心臟再同步治療的選擇及發(fā)展

羅素新,黃泰源

(重慶醫(yī)科大學(xué)附屬第一醫(yī)院心血管內(nèi)科 400016)

羅素新

心臟再同步治療(cardiac resynchronisation therapy，CRT)是在左室收縮功能障礙或心室收縮不同步的患者體內(nèi)通過起搏左室或雙心室進(jìn)而模擬生理性電活動(dòng)的起搏方式，包含CRT-P(只具有起搏功能)和CRT-D[CRT與植入式心律轉(zhuǎn)復(fù)除顫器(ICD)的結(jié)合]，同時(shí)包含一個(gè)皮下脈沖發(fā)生器及三個(gè)起搏電極，分別位于右心房、右心室及左室，后者起搏電極通常位于冠狀竇(少數(shù)可位于左心室心內(nèi)膜及心外膜)。

1 CRT植入指征

2017年美國心臟病學(xué)會(huì)(ACC)、美國心臟協(xié)會(huì)(AHA)以及美國心力衰竭學(xué)會(huì)(HFSA)指南推薦[1]，美國紐約心臟病學(xué)會(huì)(NYHA)心功能分級(jí)Ⅱ～Ⅳ級(jí),左心室射血分?jǐn)?shù)(LVEF)≤35%,正常心電圖中幅度最大的波群(QRS)≥150 ms，呈左束支傳導(dǎo)阻滯(LBBB)的患者行CRT或CRT-D植入，推薦等級(jí)Ⅰ級(jí)。但特別提到要注意以下幾點(diǎn)。

1.1以上指征需在確診射血分?jǐn)?shù)降低心力衰竭(HFrEF)(或心肌梗死40 d后)并啟動(dòng)優(yōu)化藥物治療(optimal pharmacologic therapy，OPT)至少3個(gè)月后才考慮。

1.2對(duì)于LVEF≤35%者,(1) QRS≥150 ms合并LBBB者：如果心功能介于NYHAⅡ～Ⅳ級(jí)，除滿足CRT植入指征外，還符合ICD作為心源性猝死(SCD)一級(jí)預(yù)防植入指征；對(duì)于NYHAⅠ級(jí)合并缺血性心肌病者(ICM)，同樣推薦行CRT植入，在此基礎(chǔ)上合并LVEF<30%者，考慮ICD作為SCD一級(jí)預(yù)防。(2)QRS≥150 ms不合并LBBB者：心功能處于NYHA Ⅲ～Ⅳ級(jí)者，作CRT植入推薦，對(duì)于NYHAⅡ級(jí)及以下者，不作常規(guī)推薦。(3)QRS<150 ms者：①介于130～149 ms，合并LBBB，NYHAⅡ～Ⅳ級(jí)者，作CRT推薦；②介于120～149 ms，不合并LBBB，OPT基礎(chǔ)上心功能NYHAⅢ～Ⅳ級(jí)之間且反復(fù)因心力衰竭入院者，建議完善利弊評(píng)估后進(jìn)一步明確。

1.3LVEF介于35%～50%，QRS>150 ms,NYHA介于Ⅲ～Ⅳ級(jí)者，在這一類人群中尚未作出明確的建議。

2 如何選擇CRT-P與CRT-D

目前美國、歐洲及加拿大指南在關(guān)于CRT-P及CRT-D的選擇上基于大型隨機(jī)對(duì)照試驗(yàn)的臨床證據(jù)較為缺乏，均未作詳細(xì)的闡述。而在臨床工作中如何選擇最適合患者的植入設(shè)備，一直是較為模糊的。目前大部分認(rèn)為LVEF<35%滿足CRT指征的心力衰竭患者同時(shí)滿足ICD植入指征，優(yōu)先選擇CRT-D。經(jīng)過大量的臨床觀察研究，仍可明確對(duì)于部分人群具有決策指導(dǎo)價(jià)值的參考因素。

