# Mediators of Systemic Inflammation and Heart Failure Risk in the Community

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2020 · $816,522

## Abstract

PROJECT SUMMARY/ABSTRACT
Chronic inflammation, defined by a persistent elevation of local and systemic pro-inflammatory factors, has
been implicated in the development and progression of heart failure in the community. Nonetheless, evidence
in humans is scant and conflicting regarding the potential for specific inflammatory pathways to serve as key
mechanistic drivers of disease and, in turn, as potentially high-yield therapeutic targets. This problem has
arisen, in part, from a predominant prior focus on downstream rather than upstream mediators of inflammation.
Accumulating evidence suggests that upstream mediators of inflammation are more likely to play a causal role
in disease pathogenesis and, thus, serve as effective therapeutic targets. The upstream initiation of
inflammation in humans is governed primarily by small lipid molecule effectors of polyunsaturated fatty acid
metabolism, termed eicosanoids. These bioactive lipid species exhibit both pro- and anti-inflammatory activity
and include prostaglandins, lipoxins, and leukotrienes. To date, the interactions between eicosanoid pathways
and heart failure traits and outcomes remain poorly understood. Therefore, we proposed to provide a more
detailed understanding of how upstream eicosanoid pathways can be variably active, imbalanced, and
perturbed in relation to an individual’s propensity for developing heart failure. Advanced mass spectrometry
methods now allow for the rapid and accurate quantification of up to hundreds of upstream eicosanoid
mediators representing multiple enzymatic origins. We will use these methods to comprehensively assay
distinct pro- and anti-inflammatory eicosanoids and examine their relation to heart failure risk factors and
outcomes in a longitudinal study of men and women living in the community. In parallel, we will profile
eicosanoids in a longitudinal study of an animal model of impending heart failure. Our specific aims are: (1) to
assess whether circulating eicosanoid mediators of inflammation are associated with heart failure risk factors
and incidence in the community; (2) to relate circulating eicosanoids with adverse outcomes in the setting of
established heart failure; and, (3) to investigate the temporal and tissue-specific correlates of eicosanoid
variation in an experimental model of heart failure. Our systematic approach to comprehensively investigating
the components of upstream inflammatory activity in relation to heart failure outcomes across the spectrum of
risk promises to yield important insights into the determinants of clinically important cardiac dysfunction. Given
its focus on upstream inflammatory activity, this work will pave the way for follow-up studies investigating the
efficacy of anti-inflammatory therapies (both existing and novel agents) for modulating variation in distinct
eicosanoids as well as outcomes.

## Key facts

- **NIH application ID:** 9894845
- **Project number:** 5R01HL143227-02
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Susan Cheng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $816,522
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9894845

## Citation

> US National Institutes of Health, RePORTER application 9894845, Mediators of Systemic Inflammation and Heart Failure Risk in the Community (5R01HL143227-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9894845. Licensed CC0.

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