高尿酸血癥與心房顫動(dòng)的關(guān)系

劉彤 楊亞娟

·高尿酸血癥/痛風(fēng)相關(guān)代謝性疾病專欄·

高尿酸血癥與心房顫動(dòng)的關(guān)系

劉彤 楊亞娟

心房顫動(dòng)是臨床上最常見的持續(xù)性心律失常，可能導(dǎo)致心力衰竭、血栓栓塞等并發(fā)癥。心房顫動(dòng)的發(fā)生、發(fā)展可能與心房重構(gòu)、炎性反應(yīng)及氧化應(yīng)激有關(guān)。人體內(nèi)血尿酸不僅與心房氧化應(yīng)激程度密切相關(guān)，還與炎性標(biāo)志物水平相關(guān)，因此血尿酸水平與多種心血管疾病密切相關(guān)。近年來，越來越多的研究表明，血尿酸水平升高和心房顫動(dòng)的發(fā)生風(fēng)險(xiǎn)密切相關(guān)，其可能機(jī)制一方面是高尿酸血癥可以使高血壓、腎功能衰竭等疾病發(fā)生風(fēng)險(xiǎn)增加，而后者是心房顫動(dòng)發(fā)生的重要危險(xiǎn)因素；另一方面氧化應(yīng)激和炎性反應(yīng)參與了心房顫動(dòng)的發(fā)生，這可能是高尿酸血癥和心房顫動(dòng)聯(lián)系的中間環(huán)節(jié)。

高尿酸血癥； 尿酸； 黃嘌呤氧化酶； 心房顫動(dòng)

心房顫動(dòng)是臨床上最常見的持續(xù)性心律失常，可引起心力衰竭、血栓栓塞等嚴(yán)重并發(fā)癥，已經(jīng)成為全球重要的公共衛(wèi)生問題[1]。心房顫動(dòng)發(fā)生的具體病理生理機(jī)制尚不完全清楚，心房電重構(gòu)、結(jié)構(gòu)重構(gòu)、炎性反應(yīng)和氧化應(yīng)激激活都參與了心房顫動(dòng)的發(fā)生和發(fā)展過程[2-7]。在心臟手術(shù)后發(fā)生心房顫動(dòng)患者的心房肌組織中可發(fā)現(xiàn)炎性細(xì)胞浸潤(rùn)及心房間質(zhì)纖維化[8]。另一項(xiàng)研究發(fā)現(xiàn)，C反應(yīng)蛋白及其他促炎性細(xì)胞因子濃度升高可以預(yù)測(cè)心房顫動(dòng)的發(fā)生風(fēng)險(xiǎn)及心房顫動(dòng)復(fù)律后的復(fù)發(fā)[5，9]。此外，氧化應(yīng)激也可能是心房顫動(dòng)發(fā)生的重要機(jī)制之一。研究表明，黃嘌呤氧化酶激活可導(dǎo)致體內(nèi)活性氧簇產(chǎn)生增加，參與心房重構(gòu)和心房顫動(dòng)的發(fā)生、發(fā)展。在快速心房起搏豬的模型中，心房快速起搏可導(dǎo)致左心耳NADPH氧化酶及黃嘌呤氧化酶活性升高，應(yīng)用黃嘌呤氧化酶抑制劑后過氧化物產(chǎn)生顯著減少[10]。

1 高尿酸血癥與心血管疾病

血清中的尿酸是黃嘌呤經(jīng)過黃嘌呤脫氫酶和黃嘌呤氧化酶的降解最終形成的代謝產(chǎn)物，而這個(gè)過程受黃嘌呤氧化酶調(diào)節(jié)。黃嘌呤氧化酶是人體內(nèi)活性氧簇產(chǎn)生的一個(gè)關(guān)鍵酶，可以反映體內(nèi)氧化應(yīng)激水平[11-12]。因此，尿酸水平升高反映黃嘌呤氧化酶活性增加，可能與心房氧化應(yīng)激程度密切相關(guān)。另一方面，血清尿酸水平與多種炎性標(biāo)志物呈正相關(guān)，這些炎性標(biāo)志物包括高敏C反應(yīng)蛋白、白細(xì)胞介素-1、白細(xì)胞介素-6、腫瘤壞死因子-α等。尿酸還可以通過激活促炎性細(xì)胞因子或局部組織血管緊張素-醛固酮系統(tǒng)來促進(jìn)炎性反應(yīng)。

