Advances in Clinical Medicine
Vol. 10  No. 03 ( 2020 ), Article ID: 34484 , 10 pages
10.12677/ACM.2020.103036

The Research Progress of Cardiac Implantable Electronic Device-Identified Atrial Fibrillation

Jiangting Lu1,2, Zhida Shen1,2, Ying Yang1,2*

1Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang

2Key Laboratory of Cardiovascular Intervention and Regenerative Repair, Hangzhou Zhejiang

Received: Feb. 18th, 2020; accepted: Mar. 4th, 2020; published: Mar. 11th, 2020

ABSTRACT

The widespread use of cardiac implantable electronic devices has led to detection in a significant proportion of patients with subclinical high-frequency atrial seizures, confirmed by intraluminal electrocardiography, most of which are atrial fibrillation (AF) or other atrial tachyarrhythmias. These asymptomatic arrhythmias have been shown to be associated with an increased risk of stroke and subsequent development of clinical atrial fibrillation, heart failure, and so on. Atrial fibrillation of cardiac implanted electronic devices is different from clinical atrial fibrillation. This review focuses on the latest research on the incidence, pathogenesis, complications and treatment of atrial fibrillation of cardiac implanted electronic devices.

Keywords:Cardiac Implantable Electronic Device-Identified Atrial Fibrillation, Stroke, Heart Failure, Treatment

心脏植入式电子设备相关心房颤动 最新研究进展

卢江婷1,2,沈智达1,2,杨莹1,2*

1浙江大学医学院附属邵逸夫医院心血管内科,浙江 杭州

2浙江省心血管介入与再生修复研究重点实验室,浙江 杭州

收稿日期:2020年2月18日;录用日期:2020年3月4日;发布日期:2020年3月11日

摘 要

心脏植入式电子设备的广泛应用,已导致相当比例的患者检测出心房亚临床高频率发作,经腔内心电图确认,大部分是心房纤颤(房颤)或其他心房快速性心律失常。这些无症状性心律失常已经被证明与中风的风险增加和随后发展为临床房颤、心力衰竭等相关。心脏植入电子设备心房颤动不同于临床心房颤动,本综述围绕心脏植入式电子设备相关心房颤动的发病率、发病机制、并发症和治疗等方面最新的研究进展做进一步阐述。

关键词 :心脏植入式电子设备相关心房颤动,卒中,心力衰竭,治疗

Copyright © 2020 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 背景

1932年Hyman首次提出“人工心脏起搏器”这一概念 [1]。1958年10月,来自瑞典的Elmqvist和Senning共同完成植入了第一台使用心外膜导线和可充电电池的人工起搏器 [2]。起搏器的问世,使许多心脏疾病患者从中获益。心脏植入式电子设备(CIED: cardiac implantable electronic devices)可以延长患者生存期,并改善生活质量。据统计全球每年近100万人因各类适应症进行CIEDs植入手术 [3]。心脏植入式电子设备的适应症日益增多,导致全球CIEDs的植入数量不断增加,同时并发症也随之增加 [4]。由于导线的植入,对心脏结构产生了影响,导致心房颤动、心力衰竭等不良反应。同时CIEDs的监测,使得无症状型心房颤动被大幅度监测出来,从而产生了心脏植入式电子设备相关心房颤动这一概念。心脏植入式电子设备相关心房颤动,又名亚临床心房颤动(SCAF: Subclinical atrial fibrillation),是指先前心电图或动态心电图监测未检测到,心腔内心电图检测到并确认的无症状性心房颤动 [5]。不同于常规的心房颤动,目前针对心脏植入电子设备术后心房颤动的诊疗尚未明确,尤其是是否需要抗凝等治疗尚存在争议,本综述将就目前最新的治疗概况进行论述。

