# Eicosanoid Profiles as Determinants of HFpEF

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $592,670

## Abstract

Project Summary/Abstract
Heart failure (HF) is a major public health problem worldwide, and half of patients presenting with HF have
preserved (HFpEF), rather than reduced ejection fraction. However, HFpEF remains a therapeutic challenge,
given current limited understanding of causal and contributing factors, and clinical heterogeneity within HFpEF
subphenotypes. Comorbidities such as obesity and hypertension are thought to induce a systemic pro-
inflammatory state that, in turn, drives cardiovascular dysfunction and remodeling leading to HFpEF. Indeed,
downstream markers of inflammation have been observed in HFpEF. However, accumulating evidence
suggests that upstream mediators of inflammation are more likely to play a causal role in disease pathogenesis
and, in turn, serve as effective therapeutic targets. Upstream initiation of inflammation in humans is governed
primarily by small molecule effectors of arachidonic acid metabolism, termed eicosanoids. These bioactive
lipids include thromboxanes, prostaglandins, lipoxins, and leukotrienes, and harbor pro- and anti-inflammatory
activity, vasoactivity, and direct modulation of cardiomyocyte signaling and contractile function. To date, the
interaction between eicosanoid pathways and development of HFpEF remain poorly understood, thus limiting
our ability to harness their therapeutic potential. Advanced methods using mass spectrometry now allow for the
rapid and accurate quantification of >150 upstream eicosanoid mediators representing multiple enzymatic
origins. To provide a more detailed understanding of how upstream eicosanoid pathways may underlie the
progression from risk factors to HFpEF, and shed light onto HFpEF subphenotypes, we will pursue two related
lines of investigation: In Aim 1, we will investigate the association of circulating eicosanoids with clinical risk
factors, subclinical cardiac remodeling, and incident HFpEF in the community. In Aim 2, we will examine the
association of eicosanoid profiles with HFpEF subphenotypes, including distinct cardiac and extracardiac
vascular dysfunction among clinical HFpEF patients. This proposal leverages a unique multidisciplinary team
of collaborators with expertise in clinical epidemiology, advanced imaging, exercise physiology, bioinformatics,
analytical chemistry, and lipidomics. Our systematic approach to comprehensively investigating the
components of upstream inflammatory activity in two large, well-phenotyped community-based cohorts,
complemented by a group of clinical HFpEF patients with comprehensive exercise hemodynamic evaluations
and deep physiologic phenotyping to assess distinct aspects of cardiovascular dysfunction, promises to yield
important insights into the molecular determinants of HFpEF. Importantly, these studies will lay the foundation
for future investigations focused on disease prevention and optimal therapies tailored to HFpEF subphenotype.

## Key facts

- **NIH application ID:** 10063013
- **Project number:** 5R01HL140224-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Jennifer E Ho
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $592,670
- **Award type:** 5
- **Project period:** 2017-12-15 → 2021-11-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10063013

## Citation

> US National Institutes of Health, RePORTER application 10063013, Eicosanoid Profiles as Determinants of HFpEF (5R01HL140224-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10063013. Licensed CC0.

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