Heart Failure Reviews

, Volume 16, Issue 2, pp 179–193 | Cite as

Pharmacologic modulation of parasympathetic activity in heart failure

  • Monali Y. Desai
  • Mari A. Watanabe
  • Abhay A. Laddu
  • Paul J. Hauptman


In the congestive heart failure state, autonomic dysregulation involves an increase in sympathetic tone and decrease in parasympathetic tone and is associated with increased mortality. It is possible that augmentation of the parasympathetic nervous system (PNS) with pharmacologic therapy may lead to improved symptoms and/or clinical outcomes. There are several new and established pharmacologic interventions that have been studied for their effect on the PNS, including antagonists of the renin–angiotensin system, beta-adrenergic antagonists, digoxin, and vasodilators. In this review, we discuss the current status of the published literature on pharmacologic influences on the PNS by both conventional and experimental drugs targeting heart failure as well as drugs that more directly influence vagal tone. While these analyses have been largely limited to putative surrogates for clinical outcomes like heart rate variability, and it is often difficult to differentiate between indirect and direct pharmacologic effects on the PNS, significant insight into potential mechanisms of action can be derived. The future evaluation of drugs in development for heart failure treatment should include a careful, scientifically sound exploration of the potential impact of the intervention on PNS activity.


Pharmacologic treatment Vagus nerve 


  1. 1.
    Olshansky B, Sabbah N, Hauptman PJ, Colucci WS (2008) The parasympathetic nervous system and heart failure: pathophysiology and implications for therapy. Circulation 118:863–871PubMedCrossRefGoogle Scholar
  2. 2.
    Schwartz PJ, De Ferrari GM, Sanzo A, Landolina M, Rordorf R, Raineri C, Campana C, Revera M, Ajmone-Marsan N, Tavazzi L, Odero A (2008) Long term vagal stimulation in patients with advanced heart failure: first experience in man. Eur J Heart Fail 10:884–891PubMedCrossRefGoogle Scholar
  3. 3.
    Osterziel K, Dietz R (1996) Improvement of vagal tone by ACE inhibition: a mechanism of cardioprotection in patients with mild-to-moderate heart failure. J Cardiovasc Pharmacol 27(2):25–30CrossRefGoogle Scholar
  4. 4.
    Osterziel K, Rohrig N, Dietz R, Manthey J, Hecht J, Kubler W (1988) Influence of captopril on the arterial baroreceptor reflex in patients with heart failure. Eur Heart J 9:1137–1145PubMedGoogle Scholar
  5. 5.
    Task Force of the European Society of Cardiology and the North American Society of Pacing Electrophysiology (1996) Heart rate variability: standards of measurement, physiological interpretation, and clinical use. Circulation 93:1043–1065Google Scholar
  6. 6.
    Miyashita Y, Furukawa Y, Nakajima K, Hirose M, Kurogouchi F, Chiba S (1999) Parasympathetic inhibition of sympathetic effects on pacemaker location and rate in hearts of anesthetized dogs. J Cardiovasc Electrophysiol 10(8):1066–1076PubMedCrossRefGoogle Scholar
  7. 7.
    Colucci WS (1990) In vivo studies of myocardial beta-adrenergic receptor pharmacology in patients with congestive heart failure. Circulation 82(2 Suppl):I44–I51PubMedGoogle Scholar
  8. 8.
    Khamssi M, Brodde OE (1990) The role of cardiac beta1- and beta2-adrenoceptor stimulation in heart failure. J Cardiovasc Pharmacol 16(Suppl 5):S133–S137PubMedGoogle Scholar
  9. 9.
    Janse MJ (2004) Electrophysiological changes in heart failure and their relationship to arrhythmogenesis. Cardiovasc Res 61(2):208–217PubMedCrossRefGoogle Scholar
  10. 10.
    Palatini P (2001) Heart rate as a cardiovascular risk factor: do women differ from men? Ann Med 33(4):213–221PubMedCrossRefGoogle Scholar
  11. 11.
    Hjalmarson A (1998) Significance of reduction in heart rate in cardiovascular disease. Clin Cardiol 21(12 Suppl 2):II3–II7PubMedGoogle Scholar
  12. 12.