2. 心脏植入电子设备心房颤动的定义

2019年美国心脏协会的科学声明中将“亚临床心房颤动”定义为先前心电图或动态心电图监测未检测到,后通过多种心脏监测方法并确认心腔内心电图的无症状性心房颤动 [5]。其包括外部表面监测(例如,标准的12导联心电图,动态心电图监视器,心电图监护仪ZIO® XT Patch,事件监控器,苹果手表),以及心脏植入电子设备CIEDs (例如,可植入心脏监视器,双腔起搏器,双腔植入式心脏复律除颤器,心脏再同步治疗[CRT]设备),其中许多设备可以实现远程监控 [6]。心房高频率事件(AHRE: Atrial high-rate episodes)指设备检测到的心房事件,通常是快速性心律失常,符合程序性或其他特定的心房高频率标准(通常在175至220 bpm之间) [5]。SCAF属于AHRE范畴,但根据2019美国心脏协会共识两者存在一定的差异,目前的文献通常将两者互用。鉴于CIEDs的持续监控功能,本文论述的SCAF主要为CIEDs相关的心房颤动。从CIEDs获得的所有心律记录都需要裁决或由合格的临床医生进行审查,以验证诊断的准确性。从而减少检测的假阳性及假阴性。假阳性可能存在于远场R波可能导致心房导线过度感知或者房性事件早发,从而导致误测,当AF发作非常短暂时可能会被错过,造成一定的假阴性 [7] [8]。不同研究中使用的CIEDs使用的编程和检测算法也存在差异。SCAF发生率和持续时间的临界值会影响假阳性结果。ASSERT研究中定义SCAF为心房频率 > 190次/分,持续时间 > 6分钟 [9]。有研究指出,与SCAF > 190次/分,AH > 6分钟持续时间相比(假阳性为17.3%),SCAF > 190次/分且持续时间 > 6 h会降低假阳性结果,其假阳性率是3.3% [10]。目前关于SCAF的具体标准尚未制定统一。

3. 心脏植入式电子设备相关心房颤动的发生率及危险因素

一项研究SCAF的系统评价分析中指出,在CIEDs植入后随访1~2.5年的所有15,353名患者中,35%左右的患者出现SCAF [11]。该研究最终纳入11项研究,其中七项研究涉及SCAF的患病率,尽管所有研究均排除了永久性房颤患者,但既往房颤史并非必要排除标准,其中仅ASSERT研究中,将既往有阵发性房颤列入排除标准。故此项研究并不能完全代表SCAF的患病率。ASSERT研究,是一项对2580名有高血压病史但无房颤病史的患者进行的大型研究。在平均随访2.5年的CIEDs患者中,Healey等人发现有35%的患者出现心房高频率事件,并且持续时间 ≥ 6分,即SCAF [9]。Boriani等人在对来自3个前瞻性研究的数据进行了汇总分析,确定了6580例无心房颤动颤动病史且基线时未使用抗凝剂的患者,在2.4 ± 1.7年的随访期内,有2244名患者(34%)发现了SCAF,并且发现年龄 > 75岁是检测SCAF向更高房颤负荷转变的唯一重要预测变量,CHADS2评分虽然在单变量分析中提示可以预测SCAF,但在多变量回归分析中并非独立预测因素 [12]。在另一项限于既往无房颤病史的中风或短暂性缺血性发作史的病人的队列研究中,SCAF患病率为28% (平均随访1.1年) [13]。一项对没有AF病史的CIEDs植入患者进行的回顾性研究报告,在平均596天的随访中,使用起搏器检测到的SCAF持续时间 ≥ 5分钟的发生率为29% (77/262例),其中第1年为24%,第2年为34%,并且Cheung等人发现在病态窦房结患者中右心室起搏的累积百分比 ≥ 50%是AHRE发生的唯一预测因子,在房室传导阻滞的患者中高血压病史是危险因素 [14]。Witt等人在进行评估AHRE在CRT患者中的预后价值的临床研究中发现在随访4.2年,394名患者中其中79例(20%)发生AHRE [15]。Yutaka等人发现在207名心脏起搏器植入患者中平均随访3.1年,其中44例(21.3%)患者被识别新发房颤,新发AF患者CHADS2和CHA2DS2-VASc评分高于未发生新发AF的患者,并且年龄是新发AF的重要预测因素 [16];Kim等人发现SCAF的发生率为13.2%,并且心力衰竭病史,窦房结功能障碍病史,房室传导阻滞病史和左房容积指数 ≥ 38.5 mL/m2是SCAF的预测因子 [17]。Sade等人发现左房功能(左房容积、左房收缩末期峰值、左房舒张末期峰值)是CRT相关房颤的独立危险因素 [18]。Xing等人指出在起搏器植入的开始和结束时心电图中V4和V6导联的QRS波时间变化和和左心房内径是发生SCAF的独立危险因素 [19]。Israel等人发现SCAF的预测因子为年龄、CHA2DS2-VASc评分及脑微血管病变 [20]。另有学者发现左心室射血分数、心房-心房感测的时间间隔、既往睡眠呼吸暂停综合征病史也可能是SCAF的高危因素 [21] [22]。

