# Boosting NAD to Combat Heart Failure Sterile Inflammation

> **NIH VA IK2** · VA PUGET SOUND HEALTHCARE SYSTEM · 2024 · —

## Abstract

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.

## Key facts

- **NIH application ID:** 10702014
- **Project number:** 1IK2BX006111-01A1
- **Recipient organization:** VA PUGET SOUND HEALTHCARE SYSTEM
- **Principal Investigator:** Dennis Ding Hwa Wang
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2023-10-01 → 2028-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10702014

## Citation

> US National Institutes of Health, RePORTER application 10702014, Boosting NAD to Combat Heart Failure Sterile Inflammation (1IK2BX006111-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10702014. Licensed CC0.

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