Research progresses of radionuclide imaging in cardiac sudden death

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(Department of Nuclear Medicine, Tianjin Medical University Cardiovascular Clinical Institute and TEDA International Cardiovascular Hospital, Tianjin 300457, China)

心源性猝死(sudden cardiac death， SCD)指突發(fā)的、不可預(yù)料的、在癥狀出現(xiàn)后1 h之內(nèi)的死亡，具有發(fā)病突然、進(jìn)展迅速、后果嚴(yán)重、死亡率高和難以準(zhǔn)確預(yù)測(cè)等特點(diǎn)。SCD最主要原因是惡性心律失常，其中室性心動(dòng)過(guò)速和心室顫動(dòng)等最多見(jiàn)；但任何累及心臟的疾病最終均可能導(dǎo)致SCD，其確切機(jī)制尚不明確。冠狀動(dòng)脈粥樣硬化性心臟病(以下簡(jiǎn)稱(chēng)冠心病)是SCD最常見(jiàn)的病因，特別是心力衰竭患者發(fā)生SCD的概率更高；其他病因還有非粥樣硬化性冠狀動(dòng)脈疾病、心肌病和其他器質(zhì)性心臟病及遺傳性離子通道疾病。器質(zhì)性心臟病患者屬猝死高危人群，尤其是合并嚴(yán)重心力衰竭、室性心律失常、不明原因暈厥等患者。美國(guó)心力衰竭早期死亡病例中，SCD占約22%[1]，而慢性心力衰竭治療過(guò)程中，SCD約占死亡原因的50%[2]。目前指南側(cè)重于以左心室射血分?jǐn)?shù)(left ventricular ejection fraction, LVEF)作為SCD風(fēng)險(xiǎn)分層和患者管理的主要指標(biāo)[3-4]，許多LVEF正常的患者仍有發(fā)生SCD風(fēng)險(xiǎn)，而根據(jù)指南，這類(lèi)患者不符合放置植入式心臟復(fù)律除顫器(implantable cardioverter defibrillator， ICD)適應(yīng)證，單純以L(fǎng)VEF作為SCD風(fēng)險(xiǎn)分層指標(biāo)顯然缺乏敏感度和特異度。放射性核素顯像的SPECT或PET技術(shù)可從心肌血流灌注、糖或脂肪酸代謝、心臟交感神經(jīng)活性分布等角度進(jìn)行分子水平無(wú)創(chuàng)性顯像，具有較高特異度和敏感度，可以預(yù)測(cè)主要心臟不良事件(major adverse cardiac event, MACE)發(fā)生、識(shí)別高危人群，甚至篩選干預(yù)性治療適應(yīng)證，為臨床提供無(wú)創(chuàng)性診斷、評(píng)價(jià)方法。

1 心肌血流灌注顯像(myocardial perfusion imaging, MPI)

1.1 技術(shù)特點(diǎn) MPI由SPECT或PET技術(shù)獲得。由于PET的空間分辨力更高，其診斷敏感度和特異度高于SPECT。MPI顯像劑經(jīng)靜脈注射后隨冠狀動(dòng)脈血流進(jìn)入心肌細(xì)胞，其進(jìn)入心肌細(xì)胞的“量”與局部的“血流量”成正比，經(jīng)首次冠狀動(dòng)脈循環(huán)基本達(dá)到心肌最大攝取。MPI可定量或半定量化反映心肌血流減低程度，包括心肌梗死范圍、程度、LVEF及收縮同步性。有無(wú)缺血、范圍及程度、梗死瘢痕范圍及左心室功能等均與預(yù)后相關(guān)，是包括SCD在內(nèi)的MACE預(yù)測(cè)因子。

