ω-3型多不饱和脂肪酸预防猝死的研究进展

摘要：猝死是威胁人类的严重病症。早已发现食用海鱼或鱼油制剂可能有预防猝死的效应，为确定其效应，近40年来进行了大量的研究，至今未达共识。本文对其研究概况作简要的介绍，以供参考。

关键词：多不饱和脂肪酸；猝死；研究进展

中图分类号：R972+.9文献标识码：A文章编号：1672-979X(2008)07-0001-04

Progress on ω-3 Polyunsaturated Fatty Acids in Prevention of Sudden Death

WU Bao-jie

(Institute of Pharmacology, School of Medicine, Shandong University, Jinan 250012, China)

Abstract：Sudden death is a serious disease and does great harm to human beings. It is found long before that sea fishes and fish oil preparations orally may prevent sudden death. And in order to verify this effect, lots of studies have been done in recent forty years, but there is no consensus up to now. In this paper, the overview on ω-3 polyunsaturated fatty acids in prevention of sudden death is briefly introduced for reference.

Key words：polyunsaturated fatty acid; sudden death; progress

1猝死的威胁

猝死（sudden death）为意外的非创伤性突然死亡，多发生于心脏病患者，称为心脏性猝死（cardiac sudden death，CSD）；但是也发生于平素健康的青壮年甚至运动健将。由于发病急、难于及时救治，多迅速死亡。可谓防不胜防，令人闻之惊恐，形成心理上的阴影和畏惧。美国每年约有22万患者在1 h内死亡，甚至来不及赶到医院。我国每年约55万人发生猝死。如何防治猝死，是国际性的一大难题。如果在日常生活中调整饮食有效，将是预防猝死的理想方式。

2寻求预防

1978年Dyerberg等报告格陵兰爱斯基摩人的心血管病发病率和死亡率较低，调查分析认为与食用富含ω-3型多不饱和脂肪酸（ω-3 FAs）的海鱼和海生动物有关，此报告受到高度的重视。现已基本明确，ω-3 FAs对人体的发育、生理功能及病理过程等有广泛的影响[1]。有大量报道称ω-3 FAs对猝死有预防效应，显现了预防猝死的曙光。40年来对此进行了大量的研究，但是至今未得到广泛的共识。

3人体必需的脂肪酸

ω-3 FAs主要包括二十碳五烯酸（eicosapentaenoic acid，EPA）、二十二碳六烯酸 （docosahexaenoic acid，DHA）和α-亚麻酸（α-linolenic acid，ALA）。前两者主要来源于海鱼等海生动物，后者存在于某些植物油中。

另外，许多植物油中含有的大量花生四烯酸（arachidonic acid，AA）是ω-6型多不饱和脂肪酸（ω-6 FAs），与ω-3 FAs同为人体必需的脂肪酸，人体不能合成或合成偏少，只能靠饮食供应。

一般以进食富含ω-3 FAs的海鱼，或服用含较高浓度ω-3 FAs的鱼油制品或乙酯型制剂来补充ω-3 FAs。最近又有制成乳剂供注射用的报道。

4预防猝死的研究

大量的流行病学调查和临床实验报道，食海鱼或补充鱼油ω-3 FAs制剂，能有效的预防猝死。有报道[2]，对20 551名健康男性医生长达17年的前瞻性对照分析表明，食用鱼油制品者，以猝死为首发事件的心血管病发病明显减少，其血脂中ω-3 FAs的基线水平与猝死的危险性呈负相关。还有报道[3]，对近期曾发生过心肌梗死的2 033例患者进行随机多因素食物干扰二级预防实验，随访2年。在各组心脏缺血事件的发生率和血清总胆固醇水平都无显著性改变的情况下，鱼油组的死亡率下降29%。Erkkila等[4]对285例男性和130例女性患者随访5年，证明用ω-3 FAs者，血清脂质含ω-3 FAs浓度高者的死亡危险性明显降低。Singh等[5]对360例心肌梗死的患者，随机分组用安慰剂、鱼油（每日EPA + DHA 2 g）和芥子油（mustard seed oil，29 g/d）观测实验。结果鱼油组猝死发生率为11.2 %，安慰剂组为22.0 %

更有GISSI-Prevenzione大规模二级前瞻性临床实验[6]，将新近发生过心肌梗死的11 324例患者随机分为每日鱼油1.0 g（含EPA+DHA 850 mg）、维生素E （300 mg）、 鱼油＋维生素E和安慰剂对照4个组，经3.5年随访，结果在血浆胆固醇无明显改变的情况下，鱼油组猝死减少45 %。并认为与其抗心律失常有关[7]。至2002年再次分析[8-10]表明，服用ω-3 FAs较服用他汀类呈现的生存曲线改善较早，3个月时鱼油组降低猝死危险即接近显著性，第4个月猝死的相对危险性明显降低。

Mozaffarian等[11]观察ω-3 FAs对心电图参数的影响, 证实ω-3 FAs能改善导致心律失常的危险指标，减慢心率，改善房室传导和缩短QTc的延长等。表明ω-3 FAs用于初级及二级预防都可降低猝死的危险性，似与调血脂无直接关系，却与其在血浆中的浓度和抗心律失常有关。