2.1年齡大于75歲者不建議選擇CRT-D 從大量臨床研究來看，納入研究的人群多以75歲以下為主[2-3]。

2.2患非缺血性心肌病者(NICM)不建議選擇CRT-D 就相應(yīng)的循證醫(yī)學(xué)證據(jù)強(qiáng)度來看，因NICM人群發(fā)生室性心律失常導(dǎo)致SCD的風(fēng)險(xiǎn)本身較ICM低，防猝死獲益不明顯。故目前認(rèn)為傾向于在ICM人群中使用CRT-D才能帶來更大的臨床獲益[4-7]。

2.3心功能NYHAⅣ級(jí)者不建議選擇CRT-D 對(duì)于NYHAⅣ級(jí)的患者發(fā)生惡性心律失常所致SCD的風(fēng)險(xiǎn)較心功能不全所致的死亡概率更小[8-11]。

2.4左室舒張末期直徑(LVEDD)較小者安裝CRT-D有待商榷 對(duì)于LVEDD較小者安裝CRT-D臨床獲益有待進(jìn)一步商榷，有研究報(bào)道LVEDD<3.36 cm者不適合安裝CRT-D[12-13]。

2.5基本健康情況較差者不建議選擇CRT-D 除外上述介紹的心力衰竭程度限制了CRT-D的臨床使用外，由于CRT-D的手術(shù)更為復(fù)雜，術(shù)后的相關(guān)并發(fā)癥也是對(duì)于心力衰竭患者的考驗(yàn)。

3 無導(dǎo)線CRT

由于無需通過傳統(tǒng)手術(shù)方式經(jīng)血管入路植入及不再需要皮下囊袋埋藏，可極大程度減少傳統(tǒng)起搏器所帶來的感染風(fēng)險(xiǎn)，減少導(dǎo)線相關(guān)的并發(fā)癥[14-17]。目前的無導(dǎo)線CRT研究主要突破在于左室心內(nèi)膜無線起搏技術(shù)的運(yùn)用[18]。

3.1左室心內(nèi)膜起搏的指征[19]冠狀竇解剖結(jié)構(gòu)復(fù)雜，傳統(tǒng)術(shù)式難度較大者；傳統(tǒng)CRT植入后無應(yīng)答者(non-responder)；冠狀竇高起搏閾值或膈神經(jīng)激惹者；冠狀竇電極脫落或植入失敗者；既往發(fā)生感染或血栓栓塞者。

3.2左室心內(nèi)膜起搏的優(yōu)勢(shì) (1)左室心內(nèi)膜起搏和傳統(tǒng)冠狀竇起搏：①較傳統(tǒng)CRT于冠狀竇起搏而言，左室心內(nèi)膜下的心電活動(dòng)具有更快的脈沖傳播速度，從而QRS期更短，進(jìn)而更有利于左室收縮功能的改善[20]。②膈神經(jīng)刺激發(fā)生率更小，膈神經(jīng)的解剖結(jié)構(gòu)使得CRT術(shù)后出現(xiàn)膈肌激惹的發(fā)生率較高，尤其是患者在左側(cè)臥位時(shí)更加明顯。而左室心內(nèi)膜起搏的手術(shù)方式在目前的相關(guān)研究中少有報(bào)道膈神經(jīng)刺激的發(fā)生[19，21-22]。(2)左室心內(nèi)膜起搏和左室外膜起搏：①左室心內(nèi)膜起搏較外膜起搏QRS間期縮短程度更顯著，左室縮短率更明顯，組織多普勒超聲顯示左室室間隔及游離壁的電-機(jī)械耦聯(lián)時(shí)間差(EMD)在心內(nèi)膜起搏組明顯縮短，從而能夠在血流動(dòng)力學(xué)效應(yīng)上產(chǎn)生更大獲益。②心外膜起搏時(shí)心肌透壁激動(dòng)順序逆轉(zhuǎn)可延長Q-T間期，增加尖端扭轉(zhuǎn)性室速的風(fēng)險(xiǎn)；而左室心內(nèi)膜起搏的CRT患者QT離散度明顯降低[23-26]。

