Role of endothelin in modulation of heart rate variability in patients with decompensated heart failure

Endothelin-1 (ET-1) can modulate central and peripheral sympathetic outflow. However, if increased ET-1 levels contribute to autonomic perturbations in the setting of congestive heart failure (CHF) is not known. The purpose of this study was to determine if increased ET-1 levels contribute to the depressed HRV in patients with CHF. Sixty-four patients were admitted to the hospital for treatment of decompensated CHF (mean age 59+/-12 years, NYHA Classes III [72%] and IV [28%]). Time- and frequency-domain HRV measures were obtained from 24-hour Holter recordings. Neurohormonal activation was assessed by measuring plasma renin activity (PRA), aldosterone, norepinephrine, and ET-1 levels. Among the time-domain HRV indices, ET-1 correlated negatively with the standard deviation of RR intervals (SDNN) (r = - 0.38, P = 0.002) and standard deviation of all 5-minute mean RR intervals (SDANN5) (r = - 0.48, P < 0.0001), but not with time-domain indices indicative of parasympathetic modulation. Among the frequency-domain HRV indices, ET-1 correlated negatively with the total power (r = - 0.32, P = 0.01) and ultralow frequency power (ULF) (r = - 0.43, P = 0.0004), but not with indices of parasympathetic (high frequency) or sympathovagal (low frequency) modulation. Using multiple linear regression, adjusting for clinical parameters, drug therapies, and other neurohormones, the strong negative relationship between ET-1 and SDNN (P = 0.027), SDANN5 (P = 0.002), and ULF power (P = 0.017) persisted. In conclusion, ET-1 may play an important role in the autonomic dysfunction characteristic of CHF. The correlation between ET-1 levels and prognostically important indices of overall HRV suggests that these HRV measures are better markers of neurohormonal activation in CHF, which may partially account for their greater discriminatory power for risk stratification.