Dietary Omega-3 Fatty Acids and Sudden Cardiac Death

描述（由申请人提供）：流行病学研究、临床试验（心肌梗死患者）和动物研究表明，食用鱼类或富含鱼油（omega-3多不饱和脂肪酸，n-3 PUFA）补充剂的饮食可显著降低心源性猝死的发生率。然而，n-3 PUFA与心律失常风险降低之间关系的潜在机制仍有待确定。因此，我们建议使用成熟的致死性室性心律失常犬模型来研究n-3 PUFA的安全性和有效性。将在从这些动物心脏分离的心肌细胞中检查改变心脏电生理的机制。中心假设是，在心肌梗死后心源性猝死犬模型中，n-3 PUFA长期治疗可减弱导致心源性猝死的电生理异常。以下具体目标将用于检验该假设：具体目标#1将检验长期摄入n-3 PUFA补充剂将预防缺血诱导的快速性心律失常（通过预防折返性和/或触发性心律失常）的假设。具体目的#2和#3将分别研究长期施用n-3 PUFA对从狗心脏制备的心肌细胞的电生理学和钙调节的影响。具体而言，特定目标2将检验以下假设：n-3 PUFA将a）使肌膜离子电流正常化，改善心室肌细胞动作电位，和B）减少易患室颤犬的早期和延迟后去极化。最后，具体目标#3将检验以下假设：a）n-3 PUFA将阻断L型钙电流，减少钙进入，从而防止易患心室颤动的犬中钙超载诱导的自发钙释放; B）n-3 PUFA将改变兰尼定受体功能，恢复易患心室颤动的犬中更正常的肌浆网钙释放;和c）n-3 PUFA将改变肌浆网（SR）钙负荷，在易患心室纤维性颤动的狗中恢复更正常的SR钙负荷。该项目将检查心脏病发作后鱼油补充剂的安全性。该项目还将确定鱼油补充剂在减少心脏病发作后致命的心律异常导致的猝死方面的有效性。

DESCRIPTION (provided by applicant): Epidemiological studies, clinical trials (patients with myocardial infarction), and animal studies have demonstrated that fish consumption, or diets enriched with fish oil (omega-3 polyunsaturated fatty acids, n-3 PUFAs) supplements, significantly reduced the incidence of sudden cardiac death. However, the mechanisms underlying the relationship between n-3 PUFAs and a reduced risk for cardiac arrhythmias remain to be determined. Therefore, we propose to investigate the safety and efficacy of n-3 PUFAs using a well-established canine model of lethal ventricular arrhythmias. The mechanisms altering cardiac electrophysiology will be examined in cardiac myocytes isolated from the hearts of these animals. The central hypothesis is that chronic treatment with n-3 PUFAs attenuates the electrophysiological abnormalities contributing to sudden cardiac death in a post-myocardial infarction canine model of sudden cardiac death. The following specific aims will be used to test this hypothesis: Specific Aim #1 will test the hypothesis that the chronic ingestion of n-3 PUFA supplements will prevent ischemia-induced tachyarrhythmias (by preventing re-entrant and/or triggered arrhythmias). Specific Aims #2 and #3 will investigate the effects of the chronic administration of n-3 PUFAs on the electrophysiology and calcium regulation of cardiomyocytes prepared from the hearts of the dogs, respectively. In particular, Specific Aim 2 will test the following hypotheses: n-3 PUFAs will a) normalize the sarcolemmal ion currents improving the ventricular myocyte action potential and b) reduce both early and delayed afterdepolarizations in dogs susceptible to ventricular fibrillation. Finally, Specific Aim #3 will test the following hypotheses: a) n-3 PUFAs will block L-type calcium current reducing calcium entry and thereby preventing calcium overload-induced spontaneous calcium release in dogs susceptible to ventricular fibrillation; b) n-3 PUFAs will alter ryanodine receptor function, restoring a more normal sarcoplasmic reticular calcium release in dogs susceptible to ventricular fibrillation; and c) n-3 PUFAs will alter the sarcoplasmic reticular (SR) calcium load, restoring a more normal SR calcium load in the dogs susceptible to ventricular fibrillation. Lay summary: This project will examine the safety of fish oil supplements after a heart attack. This project will also determine the effectiveness of fish oil supplements in reducing sudden death due to a lethal abnormal heart rhythm after a heart attack.