Autonomic Imbalance in Heart Failure

Heart failure is characterized by parasympathetic withdrawal and sympathetic overdrive that result in adverse physiological effects. 

Recent research has demonstrated that autonomic imbalance in heart failure is associated with an increased inflammatory response, arrhythmias, adverse cardiac performance, and poor survival.

Parasympathetic Withdrawal Is Associated with Poor Survival 

In a study of 282 chronic heart failure patients, vagal tone was measured by baroreflex sensitivity (BRS). When vagal tone was reduced (i.e. parasympathetic withdrawal), there was a relative risk increase of death of 2.0 (95% CI: 1.06-3.48). This association for increased mortality persisted even after adjustment for NYHA class, LVEF, and O2 consumption (1).

The association of parasympathetic withdrawal and poor survival was confirmed by the ATRAMI study of 1284 post-MI patients. In post MI patients with an LVEF < 35%, a low heart rate variability (standard deviation of normal RR intervals) and a low BRS carried a relative risk of 6.7 (95% CI: 3.1-14.6) and 8.7 (4.3-17.6) respectively compared with patients with a higher LVEF and less impaired vagal tone (2).

Inflammatory Response Is Elevated in Heart Failure Patients

Recent research has identified an important link between an increase in inflammation and poor outcomes in patients with heart failure. In patients with heart failure, investigators have documented an increase in plasma levels of the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6). The levels were progressively elevated as functional class worsened (3).  IL-6 and TNF-α are inhibited by acetylcholine and parasympathetic tone (4). Furthermore, circulating IL-6 is independently associated with reduced systolic function in healthy individuals free of cardiovascular disease, suggesting a pathogenic link between inflammatory response and left ventricular dysfunction (5).

Adverse Cardiac Performance from Altered Nitric Oxide Expression

Three isoforms of nitric oxide synthase (NOS) exist: endothelial (eNOS/NOS III); neuronal (nNOS/NOS I); and inducible (iNOS/NOS II). All isoforms are localized within the heart with independent effects on cardiac structure and function (6).  Hare and colleagues demonstrated that NO mediates the vagal inhibition of the inotropic response to dobutamine in normal dogs.(7)  In experimental models of heart failure, the expression of nitric oxide through each of the isoforms is altered (8,9,10). Like inflammatory cytokines, changes in nitric oxide expression may exert an initial protective role in heart failure that later becomes maladaptive (11).

Autonomic Imbalance Promotes Arrhythmias

In a myocardial infarction experimental model, dogs more susceptible to sympathetic activation of ventricular fibrillation had greater vagal withdrawal (12).  In a later experimental study of 192 post-MI dogs, the probability of venticular arrhythmia was inversely related to vagal tone, as measured by baroreflex sensitivity (13).


  1. Mortara A, La Rovere MT, Pinna GD, et al. Arterial baroreflex modulation of heart rate in chronic heart failure: clinical and hemodynamic correlates and prognostic implications. Circulation 1997;96:3450–8.
  2. La Rovere MT, Bigger JT Jr, Marcus FI, Mortara A, Schwartz PJ. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Lancet. 1998;351(9101):478-84.
  3. Torre-Amione G, Kapadia S, Benedict C, Oral H, Young JB, Mann DL. 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(5):1201-6.
  4. Tracey, K. The inflammatory reflex. Nature. 2002;420(6917):19-26.
  5. Yan AT, Yan RT, Cushman M, et al. Relationship of interleukin-6 with regional and global left-ventricular function in asymptomatic individuals without clinical cardiovascular disease: insights from the Multi-Ethnic Study of Atherosclerosis. Eur Heart J. 2010;31(7):875-82.
  6. Barouch LA, Harrison RW, Skaf MW, et al. Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms. Nature. 2002;416(6878):337-9. 
  7. Hare JM, Keaney JF Jr, Balligand JL, Loscalzo J, Smith TW, Colucci WS. Role of nitric oxide in parasympathetic modulation of beta-adrenergic myocardial contractility in normal dogs. J Clin Invest. 1995;95(1):360-6.
  8. Damy T, Ratajczak P, Shah AM, et al. Increased neuronal nitric oxide synthase-derived NO production in the failing human heart. Lancet. 2004;363(9418):1365-7.
  9. Drexler H, Kästner S, Strobel A, Studer R, Brodde OE, Hasenfuss G. Expression, activity and functional significance of inducible nitric oxide synthase in the failing human heart. J Am Coll Cardiol. 1998;32(4):955-63.
  10. Mital S, Barbone A, Addonizio LJ, et al. Endogenous endothelium-derived nitric oxide inhibits myocardial caspase activity: implications for treatment of end-stage heart failure. J Heart Lung Transplant. 2002 May;21(5):576-85.
  11. Li W, Olshansky B. Inflammatory cytokines and nitric oxide in heart failure and potential modulation by vagus nerve stimulation. Heart Fail Rev. 2011;16(2):137-45.
  12. Billman GE, Schwartz PJ, Stone HL. Baroreceptor reflex control of heart rate: a predictor of sudden cardiac death.Circulation. 1982;66:874-880.
  13. Schwartz PJ, Vanoli E, Stramba-Badiale M, De Ferrari GM, Billman GE, Foreman RD. Autonomic mechanisms and sudden death. New insights from analysis of baroreceptor reflexes in conscious dogs with and without a myocardial infarction. Circulation. 1988;78(4):969-79.
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