    Brown MD, Davies MK, Hudlicka O (2005) Angiogenesis in ischaemic and hypertrophic hearts induced by long-term bradycardia. Angiogenesis 8(3):253–262. Epub 2005 Nov 25Google Scholar
  13. 13.
    Flannery G, Gehrig-Mills R, Billah B, Krum H (2008) Analysis of randomized controlled trials on the effect of magnitude of heart rate reduction on clinical outcomes in patients with systolic chronic heart failure receiving beta-blockers. Am J Cardiol 101(6):865–869. Epub 2008 Feb 21Google Scholar
  14. 14.
    Alboni P, Scarfò S, Fucà G (2001) Development of heart failure in bradycardic sick sinus syndrome. Ital Heart J 2(1):9–12PubMedGoogle Scholar
  15. 15.
    Wolf MM, Varigos GA, Hunt D, Sloman JG (1978) Sinus arrhythmia in acute myocardial infarction. Med J Aust 2(2):52–53PubMedGoogle Scholar
  16. 16.
    Akselrod S, Gordon D, Ubel FA, Shannon DC, Barger AC, Cohen RJ (1981) Power spectrum analysis of heart rate fluctuation: a quantitative probe of beat to beat cardiovascular control. Science 213:220–222PubMedCrossRefGoogle Scholar
  17. 17.
    Coumel P, Maison-Blanche P, Catuli D et al (1994) Heart rate and heart rate variability in normal young adults. J Cardiovasc Electrophysiol 5:899–911PubMedCrossRefGoogle Scholar
  18. 18.
    Malik M (2004) Standard measurement of heart rate variability in dynamic electrocardiography. In: Malik M, Camm AJ (eds) Dynamic electrocardiography. Blackwell Futura, Malden, MACrossRefGoogle Scholar
  19. 19.
    Guzik P, Piskorski J, Krauze T, Schneider R, Wesseling KH, Wykretowicz A, Wysocki H (2007) Correlations between the Poincaré plot and conventional heart rate variability parameters assessed during paced breathing. J Physiol Sci 57(1):63–71PubMedCrossRefGoogle Scholar
  20. 20.
    Pagani M, Lombardi F, Guzzetti S et al (1986) Power spectral analysis of heart rate and arterial pressure variabilities as a marker of smypatho-vagal interaction in man and conscious dog. Circ Res 59:178–193PubMedGoogle Scholar
  21. 21.
    Steptoe A, Vögele C (1990) Cardiac baroreflex function during postural change assessed using non-invasive spontaneous sequence analysis in young men. Cardiovasc Res 24(8):627–632PubMedCrossRefGoogle Scholar
  22. 22.
    Frankel RA, Metting PJ, Britton SL (1993) Evaluation of spontaneous baroreflex sensitivity in conscious dogs. J Physiol 462:31–45PubMedGoogle Scholar
  23. 23.
    Ducher M, Fauvel JP, Gustin MP, Cerutti C, Najem R, Cuisinaud G, Laville M, Pozet N, Paultre CZ (1995) A new non-invasive statistical method to assess the spontaneous cardiac baroreflex in humans. Clin Sci (Lond) 88(6):651–655Google Scholar
  24. 24.
    Watanabe MA, Schmidt G (2004) Heart rate turbulence: a 5-year review. Heart Rhythm 6:732–738CrossRefGoogle Scholar
  25. 25.
    Schmidt G, Malik M, Barthel P, Schneider R, Ulm K, Rolnitzky L, Camm JA, Bigger JT Jr, Schömig A (1999) Heart-rate turbulence after ventricular premature beats as a predictor of mortality after acute myocardial infarction. Lancet 353:1390–1396PubMedCrossRefGoogle Scholar
  26. 26.
    Ghuran A, Reid F, La Rovere MT, Schmidt G, Bigger JT Jr, Camm AJ, Schwartz PJ, Malik M (2002) ATRAMI Investigators. Heart rate turbulence-based predictors of fatal and nonfatal cardiac arrest (The autonomic tone and reflexes after myocardial infarction substudy). Am J Cardiol 89:184–190PubMedCrossRefGoogle Scholar
  27. 27.
