PROJECT SUMMARY/ABSTRACT Heart failure (HF) affects more than 6 million adults in the U.S. alone, with increasing prevalence. Cardiovascular congestion with resultant limitation in physical activity is the hallmark of chronic and decompensated HF. The current HF physiologic model suggests that congestion is the result of volume retention and, therefore, therapies (such as diuretics) have generally been targeted at volume overload. Yet therapeutic approaches to reduce congestion have failed to show significant benefit on clinical outcomes, potentially due to an untargeted approach of decongestive therapies. Our preliminary work suggested a complimentary contribution of volume redistribution to the mechanism of cardiac decompensation. We identified the splanchnic nerves as a potential therapeutic target and showed that short-term interruption of the splanchnic nerve signaling could have favorable effects on cardiovascular hemodynamics and symptoms. As part of our proposal, we will: (1) Investigate the impact of prolonged splanchnic nerve blockade on the cardiovascular system in patients with HF and reduced ejection fraction (HFrEF); (2) Visualize splanchnic nerves using intravascular imaging tools, and demonstrate technical success of the splanchnic nerve blockade; and (3) Define the mechanisms of action of splanchnic nerve blockade and identify congestion phenotypes that respond favorably to splanchnic nerve blockade. The results of the proposed scientific aims will help test the paradigm shifting hypothesis of volume redistribution as a driver of cardiovascular congestion and functional limitations and pave the way for splanchnic nerve blockade as a novel therapeutic approach to HF.