综上所述:在有CIEDs植入及无房颤病史的患者中,SCAF的检出率约为13.2%~35%。并且随着随访时间延长,SCAF率上升。但对于CIEDs植入且无AF史的患者,尚无一致的SCAF预测指标,年龄、右心室起搏比例、高血压病史、心力衰竭病史、脑微血管病变、既往睡眠呼吸暂停综合征病史、CHADS2和CHA2DS2-VASc评分、左心房内径、左房功能、左心室射血分数、心房-心房感测的时间间隔等可能为SCAF的危险因素。

4. 心脏植入式电子设备相关心房颤动发生可能的机制

诱发心房颤动的临床因素以及所涉及的细胞和分子机制极为复杂。异位激发和折返活动已被确定为心律失常启动和维持的主要机制。此外,心房颤动的所有促进和维持机制均受到心房颤动和心血管疾病的重塑的动态调节。心房颤动发生的机制主要包括以下四点:钙离子的调控、离子通道功能障碍、结构重构(主要为心房纤维化)、自主神经功能紊乱 [23] [24]。CIEDs植入可能直接致心脏纤维化、心房扩张,导致心脏重构,形成折返环路,另一方面可能产生心动过速,心动过速重塑可促进心房收缩功能障碍并引起心房扩张 [25]。心房扩张通过增加心房舒张来促进心房重构和纤维化 [26]。CIEDs起搏由于右心室收缩比例较高,可能导致左室收缩不同步进而会导致乳头状肌功能障碍,二尖瓣返流,左心房扩大及压力升高,导致房颤 [27]。此外,R. P. Martins等人在1例案例报告中描述了起搏器VIP模式的一种新的促心律失常效应,当AV延迟 + VIP扩展内未感应到内在R波时,AV延迟可能被认为原始编程值,从而导致维持长时间的AV延迟,这可能有利于逆行VA传导,并启动心脏起搏器介导心动过速,从而产生SCAF [28] [29]。目前关于SCAF机制的研究较少,具体机制尚未完全明确。

5. 心脏植入式电子设备相关心房颤动的并发症及最新治疗

心房颤动常并发卒中、心力衰竭等并发症,它的治疗主要在急性管理,基础和伴随心血管疾病的治疗,中风预防治疗,速率控制和节奏控制五个领域进行长期的多维管理 [30]。亚临床房颤,尽管不同于临床房颤,但是它对临床房颤有很强的预测作用。本综述将围绕SCAF导致卒中、心力衰竭等并发症及最新研究进行进一步论述。

