# Investigating the Role of Macrophages in Heart Failure with Preserved Ejection Fraction

> **NIH NIH K99** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $163,868

## Abstract

CHALLENGE: Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome that
presents with heart failure symptoms, unaltered left ventricular ejection fraction, and is associated with
comorbidities including obesity, diabetes and metabolic syndrome. HFpEF accounts for ~50% of all heart failure
(HF) and is characterized by diastolic dysfunction and extensive cardiac fibrosis. The pathophysiology of HFpEF
is not well understood, and there are no evidence-based therapies to treat HFpEF. In pilot studies, we utilized
two-independent HFpEF models – i) 2-hit HFpEF model of hypertension and high-fat diet in mice and ii) obese
ZSF1 rats. Both HFpEF models exhibit diastolic dysfunction, obesity and glucose intolerance. In the mouse
HFpEF model, we observed increased numbers of inflammatory cells in the heart. We also observed an increase
in fibroblast differentiation into myofibroblasts, upregulation of extracellular matrix (ECM) genes and complement
signaling in the hearts HFpEF mice. We hypothesize that exaggerated macrophage infiltration into the left
ventricle (LV) mediates pathological cardiac remodeling in HFpEF by modulating cardiac fibroblast differentiation
and function.
GOAL: Here, we propose to investigate the mechanisms by which inflammatory macrophages cause cardiac
remodeling in HFpEF at the cellular, molecular and functional levels. In Aim 1, we will investigate the mechanisms
by which inflammatory macrophages mediate fibroblast differentiation. We will also assess the contribution of
macrophages to cardiac remodeling and diastolic dysfunction in two independent HFpEF models by depleting
macrophages with clodronate liposomes. In Aim 2, we will determine the effect of complement signaling on
macrophage polarization. We will characterize cardiac macrophage populations in HFpEF models after
complement depletion and examine the role of NLRP3 inflammasome activation in cardiac fibroblast function.
The long-term goal of this study is to understand the molecular basis of inflammation-mediated cardiac
remodeling in HFpEF. To facilitate my transition from a mentored postdoctoral fellowship to a stable independent
research position, the K99 phase will be conducted as integrated mentored career development and research
activities, and the R00 phase will be devoted to execution of the proposed research, establishing collaborations,
and writing a DP2 and an R01 grant.
INNOVATION: The proposed work pushes the envelope on multiple novel frontiers. It aims to uncover
mechanisms at the molecular, cellular and functional levels of organization. It integrates two orthogonal fields –
intercellular signaling in cardiovascular disease and regulation of fibroblast function by inflammatory signals. Our
studies will for the first time characterize inflammatory signals that mediate fibroblast activation and cardiac
remodeling in HFpEF. Understanding these mechanisms will help identify therapeutic targets to mitigate cardiac
remodeling in HF.

## Key facts

- **NIH application ID:** 10449478
- **Project number:** 1K99HL157689-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Niranjana Natarajan
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $163,868
- **Award type:** 1
- **Project period:** 2022-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10449478

## Citation

> US National Institutes of Health, RePORTER application 10449478, Investigating the Role of Macrophages in Heart Failure with Preserved Ejection Fraction (1K99HL157689-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10449478. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*