Dietary Saturated Fat Promotes Arrhythmia by Activating NOX2 (NADPH Oxidase 2)

Abstract

Background: Obesity and diets high in saturated fat increase the risk of arrhythmias and sudden cardiac death. However, the molecular mechanisms are not well understood. We hypothesized that an increase in dietary saturated fat could lead to abnormalities of calcium homeostasis and heart rhythm by a NOX2 (NADPH oxidase 2)-dependent mechanism. Methods: We investigated this hypothesis by feeding mice high-fat diets. In vivo heart rhythm telemetry, optical mapping, and isolated cardiac myocyte imaging were used to quantify arrhythmias, repolarization, calcium transients, and intracellular calcium sparks. Results: We found that saturated fat activates NOX (NADPH oxidase), whereas polyunsaturated fat does not. The high saturated fat diet increased repolarization heterogeneity and ventricular tachycardia inducibility in perfused hearts. Pharmacological inhibition or genetic deletion of NOX2 prevented arrhythmogenic abnormalities in vivo during high statured fat diet and resulted in less inducible ventricular tachycardia. High saturated fat diet activates CaMK (Ca 2+ /calmodulin-dependent protein kinase) in the heart, which contributes to abnormal calcium handling, promoting arrhythmia. Conclusions: We conclude that NOX2 deletion or pharmacological inhibition prevents the arrhythmogenic effects of a high saturated fat diet, in part mediated by activation of CaMK. This work reveals a molecular mechanism linking cardiac metabolism to arrhythmia and suggests that NOX2 inhibitors could be a novel therapy for heart rhythm abnormalities caused by cardiac lipid overload.

NADPH Oxidase 2 Mediates Myocardial Oxygen Wasting in Obesity

“…Apocynin treatment and the ablation of NOX2 partly normalized superoxide derived EOH, but had no effect on ethidium, suggesting reduced NOX2 activity when compared to reduced NOX4 (which primarily produces H 2 O 2 ). Our results are also in line with previous data showing reduced cardiac NOX2 activity in diabetes and high fat feeding of mice following both the genetic ablation of NOX2 [8,44] and pharmacological treatment with NOX2-inhibitors [8,11].…”

“…While SHFD induced heart rhythm abnormalities in WT mice, this was absent in NOX2 KO hearts and following apocynin treatment. Additionally, the oxidation of the RYR2 promotes calcium leak and increased calcium sparks, which were also absent in NOX2 KO hearts from mice that were fed a SHFD [44]. Other studies have reported a negative impact of NOX2-derived superoxide following acute exposure to FA load [25] and in other types of heart failure [28].…”

“…Impaired calcium handling is well documented in diabetic hearts and includes altered sarcoplasmic reticulum Ca 2+ -ATPase2 (SERCa2) activity [48], elevated intracellular Ca 2+ -levels, and increased ryanodine receptor 2 (RyR2)-leakage [49]. Recently, Joseph et al [44] reported profound effects of a short-term saturated high fat diet (SHFD, 4 weeks) of mice on myocardial calcium handling before the development of both obesity and ventricular structural changes. While SHFD induced heart rhythm abnormalities in WT mice, this was absent in NOX2 KO hearts and following apocynin treatment.…”

Mechanisms of Chronic Metabolic Stress in Arrhythmias

“…Similar to PUFAs, monounsaturated fatty acids (MUFAs), such as oleic acid (the major component of olive oil), also result in better cardiovascular outcomes in comparison to saturated fats [ 26 ]. Consuming foods high in saturated fat increase risk of stroke, CVD, and SCD [ 23 , 27 ]. Trans fats, which are artificial and have been banned in several countries as food ingredients, further increase the risk of adverse cardiovascular events beyond that of saturated fat [ 28 ].…”

“…This substrate can lead to RIRR, as mentioned earlier, and may further cause heterogeneous repolarization of cardiac myocytes, a mechanism of arrhythmic propagation. In fact, we have previously shown via optical mapping that rodents fed a high-saturated-fat diet have significantly greater repolarization heterogeneity and increased action potential duration (APD) than mice fed standard chow [ 27 ]. This could contribute to sustained arrhythmias.…”