# Resolution of Inflammation in Heart Failure Post-Myocardial Infarction

> **NIH NIH R01** · UNIVERSITY OF SOUTH FLORIDA · 2020 · $373,750

## Abstract

Heart failure (HF) after myocardial infarction (MI) is a significant cause of morbidity and mortality. Identifying
the events that limit adverse remodeling of the left ventricle (LV) post-MI will provide therapeutic targets to
prevent, slow, or reverse progression to HF. MI initiates the “get-in” signal for immune cells including
neutrophils, which if unchecked causes uncontrolled pro-inflammatory activity that in turn leads to HF. Our
post-MI studies suggest that spleen coordinates the resolution of inflammation through a cardiosplenic
pathway. These findings reveal an urgent clinical need to establish the mechanisms by which the spleen
mediates this resolution. It was previously believed that resolution of inflammation is an inert process, but
emerging data confirms that this is an active process managed by specialized pro-resolving molecules (SPMs)
derived from omega-3 and omega-6 fatty acids. Our R00 study in an HF setting confirms that the spleen
produces various SPMs, including lipoxins, resolvins, and maresins post-MI, and exogenous treatment with
resolvin D1 (RvD1) clears inflammation in a cardiosplenic manner. We discovered that exogenous RvD1 clears
neutrophils and resolves inflammation by activating neutrophil-expressed formyl peptide receptor 2 (FPR2) in
the left ventricle and spleen post-MI. This proof-of-concept study using RvD1 in mice provides the foundation
for investigation of the resolvins-mediated mechanism of action in chronic HF. These data implicate activation
of neutrophil receptors in promoting the “get-out” signal for effective resolution of inflammation post-MI. To
achieve our overall goal of activating immune cells in the healing phase after MI, we propose to establish: 1)
the role of RvD1 in resolution of inflammation in chronic HF; 2) whether activation of this “get-out” signal is
enough to resolve post-MI inflammation in HF using FPR2 knockout mice to abolish RvD1 action and resultant
HF; and 3) the novel mechanism of action of RvD1 on neutrophil-expressed CD10 in the cardiosplenic axis, as
suggested by our innovative in silico computational modeling. Our initial studies in mice have confirmed the
role of RvD1 in acute HF. Now, we propose a mechanistic study to extend in silico, ex vivo, and acute HF (day
5) outcomes to chronic HF (day 28), which is key for translation and to indicate survival benefit to HF patients.
Non-immunosuppressive pro-resolving therapy is an unmet medical need and has the potential to be the first
ever effective therapy to control chronic inflammation and delay HF in a cardiosplenic manner. These studies
will identify immune cell-specific novel targets for lipid mediators in a ligand-receptor-specific pathway, rather
than antibody or cytokine-specific inhibition, which will likely enhance therapeutic applications in patients with
HF within the next 5-6 years.

## Key facts

- **NIH application ID:** 10085520
- **Project number:** 7R01HL132989-05
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** Ganesh V Halade
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $373,750
- **Award type:** 7
- **Project period:** 2016-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10085520

## Citation

> US National Institutes of Health, RePORTER application 10085520, Resolution of Inflammation in Heart Failure Post-Myocardial Infarction (7R01HL132989-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10085520. Licensed CC0.

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