藍(lán)云鋒，李 泱

（1解放軍總醫(yī)院海南分院保健科，三亞 572000；2解放軍總醫(yī)院老年心血管病研究所，北京 100853）

n-3多不飽和脂肪酸（omega-3 polyunsaturated fatty acids，n-3PUFAs）包括二十碳五烯酸（eicosapentaenoic acid，EPA）、二十二碳六烯酸（docosahexaenoic acid，DHA）和α-亞麻酸(alpha-linolenic acid，ALA)，被認(rèn)為是人體的必需脂肪酸[1]，具有廣泛的抗心律失常作用。從目前有限的研究結(jié)果表明，n-3PUFAs各個(gè)成分抗心律失常作用的大小關(guān)系為DHA≥EPA＞ALA[2]，但越來越多的研究表明，n-3PUFAs有抗心律失常及致心律失常的雙重作用[2]。本文通過分析n-3PUFAs抗心律失常作用及其機(jī)制的多樣性，闡明n-3PUFAs在抗心律失常方面具有兩面性。

1 n-3PUFAs具有抗心律失常作用

n-3PUFAs在保護(hù)心血管作用過程中發(fā)揮多種作用，降低心率[3,4]及心率變異性[5]，減少惡性心律失常及心房顫動(dòng)（簡稱：房顫）[6]發(fā)生，預(yù)防心源性猝死[7]（sudden cardiac death，SCD）。

1.1 減少室性心律失常發(fā)生，預(yù)防SCD

流行病學(xué)調(diào)查表明，紅細(xì)胞膜上n-3PUFAs水平比例超過總脂肪酸的5%則心源性猝死風(fēng)險(xiǎn)減少75%。n-3PUFAs能使心肌梗死后人群的猝死率降低達(dá)45%[12]，能降低無心血管疾病的男性冠心病和SCD發(fā)生的風(fēng)險(xiǎn)[13]，減少急性心肌梗死患者室性心律失常的發(fā)生，特別是ALA上述作用更明顯，而DHA＋EPA的效果則不明顯（P＝0.06）[14]。動(dòng)物實(shí)驗(yàn)表明，n-3PUFAs能減少各種病因（急性心肌梗死[15]、心肌梗死后[16]、缺血-再灌注等）誘發(fā)的室性心律失常，也能提高室顫閾值或直接減少室顫發(fā)生。

1.2 預(yù)防房顫

n-3PUFAs可減少房顫發(fā)生率，降低全因死亡率及減少心肌梗死后房顫的發(fā)生率，可預(yù)防消融術(shù)后房顫的復(fù)發(fā)，也能降低持續(xù)性房顫的復(fù)發(fā)[18]和血液透析患者的房顫發(fā)生率[19]，減輕心力衰竭房顫導(dǎo)致的心房纖維化及心房傳導(dǎo)異常，縮短房顫的持續(xù)時(shí)間[20]，DHA還能降低房顫敏感性而EPA不能[21]。動(dòng)物房顫模型研究發(fā)現(xiàn)[22,20]，n-3PUFAs對(duì)持續(xù)性房顫有治療作用，也能減輕炎癥反應(yīng)，但需在電生理或組織重構(gòu)發(fā)生之前給予干預(yù)才有益于治療或預(yù)防房顫復(fù)發(fā)[23]。

2 n-3PUFAs的抗心律失常作用尚存在不確定性

n-3PUFAs雖然在抗心律失常方面有驚人表現(xiàn)，但也存在不一致的結(jié)果。在預(yù)防室性心律失常及SCD方面，Hu等[24,25]對(duì)84 688名冠心病女性志愿者進(jìn)行長達(dá)16年的隨訪調(diào)查發(fā)現(xiàn)，長期服用n-3PUFAs與預(yù)防SCD無相關(guān)性，也不能降低糖尿病女性SCD的發(fā)生率，也不能減少糖代謝異常人群的總體病死率及心血管病死率[26]，還可能增加心肌梗死后心肌細(xì)胞的舒張性鈣波而誘發(fā)室性心律失常[27]。研究植入除顫器及心力衰竭患者發(fā)現(xiàn)，n-3PUFAs與其室性心律失常的發(fā)生率無相關(guān)性[28]，甚至可能增加其室性心律失常的發(fā)生[29,30]。因此，n-3PUFAs減少室性心律失常及預(yù)防SCD的有效性及安全性尚需進(jìn)一步明確[2]。在預(yù)防房顫方面也有很多不一樣的結(jié)果。Gronroos等[31]對(duì)14 222人（其中房顫1604人）進(jìn)行長達(dá)17.6年的隨訪發(fā)現(xiàn)，不論直接食用海魚或DHA＋EPA，還是靜脈給予DHA＋EPA，均與房顫發(fā)生率無相關(guān)性，高水平的血清EPA[32]或組織EPA[33]可能增加房顫發(fā)生風(fēng)險(xiǎn)。單中心或多中心雙盲對(duì)照試驗(yàn)研究結(jié)果表明，n-3PUFAs不能減少冠狀動(dòng)脈旁路移植術(shù)后房顫的發(fā)生[34?38]，兩者呈U型關(guān)系，當(dāng)DHA水平太高或太低均能促進(jìn)術(shù)后房顫的發(fā)生[39]。

