Background: Abnormal cardiac response to β-adrenergic receptor (AR) stimulation contributes to exercise (Ex) intolerance in heart failure (HF). Previous studies indicate that elevated levels of tumor necrosis factor-α (TNF-α) in HF patients diminish cardiac positive inotropic response to β-AR stimulation. In HF, Ex may cause increased TNF-α activation and contribute to the abnormal Ex response. However, its function effects in HF during Ex are unclear. We test the hypothesis that antagonizing TNF-α with Etanercept (ETA) may improve LV systolic and diastolic function and improve Ex performance in HF.Methods: We compared left ventricular (LV) systolic and diastolic responses and plasma TNF-α levels at rest and during Ex before and after receiving Etanercept (ETA) ETA (0.3 mg/kg iv) at 1, 7, and 24 hours (H) in 10 dogs with pacing-induced HF.Results: After HF, ETA significantly reduced the plasma TNF-α (control: 26 pg/ml; ETA: 1H, 14 pg/ml; 24H, 12 pg/ml), which was correlated with sustained augmentation of LV contraction and relaxation. Compared with control, 24 H after ETA, heart rate, LV end-systolic pressure (P), and arterial elastance were unchanged. Stroke volume (V) (15.9 vs 13.7 ml) and LV contractility, measured as the slopes of LV P-V relations, significantly increased (EES: 7.6 vs 4.5 mmHg/ml; Msw: 70.2 vs 60.6 mmHg). The time constant of LV relaxation (τ) decreased (32.7 vs 40.5 ms). LV mechanical efficiency, determined as the ratio of stroke work to total P-V area, improved (0.58 vs 0.42) (p<0.05). These beneficial actions persisted during Ex. After HF, without ETA, Ex increased τ (49.4 vs 40.5 ms), PED and minimum LV P (LVPmin). The peak mitral flow (dV/dtmax, 220 vs 163 ml/s)increased due entirely to elevated mean left atrial P (32.8 vs 22.9 mmHg). In contrast, with ETA, Ex significantly decreased τ (34.1 vs 40.5 ms) and LVPmin(10.7 vs 19.4 mmHg) witha leftward and downward shift of LV P-V loop; thus, dV/dtmax was further augmented (298 ml/s) without change in mean LA P. Ex duration also increased (5.8 vs 4.5 min) after ETA.Conclusion: After HF, a clinically relevant dose of ETA infusion causes sustained reduction of plasma TNF-α; increases LV relaxation, contractility, LV arterial coupling and mechanical efficiency; and thus, improves Ex performance.