# Elucidating Mechanistic Relationships Between Atrial Ectopy, Atrial Remodeling and Atrial Fibrillation

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $801,247

## Abstract

Project Summary/Abstract
The proposal seeks to establish a pathophysiologic link between premature atrial contractions (PACs) and atrial
fibrillation (AF). It has been well established that patients with frequent PACs are more likely to develop incident
AF. But whether PACs are causative, or an epiphenomenon, is unclear. We hypothesize that PACs from the
pulmonary veins or lateral left atrium (LA) lead to more atrial dyssynchrony compared to PACs from other regions,
and that this dyssynchrony leads to atrial structural remodeling (via increased wall stress) and fibrosis that serves
to facilitate AF maintenance. Our preliminary data in a swine model of chronic PACs demonstrates that chronic
PACs lead to atrial electrophysiologic (slow conduction) and structural (fibrosis) remodeling, which is more
pronounced for dyssynchronous PACs from the lateral left atrium compared to synchronous PACs from the septum
or controls without PACs. In our first Aim, we will explore in the swine model how differences in PAC coupling-
interval and atrial rate affect the degree of atrial remodeling and whether PAC cessation leads to complete
regression of remodeling. We will test whether an antifibrotic drug, pirfenidone, prevents adverse atrial structural
and electrical remodeling in the presence of PACs. We will also assess which molecular changes precede the
development of cardiomyopathy to determine the critical molecular pathways leading to PAC mediated atrial
remodeling. In our second Aim, we will establish the importance of these findings in humans by performing a
longitudinal case-control study of patients with a high burden of atrial ectopy to identify if chronic PAC-induced
atrial dyssynchrony leads to echocardiographic atrial remodeling. We will determine whether patients with frequent
PACs have more echocardiographic left atrial remodeling and AF over time compared to those without PACs. We
will also determine whether specifically dyssynchronous PACs are more likely to lead to atrial remodeling and AF
than synchronous PACs. The significance of the proposed work is that if frequent PACs are found to lead to
remodeling that leads to the development of incident AF, early intervention in patients with frequent PACs, with
medical therapy or catheter ablation, may prevent the later development of atrial remodeling and AF. Successful
prevention of AF could mean that millions of individuals could avoid debilitating loss of quality of life and enormous
healthcare costs.

## Key facts

- **NIH application ID:** 10641001
- **Project number:** 5R01HL159069-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Edward Paul Gerstenfeld
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $801,247
- **Award type:** 5
- **Project period:** 2022-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10641001

## Citation

> US National Institutes of Health, RePORTER application 10641001, Elucidating Mechanistic Relationships Between Atrial Ectopy, Atrial Remodeling and Atrial Fibrillation (5R01HL159069-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10641001. Licensed CC0.

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