Red Blood Cell Omega-3 Fatty Acids and Coronary Artery Disease

描述(由申请人提供)：关于omega-3脂肪酸(n-3FA)对心血管风险的影响的数据不一致。一些观察性研究和随机试验表明，n-3FA可能通过抗心律失常作用降低心脏性猝死(SCD)和冠状动脉事件的风险。相比之下，其他研究报告称，n-3FA可降低非致命性冠状动脉事件的风险，但不能降低致命性事件或SCD的风险。尽管动物研究一直证明n-3FA的抗心律失常作用，但在3项专门为评估n-3FA对植入型心律转复除颤器患者的抗心律失常效果而设计的随机临床试验中，只有一项显示了n-3FA的抗心律失常特性。此外，最近对其他随机试验的荟萃分析显示，长链或短链n-3FA对心血管疾病和全因死亡率的风险都没有明显的益处。尽管红细胞(RBC)中n-3FA与心肌细胞膜的相关性较高，但使用这一新技术评估n-3FA对冠状动脉疾病(CAD)、心血管(CVD)死亡或心肌梗死(MI)的影响的研究有限。鉴于目前的不一致之处，需要按照2005年关于n-3 FA的研讨会的建议，对关于CAD的n-3 FA进行额外研究。由于短链FA可以在体内转化为长链FA，而且许多常见的食品可以富含短链FA，因此基于这种强化食品的干预试验可能比补充剂试验具有更好的长期依从性。目前的应用将使用前瞻性、嵌套、病例对照设计来检查来自红细胞膜和饮食的短链和长链n-3脂肪酸是否与医生健康研究(PHS)中致命的CAD、CVD死亡和MI的风险较低相关。本项目将检验以下假设：(I)较高水平的RBC长链和短链n-3FA与较低的致命性CAD、CVD死亡和MI风险相关；(Ii)较高水平的RBC n-3FA与饮食n-3FA呈正相关；(Iii)与RBC n-3FA相反，较高的饮食n-3FA水平与较低的致命性CAD、CVD死亡和MI风险适度相关。主要目的是研究RBC长链n-3FA与致命性冠心病、心血管疾病死亡和心肌梗死风险之间的关系。第二个目标将评估RBC短链和饮食n-3FA对致命性冠心病、心血管死亡和心肌梗死风险的影响；以及饮食和RBC n-3FA之间的相关性。小灵通的几个特点使其成为回答这些重要问题的极好且经济高效的资源：1)在基线时收集了17,469名男性中的冷冻红细胞；2)系统地收集和验证了死亡率和冠状动脉终点的数据；3)我们收集了包括饮食因素在内的关键协变量的数据，以控制主要的混杂因素。这项拟议的研究将增加我们对n-3脂肪酸在冠心病中作用的了解，并将为未来的申请提供试点数据，以寻求资金进行更大规模的一级预防试验，以调查n-3强化食品对冠心病的有益影响。这项研究的结果可能有助于确定哪些n-3脂肪酸可以用于丰富食物，并可能导致显著改善冠心病的一级预防，这是公共卫生的当务之急。与公共健康相关：心脏病发作是美国主要的死亡原因之一。目前的项目将研究omega-3脂肪酸--一种多不饱和脂肪，主要存在于富含脂肪的鱼、亚麻籽或菜籽油中--是否可以降低参与维生素补充剂试验的美国男性医生发生致命冠状动脉事件、心血管死亡或心脏病发作的风险。这项研究的结果可能会提供重要的信息，可能会形成预防冠状动脉事件的饮食建议。

DESCRIPTION (provided by applicant): Data on the effects of omega-3 fatty acids (n-3 FA) on cardiovascular risk are inconsistent. Some observational studies and randomized trials have suggested that n-3 FA may lower the risk of sudden cardiac death (SCD) and coronary events, possibly through antiarrhythmic effects. In contrast, other studies have reported that n-3 FA reduce the risk of nonfatal coronary events but not fatal events or SCD. Although animal studies have consistently demonstrated antiarrhythmic effects of n-3 FA, only one of the 3 randomized clinical trials specifically designed to evaluate antiarrhythmic effects of n-3 FA supplements among patients with implantable cardioverter defibrillators showed antiarrhythmic properties of n-3 FA supplements. In addition, a recent meta-analysis of other randomized trials showed no clear benefit of either long-chain or short-chain n-3 FA on the risk of cardiovascular disease and all-cause mortality. While a higher correlation between n-3 FA in red blood cell (RBC) and cardiac cell membranes has been reported, limited studies have used this novel technique to assess the effects of n-3 FA on coronary artery disease (CAD) death, cardiovascular (CVD) death, or myocardial infarction (MI). Given the current inconsistencies, additional studies of n-3 FA on CAD are needed as recommended by the 2005 workshop on n-3 FA. Since short-chain FA can be converted into long-chain FA in vivo and many familiar food products can be enriched with short-chain FA, an intervention trial based on such enriched foods might have a better long-term compliance than a supplement trial. The current application will use a prospective, nested, case-control design to examine whether or not short-chain and long-chain n-3 FA from RBC membranes and from the diet are associated with a lower risk of fatal CAD, CVD death, and MI in the Physicians' Health Study (PHS). This project will test the following hypotheses: (i) higher levels of RBC long- and short-chain n-3 FA are associated with a lower risk of fatal CAD, CVD death, and MI; (ii) higher levels of RBC n-3 FA are positively correlated with dietary n-3 FA; (iii) contrary to RBC n-3 FA, higher levels of dietary n-3 FA are modestly associated with a lower risk of fatal CAD, CVD death, and MI. The primary aim is to examine the association between RBC long-chain n-3 FA on the risk of fatal CAD, CVD death, and MI. The secondary aim will assess the effects of RBC short-chain and dietary n-3 FA on the risk of fatal CAD, CVD death, and MI; and the correlation between dietary and RBC n-3 FA. Several features of the PHS make it an excellent and cost-effective resource to answer these important questions: 1) frozen red blood cells were collected among 17,469 men at baseline; 2) data on mortality and coronary endpoints are systematically collected and validated; 3) we have collected data on key covariates including dietary factors, to control for major confounding factors. The proposed study will increase our understanding on the role of n-3 FA on CAD and will provide pilot data to support a future application seeking funding for a larger primary prevention trial to investigate beneficial effects of n-3 enriched foods on CAD. The results of this study may help identify which n-3 FA could be used to enrich foods and may lead to significant improvement in primary prevention of CAD, which is a public health imperative. PUBLIC HEALTH RELEVANCE: Heart attack is one of the leading causes of deaths in the US. The current project will examine whether omega-3 fatty acids - a type of polyunsaturated fats found mostly in fatty fish, flaxseed or canola oils - can lower the risk of fatal coronary events, cardiovascular death, or heart attack among US male physicians who participated in a trial of vitamin supplements. Findings of this study may provide important information that could shape dietary recommendations to prevent coronary events.