Skip to main content
Annals of Noninvasive Electrocardiology logoLink to Annals of Noninvasive Electrocardiology
. 2006 Oct 27;6(2):98–106. doi: 10.1111/j.1542-474X.2001.tb00093.x

Effect of Beta‐Blockade on Autonomic Modulation of Heart Rate and Neurohormonal Profile in Decompensated Heart Failure

Doron Aronson 1, Andrew J Burger 1,
PMCID: PMC7027697  PMID: 11333166

Abstract

Background: One of the putative mechanisms for the salutary effects of beta‐blockers in patients with congestive heart failure (CHF) is their ability to improve autonomic dysfunction. However, patients with profound neurohumoral abnormalities derive little survival benefit from beta‐blockers. The purpose of the current study was to evaluate the effect of beta‐blockers on heart rate variability (HRV) in decompensated CHF.

Methods: Time and frequency domain HRV indices were obtained from 24‐hour Holter recordings and compared to assess the role of beta‐blockade in 199 patients (mean age 60 ± 14 years) with decompensated CHF. Neurohormonal differences were assessed by measuring norepinephrine, endothelin‐1, tumor necrosis factor‐a, and interleukin‐6 in a subset of 64 patients.

Results: All HRV indices were markedly suppressed but were substantially higher in patients who were on beta‐blockers. Time domain measures of parasympathetic cardiac activity, the percentage of R‐R intervals with > 50 ms variation (4.9 ± 0.6 vs 7.7 ± 1.2%, P = 0.006) and the square root of mean squared differences of successive R‐R intervals (22.7 ± 2.0 vs 31.6 ± 4.1 ms, P = 0.004), were higher in the beta‐blocker group. Spectral analysis revealed that the total power and the ultra‐low frequency power were significantly higher in patients on beta‐blockers (82% and 59%, respectively). The high frequency power, a spectral index of parasympathetic modulation, was 41% higher in the beta‐blocker group (121 ± 25 vs 171 ± 27 ms2, P = 0.02). Norepinephrine and interleukin‐6 levels were substantially lower in patients on beta‐blockers (28% and 61%, respectively). However, these differences did not reach statistical significance.

Conclusions: Beta‐blockers improve the impaired cardiac autonomic regulation during high sympathetic stress of decompensated CHF. This effect may play an important role in protecting the myocardium and preventing arrhythmias during transient increases in sympathetic activity. A.N.E. 2001;6(2):98–106

Keywords: heart rate variability, heart failure, beta‐adrenergic blockers, cytokines

