Heart Failure (HF) affects more than 6 million Americans with annual direct medical expenditures exceeding $30 billion. Within the VA system, HF is prevalent among 5% of US veterans with a disproportional annual mortality rate of 14.5%. A chronic sterile inflammatory state, marked by sustained mild elevations of circulating proinflammatory cytokines, is associated with poor clinical outcomes in HF. Large randomized trials that target specific cytokines, such as TNFα and IL-1β, yielded variable results, indicating a knowledge gap in the mechanism linking inflammation and HF. Specifically, it remains unclear what the inflammatory signals are and how the peripheral immune cells—the primary effectors of inflammation—respond to and propagate those inflammatory signals in HF. These gaps have halted the development of effective therapies. Here, we postulate a novel model to mechanistically link inflammation to HF progression, such that plasma extracellular vesicles (EV) encapsulating mitochondrial damage-associated molecular patterns (MitoDAMP) serves as mediators to propagate the proinflammatory signal. On the other hand, in pre-clinical and small clinical studies, boosting NAD+ has been shown to be anti-inflammatory. Further, NAD+ deficiency is reported in pathologic states associated with elevated inflammation, such as aging and HF. Our central hypothesis is that circulating immune cells amplifies the MitoDAMP mediated inflammatory signal, and boosting NAD+ may be inhibitory to this process. First, we plan to test hypothesis that the immunogenic factors in HF plasma are the MitoDAMPs encapsulated in EVs. Second, given our preliminary data implicating monocytes as a potential source of EV in HF plasma, we will study the cellular mechanism of EV release in monocytes. Lastly, we will study how boosting cellular NAD+ by a metabolic precursor, nicotinamide riboside (NR), may inhibit the monocytes from releasing EVs in vivo and in vitro. The proposed study aims to define a novel HF disease mechanism that may ultimately lead to the identification of new therapeutic targets. Completion of the proposed project will further my career by positioning me in a scientific niche that intersects clinical HF and immunometabolism, providing me with new research skills, and laying a strong foundation for my independent research program.