5.1. 心脏植入式电子设备相关心房颤动与卒中

5.1.1. 心脏植入式电子设备相关心房颤动与卒中风险

房颤与缺血性卒中密切相关。血管栓塞性事件在很大程度上可以通过抗凝治疗来预防 [31]。目前指南指出阵发性性以及持续性心房颤动的应进行CHA2DS2-VASc和HAS-BLED评分权衡利弊行预防性抗凝治疗 [32]。然而,在有阵发性心房颤动的患者中,心房颤动的频率和持续时间是高度可变的,传统的检测方法缺少长期监测,不能对房颤负荷进行量化。本文涉及的SCAF多表现为无症状房颤,这为抗凝时机的选择增加了难度。我们提出这样一个疑问:是否存在房颤负荷临界值,SCAF相关的卒中风险明显增加。

不同的研究对于SCAF定义存在不同,并且血管栓塞事件发生率也存在差异。RATE研究对5379名CIEDs植入患者进行了22.9个月的随访,比较心动过速和/或房颤(device-documented atrial tachycardia and/or fibrillation) (AT/AF)短暂发作与无AT/AF事件发现增加的临床事件风险无差异 [33]。TRENDS也验证了这一观点,该研究发现患者30天内无或较低的AF负荷与血管栓塞事件发生无关。但当血管栓塞事件发生的前30天内AF持续时间 > 5.5小时,血管栓塞事件发生风险翻倍 [34]。ASSERT研究中,Healey等人发现SCAF持续时间 > 17.7 h小时是缺血性中风或系统性栓塞的独立风险因素,并且是无SCAF发生卒中风险的2.5倍 [9]。Van等人对ASSERT实验进一步探索发现SCAF的持续时间与卒中或系统性栓塞的风险中有关,并且该研究进一步指出SCAF > 24小时可能是卒中风险较高的阈值 [35]。SCAF的持续时间与卒中风险之间存在相关性,高风险与较长发作期相关 [33]。MOST、PANORAMA研究也发现了SCAF与血管栓塞事件密切相关 [36] [37] [38]。不同于ASSSERT,MOST,TRENDS、PANORAMA三项研究的并未除外既往存在房颤病史的患者。结果存在一定的偏移。Botto等人尝试通过将SCAF的负荷与CHADS2分数相结合来分层中风的风险,此项研究发现CHADS2 = 1分、SCAF > 24小时的患者,以及具有CHADS2 > 2分和SCAF ≥ 5分/天的患者,与CHADS2得分较低的SCAF的患者相比,中风的风险明显增加(每年约5%) [39]。SOS AF研究来自5个研究中的10,016患者中,发现随访期间95例患者发生缺血性卒中或TIA,年发生率为0.39%。设备检测到的心房颤动日负荷与CIEDs患者中缺血性卒中风险增加相关。心房颤动每日持续时间每增加1 h,栓塞事件增加3%。其中心房颤动日负荷的增加与年龄、CHADS2评分和既往卒中的存在显著相关。并且发现1小时为卒中风险增加的阈值 [38]。SOS AF研究同样未除外既往存在房颤病史的患者。Giuseppe等人进一步研究,选取部分SOS AF研究的部分数据,来自3个研究项目的6580名CIEDs植入患者,既往无房颤病史及无使用抗凝药物史,发现AF日负荷越高,CHADS2 ≥ 2分,越易进展为更高负荷的心房颤动。从较低AF负担向较高AF负担转变的独立预测因子为年龄 > 75岁,男性,高血压。并且AF负荷增加与卒中风险增加相关 [12]。Van Gelder等人指出SCAF在许多病例中可能为因果关系;但他们也发现在超过40%的病例中,SCAF可能只是作为一种风险标记 [35]。此项研究的SCAF患者通常是老年人,有心血管疾病和高血压病史,这使他们处于中风的高风险中。SCAF致卒中涉及的机制可能更复杂,不仅仅是左房血液淤积、血栓形成,可能造成心房和血管内皮功能障碍,SCAF在某些情况下可能是因果关系,而在其他许多情况下,大多数SCAF持续时间 < 48小时,尚未能形成附壁血栓,SCAF可能只是作为血管风险标记。