References

  • 1. Floras JS. Clinical aspects of sympathetic activation and parasympathetic withdrawal in heart failure. J Am Coll Cardiol 1993;22:72A–84A. [DOI] [PubMed] [Google Scholar]
  • 2. Packer M. The neurohormonal hypothesis: A theory to explain the mechanism of disease progression in heart failure. J Am Coll Cardiol 1992;20:248–254. [DOI] [PubMed] [Google Scholar]
  • 3. 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. [DOI] [PubMed] [Google Scholar]
  • 4. Swedberg K, Eneroth P, Kjekshus J, et al. Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. CONSENSUS Trial Study Group. Circulation 1990;82: 1730–1736. [DOI] [PubMed] [Google Scholar]
  • 5. Wei CM, Lerman A, Rodeheffer RJ, et al. Endothelin in human congestive heart failure. Circulation 1994;89:1580–1586. [DOI] [PubMed] [Google Scholar]
  • 6. Torre‐Amione G, Kapadia S, Benedict C, et al. Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: A report from the Studies of Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol 1996;27:1201–1206. [DOI] [PubMed] [Google Scholar]
  • 7. Tsutamoto T, Hisanaga T, Wada A, et al. Interleukin‐6 spillover in the peripheral circulation increases with the severity of heart failure, and the high plasma level of interleukin‐6 is an important prognostic predictor in patients with congestive heart failure. J Am Coll Cardiol 1998;31:391–398. [DOI] [PubMed] [Google Scholar]
  • 8. Finkel MS, Oddis CV, Jacob TD, et al. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 1992;257:387–389. [DOI] [PubMed] [Google Scholar]
  • 9. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT‐HF) [see comments]. Lancet 1999;353: 2001–2007. [PubMed] [Google Scholar]
  • 10. The Cardiac Insufficiency Bisoprolol Study II (CIBIS‐Il): A randomized trial [see comments]. Lancet 1999;353: 9–13. [PubMed] [Google Scholar]
  • 11. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group [see comments]. N Engl J Med 1996;334: 1349–1355. [DOI] [PubMed] [Google Scholar]
  • 12. Richards AM, Doughty R, Nicholls MG, et al. Neurohumoral prediction of benefit from carvedilol in ischemic left ventricular dysfunction. Australia‐New Zealand Heart Failure Group. Circulation 1999;99: 786–792. [DOI] [PubMed] [Google Scholar]
  • 13. Vantrimpont P, Rouleau JL, Wun CC, et al. Additive beneficial effects of beta‐blockers to angiotensin‐converting enzyme inhibitors in the Survival and Ventricular Enlargement (SAVE) Study. SAVE Investigators. J Am Coll Cardiol 1997;29: 229–236. [DOI] [PubMed] [Google Scholar]
  • 14. 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. [PubMed] [Google Scholar]
  • 15. Rottman JN, Steinman RC, Albrecht P, et al. Efficient estimation of the heart period power spectrum suitable for physiologic or pharmacologic studies. Am J Cardiol 1990;66:1522–1524. [DOI] [PubMed] [Google Scholar]
  • 16. Davis GC, Kissinger PT, Shoup RE. Strategies for determination of serum or plasma norepinephrine by reverse‐phase liquid chromatography. Anal Chem 1981;53:156–159. [DOI] [PubMed] [Google Scholar]
  • 17. Suzuki N, Matsumoto H, Kitada C, et al. A sensitive sandwich‐enzyme immunoassay for human endothelin. J Immunol Methods 1989;118: 245–250. [DOI] [PubMed] [Google Scholar]
  • 18. Bigger JT, Jr. , Fleiss JL, Steinman RC, et al. R‐R variability in healthy, middle‐aged persons compared with patients with chronic coronary heart disease or recent acute myocardial infarction. Circulation 1995;91:1936–1943. [DOI] [PubMed] [Google Scholar]
  • 19. Nolan J, Batin PD, Andrews R, et al. Prospective study of heart rate variability and mortality in chronic heart failure: Results of the united kingdom heart failure evaluation and assessment of risk trial (UK‐heart). Circulation 1998;98:1510–1516. [DOI] [PubMed] [Google Scholar]
  • 20. Binkley PF, Nunziata E, Haas GJ, et al. Parasympathetic withdrawal is an integral component of autonomic imbalance in congestive heart failure: Demonstration in human subjects and verification in a paced canine model of ventricular failure. J Am Coll Cardiol 1991;18:464–472. [DOI] [PubMed] [Google Scholar]
  • 21. Benedict CR, Johnstone DE, Weiner DH, et al. Relation of neurohumoral activation to clinical variables and degree of ventricular dysfunction: A report from the Registry of Studies of Left Ventricular Dysfunction. SOLVD Investigators. J Am Coll Cardiol 1994;23: 1410–1420. [DOI] [PubMed] [Google Scholar]
  • 22. Francis GS, Benedict C, Johnstone DE, et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation 1990;82: 1724–1729. [DOI] [PubMed] [Google Scholar]
