鄭濤 　綜述　凌智瑜　審校

(1.重慶醫(yī)科大學研究生院，重慶400010；2.重慶醫(yī)科大學附屬第二醫(yī)院心血管內科，重慶 400010)

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心外膜脂肪組織與心房顫動

鄭濤1綜述凌智瑜1,2審校

(1.重慶醫(yī)科大學研究生院，重慶400010；2.重慶醫(yī)科大學附屬第二醫(yī)院心血管內科，重慶 400010)

心房顫動是臨床上常見的心律失常，其發(fā)生機制尚未完全闡明。近年的研究發(fā)現(xiàn)，心外膜脂肪組織與心房顫動的發(fā)生發(fā)展密切相關。心外膜脂肪組織導致心房顫動的機制可能為：(1)心外膜脂肪組織中存在大量的自主神經(jīng)節(jié)，心外膜脂肪組織增加可導致自主神經(jīng)活動紊亂，神經(jīng)節(jié)內的交感神經(jīng)元興奮，釋放更多的去甲腎上腺素，引起神經(jīng)節(jié)附近的肺靜脈及心房內的心肌細胞鈣負荷增加，誘發(fā)早期后除極，從而形成肺靜脈及心房內的異常放電，并可導致心房有效不應期縮短，使心房組織產(chǎn)生電重構。(2)心外膜脂肪組織是心房組織局部炎性介質的源泉，心外膜脂肪組織的增加可導致炎性介質過度表達促使心房肌纖維化的進展，并導致心房產(chǎn)生結構重構，為心房顫動的發(fā)生及維持提供了基質。

心外膜脂肪組織；心房顫動；神經(jīng)節(jié)；炎性介質

炎性因子是心房顫動發(fā)生的危險因素。其中肥胖導致心房顫動發(fā)生的增加可能與心外膜脂肪組織(epicardial adipose tissue,EAT)容積增加有關。EAT是心臟周圍的一個脂肪庫，主要存在于心室周圍，而心房組織周圍的脂肪墊同樣含有豐富的迷走神經(jīng)節(jié)，EAT的增加可導致炎癥介質的釋放增加，與心房顫動的發(fā)生密切相關[1-2]?，F(xiàn)就目前EAT與心房顫動的相關性和機制方面做一綜述。

1　EAT與心房顫動的關系

1.1EAT是心房顫動發(fā)生的獨立危險因素

近年來的研究表明，EAT是心房顫動發(fā)生的獨立危險因素。其中，近期發(fā)表的Framingham Heart Study研究[3]納入了3 217例患者，采用多層螺旋CT檢查并測定EAT體積。發(fā)現(xiàn)經(jīng)校正年齡、性別、身體質量指數(shù)(BMI)、收縮壓、血壓控制情況、PR間期、瓣膜性心臟病危險因素后，EAT體積的增大與心房顫動的發(fā)生仍存在密切關系，是預測心房顫動發(fā)生的獨立危險因素。Greif等[4]通過分析1 288例患者的冠狀動脈CT，并計算EAT的體積、左房內徑，將患者分為陣發(fā)性心房顫動組、持續(xù)性心房顫動組和非心房顫動組，結果發(fā)現(xiàn)EAT體積與心房顫動的發(fā)生有關，尤其是與持續(xù)性心房顫動及增大的左房直徑密切相關，提示EAT的體積增大是心房顫動發(fā)生及左房重構的獨立危險因素。近期的多項研究[5-8]也均顯示，EAT體積的增大不僅與新發(fā)的非瓣膜性心房顫動相關，還與慢性心房顫動及導管消融的預后相關。除了采用CT測量EAT體積外，亦有采用核磁共振(MRI)測量心房顫動和非心房顫動患者的EAT體積的相關研究，其結果也支持增大的EAT體積與心房顫動的發(fā)生密切相關[9-10]。