    Barthel P, Schneider R, Bauer A, Ulm K, Schmitt C, Schömig A, Schmidt G (2003) Risk stratification after acute myocardial infarction by heart rate turbulence. Circulation 108(10):1221–1226. Epub 2003 Aug 25Google Scholar
  28. 28.
    Sade E, Aytemir K, Oto A, Nazli N, Ozmen F, Ozkutlu H, Tokgözoglu L, Aksöyek S, Ovünç K, Kabakçi G, Ozer N, Kes S (2003) Assessment of heart rate turbulence in the acute phase of myocardial infarction for long-term prognosis. Pacing Clin Electrophysiol 26(2 Pt 1):544–550PubMedCrossRefGoogle Scholar
  29. 29.
    Flapan A, Nolan J, Neilson J, Ewing D (1992) Effect of captopril on cardiac parasympathetic activity in chronic cardiac failure secondary to coronary artery disease. Am J Cardiol 69:532–535PubMedCrossRefGoogle Scholar
  30. 30.
    Binkley P, Haas G, Starling R, Nunziata E, Hatton P, Leier C, Cody R (1993) Sustained augmentation of parasympathetic tone with angiotensin-converting enzyme inhibition in patients with congestive heart failure. JACC 21(3):655–661PubMedGoogle Scholar
  31. 31.
    Zhang Y, Song Y, Jun Z, Tao-hong H, Li-li W (1995) Effects of enalapril on heart rate variability in patients with congestive heart failure. Am J Cardiol 76:1045–1048PubMedCrossRefGoogle Scholar
  32. 32.
    Guedon-Moreau L, Pinaud A, Logier R, Caron J, Lekieffre J, Dupuis B, Libersa C (1997) Effect of ramipril on heart rate variability in digitalis-treated patients with chronic heart failure. Cardiovasc Drugs Ther 11:531–536PubMedCrossRefGoogle Scholar
  33. 33.
    Kamen P, Krum H, Tonkin A (1997) Low-dose but not high-dose captopril increases parasympathetic activity in patients with heart failure. J Cardiovasc Pharmacol 30(1):7–11PubMedCrossRefGoogle Scholar
  34. 34.
    Adigun A, Asiyanbola B, Ajayi A (2001) Cardiac autonomic function in blacks with congestive heart failure: vagomimetic action, alteration in sympathovagal balance, and the effect of ACE inhibition on central and peripheral vagal tone. Cell Mol Biol 47(6):1063–1066PubMedGoogle Scholar
  35. 35.
    Ondocin P, Narsipur S (2006) Influence of angiotensin converting enzyme inhibitor treatment on cardiac autonomic modulation in patients receiving haemodialysis. Nephrology 11:497–501PubMedCrossRefGoogle Scholar
  36. 36.
    Dibona G, Jones S, Sawin L (1998) Angiotensin receptor antagonist improves cardiac reflex control of renal sodium handling in heart failure. Am J Physiol Heart Circ Physiol 274:636–641Google Scholar
  37. 37.
    Tambara K, Fujita M, Sumita Y, Miyamoto S, Sekiguchi H, Eiho S, Komeda M (2004) Beneficial effect of candesartan treatment on cardiac autonomic nervous activity in patients with chronic heart failure: simultaneous recording of ambulatory electrocardiogram and posture. Clin Cardiol 27:300–303PubMedCrossRefGoogle Scholar
  38. 38.
    Petretta M, Spinelli L, Marciano F, Apicella C, Vicario M, Testa G, Volpe M, Bonaduce D (2000) Effects of losartan treatment on cardiac autonomic control during volume loading in patients with DCM. Am J Physiol Heart Circ Physiol 279:86–92Google Scholar
  39. 39.
    Ozdemir M, Arslan U, Turkoglu S, Balcioglu S, Cengel A (2007) Losartan improves heart rate variability and heart rate turbulence in heart failure due to ischemic cardiomyopathy. J Cardiac Fail 13:812–817CrossRefGoogle Scholar
  40. 40.
    Vaile J, Chowdhary S, Osman F, Ross H, Fletcher J, Littler W, Coote J, Townend J (2001) Effects of angiotensin II (AT1) receptor blockade on cardiac vagal control in heart failure. Clin Sci 101:559–566PubMedCrossRefGoogle Scholar
  41. 41.