大量證據(jù)表明，血清尿酸水平與多種心血管疾病密切相關(guān)。Krishnan等[13]研究顯示，高尿酸血癥是急性心肌梗死發(fā)生的獨(dú)立預(yù)測(cè)因素。Choi和Curhan[14]報(bào)道，有痛風(fēng)病史患者發(fā)生心血管事件風(fēng)險(xiǎn)和總死亡率明顯升高。另外，多項(xiàng)研究表明高尿酸血癥是高血壓的一個(gè)獨(dú)立危險(xiǎn)因素，且尿酸水平與新發(fā)高血壓關(guān)系更為密切[12]。除此之外，高尿酸血癥與冠心病有密切聯(lián)系，尤其是在心血管疾病風(fēng)險(xiǎn)較高的人群及女性人群中兩者聯(lián)系更加顯著[15]。

2 高尿酸血癥與心房顫動(dòng)

近年來，越來越多的研究證實(shí)血尿酸水平升高和心房顫動(dòng)的發(fā)生風(fēng)險(xiǎn)密切相關(guān)[16]。Suzuki等[17]發(fā)現(xiàn)，心房顫動(dòng)患者血尿酸水平明顯高于非心房顫動(dòng)患者，表明高尿酸血癥是心房顫動(dòng)發(fā)生的一個(gè)重要危險(xiǎn)因素。另外，研究者還發(fā)現(xiàn)在調(diào)整協(xié)變量后，血尿酸水平在女性人群中仍是心房顫動(dòng)的一個(gè)獨(dú)立危險(xiǎn)因素(OR=1.888, 95%CI： 1.278～2.790)，然而在男性人群中血尿酸水平無法預(yù)測(cè)心房顫動(dòng)的發(fā)生風(fēng)險(xiǎn)(OR=1.176, 95%CI：0.935～1.478)，提示高尿酸血癥對(duì)心房顫動(dòng)的預(yù)測(cè)價(jià)值可能存在性別差異。Tamariz等[18]入選15 382名無心房顫動(dòng)病史的普通人群進(jìn)行前瞻性隊(duì)列研究，以新發(fā)心房顫動(dòng)為主要研究終點(diǎn)，在調(diào)整了年齡、性別、種族等因素后，研究者發(fā)現(xiàn)血尿酸水平可以預(yù)測(cè)心房顫動(dòng)的發(fā)生(HR=1.16, 95%CI：1.06～1.26)， 且兩者間的關(guān)系與性別和種族相關(guān)(在黑種人及女性人群中兩者相關(guān)性更明顯)。然而，另一些研究未能顯示高尿酸血癥與心房顫動(dòng)的關(guān)系存在性別差異。中國(guó)臺(tái)灣的一項(xiàng)研究提示，高尿酸血癥預(yù)測(cè)心房顫動(dòng)發(fā)生的風(fēng)險(xiǎn)比在男性(1.288)和女性(1.115)相似[19]。同樣，Nyrnes等[20]的研究中也提出無論是在男性人群還是女性人群中，血尿酸水平升高都是發(fā)生心房顫動(dòng)的一個(gè)獨(dú)立危險(xiǎn)因素。因此，尿酸與心房顫動(dòng)的關(guān)系是否受性別影響還需要更多的研究來進(jìn)一步證實(shí)。

多項(xiàng)研究在不同人群中評(píng)價(jià)高尿酸血癥與心房顫動(dòng)發(fā)生的關(guān)系。筆者的研究入選了451例原發(fā)性高血壓患者，將其分為心房顫動(dòng)組和非心房顫動(dòng)組，多元回歸分析顯示，尿酸水平是心房顫動(dòng)發(fā)生的獨(dú)立預(yù)測(cè)因素(OR=1.008，95%CI: 1.003～1.013,P=0.002)[21]。Chuang等[22]發(fā)現(xiàn)，在非高血壓的老年人群(≥65歲)中高尿酸血癥與心房顫動(dòng)之間有密切關(guān)系(HR=3.78, 95%CI: 1.24～11.59)，但是在合并高血壓的老年人群中并未發(fā)現(xiàn)兩者間的聯(lián)系(HR=1.20，95%CI:0.74～1.94)。Valbusa等[23]的前瞻性隊(duì)列研究入選了400例無心房顫動(dòng)病史的糖尿病患者并對(duì)其進(jìn)行了10年隨訪，結(jié)果發(fā)現(xiàn)血尿酸水平升高可增加心房顫動(dòng)的發(fā)生風(fēng)險(xiǎn)(OR=2.44, 95%CI：1.6～3.9,P<0.000 1)。此外，Memetoglu等[24]發(fā)現(xiàn)，在擬行冠狀動(dòng)脈搭橋術(shù)的患者中，術(shù)后發(fā)生心房顫動(dòng)患者的術(shù)前血尿酸水平明顯高于沒有發(fā)生心房顫動(dòng)的患者[(7.8±1.1) mg/dlvs. (5±0.9) mg/dl,P<0.05]，多元回歸分析顯示，術(shù)前高尿酸血癥是發(fā)生術(shù)后心房顫動(dòng)的獨(dú)立危險(xiǎn)因素(OR=3.137, 95%CI: 1.873～5.256,P<0.001)。Chao等[19]發(fā)現(xiàn)，高尿酸血癥與左心房直徑密切相關(guān)，并可以增加新發(fā)心房顫動(dòng)的發(fā)生風(fēng)險(xiǎn)(HR=1.191, 95%CI：1.098～1.292,P<0.001)。最新1篇薈萃分析入選了9 篇有關(guān)血尿酸水平與心房顫動(dòng)關(guān)系的相關(guān)研究，橫斷面研究結(jié)果顯示，心房顫動(dòng)患者較非心房顫動(dòng)患者血尿酸水平顯著升高，前瞻性隊(duì)列研究的薈萃分析提示，高尿酸血癥可增加心房顫動(dòng)風(fēng)險(xiǎn)1.67倍[25]。