5.1.2. 心脏植入式电子设备相关心房颤动与隐匿性卒中

亚临床房颤是临床房颤较强的预测因子,并与卒中风险升高相关,尽管其风险低于临床房颤 [11]。一部分的短期监测研究也表明,亚临床性房颤在一些隐源性卒中患者中存在 [40] [41]。ASSERT研究指出亚临床心房纤维性颤动与隐源性卒中之间存在联系。亚临床房颤常先于临床房颤发生。在没有临床房颤的CIEDs患者中,发生SCAF明显增加了继发卒中的风险 [9]。CRYSTAL AF研究中发现植入式心脏设备在隐源性卒中之后AF的监测(8.9%)高于普通动态心电图监测(1.4%),其中年龄、PR间期是独立因素 [42]。另一项研究指出72%急性卒中患者在卒中发生30天内有房颤、新发房颤或房颤加重现象,房早 ≥ 500次/24小时可以令SCAF检出率 ≥ 25% [43]。Sieweke等人发现房间隔总传导时间可能是是隐匿性卒中患者合并亚临床AF的独立预测因子,可能协助这些患者进行风险分层的临床决策 [44]。根据目前的研究可以明确隐匿性卒中与SCAF密切相关,隐源性中风后AF的检测可能会将治疗方法从抗血小板治疗改为口服抗凝剂,以预防继发性中风。但缺乏证据进一步明确两者的时间关系及是否互为因果关系。

5.1.3. 抗凝治疗

Alexander等人发现在一项回顾性研究发现,目前SCAF患者使用抗凝治疗明显低于临床房颤,SCAF 90天内的抗凝治疗差异较大,随着房颤负荷增加,卒中风险也明显增加 [45]。由于缺乏充分证据,目前SCAF的治疗尚未明确。对于低中风险患者的抗凝治疗的获益与否,如何防止AF进展的风险管理,以及新的风险分层新方法,仍然存在疑问。有学者提出SCAF发生至少1次且持续时间 > 24小时的患者,中风的风险最高,接受抗凝治疗的患者的卒中风险降低 [45]。对于CHA2DS2-VASc评分 ≥ 2分且SCAF持续时间 ≤ 6分钟,中风的风险非常低,不开始抗凝治疗是合理的;然而,对于在CHA2DS2-VASc评分 ≥ 2分,SCAF持续时间从6分钟到24小时不等的患者,进行抗凝治疗的风险与益处几乎没有共识 [46]。欧洲心律协会(EHRA)建议每日AHRE ≥ 5.5小时且CHA2DS2-VASc得分 ≥ 2 (女性 ≥ 3)的患者进行抗凝治疗。在具有多种危险因素的患者中,AHRE持续时间较短的患者也应考虑抗凝治疗 [47]。目前正在进行的2项随机对照试验,ARTESiA (NCT01938248) [48] 和NOAH-AFNET 6 (NCT02618577) [49] 将进一步明确SCAF的抗凝治疗方案。在ARTESiA研究中,在至少发生1次SCAF持续 ≥ 6分钟,但<24小时的患者中,分别使用阿哌沙班与小剂量阿司匹林进行预防性抗凝治疗。主要疗效为卒中或全身性栓塞;关键的安全终点是大出血。其目的为评估房颤高发期患者口服抗凝治疗的益处和风险 [50]。在NOAH研究中,相似的患者被随机分为依多沙班和小剂量阿司匹林或安慰剂组。主要的疗效结果是卒中、全身性栓塞或心血管死亡的综合指标,而主要的安全终点是大量出血或全因死亡 [51]。