    De Tommasi E, Iacoviello M, Romito R, Ceconi C, Guida P, Massari F, Francolini G, Bertocchi F, Ferrari R, Rizzon P, Pitzalis M (2003) Comparison of the effect of valsartan and lisinopril on autonomic nervous system activity in chronic heart failure. Am Heart J 146:e17PubMedGoogle Scholar
  42. 42.
    MacFadyen R, Barr C, Struthers A (1997) Aldosterone blockade reduces vascular collagen turnover, improves heart rate variability and reduces early morning rise in heart rate in heart failure patients. Cardiovasc Res 35:30–34PubMedCrossRefGoogle Scholar
  43. 43.
    Yee K, Pringle S, Allan D, Struthers A (2001) Circadian variation in the effects of aldosterone blockade on heart rate variability and QT dispersion in congestive heart failure. J Am Coll Cardiol 37:1800–1807PubMedCrossRefGoogle Scholar
  44. 44.
    Korkmaz M, Muderrisoglu H, Ulucam M, Ozin B (2000) Effects of spironolactone on heart rate variability and left ventricular systolic function in severe ischemic heart failure. Am J Cardiol 86:649–653PubMedCrossRefGoogle Scholar
  45. 45.
    Shehab A, Elnour A, Struthers A (2008) A randomized, controlled, double-blind, cross-over pilot study assessing the effects of spironolactone, losartan and their combination on heart rate variability and QT dispersion in patients with chronic heart failure. Cardiovasc J Afr 19:292–296PubMedGoogle Scholar
  46. 46.
    Farquharson C, Struthers A (2002) Increasing plasma potassium with amiloride shortens the QT interval and reduces ventricular extrasystoles but does not change endothelial function or heart rate variability in chronic heart failure. Heart 88:475–480PubMedCrossRefGoogle Scholar
  47. 47.
    Sal’nikov E (2009) Heart rate variability in rats with experimental chronic heart failure and long-term exposure to β-adrenoblockers. Bull Exp Biol Med 147(2):181–184PubMedCrossRefGoogle Scholar
  48. 48.
    Akdeniz B, Guneri S, Savas I, Aslan O, Baris N, Badak O, Kirimli O, Goldeli O (2006) Effects of carvedilol therapy on arrhythmia markers in patients with congestive heart failure. Int Heart J 47:565–573PubMedCrossRefGoogle Scholar
  49. 49.
    Hennersdorf M, Perings C, Vester E (1999) Hemodynamic effects of celiprolol in patients with ischemic and non-ischemic cardiomyopathy. Int J Cardiol 68:289–295PubMedCrossRefGoogle Scholar
  50. 50.
    Copie X, Pousset F, Lechat P, Jaillon P, Guize L, Le Heuzey J (1996) Effects of beta-blockade with bisoprolol on heart rate variability in advanced heart failure: analysis of scatterplots of R-R intervals at selected heart rates. Am Heart J 132:369–375PubMedCrossRefGoogle Scholar
  51. 51.
    Bullinga J, Alharethi R, Schram M, Bristow M, Gilbert E (2005) Changes in heart rate variability are correlated to hemodynamic improvement with chronic carvedilol therapy in heart failure. J Card Fail 11:693–699PubMedCrossRefGoogle Scholar
  52. 52.
    Piccirillo G, Leonetti R, Celli V, Moise A, Lionetti M, Marigliano V, Cacciafesta A (2000) Effects of carvedilol on heart rate and blood pressure variability in subjects with chronic heart failure. Am J Cardiol 86:1392–1395PubMedCrossRefGoogle Scholar
  53. 53.
    Goldsmith R, Bigger J, Bloomfield D, Krum H, Steinman R, Sackner-Bernstein J, Packer M (1997) Long-term carvedilol therapy increases parasympathetic nervous system activity in chronic congestive heart failure. Am J Cardiol 80:1101–1104PubMedCrossRefGoogle Scholar
  54. 54.
    Aronson D, Burger A (2001) Effect of beta blockade on autonomic modulation of heart rate and neurohormonal profile in decompensated heart failure. A.N.E 6(2):98–106PubMedGoogle Scholar
  55. 55.
