# Molecular mechanisms of arrhythmia caused by high-fat diet

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $400,000

## Abstract

Obese patients have an increased risk of arrhythmias and twice the risk of sudden cardiac death, which
is often caused by ventricular tachycardias (VT). Cardiomyocytes from obese patients have increased lipid
content, which is thought to contribute to the pathophysiology of arrhythmia. Furthermore, higher levels of
serum fatty acids and higher saturated fat intake in the diet predict sudden cardiac death. This suggests that
the arrhythmogenic effects of saturated fat can occur without obesity. An unanswered question is: What are
the molecular mechanisms causing arrhythmias during obesity and high-fat diet?
 The most common electrophysiologic abnormalities found in obese patients are increased frequency of
ventricular ectopy and prolongation of the QT interval. We have previously shown that wild type (WT) mice with
high-fat diet induced obesity (DIO) have long QT and increased ventricular ectopy, mimicking the abnormalities
found in obese humans. Our preliminary data now show that a high saturated fat diet is sufficient to cause
ventricular ectopy and prolong the QT interval, and to promote inducibility of VT/VF. Further, mice fed a diet
with an equivalent amount of monounsaturated fat from olive oil do not have heart rhythm abnormalities. We
discovered that a high saturated fat diet increases cardiac NAPDH oxidase 2 (NOX2) activity, whereas the
olive oil high-fat diet does not. The NOX2 inhibitor apocynin, when given during a high saturated fat diet,
prevents heart rhythm abnormalities. Additional experiments with isolated cardiac myocytes show that NOX2 is
necessary for the oxidative stress and mitochondrial dysfunction caused by saturated fat. We will use both in
vivo experiments and cardiomyocytes to determine the pathways linking cardiac lipid metabolism to
arrhythmia. Our central hypothesis is that NOX2 activation causes the arrhythmogenic effect of saturated fat
by causing sarcoplasmic reticulum calcium leak, which in turn promotes mitochondrial dysfunction.
 We propose the following independent aims:
1. Determine if NOX2 activation causes arrhythmia during high fat diet, by using genetic gain and loss.
2. Determine how TLR4 signaling contributes to the arrhythmogenic effects of dietary saturated fat.
3. Determine if the mitochondrial abnormalities caused by NOX2 activation promote arrhythmia.

## Key facts

- **NIH application ID:** 10316166
- **Project number:** 5R01HL136758-05
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** John Pearce Morrow
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $400,000
- **Award type:** 5
- **Project period:** 2018-01-15 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10316166

## Citation

> US National Institutes of Health, RePORTER application 10316166, Molecular mechanisms of arrhythmia caused by high-fat diet (5R01HL136758-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10316166. Licensed CC0.

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