Congestion is a major determinant of clinical outcomes in heart failure (HF). We compared the acute hemodynamic effects of occlusion of the superior (SVC) versus the inferior vena cava (IVC) and tested a novel SVC occlusion system in swine models of HF. IVC occlusion acutely reduced left ventricular (LV) systolic and diastolic pressures, LV volumes, cardiac output (CO), and mean arterial pressure (MAP). SVC occlusion reduced LV diastolic pressure and volumes without affecting CO or MAP. The preCARDIA system is a balloon occlusion catheter and pump console which enables controlled delivery and removal of fluid into the occlusion balloon. At 6, 12, and 18 h, SVC therapy with the system provided a sustained reduction in cardiac filling pressures with stable CO and MAP. Intermittent SVC occlusion is a novel approach to reduce biventricular filling pressures in HF. The VENUS-HF trial will test the safety and feasibility of SVC therapy in HF.