Project Details
Description
Patients with obesity or diabetes have an increased risk of developing heart failure, arrhythmias, and sudden cardiac death, which is often caused by ventricular tachycardias. Cardiomyocytes from obese and diabetic patients have increased lipid accumulation, which is thought to contribute to the pathophysiology of heart failure and arrhythmia. Furthermore, higher levels of serum fatty acids and higher dietary saturated fat intake predict sudden cardiac death. This suggests that the pro-arrhythmic effects of saturated fat on the heart may be more important than obesity. An unanswered question is: What are the molecular mechanisms causing arrhythmias during cardiac lipid overload? The most common electrophysiologic abnormalities found in obese patients are increased frequency of ventricular ectopy and prolongation of the QT interval (LQT). Our prior work showed that wild type (WT) high-fat diet induced obese (DIO) mice have long QT and increased ventricular ectopy, similar to obese humans. We now show that high saturated fat intake is sufficient to rapidly cause heart rhythm abnormalities, before the onset of obesity. Further, mice fed a diet with an equivalent amount of the monounsaturated fat oleate (from olive oil) do not have heart rhythm abnormalities. The goal of this project is to identify the mechanisms by which saturated fat causes pro-arrhythmic abnormalities. Reactive oxygen species (ROS) are a likely mechanistic link between lipid metabolism and arrhythmia. To better understand the cellular biology of cardiac lipotoxicity, we performed a series of experiments with WT adult mouse ventricular myocytes (AMVM), loaded for several hours with the saturated fatty acid palmitate (PA) or oleate (the major fat in olive oil). PA, but not oleate, activates PKC and causes an increase in both total cellular ROS and mitochondrial ROS. Genetic deletion of NOX2 prevents PA-induced ROS in cardiomyocytes, demonstrating that NOX2 activation is required for amplification of mitochondrial ROS. The increase in ROS causes mitochondrial dysfunction and abnormal calcium homeostasis. To determine the importance of NOX2 in vivo, we treated mice with the NOX2 inhibitor apocynin during high saturated fat diet, and found that this prevents ventricular ectopy and LQT, supporting our model. Our central hypothesis is that NOX2 activation is necessary and sufficient to cause arrhythmia. Additional preliminary data indicates that toll-like receptor 4 (TLR4) is upstream of NOX2. (AHA Program: Grant-in-Aid)
Status | Finished |
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Effective start/end date | 7/1/16 → 2/1/18 |
Funding
- American Heart Association: US$154,000.00
ASJC Scopus Subject Areas
- Cardiology and Cardiovascular Medicine