Background: Patients with heart failure (HF) display a number of breathing abnormalities including periodic breathing (PB) at rest. Although the mechanism(s) contributing to PB remain unclear, we examined whether changes in pulmonary wedge pressure (PWP) and pulmonary vascular resistance (PVR) alter PB in patients with established HF. Methods: We studied 12 male patients with HF (age, 50 ± 11 years; ejection fraction, 18.3 ± 3.8 %; New York Heart Association class, 3.2 ± 0.4), with PB at rest, who are undergoing right heart catheterization with infusion of nitroprusside. Results: At baseline, patients with HF displayed minute ventilation (VE) oscillations with amplitude of 5.5 ± 2.7 L/min (57 ± 34% of the average VE) and cycle length of 61 ± 18 seconds. Cardiac index (CI), PVR, and mean PWP averaged 2.0 ± 0.4 L min-1 m-2, 281.9 ± 214.9 dyne/s per cm-5, and 28.3 ± 5.4 mm Hg, respectively. During nitroprusside infusion, CI increased to 3.1 ± 0.6 L min-1 m-2, PVR decreased to 163.9 ± 85.2 dyne/s per cm-5, and PWP fell to 10.0 ± 4.2 mm Hg. Nitroprusside reduced the amplitude (2.6 ± 2.4 L/min, 23 ± 21% of average VE; P < .01) and cycle length (41.4 ± 28.8 seconds; P < .01) of VE oscillations while abolishing oscillations in 3 patients. Although average VE and Paco2 remained unchanged, there was a significant increase in the ratio of tidal volume to inspiratory time (VT/TI; P < .01), suggesting an increase in ventilatory drive. The change in the amplitude of VE oscillations was positively correlated with the change in PWP (r = 0.75; P < .01), negatively correlated with the change in PVR (r = 0.63; P < .05), and not correlated with the change in CI. Conclusions: These data suggest that PWP (left atrial pressure) may play a direct role in the PB observed in HF at rest.