# Characterization of Functional Iron Deficiency and Repletion in Heart Failure with Preserved Ejection Fraction

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $601,100

## Abstract

Project Summary/Abstract
Heart failure (HF) is a major public health problem worldwide, and half of patients presenting with HF have
preserved ejection fraction (HFpEF), rather than reduced ejection fraction (HFrEF). However, HFpEF remains
a therapeutic challenge, given current limited understanding of causal and contributing factors. Functional iron
deficiency (FID, defined as a ferritin level < 100 ng/ml or transferrin saturation (Tsat) < 20% with ferritin < 300
ng/ml) is present in approximately half of all patients with either HFpEF or HFrEF. In patients with HFrEF, FID
is associated with reduced exercise capacity, poorer quality of life, and increased mortality regardless of
hemoglobin level. Correction of FID consistently and durably improves exercise capacity in HFrEF, however
less is known about the functional impact of FID in patients with HFpEF or in the general population. Beyond
its role in erythropoiesis, iron is an obligate component of myoglobin and enzymes involved in cellular
respiration, oxidative phosphorylation, vascular homeostasis, nitric oxide generation, and the citric acid cycle,
which all can be negatively impacted by iron deficiency. Hepcidin, a hormone synthesized by the liver, is
considered the master regulator of iron homeostasis. Hepcidin reduces iron bioavailability and levels are
regulated by inflammatory signaling pathways (eg, IL-6, IL-1β) and by the protein hemojuvelin which plays a
critical role in iron sensing. We have previously demonstrated that lower hepcidin levels are cardioprotective in
animal model studies and that elevated hepcidin levels in symptomatic HFrEF patients precluded normalization
of FID with oral iron supplementation in the NIH-sponsored multi-center IRONOUT-HF Trial. In our preliminary
studies of HFpEF patients undergoing comprehensive cardiopulmonary exercise testing (CPET) FID with
reduced Tsat/hepcidin ratio was associated with exercise cardiac output, peripheral O2 extraction, pulmonary
vascular resistance and peak VO2, implicating FID as an important determinant of multiple aspects of exercise
capacity. We now propose to measure iron status, hepcidin and hemojuvelin levels in a large community-
based cohort (Framingham Heart Study Gen3/OMNI2, N=3,116) and in a referral cohort with suspected
HFpEF (MGH ExS, N=450) to understand the role of FID in relation to functional capacity, leveraging existing
CPET measures of low-level, intermediate and peak exercise O2 utilization in both cohorts. Our overarching
hypothesis is that FID arises in the setting of pro-inflammatory states that precede overt HFpEF, which is
characterized by impaired ability to augment O2 utilization, as reflected by reduced peak VO2. In Aim 1A, we
will determine the prevalence, risk factors, genetic determinants, and functional significance of functional iron
deficiency (FID) in the community. In Aim 1B, we will determine how FID relates to organ-specific dysfunction
indicative of HFpEF subphenotypes in the MGH Exerc...

## Key facts

- **NIH application ID:** 10867349
- **Project number:** 5R01HL159514-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Gregory Dyer Lewis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $601,100
- **Award type:** 5
- **Project period:** 2021-08-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10867349

## Citation

> US National Institutes of Health, RePORTER application 10867349, Characterization of Functional Iron Deficiency and Repletion in Heart Failure with Preserved Ejection Fraction (5R01HL159514-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10867349. Licensed CC0.

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