    Tjeerdsma G, Szabo B, Wijk L, Brouwer J, Tio R, Crijns H, Veldhuisen D (2001) Autonomic dysfunction in patients with mild heart failure and coronary artery disease and the effects of add-on B-blockade. Eur J Heart Fail 3:33–39PubMedCrossRefGoogle Scholar
  56. 56.
    Pousset F, Copie X, Lechat P, Jaillon P, Boissel J, Hetzel M, Fillette F, Remme W, Guize L, Le Heuzey J (1996) Effects of bisprolol on heart rate variability in heart failure. Am J Cardiol 77:612–617PubMedCrossRefGoogle Scholar
  57. 57.
    Mortara A, La Rovere M, Pinna G, Maestri R, Capomolla S, Cobelli F (2000) Nonselective beta- adrenergic blocking agent, carvedilol, improves arterial baroreflex gain and heart rate variability in patients with stable chronic heart failure. J Am Coll Cardiol 36:1612–1618PubMedCrossRefGoogle Scholar
  58. 58.
    Aquilante C, Terra S, Schofield R, Pauly D, Hatton P, Binkley P, Johnson J (2006) Sustained restoration of autonomic balance with long but not short acting metoprolol in patients with heart failure. J Card Fail 12(3):171–176PubMedCrossRefGoogle Scholar
  59. 59.
    Tygesen H, Andersson B, Di Lenarda A, Rundqvist B, Sinagra G, Hjalmarson A, Waagstein F, Wennerblom B (1999) Potential risk of b-blockade withdrawal in congestive heart failure due to abrupt autonomic changes. Int J Cardiol 68:171–177PubMedCrossRefGoogle Scholar
  60. 60.
    Lin J, Chan H, Du C, Lin I, Lai C, Lin K, Wu C, Tseng Y, Lien W (1999) Long-term beta-blocker therapy improves autonomic nervous regulation in advanced congestive heart failure: a longitudinal heart rate variability study. Am Heart J 137(4):658–665PubMedCrossRefGoogle Scholar
  61. 61.
    Lin L, Hwang J, Lai L, Chan H, Du C, Tseng Y, Lin J (2004) Restoration of heart rate turbulence by titrated beta-blocker therapy in patients with advanced congestive heart failure: positive correlation with enhanced vagal modulation of heart rate. J Cardiovasc Electrophysiol 15:752–756PubMedCrossRefGoogle Scholar
  62. 62.
    Kubo T, Parker J, Azevedo E, Atchison D, Newton G, Picton P, Floras J (2005) Vagal heart rate responses to chronic beta-blockade in human heart failure to cardiac norepinephrine spillover. Eur J Heart Fail 7:878–881PubMedCrossRefGoogle Scholar
  63. 63.
    Racine N, Blanchet M, Ducharme A, Marquis J, Boucher J, Juneau M, White M (2003) Decreased heart rate recovery after exercise in patients with congestive heart failure: effect of beta blocker therapy. J Card Fail 9(4):296–302PubMedCrossRefGoogle Scholar
  64. 64.
    Sanderson J, Yeung L, Chan S, Tomlinson B, Kay R, Woo K, Bernardi L (1999) Effect of b-blockade on baroreceptor and autonomic function in heart failure. Clin Sci 96:137–146PubMedCrossRefGoogle Scholar
  65. 65.
    Sanderson J, Chan S, Yip G, Yeung L, Chan K, Raymond K, Woo K (1999) Beta-blockade in heart failure: a comparison of carvedilol with metoprolol. J Am Coll Cardiol 34:1522–1528PubMedCrossRefGoogle Scholar
  66. 66.
    Hamaad A, Lip G, Nicholls D, MacFadyen R (2007) Comparative dose titration responses to the introduction of bisoprolol or carvedilol in stable chronic systolic heart failure. Cardiovasc Drugs Ther 21:437–444PubMedCrossRefGoogle Scholar
  67. 67.
    Girgis I, Chakko S, de Marchena E, Jara C, Diaz P, Castellanos A, Myerburg R (1998) Effect of clonidine on heart rate variability in congestive heart failure. Am J Cardiol 82:335–337PubMedCrossRefGoogle Scholar
  68. 68.