1.2 在SCD中的應(yīng)用研究 對(duì)于ST段抬高型急性心肌梗死，應(yīng)通過(guò)介入技術(shù)盡早開(kāi)通梗死相關(guān)血管；而對(duì)于慢性穩(wěn)定型冠心病，尋找有無(wú)缺血及范圍的客觀證據(jù)、進(jìn)行危險(xiǎn)分層，進(jìn)而選擇藥物治療和/或血管重建更為重要[5]。一項(xiàng)對(duì)4 865例冠心病患者(LVEF>35%)MPI顯像后的風(fēng)險(xiǎn)評(píng)估研究[6]表明，負(fù)荷MPI灌注異常范圍與SCD發(fā)生相關(guān)。Piccini等[7]研究6 383例冠心病患者M(jìn)PI，進(jìn)行回顧性風(fēng)險(xiǎn)評(píng)估，發(fā)現(xiàn)MPI負(fù)荷總評(píng)分與SCD發(fā)生率相關(guān)，是心臟性猝死預(yù)測(cè)因子之一。Rijnierse等[8]指出，在缺血性心臟病患者中，心肌血流量和左心室心肌血流儲(chǔ)備分?jǐn)?shù)異常減低與電生理評(píng)估過(guò)程中心室率失常有關(guān)，表明受損心肌血流量與心臟電生理不穩(wěn)定相關(guān)，有助于對(duì)SCD患者進(jìn)行危險(xiǎn)分層。Majmudar等[9]發(fā)現(xiàn)PET測(cè)定左心室心肌血流儲(chǔ)備分?jǐn)?shù)減低與MACE事件有關(guān)。Tsai等[10]認(rèn)為在缺血性心肌病患者中應(yīng)用MPI獲得的左心室收縮同步性參數(shù)有助于預(yù)測(cè)室性心律失常(包括室性心動(dòng)過(guò)速和心室顫動(dòng))發(fā)生，后者是導(dǎo)致SCD的重要因素。

2 心肌糖代謝與脂肪酸代謝顯像

2.1 技術(shù)特點(diǎn) 在空腹、有氧生理?xiàng)l件下，脂肪酸是心肌細(xì)胞代謝主要能量來(lái)源，占ATP供給總量65%，葡萄糖和乳酸提供心肌所需能量的35%。缺血或缺氧條件下，游離脂肪酸代謝受到抑制而轉(zhuǎn)向葡萄糖代謝。18F-FDG是葡萄糖類(lèi)似物，進(jìn)入心肌細(xì)胞后被磷酸化為18F-FDG-6-磷酸，但不能參與糖原合成、糖酵解和去磷酸化等其他代謝過(guò)程，不能進(jìn)一步代謝，而以該形式滯留在心肌細(xì)胞內(nèi)，反映其攝取和利用葡萄糖速率；若心肌細(xì)胞壞死，則能量代謝活動(dòng)停止，不能攝取18F-FDG。BMIPP是游離脂肪酸分支類(lèi)似物，模擬體內(nèi)游離脂肪酸有氧氧化過(guò)程，123I標(biāo)記BMIPP反映脂肪酸代謝。123I-BMIPP減低不僅與病理?xiàng)l件下心臟脂肪酸代謝障礙有關(guān)，還與隨之發(fā)生的MACE事件，包括SCD存在關(guān)聯(lián)。

2.2 在SCD中的應(yīng)用研究 缺血、缺氧時(shí)冬眠心肌局部存在去交感神經(jīng)分布支配，此現(xiàn)象與SCD發(fā)生率有密切關(guān)系。利用18F-FDG顯像提示有冬眠心肌時(shí)，發(fā)生去交感神經(jīng)分布支配的冬眠心肌具有一定預(yù)測(cè)SCD發(fā)生的作用，有助于選擇ICD適應(yīng)證[11]。此外，心肌脂肪酸代謝障礙與室性心律失常緊密相關(guān)，代謝障礙者易發(fā)展為室性心律失常，心肌脂肪酸顯像預(yù)測(cè)心臟事件發(fā)生有一定價(jià)值[12]。Yamashita等[13]對(duì)100例缺血性心肌病患者血運(yùn)重建后植入ICD，行123I-BMIPP脂肪酸和201Tl血流顯像，對(duì)比觀察接受和未接受ICD放電治療兩組(后者占19%)，結(jié)果表明123I-BMIPP/201Tl顯像不匹配對(duì)ICD未來(lái)放電治療事件具有明顯預(yù)測(cè)價(jià)值。

