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

描述(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于心源性猝死(抗心律失常效果)。然而，也有迹象表明，鱼油可能具有促心律失常的作用(增加一些植入心脏复律/除颤器的患者VT/VF的复发，并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期使用长链n-3多不饱和脂肪酸(n-3多不饱和脂肪酸，鱼油中的有效成分)对心脏电活动的影响。本项目旨在研究鱼油补充剂的抗心律失常和可能的促心律失常作用的机制。我们认为，相关信息可以从大型动物(狗)模型中获得，重点是模拟鱼油补充剂具有抗心律失常功效的临床情况的疾病情况。此外，我们认为这样的研究应该包括n-3多不饱和脂肪酸的急性应用和慢性治疗，因为两者都有助于临床结果。我们将检验以下一般性假设：慢性鱼油补充剂通过修改“易损性因子”(易损性因子是由促进心律失常的梗塞心脏的电和结构重构过程产生的)在梗塞心脏中产生抗心律失常的作用，而当钠通道功能和细胞间偶联已经受损时，n-3PUFAs的急性作用在患病的心脏中可能是促心律失常的。提出了三个特定的目标来验证上述假设：目标1和目标2将分别确定补充鱼油对正常和慢性缺血性心肌病(ICM)犬心脏的电和结构特性的急性和慢性影响。目的3将确定慢性补充鱼油改变慢性ICM犬心脏“易损因子”的机制。这个项目的意义来自于我们采取的新概念和新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，我们还将解决新的问题：在什么条件下补充鱼油可以导致促心律失常的作用？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。该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.