除EAT容積外，研究者發(fā)現(xiàn)EAT厚度也與心房顫動存在相關性。Batal等[11]分析了169例冠心病或心房顫動患者的血管CT成像結果，測量左房中部短軸截面的EAT厚度，發(fā)現(xiàn)左房-食管之間EAT厚度與心房顫動發(fā)生密切相關。Acet等[12]使用超聲測量了61例陣發(fā)性心房顫動、63例非陣發(fā)性心房顫動和63例竇性心律患者胸骨旁長軸切面EAT厚度，發(fā)現(xiàn)右室游離壁心外膜脂肪厚度與陣發(fā)性心房顫動和非陣發(fā)性心房顫動均密切相關(陣發(fā)性心房顫動：OR4.672，95% CI 2.329～9.371，P<0.001；非陣發(fā)性心房顫動：OR 24.276, 95% CI 9.285～63.474,P<0.001)。結果表明采用超聲所測右室游離壁EAT厚度是心房顫動發(fā)生的獨立預測因素。

上述研究結果均表明，采用不同方法檢測所測定的EAT體積與EAT的厚度與心房顫動均存在密切聯(lián)系，是心房顫動發(fā)生的獨立預測危險因素。

1.2EAT與心房顫動負荷/嚴重程度相關

EAT體積和厚度不僅與心房顫動的發(fā)生有著密切聯(lián)系，也與心房顫動的負荷/嚴重程度密切相關。Batal等[11]的研究表明，持續(xù)性心房顫動患者的左房-食管心外膜脂肪厚度明顯大于陣發(fā)性心房顫動和非心房顫動患者，經(jīng)年齡、BMI、左房面積校正后，增加的左房EAT的厚度仍與心房顫動負荷密切相關(P=0.015)。Acet等[12-13]通過超聲測量右室游離壁EAT厚度的結果也表明持續(xù)性心房顫動患者EAT厚度顯著大于陣發(fā)性心房顫動和竇性心律患者。Wong等[9]采用CT測定EAT體積的研究也發(fā)現(xiàn)，EAT的體積在永久性心房顫動患者>持續(xù)性心房顫動患者>陣發(fā)性心房顫動患者>竇性心律患者。這些研究結果一致顯示，EAT的體積，左房后壁EAT的厚度及超聲所測右室游離壁EAT的厚度均與心房顫動的負荷相關。

1.3EAT與心房顫動消融術后復發(fā)相關

近期研究表明EAT與心房顫動導管消融術后復發(fā)密切相關，心房顫動消融術后復發(fā)的患者較未復發(fā)的擁有更大的心外膜脂肪體積[8-9]。Stojanovska等[5]在對169例心房顫動消融術后的患者隨訪中發(fā)現(xiàn)：在矯正年齡、性別、BMI后，EAT體積與心房顫動消融術后復發(fā)仍存在相關性(OR 1.009,P=0.02)；心房顫動患者EAT體積較大(>117 cm3)的患者射頻消融術后復發(fā)率較高(54 % vs 46 %，P=0.002)，且心房顫動復發(fā)時間更早。隨后Chao等[13-14]分別使用超聲和CT測量心外膜脂肪厚度，結果也表明增加的EAT厚度與心房顫動射頻消融術后復發(fā)成正相關，是預測術后心房顫動復發(fā)的危險因素。Tsao等[8]對68例心房顫動術后未復發(fā)(n=44)和復發(fā)(n=24)患者的術前EAT體積進行分析，結果表明心房顫動復發(fā)組術前EAT體積明顯大于未復發(fā)組，認為ETA體積是心房顫動消融術后復發(fā)的獨立危險因素。其潛在的機制可能是射頻消融術后，EAT仍持續(xù)通過直接或間接的作用促進心房顫動的發(fā)生。

1.4消融EAT減少心房顫動復發(fā)

Higuchi等[15]對60例心房顫動患者在導管消融術后3個月進行了MRI檢測，通過MRI重建獲得EAT三維圖像，并與MRI延遲成像檢測的消融所致心房瘢痕圖像融合，發(fā)現(xiàn)在無心房顫動復發(fā)的患者消融線覆蓋EAT更為廣泛，認為肺靜脈隔離(PVI)聯(lián)合消融線附近神經(jīng)節(jié)消融可提高心房顫動導管消融的成功率。Nakahara等[16]將60例持續(xù)性心房顫動患者的CT三維EAT圖像融合于NavX標測系統(tǒng)，進行PVI和EAT的消融，并與采用階梯式消融的患者比較，通過16個月的隨訪，結果顯示PVI聯(lián)合EAT消融組患者無復發(fā)的比例明顯高于對照組(78% vs 60%，P<0.05)。其機制可能為射頻消融導致消融部位周圍的心外膜脂肪損傷，使心外膜內細胞因子釋放減少和副交感神經(jīng)破壞，削弱了EAT所致心房顫動的發(fā)生、維持及復發(fā)機制。

