article  PubMed  CAS  Google Scholar 

  28. Casolo G, Balli E, Fazi A, et al. Twenty-four-hour spectral analysis of heart rate variability in congestive heart failure secondary to coronary artery disease. Am J Cardiol 1991;67:1154–1158.

    Article  PubMed  CAS  Google Scholar 

  29. Myers GA, Magid NM, Weiss J, et al. Heart rate variability in sudden cardiac death. IEEE Trans Biomed Eng 1987;34:29–33.

    Google Scholar 

  30. Myers GA, Martin GJ, Magid NM, et al. Power spectral analysis of heart rate variability in sudden cardiac death: Comparison to other methods. IEEE Trans Biomed Eng 1987;33:1149–1156.

    Google Scholar 

  31. Kligenheben T, Van de Loo A, Mellert M, et al. Circadian variation of heart rate variability is abolished in post-infarction patients surviving an episode of prehospital sudden cardiac death. PACE 1994;17,part II:859.

    Google Scholar 

  32. Huikuri HCV, Linnaluto MK, Taikama JO. Heart rate variability and its circadian rhythm in survivors of cardiac arrest. Circulation 1990;82(Suppl. III):237.

    Google Scholar 

  33. The CONSENSUS Trial Study Group. Effect of enalapril on mortality in severe congestive heart failure: Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987;316:1429–1435.

    Article  Google Scholar 

  34. Cohn JN, Johnson G, Ziesche S. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;325:303–310.

    Article  PubMed  CAS  Google Scholar 

  35. The SOLVD investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293–302.

    Article  Google Scholar 

  36. The SAVE investigators. Effect of captopril on mortality in patients with left ventricular dysfunction after myocardial infarction: Results of Survival and Ventricular Enlargement Trial (SAVE). N Engl J Med 1992;327:669–677.

    Article  Google Scholar 

  37. The AIRE investigators. Effect of ramipril on mortlity and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993;342:821–828.

    Google Scholar 

  38. Campbell BC, Sturani A, Reid JL. Evidence of parasympathetic activity of the angiotensin converting enzyme inhibitor, captopril in normotensive. Clin Sci 1985;68:49–56.

    PubMed  CAS  Google Scholar 

  39. Ajayi AA, Legs KR, Reid JL. Effects of angiotensin converting enzyme inhibitor perindopril on autonomic reflexes. Eur J Clin Pharmacol 1986;30:177–182.

    Article  PubMed  CAS  Google Scholar 

  40. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Circulation 1996;93:1043–1065.

    Google Scholar 

  41. Cody RJ, Franklin KW, Kluger J, et al. Sympathetic responsiveness and plasma norepinephrine during therapy of chronic congestive heart failure with captopril. Am J Med 1982;72:791–797.

    Article  PubMed  CAS  Google Scholar 

  42. Cody RJ, Franklin KW, Kluger J, et al. Mechanisms governing the postural response and baroreceptor abnormalities in chronic congestive heart failure: Effects of acute and long term converting enzyme inhibition. Circulation 1982;66:135–142.

    PubMed  CAS  Google Scholar 

  43. Osterziel KJ, Rohrig N, Dietz R, et al. Influence of captopril on the arterial baroreceptor reflex in patients with heart failure. Eur Heart J 1988;9:1137–1145.

    PubMed  CAS  Google Scholar 

  44. Osterziel KJ, Dietz R, Schmid W, et al. ACE inhibition improves vagal reactivity in patients with heart failure. Am Heart J 1990;120:1120–1129.

    Article  PubMed  CAS  Google Scholar 

  45. Vogt A, Unterberg C, Kreuzer H. Acute effects of the new angiotensin converting enzyme inhibitor ramipril on hemodynamics and carotid sinus baroreflex activity in congestive heart failure. Am J Cardiol 1987;59:149D–154D.

    Article  PubMed  CAS  Google Scholar 

  46. Binkley PF, Haas GJ, Starling RC, et al. Sustained augmentation of parasympathetic tone with angiotensin converting enzyme inhibition in patients with congestive heart failure. J Am Coll Cardiol 1993;21:655–661.

    PubMed  CAS  Google Scholar 

  47. Binkley PF, Haas GL, Nunziata E, et al. Time course of angiotensin converting enzyme inhibition induced baroreflex sensitization in congestive heart failure: Relation to augmented vagal tone and beat-to-beat blood pressure regulation. Circulation 1994;904:I174.

