HEART-RATE-VARIABILITY IN PATIENTS WITH MILD-TO-MODERATE HEART-FAILURE - EFFECTS OF NEUROHORMONAL MODULATION BY DIGOXIN AND IBOPAMINE

Objectives. This study assessed the effects of digoxin and ibopamine on variables of heart rate variability in relation to neurohormonal activation. Background. Analysis of heart rate variability can be used to study the autonomic dysfunction that characterizes chronic heart failure. In the Dutch Ibopamine Multicenter Trial, patients with heart failure were found to have increased neurohormonal activation with placebo therapy but not with digoxin and ibopamine therapy. Methods. We studied 59 patients with mild to moderate heart failure (mean [+/-SEM] age 60 +/- 1 years, mean ejection fraction 0.30 +/- 0.01). Patients were randomized to double-blind treatment with digoxin (0.25 mg [n = 22]), ibopamine (100 mg three times a day [n = 19]) or placebo (n = 18); background therapy consisted of furosemide (up to 80 mg). Results. After 3 months, plasma norepinephrine levels had increased with placebo, whereas they decreased with digoxin (+31 vs, -60 pg/ml, respectively, p < 0.01). With ibopamine, a nonsignificant decrease was observed (-27 pg/ml, p = 0.10). All variables of heart rate variability showed a deterioration in the placebo group. With digoxin, the percent differences between successive RW intervals >50 ms (pNN50) increased (+1.7 +/- 0.9%, p < 0.01), along with absolute and normalized high frequency power (+40 +/-33 ms(2), p < 0.05 and +2.4 +/- 1.7%, p < 0.01, respectively). These changes were observed during daytime hours only and were most pronounced in patients with the most impaired baseline heart rate variability. With ibopamine, nonsignificant trends similar to the changes with digoxin were observed, Conclusions. In patients with early stages of heart failure, digoxin may prevent a progressive deterioration in heart rate variability, whereas ibopamine does not show statistically significant effects. The changes in heart rate variability with digoxin parallel an observed decrease in neurohormonal activation. Digoxin apparently enhances cardiac vagal tone in the setting of neuroendocrine activation.