# Pathophysiological Significance of Atrial Fibrillation Electrogram Patterns

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2024 · $678,959

## Abstract

Atrial fibrillation (AF) is the most common heart rhythm disorder and is a major cause of stroke. Despite its
rapidly rising incidence, current therapies are suboptimal. This is largely because current AF therapies,
including ablation, are not targeted to the fundamental mechanisms underlying AF. AF is characterized by
complex electrical activation patterns that are difficult to map using standard activation time mapping. Yet,
there is growing evidence that AF is driven by stable sources in the atria, such as rotors or focal activity.
Unfortunately, previous attempts to use AF electrograms to detect these sources have had mixed success. We
have recently developed an electrogram morphology recurrence (EMR) analysis that appears to more
accurately reflect molecular and electrophysiological substrate for AF than previously described AF
electrogram measures of AF. Our recent studies suggest that regions of high recurrence morphology with the
shortest cycle lengths (i.e. regions of low recurrence cycle length - CLR) may correspond to regions of
increased parasympathetic innervation and/or increased oxidative injury. Furthermore, our clinical studies
suggest that in patients with persistent AF, EMR mapping is both feasible and provides important physiologic
information. Our overall hypothesis for this proposal is: ‘sites of high recurrence morphology with the shortest
cycle length (i.e. CLR) represent regions of increased autonomic signaling and/or increased oxidative injury,
which are critical to the maintenance of persistent AF.’ To test this hypothesis, we will use novel gene therapy
approaches developed in our lab, as well as a CLR-guided ablation strategy in patients with persistent AF. In
Specific Aim 1, we will assess in a canine rapid atrial pacing model of AF whether targeted inhibition of
parasympathetic signaling – by expression of plasmids expressing Gαi/o inhibitory peptides (Gαi/o_ct) at the
atrial sub-region with lowest CLR – will reverse electrical remodeling and AF. In Specific Aim 2, we will assess
in the same canine model whether targeted inhibition one or more of the two major sources of oxidative injury
in AF - by expression of NOX2 shRNA  mitochondrial catalase at the atrial sub-region with lowest CLR – will
reverse electrical remodeling, prevent progression of fibrosis and decrease AF. In Specific Aim 3, patients with
persistent AF who are undergoing catheter ablation will be randomized to a CLR guided ablation strategy or
PVI alone; we will determine whether in these patients a CLR guided ablation strategy will increase ECG
dominant frequency compared to PVI alone. Completion of all the aims will provide a clear path to using EMR
mapping as a new diagnostic method to guide therapeutic intervention for AF. This proposal leverages the
prior development and validation of EMR to test several novel targeted approaches for treating AF. As AF may
have complex underlying pathophysiology, it is feasible that one or more of these approac...

## Key facts

- **NIH application ID:** 10878744
- **Project number:** 5R01HL168117-02
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** JEFFREY J GOLDBERGER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $678,959
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10878744

## Citation

> US National Institutes of Health, RePORTER application 10878744, Pathophysiological Significance of Atrial Fibrillation Electrogram Patterns (5R01HL168117-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10878744. Licensed CC0.

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