Molecular mechanisms of anti- & pro-arrhythmic effects of fish oil supplement

描述（由申请人提供）：许多临床试验表明，摄入鱼类或补充鱼油可以保护心肌梗死后患者免受心源性猝死（抗心律失常作用）。然而，也有迹象表明鱼油可能具有促心律失常的作用（增加一些植入式心律转复/除颤器患者的VT/VF复发，增加心绞痛患者的死亡率）。后一种情况提供了一个强烈的警告信号：鱼油可能不适合某些患者。需要对鱼油补充剂的生物活性进行更多的机理研究。特别是，我们需要更多地了解长链n-3多不饱和脂肪酸（n-3 PUFAs，鱼油中的有效成分）慢性治疗对心脏电活动的影响。本项目旨在研究鱼油补充剂抗心律失常和可能的促心律失常作用的机制。我们相信可以从大型动物（狗）模型中获得相关信息，该模型关注疾病状况，模仿临床情况，其中鱼油补充剂已被证明具有抗心律失常的功效。此外，我们认为这样的研究应该包括急性应用n-3 PUFAs和慢性治疗，因为两者都有助于临床结果。我们将测试以下一般假设：慢性鱼油补充剂通过改变“易损因素”（易损因素源于梗死心脏中促进心律失常的电和结构重塑过程）在梗死心脏中产生抗心律失常作用，而当Na通道功能和细胞间偶联已经受损时，n-3 PUFAs的急性效应可能会促进患病心脏的心律失常。我们提出了三个具体目标来验证上述假设：目标1和目标2将分别确定鱼油补充剂对正常狗心脏和患有慢性缺血性心肌病（ICM）的狗心脏的电和结构特性的急性和慢性影响。目的3将确定慢性鱼油补充剂改变患有慢性ICM的狗心脏“易损因素”的机制。这个项目的意义在于，我们采用了新的概念和新的方法来解决一个看似“古老”的问题——为什么鱼油补充剂可以提供心脏保护？在此过程中，我们还将解决一个新的问题：在什么条件下鱼油补充剂会导致促心律失常的效果？项目描述：这是基础科学家和心脏病学家之间的合作，用新概念和新方法解决一个“老”问题。这个项目的信息将帮助医生向冠心病患者推荐鱼油补充剂。

DESCRIPTION (provided by applicant): Many clinical trials have suggested that fish intake or fish oil supplement can protect post-myocardial infarction patients against sudden cardiac death (anti-arrhythmic effects). However, there is also indication suggesting that fish oil may have pro-arrhythmic effects (increasing the recurrence of VT/VF in some patients with implantable cardioverter/defibrillator, and increasing the mortality in angina patients). The latter cases provide a strong warning sign: fish oil may not be suitable for certain patients. More mechanistic studies into the biological activity of fish oil supplement are needed. In particular, we need to know more about the effects of chronic treatment with long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs, active ingredients in fish oil) on cardiac electrical activity. This project is designed to study the mechanisms for the anti-arrhythmic and possible pro-arrhythmic effects of fish oil supplement. We believe relevant information can be obtained from a large animal (dog) model, focusing on diseased conditions that mimic the clinical situation in which fish oil supplement has been shown to provide an anti-arrhythmic efficacy. Furthermore, we believe such studies should include both acute application of n-3 PUFAs and chronic treatment, because both contribute to the clinical outcomes. We will test the following general hypothesis: chronic fish oil supplement produces anti- arrhythmic effects in infarcted hearts by modifying 'vulnerability factors' (vulnerability factors result from electrical and structural remodeling processes in infarcted hearts that promote arrhythmia), while acute effects of n-3 PUFAs can be pro-arrhythmic in diseased hearts when Na channel function and intercellular coupling are already compromised. Three Specific Aims are proposed to test the above hypothesis: Aims 1 & 2 will determine acute and chronic effects of fish oil supplement on the electrical and structural properties of normal dog hearts and dog hearts suffering from chronic ischemic cardiomyopathy (ICM), respectively. Aim 3 will determine the mechanism by which chronic fish oil supplement modifies 'vulnerability factors' in dog heart suffering from chronic ICM. The significance of this project derives from the new concepts and new approaches we take to address a seemingly 'old' question - why can fish oil supplement provide cardiac protection? Along the way, we will also address the new question: under what conditions can fish oil supplement lead to pro-arrhythmic effects? PROJECT NARRATIVE: This is a collaboration between basic scientists and cardiologists to address an 'old' question with new concepts and new approaches. Information from this project will help physicians make recommendation of fish oil supplement to coronary heart disease patients.