2　EAT導致心房顫動的機制

目前EAT導致心房顫動的機制還不是很明確，主要集中在EAT導致心房電重構、自主神經(jīng)活動紊亂、炎癥介質等幾個方面。

2.1EAT可導致心房電重構

心臟自主神經(jīng)系統(tǒng)包含交感和副交感神經(jīng)，心臟自主神經(jīng)激活可導致乙酰膽堿和兒茶酚胺過度釋放，進一步觸發(fā)肺靜脈及心房組織的快速電活動，并導致心房不應期縮短和復極離散度增加，從而誘發(fā)心房顫動[17]。研究表明，心房顫動患者心房高主頻電位區(qū)域與EAT覆蓋部位一致[18-19]，并認為心房有效不應期(AERP)縮短是EAT引起心房顫動的重要電生理機制?？s短的AERP使心房顫動易于誘發(fā)和維持。研究發(fā)現(xiàn)通過刺激EAT或快速心房起搏，可引起副交感活動增強和AERP縮短，切除EAT后可以減少刺激導致的AERP縮短和心房顫動的誘發(fā)率[18-19]。此外，心房電機械延遲(AEMD)心房肌電活動紊亂的標志，是心房顫動發(fā)生的重要預測因子[20-21]。EAT的厚度與AEMD密切相關，是AEMD的獨立預測因素，并認為AEMD可能是EAT導致心房顫動的重要電生理基礎[22]。

2.2自主神經(jīng)活動紊亂機制

EAT里含有豐富的神經(jīng)叢，該神經(jīng)叢中自主神經(jīng)的激活在心房顫動的發(fā)生和維持中扮演重要角色[23-24]。EAT中的心臟神經(jīng)節(jié)可對調節(jié)心臟電活動的交感和副交感神經(jīng)系統(tǒng)產(chǎn)生影響[25]。EAT體積增大的患者可能會導致外周腎上腺素能和膽堿能神經(jīng)元增加，腎上腺素能神經(jīng)激活可導致鈣內流增加，然而膽堿能神經(jīng)激活可導致動作電位時限縮短，動作電位時程3相晚期大量的鈣離子瞬時進入細胞內，導致3相晚期的早后除極，形成肺靜脈與心房肌的觸發(fā)激動，這使得心房顫動易于觸發(fā)和發(fā)展[23]。在動物模型中，刺激EAT可使AERP縮短導致心房顫動發(fā)生率增加；切除EAT后可抑制心外膜刺激時導致的AERP縮短，減少心房顫動的發(fā)生率[26]。綜上所述，體積增大的EAT可導致自主神經(jīng)功能紊亂、肺靜脈和心房電活動改變，使心房顫動易于發(fā)作和維持，是心房顫動發(fā)生和維持的一個重要機制。

2.3EAT可產(chǎn)生炎性介質

EAT可產(chǎn)生多種細胞因子，如炎癥因子和脂肪細胞因子[27]。其中炎癥細胞、生長因子(活性素A)、基質金屬蛋白酶是心房顫動發(fā)病機制中的一個重要因素[28-29]。研究發(fā)現(xiàn)在心房顫動患者中超敏C反應蛋白是非心房顫動患者的兩倍，且慢性心房顫動高于陣發(fā)性心房顫動患者[28]。此外白介素-6, 白介素-8, 白介素-1b, 腫瘤壞死因子-α也是心房顫動發(fā)生的獨立預測因子，這些炎癥因子均來自于EAT，其分泌量與EAT的厚度或者體積大小正相關[7, 30]。

