# Atrial Remodeling and Susceptibility to Fibrillation

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $430,401

## Abstract

PROJECT SUMMARY
Long before the onset of permanent AF, AF risk factors promote fibrotic remodeling with ensuing progressive
atriomyopathy. After the onset of permanent AF, electrical remodeling and transcriptional remodeling have
occurred. Mechanisms underlying how these three remodeling processes relate to one another and to the
evolution of AF from susceptibility in the clinical phase to permanence in the clinical phase are unknown. If the
critical gap of knowledge regarding the cellular determinants of preclinical electrical remodeling is not elucidated,
golden opportunities for intervention with risk-modifying and preventive therapies provided by the long preclinical
phase of AF will remain missed. The long-term goal is to discover a novel preventive strategy for permanent AF.
The overall objective in this application is to determine whether myocyte electrical remodeling is the final common
pathway in preclinical atriomyopathy that increases the vulnerability of atrial myocytes to arrhythmia triggers and
consequently of the fibrotic atrial tissue to AF. The central hypothesis is that whereas fibrosis initiates the
preclinical phase of AF susceptibility, subsequent electrical remodeling is critical to transition from the preclinical
to clinical phase of AF permanence. This hypothesis is formulated based on compelling preliminary data from
the applicant's six novel robust and clinically relevant rat and rabbit models of AF susceptibility and permanence.
An integrative multidisciplinary approach that incorporates technical innovations in electrophysiology, genomics,
and computational biology will be used to test a novel, transformative mechanistic concept. Two aims are
proposed to define how myofibroblast- and myocyte-centric mechanisms work independently and in synergy with
stress to contribute to AF development and maintenance. Specifically, each aim is designed to determine
whether preclinical electrical remodeling of atrial myocytes is caused by myocyte-myofibroblast electrical
communication (Aim 1) and/or (2) remodeling of the gene expression of critical myocyte ionic currents (Aim 2).
Both mechanisms will be investigated in the absence and presence with stress synergy. The proposal is
significant because it will identify potential targets for early risk-modifying intervention in the preclinical phase.
The study is conceptually innovative because we introduce six novel robust animal models of AF susceptibility
and permanence and advance the novel mechanistic concept of atrial AP ventricularization as a driver for the
transformation of AF from susceptibility to permanence. The study is also technically innovative because it will
generate the first RiboTag rat model, the first single cell transcriptomic profiling using 10x Genomics for
cardiomyocytes, and the first dynamic clamp application in atrial tissue.

## Key facts

- **NIH application ID:** 10337131
- **Project number:** 5R01HL141452-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Thao P. Nguyen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $430,401
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10337131

## Citation

> US National Institutes of Health, RePORTER application 10337131, Atrial Remodeling and Susceptibility to Fibrillation (5R01HL141452-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10337131. Licensed CC0.

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