3 心臟神經(jīng)顯像

3.1 技術(shù)特點(diǎn) 心臟自主神經(jīng)系統(tǒng)包括交感神經(jīng)與副交感神經(jīng)。交感神經(jīng)末梢釋放去甲腎上腺素和腎上腺素，作用于心肌細(xì)胞β1腎上腺素能受體；副交感神經(jīng)末梢釋放乙酰膽堿，作用于心肌毒蕈堿受體。去甲腎上腺素及乙酰膽堿都可以被神經(jīng)末梢重新攝取回神經(jīng)細(xì)胞內(nèi)。心力衰竭者心肌的顯著特征之一是交感神經(jīng)前突觸去甲腎上腺素?cái)z取明顯減少和后突觸β-腎上腺素能受體密度降低[14]。

MIBG類(lèi)似于去甲腎上腺素，參與神經(jīng)遞質(zhì)特異度攝取與儲(chǔ)存，但不同于去甲腎上腺素，MIBG被攝取分布后不被代謝，從而可顯示其分布[15]。123I-MIBG-SPECT平面成像分為早期像(注射后15～30 min)與延遲像(注射后3～4 h)，采用心臟/縱隔比值(heart mediastinal ratio, HMR)，即ROI技術(shù)勾畫(huà)心臟和縱隔區(qū)域ROI，計(jì)算二者ROI平均計(jì)數(shù)比值，可對(duì)圖像進(jìn)行半定量評(píng)估。此外，比較早期像與延遲像心臟區(qū)域MIBG計(jì)數(shù)比值，即MIBG在心臟神經(jīng)元內(nèi)洗脫，可作為反映去甲腎上腺素在心臟神經(jīng)元內(nèi)滯留的參數(shù)。

3.2 在SCD中的應(yīng)用研究 心臟交感神經(jīng)干走行分布與冠狀動(dòng)脈分布一致，其損傷位置往往呈現(xiàn)在心肌損傷處及其遠(yuǎn)端，且對(duì)缺血性損傷十分敏感，受損后修復(fù)緩慢?；诖耍琈IBG顯像被用來(lái)顯示“缺血記憶”，即“缺血記憶”顯像[16]。MIBG延遲像獲得的HMR是反映生存預(yù)后的參數(shù)之一，其閾值一般為1.2，HMR≤1.2預(yù)示生存預(yù)后較差，SCD發(fā)生率較高，與LVEF具有較好相關(guān)性。對(duì)心力衰竭患者的123I-MIBG顯像對(duì)照研究[17]顯示，在年齡60歲以上心肌梗死患者(心功能NYHA分級(jí)為Ⅲ～Ⅳ級(jí))中，延遲像HMR減低是SCD的預(yù)測(cè)因子。Nakajima等[18]對(duì)接受123I-MIBG顯像的955例慢性心力衰竭患者隨訪(fǎng)5年，發(fā)現(xiàn)205例死亡者中30%為SCD，且與MIBG顯像HMR危險(xiǎn)度分級(jí)明顯相關(guān)，從而肯定了MIBG顯像在心力衰竭患者中預(yù)測(cè)SCD的明顯增益價(jià)值。ADMIR-HF多中心研究[19]表明，HMR<1.60組心力衰竭患者2年心性死亡率和全因死亡率為11.2%和16.1%，而HMR≥ 1.60組分別為1.8%和3.0%，二者差異明顯。

