# Immune Basis of how Inflammation, Atherosclerosis, and Aging Enhance Atrial Fibrillation

> **NIH NIH F32** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $44,281

## Abstract

Project Summary
 Two and a half million people suffer from atrial fibrillation (AF) in the United States, costing $26 billion
annually. It is currently unknown whether age-induced inflammation from atherosclerosis induces atrial
remodeling and fibrosis resulting in AF, although both age and atherosclerosis are major risk factors for
developing AF. Age-specific therapies for AF are currently lacking and pose significant risks in the elderly,
including increased risk of bleeding and falls. The long-term goals of this research are to determine the
mechanisms of how aging, atherosclerosis, and inflammation interact to enhance AF and to develop novel
therapies targeting these inflammatory mechanisms. The focus of this proposal is to test the hypothesis that
macrophages in the atrial myocardium or epicardial adipose tissue mediate inflammation with atherosclerosis
and aging which dysregulates ion channels and leads to AF. To test this hypothesis, we will use a murine
model of atherosclerosis, the low-density lipoprotein receptor knockout (Ldlr-/-) mouse, and we will pursue 2
specific aims. First, we will determine if AF inducbility is dependent on inflammation and metabolic
derangement from atherosclerosis. In order to complete this aim, we will maintain young wild-type (WT) mice
on a chow diet or switch them to a high fat diet (HFD) for 3 months, and we will treat young Ldlr-/- mice
similarly. We will determine whether vascular inflammation in the Ldlr-/- mice fed a HFD on top of metabolic
derangement in WT mice fed a HFD is required for AF. We will also assess atrial remodeling, inflammation,
macrophage accumulation and phenotype, and ion channel dysfunction. Our second aim will be to determine
the role of atrial macrophages on AF inducibility during atherosclerosis and aging. Based on our preliminary
data, we hypothesize that macrophages are critical for AF. Thus, we will enumerate and phenotype
macrophages in the atrial myocardium in young and aged Ldlr-/- and WT mice fed a chow diet or switched to a
HFD for 3 months. We will also acutely deplete macrophages via pharmacologic approaches to determine if
their absence reduces AF. Again, we will assess atrial remodeling, ion channel properties, and macrophage
accumulation and phenotype. The proposed research will provide novel insights into the complex interplay
between aging, atherosclerosis, and AF and will generate new cellular and molecular pathways to be
developed into therapies to reduce the burden of AF in older people.

## Key facts

- **NIH application ID:** 9839665
- **Project number:** 5F32HL140728-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Daniel Tyrrell
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $44,281
- **Award type:** 5
- **Project period:** 2017-12-28 → 2020-07-27

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9839665

## Citation

> US National Institutes of Health, RePORTER application 9839665, Immune Basis of how Inflammation, Atherosclerosis, and Aging Enhance Atrial Fibrillation (5F32HL140728-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9839665. Licensed CC0.

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