(1) Baroreceptor function: In lowoutput HF models, there is attenuation of carotid sinus baroreceptor discharge sensitivity. Administration of digoxin produces improvement in baroreceptor function that results in decreased activation of the sympathetic nervous system. 5 (2) Vagomimetic effect: Digoxin at therapeutic doses increases vagal tone (ie, decreases sinoatrial and atrioventricular conduction). 10 (3) Sympathoinhibitory effects: Digoxin has a direct sympathoinhibitory effect that does not appear to be related to an increase in the cardiac output produced by the drug. Although dobutamine and digoxin cause a similar increase in cardiac output in HF, only the latter decreases sympathetic nerve discharge. 11 (4) Circulating neurohormones: Therapeutic doses of digoxin decrease the serum norepinephrine concentrations and plasma renin activity. 12 (5) Dose related effects on neurohormones: A low dose of digoxin that has no effect on cardiac contractility or hemodynamics decreases cardiac norepinephrine spillover in severe HF. 13 Increasing the dose within therapeutic range continues to improve the hemodynamics without further improvement of the neurohormonal profile. 14 (6) Antifibrotic effects: Patients with HF often have chronically high levels of aldosterone. Aldosterone stimulation of the sodium pump may lead to perivascular fibrosis that experimentally may be prevented by digoxin administration. 15