n-3PUFAs抗心律失常作用的不確定性還表現(xiàn)在，不同病因或動(dòng)物的效果卻不盡相同，甚至相反。研究缺血-再灌注大鼠模型發(fā)現(xiàn)，喂食n-3PUFAs 3個(gè)月后，心室顫動(dòng)（簡稱室顫）的發(fā)生明顯減少。但研究犬心肌梗死模型卻發(fā)現(xiàn)，急性靜脈給予EPA或DHA能減少致死性心律失常[40]，而長期給予n-3PUFAs在體研究未發(fā)現(xiàn)可以減少室顫發(fā)生，對(duì)照組和實(shí)驗(yàn)組室顫發(fā)生比例分別為9/17和22/45；細(xì)胞水平則發(fā)現(xiàn)，心肌細(xì)胞鈣火花、舒張性鈣波增多而可能促進(jìn)室性心律失常發(fā)生[27]。在治療不同病因所致的房顫方面，n-3PUFAs的表現(xiàn)也不盡如人意[31?39]，n-3PUFAs對(duì)陣發(fā)性房顫、電除顫復(fù)律的房顫復(fù)發(fā)無治療作用[41,42]，而且也不能改善陣發(fā)性房顫的炎癥反應(yīng)。另外，n-3PUFAs抗心律失常作用的不確定性還表現(xiàn)在不同干預(yù)方式效果也不一樣，不僅整體動(dòng)物水平不一樣，還表現(xiàn)在細(xì)胞水平各種電流及鈣穩(wěn)態(tài)方面。

3 n-3PUFAs抗心律失常作用機(jī)制的多樣性

n-3PUFAs幾乎對(duì)所有心臟離子通道或離子泵都有不同程度的影響，其中，對(duì)Na+、Ca2+電流影響最敏感[43]。目前研究發(fā)現(xiàn)，急性和慢性給予n-3PUFAs進(jìn)行生理性干預(yù)所引起的電生理作用機(jī)制會(huì)有所不同，甚至截然相反[2]。

3.1 動(dòng)作電位時(shí)程、膜興奮性及傳導(dǎo)的影響[44]

研究新生大鼠心室肌細(xì)胞發(fā)現(xiàn)，給予EPA（10μmmol/L）急性干預(yù)能縮短動(dòng)作電位時(shí)程（action potential duration，APD），而成年大鼠心室肌細(xì)胞，給予低濃度n-3PUFAs（＜10μmol/L）時(shí)，APD隨濃度增加而逐漸延長，高濃度n-3PUFAs（10～20μmol/L）急性處理APD則出現(xiàn)縮短，而在相同條件下研究豚鼠，2～20μmol/L n-3PUFAs使APD隨濃度增加逐漸縮短。不同動(dòng)物或不同發(fā)育階段，相同干預(yù)方式結(jié)果不盡相同。長期給予n-3PUFAs進(jìn)行干預(yù)，豬心肌細(xì)胞APD也縮短。兔長期喂食ALA后QT間期縮短，而直接用含ALA＋EPA（1～20μmol/L）的灌流液對(duì)離體心臟進(jìn)行灌注，QT間期則延長。用EPA＋DHA（5～10μmol/L）急性處理單個(gè)心肌細(xì)胞可延長相對(duì)不應(yīng)期，而表現(xiàn)出心肌細(xì)胞膜興奮性降低。給予EPA＋DHA（1～20μmol/L）急性處理兔離體心臟也發(fā)現(xiàn)，誘發(fā)室性期前收縮的閾值增加，且隨著濃度增加而增加，縱向和橫向傳導(dǎo)速率均發(fā)生降低。而給予長期喂食n-3PUFAs后發(fā)現(xiàn)，豬心室肌細(xì)胞興奮性及傳導(dǎo)速度均無改變。因此，n-3PUFAs延長或縮短APD，取決于不同種屬的動(dòng)物、動(dòng)物發(fā)育階段及干預(yù)方式（含給藥時(shí)間長短及濃度）。n-3PUFAs急性干預(yù)能降低膜興奮性及傳導(dǎo)速率，而長期慢性攝入對(duì)上述兩者則無影響。