Canpolat等[26]發(fā)現(xiàn)，血尿酸水平升高是心房顫動(dòng)射頻消融術(shù)后復(fù)發(fā)的一個(gè)獨(dú)立危險(xiǎn)因素(HR=1.96, 95%CI: 1.49～2.59,P<0.001)。然而，不同研究間結(jié)果有所差異，筆者剛剛發(fā)表的一項(xiàng)薈萃分析入選4項(xiàng)相關(guān)研究并未發(fā)現(xiàn)血清高尿酸是導(dǎo)管消融術(shù)后心房顫動(dòng)復(fù)發(fā)的一個(gè)獨(dú)立危險(xiǎn)因素(OR=1.37, 95%CI: 0.98～1.93,P=0.07)[27]。

綜上所述，血尿酸水平升高導(dǎo)致心房顫動(dòng)發(fā)生的機(jī)制尚不十分清楚，主要推測(cè)與以下因素有關(guān)。首先，血尿酸水平升高可導(dǎo)致平滑肌細(xì)胞增生，內(nèi)皮細(xì)胞功能紊亂，一氧化氮合成減少及局部組織腎素-血管緊張素-醛固酮系統(tǒng)激活，增加高血壓，腎功能衰竭的發(fā)生風(fēng)險(xiǎn)；而高血壓、腎功能衰竭可增加心房顫動(dòng)的發(fā)生風(fēng)險(xiǎn)[28-30]。另外，已有許多研究表明血尿酸水平與體內(nèi)炎性反應(yīng)和氧化應(yīng)激標(biāo)志物呈正相關(guān)，且血尿酸水平可以反映心房組織水平黃嘌呤氧化酶激活和活性氧簇水平升高，而炎性和氧化應(yīng)激是心房顫動(dòng)發(fā)生、發(fā)展的重要機(jī)制，因此炎性反應(yīng)和氧化應(yīng)激激活可能是兩者相關(guān)的核心環(huán)節(jié)。臨床上抑制黃嘌呤氧化酶活性的藥物如別嘌呤醇可以顯著降低血尿酸水平，有望成為心房顫動(dòng)上游治療的藥物選擇之一。

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Relationshipbetweenhyperuricemiaandatrialfibrillation

LiuTong,YangYajuan.

TianjinKeyLaboratoryofIonic-MolecularFunctionofCardiovascularDisease,DepartmentofCardiology,TianjinInstituteofCardiology,SecondHospitalofTianjinMedicalUniversity,Tianjin300211,China

Correspondingauthor:LiuTong,Email:liutongdoc@126.com

As the most common sustained arrhythmia, atrial fibrillation (AF) can lead to complications such as heart failure, thromboembolism. Atrial electrical and structural remodeling, inflammatory reaction and oxidative stress may play important roles in the occurrence and progress of AF. Uric acid is closely related to not only the degree of oxidative stress, but also the level of inflammatory markers, which contributes to the relationship between uric acid and cardiovascular diseases. In recent years, more and more studies confirmed that hyperuricemia can increase the risk of AF. On the one hand, elevated level of serum uric acid increases the risk of hypertension and renal failure, which are the risk factors of AF. On the other hand, oxidative stress and inflammatory reaction process are involved in the occurrence of AF, which may be a hub for the relationship between hyperuricemia and AF.

Hyperuricemia; Uric acid; Xanthine oxidase; Atrial fibrillation

國(guó)家自然科學(xué)基金資助項(xiàng)目(81270245, 81570298)

10.3760/cma.j.issn.1673-4157.2016.04.02

300211 天津市心血管病離子與分子機(jī)能重點(diǎn)實(shí)驗(yàn)室，天津醫(yī)科大學(xué)第二醫(yī)院心臟科，天津心臟病學(xué)研究所

劉彤，Email:liutongdoc@126.com

FundprogramNational Natural Science Foundation of China(81270245, 81570298)

2016-05-20)