活性素A是轉化生長因子-β超家族的一員，具有促進肝纖維化的作用。在人群中研究發(fā)現(xiàn)與外周脂肪組織相比，活性素A在EAT中高表達，并促進心房纖維化，而使用中和抗體可拮抗活性素A的促纖維化作用[31]。培養(yǎng)基中注入外源性EAT分泌組蛋白重組人活性素A可復制出心房肌纖維化，而活性素A抗體可阻斷EAT分泌蛋白組的這種纖維化作用[28]。

基質金屬蛋白酶是細胞外基質穩(wěn)態(tài)重要的調節(jié)點，包括對各種膠原纖維和基底膜成分的調節(jié)。心房顫動發(fā)生時部分基質金屬蛋白酶的活性會顯著上調，導致心肌間質纖維化的積累[28]。在心力衰竭患者中活性素A和基質金屬蛋白酶8的表達水平升高。在2型糖尿病患者中，活性素A在EAT中表達水平明顯高于非糖尿病患者[32]。心力衰竭和糖尿病均是預測心房顫動較好的危險因素，在這些流行病學關系中，EAT的生物活性可能對心房顫動的發(fā)生產(chǎn)生了顯著的作用[28]。研究表明EAT體積越大與之相關的炎癥性細胞因子生物活性越高[33]，而使用具有抗炎作用的瑞舒伐他汀治療可以降低心房顫動的發(fā)生率[34]。綜上所述，炎癥介質與心房顫動的發(fā)生和維持密切相關，其機制可能是EAT中過表達的炎癥介質改變左房細胞基質結構，導致心房顫動發(fā)作。

3　結語

EAT與心房顫動的發(fā)生和維持密切相關，EAT的體積和厚度與心房顫動的負荷/嚴重程度相關，且與心房顫動射頻消融術后的復發(fā)率呈正相關。EAT體積增大或者厚度增加導致心房顫動發(fā)生增加的機制可能為：(1)EAT中自主神經(jīng)功能紊亂導致心房重構，使心房顫動易于發(fā)作和維持。(2)EAT中過表達的炎癥介質促進心房肌纖維化，導致心房結構改變，為心房顫動的發(fā)生提供了基質。隨著對EAT及心房顫動研究的深入，將不斷闡明EAT在心房顫動的發(fā)生及發(fā)展中所起的重要作用，為心房顫動的治療提供新的治療靶點和干預手段。

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Epicardial Adipose Tissue and Atrial Fibrillation

ZHENG Tao1, LING Zhiyu1,2

(1.ChongqingMedicalUniversityGraduateSchool,Chongqing400010,China; 2.DepartmentofCardiology,TheSecondAffiliatedHospitalofChongqingMedicalUniversity,Chongqing400010,China)

Atrial fibrillation is one of the most common arrhythmias encountered in clinical practice, however its mechanism is not yet fully understood. Recent studies have shown that epicardial adipose tissue(EAT) plays an important role in the occurrence and development of atrial fibrillation. There are two potential mechanisms explaining for how EAT impacts the atria: (1) EAT contains abundant ganglionated plexi, and an increase in EAT may provoke abnormal autonomic nervous activity and increase the secretion of noradrenaline. This may cause calcium overload nearby pulmonary veins of the left atria, leading to the development of early after depolarizations, and resulting in abnormal electric activities in the pulmonary vein and atria. Additionally it can shorten the effective refractory period and lead to the electrical remodeling of atria. (2) Mechanism is that EAT is also the source of inflammatory medium, and an increase of EAT may cause the overexpression of inflammatory biomarkers and prompt the progress of the atrial fibrosis, which can result in structural remodeling of the atria, and provide the substrate for initiation and maintenance of atrial fibrillation.

Epicardial adipose tissue;Atrial fibrillation;Ganglionated plex; Inflammatory mediator

2016-01-13修回日期：2016-02-25

重慶市衛(wèi)生局重點課題(2011-1-045)

鄭濤(1990—),在讀碩士，主要從事心律失常、心力衰竭的治療研究。Email:cardiologzhengtao@163.com

凌智瑜(1977—),副教授，碩士生導師，博士，主要從事心律失常、心力衰竭、冠心病等的哈治療研究。Email:13512362075@163.com

R541.7+5

A【DOI】10.16806/j.cnki.issn.1004-3934.2016.04.012