最近Wang等[12]根据大量报道资料综合分析了食用鱼和ω-3 FAs与心血管病的关系，按不同情况分门别类进行系统评价。证明除ALA外，ω-3 FAs确能减少心血管病总死亡率和猝死，且二级预防强于初级预防。实际上，也有关于ALA预防猝死的报道[13,14]。但是同年Hooper等[15]根据48项随机对照研究和41项群组研究的资料，对ω-3 FAs的有效性进行系统评价，得出ω-3 FAs对心血管病等无效的结论, 博得广泛的关注，正在进一步评论和探讨中。

5有效机制的研究

虽然存在着不同的观点，但是大部分研究者倾向预防有效的看法，并对ω-3 FAs抗猝死的机制进行了深入的研究。猝死的原因复杂，ω-3 FAs的作用又是多方面，如调血脂、抗血栓、抗炎、保护动脉内皮、稳定斑块、阻滞急性冠脉综合征发作等。目前认为抗心律失常是关键环节。抗心律失常，阻滞心律失常恶化，保护心脏功能，是ω-3 FAs预防猝死的主要途径。

离体兔心灌注实验已证明，ω-3 FAs能提高发生心律失常的阈值[16]。用多种病理模型证明了ω-3 FAS能预防心室颤动[17-20]。进一步发现心肌细胞膜磷脂中ω-3 FAs含量和ω-3 FAs/ω-6 FAs的比值与心室颤动及猝死密切相关[21-24]。

心肌细胞培养实验证明，提高培养液的Ca2+ 浓度或加用哇巴因等致心律失常物质所引起的心律失常，可因加入ω-3 FAs而消失；若将ω-3 FAs洗除，心律失常可再度发生。推断认为，ω-3 FAs是以游离脂肪酸的形式融附于细胞浆膜磷脂易感应的疏水性侧面，以负电荷脂肪酸发挥作用。酯化的ω-3 FAs不能直接生效。口服的ω-3 FAs可能参与磷脂的组成，逐渐释放游离ω-3 FAs发挥效应[25]。

Kang等[26,27]的研究表明，ω-3 FAs抗心律失常是通过调整浆膜电位和离子通透性，降低Na＋电流、缩短动作电位、改变兴奋阈值和延长相对不应期。用膜片钳于全细胞证明，游离ω-3 FAs能灵活地进入心脏细胞膜Na+ 通道α-亚单位（hH1幔种a+ 电流，延长恢复期。hH1α1-区6段（D1-S6）406位的天冬氨酸是关键部位。Xiao 等[28,29] 的实验表明，ω-3 FAs作为抗心律失常药，在整体正常和Ca2+超负荷细胞中主要是阻断电压门控L-型Ca2+电流，减少Ca2+ 进入。最近Xiao 等[30,31]实验证明，ω-3 FAs对电压依赖性K+ 通道也有一定的影响，对短暂性外向钾电流和延迟整流钾电流作用较弱，从而对保持正常静息膜电位的内向整流基本没有影响。

肾上腺素β受体过度兴奋是导致心律失常的因素之一。它通过一系列酶促反应，特别是腺苷酸环化酶（AC）活性增强，增加L-Ca2+ 通道和Na+通道的通透性，促使异常自律形成；同时降低K+电导性抑制外向电流，使4相自动除极加快，提高心室自律性。实验证明ω-3 FAs能抑制AC，控制β受体的过度兴奋[32]。

有学者[8]认为，病理状态下心肌缺血区中心细胞缺乏ATP，Na+、K+-ATP酶功能紊乱，缺血区间质K+ 浓度升高，而周围细胞仅部分除极，静息膜电位降低，接近阈电位，易被激活，心电周期的脆弱和组织传导途径的非均匀性，易致折返性传导。ω-3 FAs的作用在于使Na+通道的可激活性降低，部分除极的心肌细胞不易引起动作电位，从而化解潜在的心律失常。

还有研究认为[33,34]，心肌缺血再灌注可能激活纤维膜的Na+/H+交换体，使细胞内Na+浓度升高，导致细胞内Ca2+超负荷，引起心律失常；ω-3 FAs能抑制Na+/H+交换。还有资料进一步证明，ω-3 FAs降低心肌细胞Ca2+和对去甲肾上腺素的反应。

随着研究的深入，最近关于ω-3 FAs和人体心律失常的关系出现了某些新异的报道[35,36]。Geelen等[37]报道ω-3 FAs对正常人体心电指标没有影响。Brouwer等[38]报道，对于室性心律失常而带有植入式心脏除颤器（ICD）的患者，ω-3 FAs无抗室性心律失常的作用。Coronel 等[39]则认为ω-3 FAs既能抗心律失常又能促进心律失常。Sakabe 等[40]证明ω-3 FAs可预防心力衰竭患者的房颤，对重构性房速无效；并认为可能与抑制分裂-活化的蛋白激酶有关。Laurent 等[41]用新型起搏模型实验证明，ω-3 FAs减少房颤易损性, 其机制可能与减弱胶原转化有关。这些报道将ω-3 FAs与心律失常的关系推向了更复杂、深入和细致的境地。究竟ω-3 FAs是否抗心律失常？抗何种心律失常？抗心律失常是否是预防猝死的主要原因？仍然是难以回答的问题。

6瞻望

鱼油和ω-3 FAs制剂预防猝死是个可喜的发现，近40年来对其来源、效能和作用机制进行了大量的探讨性研究，取得了许多可贵的资料，增加了希望和信心。但是也发现了某些新问题和一定的分歧，有待进一步更细致和深入地探讨，进一步探明矛盾的所在，以便彻底认清这颗有希望的明珠。

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