故盡管兩種起搏方式均能達(dá)到快速激動(dòng)左室的目的，左室心內(nèi)膜的起搏能夠帶來更大的血流動(dòng)力學(xué)效應(yīng)。

3.3無線起搏的優(yōu)勢(shì) 近年來的左室心內(nèi)膜起搏的手術(shù)方式主要包括[27]：經(jīng)房間隔及二尖瓣入路；經(jīng)劍突下及心尖到達(dá)左室；經(jīng)室間隔到達(dá)左室。

關(guān)于無導(dǎo)線起搏技術(shù)在CRT中的應(yīng)用還將不斷探索和研究，WISE-CRT研究中暴露出的安全性問題也為未來的CRT提供了新的發(fā)展思路。CRT-P的改良方向在于右心系統(tǒng)全部實(shí)現(xiàn)無線起搏，左心實(shí)現(xiàn)心外膜無線起搏；CRT-D則是在無線CRT-P的基礎(chǔ)上合并皮下ICD，進(jìn)一步減少目前CRT的不良反應(yīng)，確保臨床獲益。目前相關(guān)的臨床研究正在進(jìn)行中，未來將為心力衰竭患者CRT的使用提供更多的解決方案。

[1]YANCY C W,JESSUP M,BOZKURT B,et al.2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure:a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America[J].J Card Fail,2017,23(8):628-651.

[2]SABA S,ADELSTEIN E,WOLD N,et al.Influence of patients′ age at implantation on mortality and defibrillator shocks[J].Europace,2017,19(5): 802-807.

[3]ADELSTEIN E C,SCHWARTZMAN D,JAIN S,et al.Left ventricular dimensions predict risk of appropriate shocks but not mortality in cardiac resynchronization therapy-defibrillator recipients with left bundle-branch block and non-ischemic cardiomyopathy[J].Europace,2017,19(10): 1689-1694.

[4]K?BER L,THUNE J J,NIELSEN J C,et al.DANISH defibrillator implantation in patients with nonischemic systolic heart failure[J].N Engl J Med,2016,375(13): 1221-1230.

[5]BRISTOW M R,SAXON L A,BOEHMER J,et al.Comparison of Medical Therapy,Pacing,and Defibrillation in Heart Failure (COMPANION) Investigators:Cardiac resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure[J].N Engl J Med,2004,350(21): 2140-2150.

[6]LAM S K,OWEN A.Combined resynchronisation and implantable defibrillator therapy in left ventricular dysfunction: Bayesian network meta-analysis of randomised controlled trials[J].BMJ,2007,335(7626): 925.

[7]AL-MAJED N S,MCALISTER F A,BAKAL J A,et al.Meta-analysis: cardiac resynchronization therapy for patients with less symptomatic heart failure[J].Ann Intern Med,2011,154(6):401-412.

[8]MARIJON E,LECLERCQ C,NARAYANAN K,et al；CeRtiTuDe Investigators.Causes-of-death analysis of patients with cardiac resynchronization therapy: an analysis of the CeRtiTuDe cohort study[J].Eur Heart J,2015,36(41): 2767-2776.

[9]LOOI K L,GAJENDRAGADKAR P R,KHAN F Z,et al.Cardiac resynchronisation therapy: pacemaker versus internal cardioverter-defibrillator in patients with impaired left ventricular function[J].Heart,2014,100(10): 794-799.

[10]KUTYIFA V,GELLER L,BOGYI P,et al.Effect of cardiac resynchronization therapy with implantable cardioverter defibrillator versus cardiac resynchronization therapy with pacemaker on mortality in heart failure[J].Eur J Heart Fail,2014,16(12): 1323-1330.

[11]GOLD M R,DAUBERT J C,ABRAHAM W T,et al.Implantable defibrillators improve survival in patients with mildly symptomatic heart failure receiving cardiac resynchronization therapy: analysis of the long-term follow-up of remodeling in systolic left ventricular dysfunction (REVERSE)[J].Circ Arrhythm Electrophysiol,2013,6(6): 1163-1168.