3.2 離子電流的影響

通過全細(xì)胞膜片鉗技術(shù)發(fā)現(xiàn)，n-3PUFAs使鈉通道的失活閾值左移，降低細(xì)胞的興奮性，減弱晚鈉電流[45]，通過抑制ICa-L通道及鈉鈣交換體減少鈣離子內(nèi)流，也相應(yīng)地減少瞬時(shí)鈣電流所引起的去極化振幅，抑制Ito，Ikr及Ikur鉀電流。急性干預(yù)的n-3PUFAs直接作用離子通道，而慢性攝入的n-3PUFAs往往嵌入到細(xì)胞膜，通過改變細(xì)胞膜的特性（如細(xì)胞膜的流動(dòng)性）間接影響離子電流發(fā)揮作用[46]。乙酯化的DHA抵抗DHA對(duì)血管平滑肌BK通道的刺激效應(yīng)[47]。正是由于急性干預(yù)的n-3PUFAs與慢性攝入的具有完全不同的離子通道作用機(jī)制，因此對(duì)電流的影響也不一樣[2]。例如，INa在n-3PUFAs急性干預(yù)時(shí)減小，而慢性攝入時(shí)，無論是大鼠還是豬的心肌細(xì)胞INa均未見明顯改變。急性干預(yù)降低Ito和Ikr，明顯增加Iks（DHA，約增加32%），而長期干預(yù)時(shí)，Ito和Ikr未見變化，而Ik1激活，Iks進(jìn)一步增大（約增加70%）。長期攝入EPA也能通過穩(wěn)定Kv1.5蛋白運(yùn)輸而增加Ikur。這個(gè)電流的激活可以縮短APD而促進(jìn)房顫的發(fā)生。這也許能解釋為何有研究表明EPA增加房顫發(fā)生的風(fēng)險(xiǎn)[48]。

3.3 鈣轉(zhuǎn)運(yùn)的影響

n-3PUFAs介導(dǎo)心肌細(xì)胞的鈣轉(zhuǎn)運(yùn)機(jī)制，影響肌漿網(wǎng)及其受體功能調(diào)節(jié)細(xì)胞內(nèi)鈣離子水平[49]，n-3PUFAs干預(yù)方式不一樣產(chǎn)生的作用也不盡相同。急性干預(yù)可降低ICa-L，而慢性干預(yù)則沒有影響[16]，或通過抑制動(dòng)作電位平臺(tái)期，該通道重新激活，也降低該電流。后者這樣的變化可減弱早后除極而預(yù)防尖端扭轉(zhuǎn)型室性心動(dòng)過速[50]。慢性給予而嵌入細(xì)胞膜的n-3PUFAs也能阻止急性干預(yù)進(jìn)一步縮短APD的作用[51]。當(dāng)急性分離的大鼠心肌細(xì)胞在n-3PUFAs直接干預(yù)下，肌漿網(wǎng)鈣攝取和鈣釋放均降低，繼而引起自發(fā)性鈣波發(fā)生頻率減少。還有研究發(fā)現(xiàn)，單獨(dú)給予EPA干預(yù)時(shí)，鈣火花減少更明顯。這有利于減少心律失常的發(fā)生。n-3PUFAs長期干預(yù)則結(jié)果完全不一樣。研究犬心肌梗死后模型發(fā)現(xiàn)，長期補(bǔ)充n-3PUFAs不能改善心肌梗死后心肌細(xì)胞的Ca2+循環(huán)重構(gòu)，增加鈣火花和舒張性鈣波發(fā)生，誘發(fā)心律失常。這表明，長期攝入n-3PUFAs對(duì)于預(yù)防心肌梗死后惡性心律失常發(fā)生無益，可能反而增加風(fēng)險(xiǎn)[27]。

4 總結(jié)與展望

縮短APD或降低心臟興奮性的藥物能改善觸發(fā)活動(dòng)增加導(dǎo)致的心律失常，但可能促進(jìn)折返的發(fā)生；延長APD的藥物能改善折返所致的心律失常，但可能會(huì)增加早后除極的發(fā)生，甚至引發(fā)尖端扭轉(zhuǎn)型室性心動(dòng)過速。長期攝入n-3PUFAs能縮短APD，急性干預(yù)則降低心室傳導(dǎo)性，因此，折返所致的心律失常在n-3PUFAs存在時(shí)（不論急性或長期干預(yù)所致）則更容易發(fā)生。n-3PUFAs抗心律失常的效果取決于干預(yù)對(duì)象種屬、發(fā)育階段、用藥時(shí)間長短及濃度，更重要的是與心律失常發(fā)生的機(jī)制密切相關(guān)[52]。n-3PUFAs發(fā)揮抗/致心律失常作用是其各種機(jī)制綜合作用的結(jié)果，而心律失常的發(fā)生既有折返激動(dòng)也有觸發(fā)活動(dòng)或自律性異常的因素，所以，n-3 PUFAs對(duì)心律失常的影響具有多樣性也就不足為奇了[53,54]。因此，臨床應(yīng)用n-3PUFAs治療心律失常還需謹(jǐn)慎，有必要依據(jù)心律失常發(fā)生機(jī)制進(jìn)一步研究，選擇最優(yōu)的干預(yù)方式，發(fā)揮最大的抗心律失常作用。

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