# Quantifying the role of myocyte ultrastructure in atrial health and disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2021 · $469,027

## Abstract

PROJECT SUMMARY: Atrial fibrillation (AF) is the most common cardiac arrhythmia (affecting ~1-2% of the
general population), resulting in markedly reduced quality of life and increased mortality, due to a combination
of altered hemodynamics, progressive atrial and ventricular dysfunction, and embolic stroke. Many diseases and
conditions, like heart failure, are known to contribute to pathological changes leading to AF. Limitations in current
therapy allow AF paroxysms to progress to persistent and chronic AF, as a result of extensive atrial structural
and electrical changes that facilitate AF maintenance (“AF begets AF”). The development of urgently needed
new strategies for AF treatment hinges upon improved understanding of how abnormalities in cellular function
trigger and sustain arrhythmia in atrial tissue. At the cellular level, a hallmark structural change of many chronic
cardiac diseases is degradation of the intricate membrane architecture that couples cardiac electrical excitation
to intracellular Ca2+ release and myocardial contraction (EC coupling) – i.e., the transverse tubule (TT) structures,
which project orthogonally from the cell surface to its interior and thereby synchronize EC coupling throughout
the cell. Degradation of the TT architecture is generally associated with arrhythmia, but it is not yet clear whether
TT loss is a direct contributor to arrhythmia, a compensatory maladaptation, or an epiphenomenon. This is even
less clear in atria, as atrial myocytes exhibit a vastly variable range of TT architectures, with prominent axial
tubules. Further, TT degradation induced by the process of isolating atrial myocytes (vs. denser TTs in intact
tissues) and challenges in experimentally detubulating intact cardiac tissue has so far limited the design of
mechanistic myocyte and tissue studies. As a result, the literature surrounding the role of subcellular structural
(ultrastructural) remodeling in AF has remained fractured, and currently we know relatively little about its role in
contributing to AF pathophysiology. The overarching goal of this proposal is to discriminate the role of changes
in atrial myocyte ultrastructure from other disease-associated sequelae by combining detailed multi-level
experimental analyses of rabbit atrial myocytes and rabbit and human atrial tissues with extensive quantitative
multi-scale computational modeling. The project will develop and validate a suite of modeling tools used to
investigate the mechanisms by which: (1) naturally occurring variations in atrial TTs influence EC coupling and
membrane stability in isolated atrial myocytes; (2) tissue gradients in TT organization influence tissue-level
electrophysiological and EC coupling outcomes; (3) ultrastructural remodeling synergizes with ionic remodeling
to favor atrial arrhythmogenesis in atrial cardiomyopathy. We contend that quantifying the role of atrial
ultrastructure in AF pathology may shed new mechanistic insight into AF management. Each a...

## Key facts

- **NIH application ID:** 10296281
- **Project number:** 2R01HL131517-06A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Eleonora Grandi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $469,027
- **Award type:** 2
- **Project period:** 2016-06-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10296281

## Citation

> US National Institutes of Health, RePORTER application 10296281, Quantifying the role of myocyte ultrastructure in atrial health and disease (2R01HL131517-06A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10296281. Licensed CC0.

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