  • 23. Goldsmith RL, Bigger JT, Bloomfield DM, et al. Long‐term carvedilol therapy increases parasympathetic nervous system activity in chronic congestive heart failure. Am J Cardiol 1997;80:1101–1104. [DOI] [PubMed] [Google Scholar]
  • 24. Pousset F, Copie X, Lechat P, et al. Effects of bisoprolol on heart rate variability in heart failure. Am JCardiol 1996;77:612–617. [DOI] [PubMed] [Google Scholar]
  • 25. Tuininga YS, Crijns HJ, Brouwer J, et al. Evaluation of importance of central effects of atenolol and metoprolol measured by heart rate variability during mental performance tasks, physical exercise, and daily life in stable postinfarct patients. Circulation 1995;92:3415–3423. [DOI] [PubMed] [Google Scholar]
  • 26. Francis GS, Cohn JN, Johnson G, et al. Plasma norepinephrine, plasma renin activity, and congestive heart failure. Relations to survival and the effects of therapy in V‐HeFT II. The V‐HeFT VA Cooperative Studies Group. Circulation 1993;87:VI4O–VI48. [PubMed] [Google Scholar]
  • 27. Jiang W, Hathaway WR, McNulty S, et al. Ability of heart rate variability to predict prognosis in patients with advanced congestive heart failure. Am J Cardiol 1997;80:808–811. [DOI] [PubMed] [Google Scholar]
  • 28. Fauchier L, Babuty D, Cosnay P, et al. Heart rate variability in idiopathic dilated cardiomyopathy: Characteristics and prognostic value. J Am Coll Cardiol 1997;30:1009–1014. [DOI] [PubMed] [Google Scholar]
  • 29. Yi G, Goldman JH, Keeling PJ, et al. Heart rate variability in idiopathic dilated cardiomyopathy: Relation to disease severity and prognosis. Heart 1997;77:108–114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. Ponikowski P, Anker SD, Chua TP, et al. Depressed heart rate variability as an independent predictor of death in chronic congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1997;79:1645–1650. [DOI] [PubMed] [Google Scholar]
  • 31. Coker R, Koziell A, Oliver C, et al. Does the sympathetic nervous system influence sinus arrhythmia in man? Evidence from combined autonomic blockade. J Physiol (Lond) 1984;356:459–464. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32. Schwartz PJ, Pagani M, Lombardi F, et al. A cardiocardiac sympathovagal reflex in the cat. Circ Res 1973;32:215–220. [DOI] [PubMed] [Google Scholar]
  • 33. Scott EM. The effect of atenolol on the spontaneous and reflex activity of the sympathetic nerves in the cat: Influence of cardiopulmonary receptors. Br J Pharmacol 1983;78:425–431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34. Murray DR, Prabhu SD, Chandrasekar B. Chronic beta‐adrenergic stimulation induces myocardial proinflammatory cytokine expression. Circulation 2000;101:2338–2341. [DOI] [PubMed] [Google Scholar]
  • 35. Huang QH, Takaki A, Arimura A. Central noradrenergic system modulates plasma interleukin‐6 production by peripheral interleukin‐1. Am J Physiol 1997;273:R731–738. [DOI] [PubMed] [Google Scholar]
  • 36. Yamauchi‐Takihara K, Ihara Y, Ogata A, et al. Hypoxic stress induces cardiac myocyte‐derived interleukin‐6. Circulation 1995;91:1520–1524. [DOI] [PubMed] [Google Scholar]
  • 37. Barron HV, Lesh MD. Autonomic nervous system and sudden cardiac death [published erratum appears in J Am Coll Cardiol 1996. Jul;28(1):2861 J Am Coll Cardiol 1996;27: 1053–1060. [DOI] [PubMed] [Google Scholar]
  • 38. Schwartz PJ, La Rovere MT, Vanoli E. Autonomic nervous system and sudden cardiac death. Experimental basis and clinical observations for postmyocardial infarction risk stratification. Circulation 1992;85: 177–191. [PubMed] [Google Scholar]
  • 39. Kardos A, Long V, Bryant J, et al. Lipophilic versus hydrophilic beta(1) blockers and the cardiac sympatho‐ vagal balance during stress and daily activity in patients after acute myocardial infarction. Heart 1998;79:153–160. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Niemela MJ, Airaksinen KE, Huikuri HV. Effect of beta‐blockade on heart rate variability in patients with coronary artery disease. J Am Coll Cardiol 1994;23:1370–1377. [DOI] [PubMed] [Google Scholar]
  • 41. 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. [DOI] [PubMed] [Google Scholar]
  • 42. Krum H, Bigger JT, Jr. , Goldsmith RL, et al. Effect of long‐term digoxin therapy on autonomic function in patients with chronic heart failure. J Am Coll Cardiol 1995;25:289–294. [DOI] [PubMed] [Google Scholar]

Articles from Annals of Noninvasive Electrocardiology are provided here courtesy of International Society for Holter and Noninvasive Electrocardiology, Inc. and Wiley Periodicals, Inc.

RESOURCES