    You-hua Z, You-cheng S, Jun Z, Xian-qi Y (1997) Sympathetic inhibition with clonidine improves autonomic balance in congestive heart failure. Int J Cardiol 59:139–144PubMedCrossRefGoogle Scholar
  69. 69.
    Cohn J, Pfeffer M, Rouleau J, Sharpe N, Swedberg K, Straub M, Wiltse C, Wright T (2003) Adverse mortality effect of central sympathetic inhibition with sustained release moxonidine in patients with heart failure (MOXCON). Eur J Heart Fail 5:659–667PubMedCrossRefGoogle Scholar
  70. 70.
    Dickstein K, Manhenke C, Aarsland T, McNay J, Wiltse C, Wright T (2000) The effects of chronic, sustained-release moxonidine therapy on clinical and neurohumoral status in patients with heart failure. Int J Cardiol 75:167–176PubMedCrossRefGoogle Scholar
  71. 71.
    Hauptman PJ, Kelly RA (2007) Digitalis Glycosides. In: Hosenpud JD, Greenberg BH (eds) Congestive heart failure, 3rd edn. Lippincott Williams & Wilkins, Philadelphia, pp 449–466Google Scholar
  72. 72.
    Krum H, Bigger J, Goldsmith R, Packer M (1995) Effect of long-term digoxin therapy on autonomic function in patients with chronic heart failure. J Am Coll Cardiol 25:289–294PubMedCrossRefGoogle Scholar
  73. 73.
    Vardas P, Kanoupakis E, Kochiadakis G, Simantirakis E, Marketou M, Chlouverakis G (1998) Effects of long-term digoxin therapy on heart rate variability, baroreceptor sensitivity, and exercise capacity in patients with heart failure. Cardiovasc Drugs Ther 12:47–55PubMedCrossRefGoogle Scholar
  74. 74.
    Slatton M, Irani W, Hall S, Marcoux L, Page R, Grayburn P, Eichhorn E (1997) Does digoxin provide additional hemodynamic and autonomic benefit at higher doses in patients with mild to moderate heart failure and normal sinus rhythm? J Am Coll Cardiol 29:1206–1213PubMedCrossRefGoogle Scholar
  75. 75.
    Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM (2003) Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA 289:871–878PubMedCrossRefGoogle Scholar
  76. 76.
    Szabo B, Van Veldhuisen D, Van Der Burgh P, Kruik J, Girbes A, Lie K (1996) Clinical and autonomic effects of ibopamine as adjunct to angiotensin-converting enzyme inhibitors in chronic heart failure. J Card Fail 2(3):185–192PubMedCrossRefGoogle Scholar
  77. 77.
    Brouwer J, Van Veldhuisen D, Man in’t Veld A, Dunselman P, Boomsma F, Haaksma J, Lie K (1995) Heart rate variability in patients with mild to moderate heart failure: effects of neurohormonal modulation by digoxin and ibopamine. J Am Coll Cardiol 26:983–990PubMedCrossRefGoogle Scholar
  78. 78.
    Aronson D, Burger A (2004) Effect of nesiritide (human b-type natriuretic peptide) and dobutamine on heart rate variability in decompensated heart failure. Am Heart J 148:e16PubMedCrossRefGoogle Scholar
  79. 79.
    Buch A, Chowdhary S, Coote J, Townend J (2004) Effects of nitroglycerin treatment on cardiac autonomic control in heart failure. Clin Auton Res 14:9–14PubMedCrossRefGoogle Scholar
  80. 80.
    Pliquett R, Cornish K, Zucker I (2003) Statin therapy restores sympathovagal balance in experimental heart failure. J Appl Physiol 95:700–704PubMedGoogle Scholar
  81. 81.
    Gao L, Wang W, Li Y, Schultz H, Liu D, Cornish K, Zucker I (2005) Simvastatin therapy normalizes sympathetic neural control in experimental heart failure roles of angiotensin II type 1 receptors and NAD(P)H oxidase. Circulation 112:1763–1770PubMedCrossRefGoogle Scholar
  82. 82.
