Circulating levels of tumor necrosis factor correlate with indexes of depressed heart rate variability: A study in patients with mild-to-moderate heart failure

Objectives: Patients with heart failure have increased circulating levels of tumor necrosis factor (TNF) and TNF receptors. It is not known whether TNF, which is known to blunt β-adrenergic responsiveness in experimental models, contributes to the loss of heart rate variability in patients with heart failure. Therefore, we examined heart rate variability in relation to circulating levels of TNF, TNF receptors, and norepinephrine in patients with heart failure and in control subjects. Methods: Heart rate variability was obtained from 24-h ambulatory ECG recordings in age-matched control subjects (n = 10) and patients with mild (n = 15) to moderate (n = 14) heart failure. Plasma levels of TNF and soluble type 1 and 2 TNF receptors were measured by enzyme-linked immunoassay; plasma norepinephrine levels were measured by high-performance liquid chromatography. Results: There was a significant inverse linear correlation between increased circulating levels of TNF, TNF receptors, and norepinephrine for time-domain and frequency-domain indexes of heart rate variability among patients with heart failure and control subjects. Multiple stepwise linear regression analysis showed that TNF was a stronger independent predictor of frequency-domain indexes of heart rate variability than norepinephrine. Conclusions: TNF is an independent predictor of depressed heart rate variability in patients with heart failure. Insofar as TNF blunts β-adrenergic signaling, this study suggests the possibility that overexpression of TNF and subsequent loss of β-adrenergic responsiveness contributes to the decrease in heart rate variability observed in heart failure.