# Novel Pathophysiological Targets in Atrial Fibrillation Susceptibility

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $476,112

## Abstract

SUMMARY
 Atrial fibrillation (AF) is the most common cardiac arrhythmia of clinical significance, and it often results in
devastating outcomes. Because current treatment is frequently ineffective, there is a critical need for an
improved understanding of the mechanisms causing AF and novel strategies to treat it. Abundant evidence has
linked oxidative stress to the pathogenesis and progression of AF, yet upstream therapy to target these
processes has been ineffective. Lipid aldehydes are a major component of oxidative stress-related injury, and
the most reactive products generated, isolevuglandins (IsoLGs), react almost instantaneously with proteins to
cause dysfunction. Dicarbonyl scavengers have been developed that preemptively bind IsoLGs before they
can interact with biologic targets. Using these tools, IsoLGs were recently identified as critical mediators in
angiotensin II-mediated hypertension and Alzheimer's disease. Diseases of oxidative stress are also linked to
proteotoxicity, or cellular dysfunction caused by misfolded proteins. In amyloid diseases like Alzheimer's,
preamyloid oligomers (PAOs) are now recognized to be the primary cytotoxic species that correlates with
disease progression. Notably, IsoLGs markedly accelerate PAO formation for amyloidogenic proteins. Based
on our preliminary data, the goal of this proposal is to test the hypotheses that both IsoLGs and PAOs are
biologically-relevant mediators that promote AF susceptibility, making them potential therapeutic targets.
 We have acquired compelling preliminary data to support the concept that IsoLGs and PAOs are drivers of
the AF substrate: PAOs are commonly detected in human atrium, with the fibrillogenic protein atrial natriuretic
peptide (ANP) a major component, and they associate with hypertension; IsoLGs and PAOs are formed in
cellular and in vivo models associated with AF susceptibility, including rapidly-stimulated atrial cells,
hypertension, obesity, and familial AF; and there is a beneficial effect of scavenging IsoLGs to reduce atrial
PAO and AF burden. Moreover, a mutant form of ANP linked to familial AF markedly enhances the formation
of cytotoxic ANP oligomers, and these PAOs accumulate in the atria of mice modeling the human disease. The
first Aim will test the hypothesis that in hypertension and obesity, oxidative stress-mediated IsoLGs promote
atrial cell injury and AF susceptibility. Aim 2 will test the hypothesis that mutant ANP oligomers alter atrial
myocyte homeostasis to generate AF susceptibility, and they promote oxidative stress/IsoLG formation that
can feed-forward to perpetuate the pathologic process. Finally, Aim 3 will test the hypothesis that in addition to
hypertension, other AF risk factors linked to oxidative stress are also associated with accumulation of IsoLGs
and/or cytotoxic PAOs, supporting their role in human disease. The proposed studies have major significance,
given that IsoLG and PAOs may provide not only common mechanistic links be...

## Key facts

- **NIH application ID:** 9921464
- **Project number:** 5R01HL133127-04
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** KATHERINE T MURRAY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $476,112
- **Award type:** 5
- **Project period:** 2017-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9921464

## Citation

> US National Institutes of Health, RePORTER application 9921464, Novel Pathophysiological Targets in Atrial Fibrillation Susceptibility (5R01HL133127-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9921464. Licensed CC0.

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