    Katircibasi M, Canatar T, Kocum H, Erol T, Tekin G, Demircan S, Tekin A, Sezgin A, Baltali M, Muderrisoglu H (2005) Decreased heart rate recovery in patients with heart failure effect of fluvastatin therapy. Int Heart J 46:845–854PubMedCrossRefGoogle Scholar
  83. 83.
    Vrtovec B, Okrajsek R, Golicnik A, Ferjan M, Starc V, Radovancevic B (2005) Atorvastatin therapy increases heart rate variability, decreases QT variability, and shortens QTc interval duration in patients with advanced chronic heart failure. J Card Fail 11(9):684–690PubMedCrossRefGoogle Scholar
  84. 84.
    Hamaad A, Sosin M, Lip G, MacFadyen R (2005) Short-term adjuvant atorvastatin improves frequency domain indices of heart rate variability in stable systolic heart failure. Cardiovasc Drugs Ther 19:183–187PubMedCrossRefGoogle Scholar
  85. 85.
    Gentlesk P, Wiley T, Taylor A (2005) A prospective evaluation of the effect of simvastatin on heart rate variability in non-ischemic cardiomyopathy. Am Heart J 150:478–483PubMedCrossRefGoogle Scholar
  86. 86.
    Zuanetti J, Latini R, Neilson J, Schwartz P, Ewing D (1991) Heart rate variability in patients with ventricular arrhythmias: effects of antiarrhythmic drugs. J Am Coll Cardiol 17:1–604CrossRefGoogle Scholar
  87. 87.
    Rohde L, Polanczyk C, Moraes R, Ferlin E, Ribeiro J (1998) Effect of partial arrhythmia suppression with amiodarone on heart rate variability of patients with congestive heart failure. Am Heart J 136:31–36PubMedCrossRefGoogle Scholar
  88. 88.
    Francis GS, Siegel RM, Goldsmith SR, Olivari MT, Levine TB, Cohn JN (1985) Acute vasoconstrictor response to intravenous furosemide in patients with chronic congestive heart failure: activation of the neurohumoral axis. Ann Intern Med 103:1–6PubMedGoogle Scholar
  89. 89.
    Tomiyama H, Nakayama T, Watanabe G, Shiojima K, Sakuma Y, Yamamoto A, Imai Y, Yoshida H, Doba N (1999) Effects of short-acting and long-acting loop diuretics on heart rate variability in patients with chronic compensated congestive heart failure. Am Heart J 137:543–548PubMedCrossRefGoogle Scholar
  90. 90.
    Shehab A, Butler R, MacFadyen R, Struthers A (2001) A placebo-controlled study examining the effect of allopurinol on heart rate variability and dysrhythmia counts in chronic heart failure. Br J Clin Pharmacol 51:329–334PubMedCrossRefGoogle Scholar
  91. 91.
    Radaelli A, Cazzaniga M, Viola A, Balestri G, Janetti M, Signorini M, Castiglioni P, Azzellino A, Mancia G, Ferrari A (2006) Enhanced baroreceptor control of the cardiovascular system by polyunsaturated fatty acids in heart failure patients. J Am Coll Cardiol 48:1600–1606PubMedCrossRefGoogle Scholar
  92. 92.
    Giannattasio C, Failla M, Stella ML et al (1995) Alterations of radial artery compliance in patients with congestive heart failure. Am J Cardiol 76:381–385PubMedCrossRefGoogle Scholar
  93. 93.
    Holguin F, Tellez-Rojo M, Lazo M, Mannino D, Schwartz J, Hernandez J, Romieu I (2005) Cardiac autonomic changes associated with fish oil vs soy oil supplementation in the elderly. Chest 127:1102–1107PubMedCrossRefGoogle Scholar
  94. 94.
    Mangin L, Swynghedauw B, Benis A, Thibault N, Lerebours G, Carre F (1998) Relationships between heart rate and heart rate variability: study in conscious rats. J Cardiovasc Pharmacol 32(4):601–607PubMedCrossRefGoogle Scholar
  95. 95.
    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 randomized, double-blind, placebo-controlled trial. Lancet 372:807–816PubMedCrossRefGoogle Scholar
  96. 96.
    Swedberg K, Kamajda M, Bohm M et al (2010) Ivabradine and outcomes in chronic heart failure (SHIFT): a randomized placebo-controlled study. Lancet 376:875–885PubMedCrossRefGoogle Scholar
  97. 97.