MIBG與MPI聯(lián)合顯像研究[20]結(jié)果顯示，交感神經(jīng)削弱和心肌灌注減低與導(dǎo)致SCD的致死性心律失常發(fā)生密切相關(guān)，有助于篩選能從ICD治療中獲益較大的患者。Kawai等[21]發(fā)現(xiàn)，MIBG顯像中顯像劑分布低評(píng)分對(duì)心力衰竭患者無(wú)需ICD治療的陽(yáng)性預(yù)測(cè)值達(dá)100%，可協(xié)助篩選ICD植入適應(yīng)證。Boogers等[22]對(duì)116例心力衰竭患者于植入ICD前行123I-MIBG顯像，MIBG顯像有明顯顯像劑分布減低(累積評(píng)分>26)患者ICD治療獲益大，提示123I-MIBG顯像所示心臟交感神經(jīng)去神經(jīng)化支配能改善因致死性心律失常而接受ICD治療者的危險(xiǎn)度分層。Nakajima等[23]指出，HMR比值低于1.6～1.8和MIBG洗脫率加速是心臟泵衰竭、SCD和致死性心律失常的高危指征，與其他指標(biāo)相比具有獨(dú)立或增益價(jià)值；HMR>2.0者則具有較好的長(zhǎng)期預(yù)后。

羥基麻黃堿(hydroxyephedrine，11C-HED)PET顯像為近期國(guó)外研究熱點(diǎn)，用于定量交感神經(jīng)末梢分布密度。11C-HED攝取與去甲腎上腺素組織濃度相關(guān)，攝取減低提示局部去交感神經(jīng)支配，是心律失常性MACE事件高危信號(hào)[24]。臨床前研究[25]表明，即使在無(wú)心肌梗死和心力衰竭情況下，有冬眠心肌者死于室速或室顫的發(fā)生率較高，且11C-HED PET顯像發(fā)現(xiàn)有廣泛的去交感神經(jīng)支配。Cain等[26]應(yīng)用11C-HED PET顯像對(duì)缺血性心肌病SCD發(fā)生危險(xiǎn)度進(jìn)行評(píng)估研究，結(jié)果顯示左心室去交感神經(jīng)支配大于37.6%是SCD發(fā)生的獨(dú)立預(yù)測(cè)因子，PET定量去交感神經(jīng)支配心肌能強(qiáng)有力預(yù)測(cè)SCD發(fā)生的危險(xiǎn)性，且獨(dú)立于LVEF、心肌梗死面積和其他參數(shù)。雖然11C-HED目前展示出了巨大前景，但由于其半衰期短，需由回旋加速器現(xiàn)場(chǎng)制備，目前應(yīng)用仍受限。LMI1195是一種基于18F的PET示蹤劑，類(lèi)似于MIBG，其半衰期較長(zhǎng)，是極具前景的新型示蹤劑。初步研究結(jié)果[27-28]表明，LMI1195有助于識(shí)別高風(fēng)險(xiǎn)SCD患者，并可以協(xié)助引導(dǎo)ICD治療。

4 小結(jié)

及時(shí)有效識(shí)別SCD高風(fēng)險(xiǎn)患者并采取相應(yīng)干預(yù)手段至關(guān)重要。目前診斷SCD主要依賴(lài)于評(píng)估LVEF，缺乏敏感度和特異度，而心臟核醫(yī)學(xué)成像提供了新型診斷手段。心肌血流、代謝、神經(jīng)成像對(duì)于識(shí)別LVEF增高或無(wú)LVEF功能障礙的患者更具優(yōu)勢(shì)。但目前仍缺乏大量的前瞻性研究，有待于進(jìn)一步驗(yàn)證心臟核素成像對(duì)于SCD的預(yù)測(cè)能力，從而發(fā)現(xiàn)過(guò)去未能識(shí)別的SCD患者，并對(duì)其進(jìn)行適當(dāng)干預(yù)，為預(yù)測(cè)包括心臟猝死在內(nèi)的心臟事件、識(shí)別高危人群乃至篩選ICD植入適應(yīng)證提供無(wú)創(chuàng)影像學(xué)方法。

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