    Google Scholar 

  48. Dadoun-Dybal M, Gibelin P, Morand P. Heart rate variability in chronic heart failure: Effects of angiotensin converting enzyme inhibitor therapy (abstr). Circulation 1993;88:132a.

    Google Scholar 

  49. Flapan AD, Nolan J, Neilson JMM, et al. Effect of captopril on cardiac parasympathetic activity in chronic cardiac failure secondary to coronary artery disease. Am J Cardiol 1992;69:532–535.

    Article  PubMed  CAS  Google Scholar 

  50. Kaufman ES, Bosner MS, Bigger JT, et al. The effect of digoxin and enalapril on heart rate variability and response to head-up tilt in normal subjects. Am J Cardiol 1993;72:95–99.

    Article  PubMed  CAS  Google Scholar 

  51. Krum H, Bigger JT, Goldsmith RL, et al. Long-term therapy with digoxin reduces sympathetic and enhances parasympathetic nervous system activity in chronic heart failure. Circulation 1993;88:I108.

    Google Scholar 

  52. Brouwer J, Van Veldhuisen DJ, Man AJ, et al. Relation between heart rate variability and neurohumoral status in patients with heart failure. Effects of neurohumoral modulation by digoxine and Ibopamine. Circulation 1993;88:I108.

    Google Scholar 

  53. Workman M, Birkett CL, Myers GA, et al. Heart rate variability in clinical heart failure: Persistence of a circadian pattern. J Am Cell Cardiol 1992;19:3,73A.

    Article  Google Scholar 

  54. Dzau VJ. Cardiac renin-angiotensin system. Am J Med 1988;84:22–27.

    Article  PubMed  CAS  Google Scholar 

  55. Lindpaintner K, Jin M, Niedermaier N, et al. Cardiac angiotensinogen and its local activation in the isolated perfused beating heart. Circ Res 1990;67:564–573.

    PubMed  CAS  Google Scholar 

  56. De Graeff PA, De Langen CDJ, Van Gilst WH. Protective effect of captopril against reperfusion ischemia induced ventricular arrythmias. Am J Med 1988;84(Suppl. IIIa) 67–74.

    Article  CAS  Google Scholar 

  57. De Mello WC, Crespo MJ, Altieri PI. Enalapril increases cardiac refractoriness. J Cardiovascul Pharmacol 1992;20:820–825.

    Article  CAS  Google Scholar 

  58. Muller CA, Opie LH, Peisach MV. Antiarrhythmic effects of the ACE inhibitor perindoprilat in a pig model of acute regional myocardial ischemia. J Cardiovasc Pharmacol 1992;19:748–754.

    PubMed  CAS  Google Scholar 

  59. Muller CA, Opie LH, Peisach MV. Chronic oral pretreatment with the angiotensin converting enzyme inhibitor, trandolapril decreases ventricular fibrillation in acute ischemia and reperfusion. Eur Heart J 1994;15:988–996.

    PubMed  CAS  Google Scholar 

  60. De Graeff PA, Wan Gilst WH, Delangen CDT, et al. Concentration dependent protection by captopril against ischemia reperfusion injury in the isolated rat heart. Arch Int Pharmacodyn Ther 1986;280:181–193.

    PubMed  CAS  Google Scholar 

  61. Van Gilst WH, De Graeff PA, Wesseling H, et al. Reduction of reperfusion arrhythmia in the ischemic isolated rat heart by angiotensin converting enzyme inhibitors: A comparison of captopril, enalapril and HOE-498. J Cardiovascular Pharmacol 1986;8:722–728.

    CAS  Google Scholar 

  62. Fletcher RD, Cintron GB, Johnson G. Enalapril decreases prevalence of ventricular tachycardia in patient with chronic cogestive heart failure. Circulation 1993;87:VI49–VI55.

    PubMed  CAS  Google Scholar 

  63. Pahor M, Ganbassi G, Carbonin P. Antiarrhythmic effects of ACE inhibitors: A matter of faith or reality? Cardiovasc Res 1994;28:173–182.

    Article  PubMed  CAS  Google Scholar 

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Guedon-Moreau, L., Pinaud, A., Logier, R. et al. Effect of Ramipril on Heart Rate Variability in Digitalis-Treated Patients with Chronic Heart Failure. Cardiovasc Drugs Ther 11, 531–536 (1997). https://doi.org/10.1023/A:1007763131888

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