    Behling A, Moraes R, Rohde L, Ferlin E, No′brega A, Ribeiro J (2003) Cholinergic stimulation with pyridostigmine reduces ventricular arrhythmia and enhances heart rate variability in heart failure. Am Heart J 146:494–500PubMedCrossRefGoogle Scholar
  98. 98.
    Serra S, Costa R, Castro R, Xavier S, Da Nobrega A (2009) Cholinergic stimulation improves autonomic and hemodynamic profile during dynamic exercise in patients with heart failure. J Card Fail 15:124–129PubMedCrossRefGoogle Scholar
  99. 99.
    Hayano T, Shimizu A, Ikeda Y, Yamamoto T, Yamagata T, Ueyama T, Furutani Y, Matsuzaki M (1999) Paradoxical effects of pirenzepine on parasympathetic activity in chronic heart failure and control. Int J Cardiol 68:47–56PubMedCrossRefGoogle Scholar
  100. 100.
    Venkatesh G, Fallen E, Kamath M, Connolly S, Yusuf S (1996) Double blind placebo controlled trial of transdermal scopolamine on heart rate variability in short term patients with chronic heart failure. Heart 76:137–143PubMedCrossRefGoogle Scholar
  101. 101.
    Jacoby DB, Gleich GJ, Fryer AD (1993) Human eosinophil major basic protein is an endogenous allosteric antagonist at the inhibitory muscarinic M2 receptor. J Clin Invest 91:1314–1318PubMedCrossRefGoogle Scholar
  102. 102.
    Casadei B, Conway J, Forfar C, Sleight P (1996) Effect of low doses of scopolamine on RR interval variability, baroreflex sensitivity, and exercise performance in patients with chronic heart failure. Heart 75:274–280PubMedCrossRefGoogle Scholar
  103. 103.
    La Rovere M, Mortara A, Pantaleo P, Maestri R, Cobelli F, Tavazzi L (1994) Scopolamine improves autonomic balance in advanced congestive heart failure. Circulation 90:838–843PubMedGoogle Scholar
  104. 104.
    Okazaki Y, Zheng C, Li M, Sugimachi M (2010) Effect of the cholinesterase inhibitor donepezil on cardiac remodeling and autonomic balance in rats with heart failure. J Physiol Sci 60:67–74PubMedCrossRefGoogle Scholar
  105. 105.
    Masuda Y, Kawamura A (2003) Acetylcholinesterase inhibitor (donepezil hydrochloride) reduces heart rate variability. J Cardiovasc Pharmacol 41(Suppl. 1):567–571Google Scholar
  106. 106.
    McLaren A, Allen J, Murray A, Ballard C, Kenny R (2003) Cardiovascular effects of donepezil in patients with dementia. Dement Geriatr Cogn Disord 15:183–188PubMedCrossRefGoogle Scholar
  107. 107.
    Giubilei F, Strano S, Imbimbo P, Tisei P, Calcagnini G, Lino S, Frontoni M, Santini M, Fieschi C (1998) Cardiac autonomic dysfunction in patients with Alzheimer disease: possible pathogenetic mechanisms. Alzheimer Dis Assoc Disord 12(4):356–361PubMedCrossRefGoogle Scholar
  108. 108.
    Siepmann M, Muck A, Engel S, Rupprecht R, Muck-Weymann M (2006) The influence of rivastigmine and donepezil on heart rate variability in patients with Alzheimer’s disease. German J Psych 9:133–135Google Scholar
  109. 109.
    Bibevski S, Dunlap M (2004) Prevention of diminished parasympathetic control of the heart in experimental heart failure. Am J Physiol Heart Circ Physiol 287:H1780–H1785PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Monali Y. Desai
    • 1
  • Mari A. Watanabe
    • 1
  • Abhay A. Laddu
    • 1
  • Paul J. Hauptman
    • 1
    • 2
  1. 1.Division of Cardiology, Department of Medicine Saint Louis University School of Medicine, Saint Louis University HospitalSaint LouisUSA
  2. 2.Division of CardiologySaint Louis University HospitalSaint LouisUSA

Personalised recommendations