Molecular mechanisms of arrhythmia caused by high-fat diet

肥胖患者发生心律失常的风险增加，心脏性猝死的风险增加一倍。 通常由室性心动过速(VT)引起。肥胖症患者的心肌细胞血脂增加 内容，这被认为有助于心律失常的病理生理学。此外，更高水平的 血清脂肪酸和饮食中较高的饱和脂肪摄入量预示着心源性猝死。这表明 饱和脂肪的心律失常效应可以在没有肥胖的情况下发生。一个悬而未决的问题是： 肥胖和高脂饮食导致心律失常的分子机制？ 肥胖症患者最常见的电生理异常是 室性异位和QT间期延长。我们之前已经证明，野生型(WT)小鼠具有 高脂饮食诱导的肥胖(DIO)具有较长的QT间期和增加的室壁异位，与上述异常相似 在肥胖的人类身上发现。我们的初步数据现在表明，高饱和脂肪饮食足以导致 室性异位，延长QT间期，促进VT/VF的诱发。此外，喂食饮食的小鼠 如果橄榄油中含有等量的单不饱和脂肪，则不会出现心律失常。我们 研究发现，高饱和脂肪饮食会增加心脏NAPDH氧化酶2(NOX2)的活性，而 橄榄油不是高脂肪饮食。NOX2抑制剂apocynin在高饱和脂肪饮食中服用时， 防止心律失常。对分离的心肌细胞的进一步实验表明，NOX2是 对于饱和脂肪引起的氧化应激和线粒体功能障碍来说是必要的。我们将在 活体实验和心肌细胞确定将心脏脂肪代谢与 心律不齐。我们的中心假设是NOX2的激活导致饱和脂肪的心律失常效应 通过导致肌浆网钙泄漏，进而促进线粒体功能障碍。 我们提出以下独立目标： 1.通过遗传得失来确定在高脂肪饮食中，NOX2的激活是否会导致心律失常。 2.确定TLR4信号在饮食饱和脂肪致心律失常中的作用。 3.确定NOX2激活引起的线粒体异常是否促进心律失常。

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.