# HFpEF Susceptibility in Women: The Role of Inflammation

> **NIH NIH K23** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $199,693

## Abstract

PROJECT SUMMARY/ABSTRACT
Heart failure (HF) is an important public health concern, affecting over 6 million individuals in the United States
alone. HF with preserved ejection fraction (HFpEF) is now the leading form of HF and the prevalence
continues to rise. HFpEF remains a therapeutic challenge, given our limited understanding of causal and
contributing factors, clinical heterogeneity within HFpEF subphenotypes, and lack of available therapies.
HFpEF is far more prevalent in women than men, driven in part by sex differences in cardiac structure and
remodeling, adaptations to physiologic stress, and comorbidity burden. Emerging data support the role of
systemic inflammation in the pathogenesis of HFpEF and sex differences in immune response have led many
to hypothesize that inflammation is an important driver of the female susceptibility to HFpEF. A better
understanding of these sex differences may offer critical insights into disease pathogenesis, particularly in light
of recent evidence highlighting potential therapeutic benefit of sacubitril/valsartan preferentially in women with
HFpEF. To date, investigations of inflammation in HFpEF have been limited to downstream markers of
inflammation. Eicosanoids are small bioactive lipids that regulate the upstream initiation of systemic
inflammation in humans. Advanced methods using mass spectrometry now allow for the rapid and accurate
quantification of >150 upstream eicosanoid mediators. We will leverage this state-of-the-art technology to
provide a more detailed understanding of how biologic sex differences in upstream eicosanoid pathways
contribute to HFpEF risk and disease progression. In Aim 1, we will examine sex differences in the association
of circulating eicosanoids with clinical antecedents of HFpEF as well as incident HFpEF in the community. In
Aim 2, we will evaluate the association of eicosanoid analytes with cardiac and extra-cardiac responses to
exercise in men and women with clinical HFpEF. In Aim 3, we will conduct a prospective observational study to
investigate the changes in inflammatory profiles and endothelial cell inflammation as ascertained by eicosanoid
metabolites and endothelial cell gene expression profiling through the menopausal transition in women and
age-matched men at risk for developing HFpEF. The overarching goal of this proposal is to evaluate the
hypothesis that sex differences in systemic inflammation may account for observed differences in HFpEF risk
and disease manifestations in men and women. This research will be accomplished in the setting of a
comprehensive career development program designed to provide Dr. Lau, an early career investigator, with the
skills needed to become an independent physician-scientist in women’s cardiovascular (CV) health. Her long-
term career goal is to identify biologic sex differences that contribute to CV risk and disease in order to refine
prevention and therapeutic strategies for women with CV disease. This proposal brings to...

## Key facts

- **NIH application ID:** 10448571
- **Project number:** 1K23HL159243-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Emily Lau
- **Activity code:** K23 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $199,693
- **Award type:** 1
- **Project period:** 2022-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10448571

## Citation

> US National Institutes of Health, RePORTER application 10448571, HFpEF Susceptibility in Women: The Role of Inflammation (1K23HL159243-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10448571. Licensed CC0.

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