[12]ADELSTEIN E C,SCHWARTZMAN D,JAIN S,et al.Left ventricular dimensions predict risk of appropriate shocks but not mortality in cardiac resynchronization therapy-defibrillator recipients with left bundle-branch block and non-ischemic cardiomyopathy[J].Europace,2017,19(10): 1689-1694.

[13]RICKARD J,BRENNAN D M,MARTIN D O,et al.The impact of left ventricular size on response to cardiac resynchronization therapy[J].Am Heart J,2011,162(4): 646-653.

[14]KIRKFELDT R E,JOHANSEN J B,NOHR E A,et al.Complications after cardiac implantable electronic device implantations: an analysis of a complete,nationwide cohort in Denmark[J].Eur Heart J,2014,35(18): 1186-1194.

[15]MORANI G,MUGNAI G,BOLZAN B,et al.Redo procedures and chronic renal dysfunction are associated with higher risk of cardiac electronic device infections[J/OL].(2018-01-05)[2018-02-05].https://www.ncbi.nlm.nih.gov/pubmed/?term=Redo+procedures+and+chronic+renal+dysfunction+are+associated+with+higher+risk+of+cardiac+electronic+device+infections.

[16]BOYLE T A,USLAN D Z,PRUTKIN J M,et al.Reimplantation and Repeat Infection After Cardiac-Implantable Electronic Device Infections: Experience From the MEDIC (Multicenter Electrophysiologic Device Infection Cohort) Database[J].Circ Arrhythm Electrophysiol,2017,10(3): e004822.

[17]HSU J C,VAROSY P D,BAO H,et al.Coronary venous dissection from left ventricular lead placement during cardiac resynchronization therapy with defibrillator implantation and associated in-hospital adverse events (from the NCDR ICD Registry)[J].Am J Cardiol,2018,121(1): 55-61.

[18]MYLLENSs W,NIJST P.Leadless left ventricular pacing:another step toward improved CRT response[J].J Am Coll Cardiol,2017,69(17): 2130-2133.

[19]REDDY V Y,MILLER M A,Neuzil P,et al.Cardiac resynchronization therapy with wireless left ventricular endocardial pacing: the SELECT-LV study[J].J Am Coll Cardiol,2017,69(17): 2119-2129.

[20]AURICCHIO A,DELNOY P P,BUTTER C,et al.Collaborative Study Group.Feasibility,safety,and short-term outcome of leadless ultrasound-based endocardial left ventricular resynchronization in heart failure patients: results of the wireless stimulation endocardially for CRT (WiSE-CRT) study[J].Europace,2014,16(5): 681-688.

[21]SEIFERT M,SCHAU T,MOELLET V,et al.Influence of pacing configurations,body mass index,and position of coronary sinus lead on frequency of phrenic nerve stimulation and pacing thresholds under cardiac resynchronization therapy[J].Europace,2010,12(7): 961-967.

[22]CHAMPAGGNE J,HEALEY J S,KRAHN A D,et al;ELECTION Investigators.The effect of electronic repositioning on left ventricular pacing and phrenic nerve stimulation[J].Europace,2011,13(3): 409-415.

[24]THOMAS D E,CHILD N M,OWENS W A,et al.Cardiac resynchronization therapy in coronary sinus atresia delivered using leadless endocardial pacing[J].HeartRhythm Case Rep,2016,2(5):432-435.

[25]VIJAYARAMAN P,BORDACHAR P,ELLENBOGEN K A.The Continued Search for Physiological Pacing: Where Are We Now?[J]J Am Coll Cardiol,2017,69(25): 3099-3114.

[26]MORGAN J M,BIFFI M,GELLER L,et al.ALSYNC Investigators.ALternate Site Cardiac ResYNChronization (ALSYNC): a prospective and multicentre study of left ventricular endocardial pacing for cardiac resynchronization therapy[J].Eur Heart J,2016,37(27): 2118-2127.

[27]GAMBLE J H P,HERRING N,GINKS M,et al.Endocardial left ventricular pacing for cardiac resynchronization: systematic review and meta-analysis[J].Europace,2018,20(1): 73-81.