# Oxidative stress contributes to atrial fibrillation by causing remodeling of the autonomic nervous system

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2021 · $575,814

## Abstract

Atrial fibrillation (AF) is a cause of significant morbidity and mortality with one in six Americans expected to
develop AF during their lifetime. As a major cause of stroke, the public health implications of AF are profound.
Ongoing research is therefore attempting to better define the mechanisms underlying AF, in order to improve
upon current treatments and to develop new therapies for AF.
 An important mechanism thought to underlie AF is altered activity of the autonomic nervous system (ANS),
with our recent work demonstrating extensive remodeling of autonomic nerves in the AF atrium. Unfortunately,
the upstream molecular mechanisms responsible for this adverse neurological remodeling are not known.
Another important mechanism thought to underlie the formation of a vulnerable substrate for AF is oxidative
stress (OS), even thought the precise molecular mechanisms by which OS contributes to AF in the intact
atrium are not known. Since OS directly or indirectly affects ANS signaling, our overall hypothesis for this
proposal is that `OS contributes to electrical substrate for AF by causing structural and functional
remodeling of the ANS.' We will test this hypothesis by using a combination of in-vivo and cellular
electrophysiology techniques, by performing direct intra-cardiac nerve recordings and by using novel gene
therapy approaches we have developed to target OS and ANS signaling in the intact atrium. We will perform
these studies in a rapid atrial pacing (i.e. atrial tachycardia or ATR) canine model of AF.
 Specific Aim 1 will test the hypothesis `Chronic OS generation in the atrium/GPs leads to parasympathetic
and sympathetic nerve sprouting in the ATR atrium, which is integral to the creation of electrical remodeling
(effective refractory period or ERP shortening) in ATR'. In this Aim, we will perform in an ATR model, long term
NOX2 inhibition in both atria (by using NOX2 shRNA) and assess: i) ERP shortening/AF and ii) autonomic
nerve growth. To determine if remodeled parasympathetic and sympathetic nerves are functional and mediate
ERP shortening, we will perform targeted Gαi/o ± Gαs inhibition in both atria and assess ATR-induced ERP
shortening and AF. Specific Aim 2 will test the hypothesis `OS increases post-ganglionic nerve firing in the
atrial GPs, leading to enhanced neurotransmitter release from remodeled/newly sprouted nerves; this helps
perpetuate electrical remodeling in ATR'. In this aim, we will assess whether targeted OS inhibition in the GPs
of dogs with established AF will attenuate spontaneous GP nerve firing, normalize autonomic responsiveness
in the atria and reverse ERP shortening. Specific Aim 3 will test the hypothesis `OS leads to the emergence of
IKH (and/or increase in IK1) in atrial myocytes, which helps perpetuate electrical remodeling in ATR.' We will
assess whether acute OS inhibition in ATR myocytes decreases IKH/IK1 density and reverses PKC signaling
changes that underlie emergence of IKH. In addition, we wil...

## Key facts

- **NIH application ID:** 10113663
- **Project number:** 5R01HL140061-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Rishi Arora
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $575,814
- **Award type:** 5
- **Project period:** 2018-01-15 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10113663

## Citation

> US National Institutes of Health, RePORTER application 10113663, Oxidative stress contributes to atrial fibrillation by causing remodeling of the autonomic nervous system (5R01HL140061-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10113663. Licensed CC0.

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