# Mechanisms of Lipotoxic Arrhythmias

> **NIH NIH R01** · MASONIC MEDICAL RESEARCH LABORATORY, INC · 2020 · $437,500

## Abstract

Project Summary/Abstract:
High-fat diet induced lipotoxicity is an epidemic that poses a significant public health problem with over one-third
of the world population being either overweight or obese, and is associated with arrhythmias. While lipotoxicity
has been linked to atrial fibrillation (AF) in patients and in animal disease models, little is known about the
underlying molecular pathways for dysregulation. We propose that a critical contributor to lipotoxic atrial disease
involves pathological dysregulation of the delayed rectifier K current IK composed of the rapidly (IKr) and slowly
activating (IKs) components, both of which are critical for cardiac repolarization. In ventricles, pathological
decreases in pore-forming subunits of IKr (hERG) and IKs (KCNQ1) have been linked by our group and others to
arrythmogenic IKr and IKs currents. We recently discovered for the first time that IK currents are upregulated in
obese guinea pigs atria contribute prominently to enhanced action potential repolarization. We also found that
palmitic acid abbreviated action potential duration and increased IKr and IKs densities; while oleic acid prolonged
action potential duration, and severely reduced IKr but had no effect on IKs. Our new preliminary data indicate
that these guinea pigs exhibit lipotoxicity with no signs of hyperglycemia or inflammation. Furthermore,
intracardiac injection of palmitic acid increased IK density and vulnerability to spontaneous atrial arrhythmias in
guinea pigs as early as 5 weeks of age. We now propose to use this unique model to more comprehensively
define the molecular mechanisms of arrhythmogenesis, to explore whether altered functional expression of IKr
and IKs contributes to the pathogenesis and maintenance of AF, and whether targeting altered IK channel
function could be an effective treatment for AF. Three specific aims are proposed: Aim 1: To examine the
downstream pathways by which lipotoxicity increases IK channel function. We will test, using genetic and
pharmacological approaches, whether increased IKr and IKs functional expression is involved in the remodeling
of the myocardium in response to lipotoxicity and whether activators of AMPK and inhibitors of PI3K
downstream pathways can normalize IK channel functional expression. Aim 2: To test the causal link between
increased IK and susceptibility to AF in lipotoxic heart. We will utilize genetic and pharmacological interventions
to see whether IK plays a role in AF and whether it may be a novel therapeutic target. Aim 3: To test
therapeutically the causal link between PP2A activation, selective downregulation of IKr and prevention of AF in
lipotoxicity. The proposed studies may identify important links between dysfunctional IKr and IKs channels,
defective lipid-dependent signaling pathways in AF, and protein kinase-phosphatase dysfunction. Our proposed
comprehensive studies are designed to provide rigorous and robust hypothesis driven testing to reveal new
understa...

## Key facts

- **NIH application ID:** 10119665
- **Project number:** 7R01HL147044-02
- **Recipient organization:** MASONIC MEDICAL RESEARCH LABORATORY, INC
- **Principal Investigator:** Ademuyiwa Aromolaran
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $437,500
- **Award type:** 7
- **Project period:** 2019-05-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10119665

## Citation

> US National Institutes of Health, RePORTER application 10119665, Mechanisms of Lipotoxic Arrhythmias (7R01HL147044-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10119665. Licensed CC0.

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