5.2. 心脏植入电子设备心房颤动与心力衰竭

心房颤动进展与心力衰竭密切相关,但两者涉及的机制尚未明确 [52]。由于SCAF的负荷时间延长而引起心动过速,持续的快速心室率增加了心室负荷导致左室功能障碍,导致心力衰竭 [16] [53] [54]。心房收缩在心力衰竭患者的心输出量中占相当大的比例,在SCAF发作期间心房收缩不规则失去了心房对心输出量的贡献,也可能是心力衰竭风险增加的部分原因 [55]。结构改变,如心房增大和房壁破裂,可能导致心房收缩障碍和二尖瓣反流。这些变化也会增加心室的负荷 [56]。心肌炎症和纤维化可能导致舒张功能障碍 [57] [58]。异常的钙处理(L型Ca+通道下调)、肾素–血管紧张素–醛固酮系统的激活以及在SCAF延长发作期间钠尿肽的调节也可能使HF发生 [53] [57] [59]。此外神经内分泌的刺激、交感神经刺激、促炎症状态也可能是造成心力衰竭的原因 [60]。

在一项涉及47个国家15,400名被诊断为心房颤动的前瞻性研究中,显示心力衰竭是最常见的死亡原因,占30%,并且心力衰竭住院的风险是中风的3倍。预防心力衰竭死亡应该是心房颤动治疗的主要重点 [61]。大多数死亡与心血管起源有关,而心力衰竭是房颤患者最常见的死亡原因。尽管房颤相关的中风风险很高,但只有7%的人死于中风 [62]。来自RE-LY (长期抗凝治疗的随机化评估)试验的18,000多例患者的数据显示,房颤患者死亡的最强预测因子不是中风,而是慢性心力衰竭或心肌梗塞病史 [63]。最近的一项荟萃分析显示,伴有心房颤动的心衰患者的心衰恶化风险显著增加(HR = 1.88) [64]。另有2项前瞻性研究显示心房颤动与心力衰竭的长期风险增加相关 [65] [66]。上述研究强调了早期心房颤动检测对预测心力衰竭的重要性。

最近的3项研究发现CIEDs患者新发的SCAF负担增加与心力衰竭恶化风险有关 [16] [21] [67]。其中Yutaka等人发现在CIEDs植入患者发生房颤,其心力衰竭恶化风险增加 [16]。Nishinarita等人对104名CIEDs植入患者进行1年的随访,观察到有34位患者出现SCAF。SCAF组的发生心力衰竭事件多于非SCAF组。根据SCAF的负荷将其分为高、低和无三组。其中12名患者(12%)出现到心力衰竭恶化。通过Cox回归分析发现SCAF和SCAF负担增加是导致心衰恶化的独立预测因素。SCAF高负荷组比非SCAF组出现心力衰竭风险更高,在6个月期间,SCAF高负荷持续时间 > 22小时的患者比未检测到SCAF的患者因心力衰竭而恶化的风险高7.9倍。但SCAF低负荷组和非SCAF组之间没有发现显着差异 [21]。SCAF是心力衰竭恶化的独立预测因素 [21]。Jorge等人在ASSERT研究中选取415位SCAF持续时间在6分钟~24小时的患者,发现有65位(15.7%)患者发生房颤进展(持续时间 > 24小时)或者临床房颤(常规心电图或者体外监测仪检测超过6分钟的房颤),心房颤动进展的年发生率为9%。并且在年龄较大,体重指数高和的SCAF持续时间较长的个体中更常见。随着CIEDs植入时间的延长,SCAF最长的持续时间也上升。SCAF进展的患者的SCAF负荷从第一年的中位数6.7小时逐渐增加到第四年的中位数153.2 h,而无进展的患者在整个随访过程中的心房颤动水平均非常低。进展的SCAF患者每年的心衰住院率为8.9%,而无进展的患者每年的住院率为2.5%。作者通过单因素统计和多因素回归分析,均发现SCAF进展是心衰住院的一个独立预测因素 [67]。

因此,我们可以通过估计CIEDs植入后早期的SCAF负荷来预测未来心力衰竭恶化的风险。无症状、长期负担的房颤应考虑早期干预,降低心力衰竭恶化的风险 [21]。当检测到SCAF时,应尽可能改变生活方式:减轻体重以改变肥胖;治疗睡眠呼吸暂停的疗法应始终贯彻和使用;减少过量饮酒;应停止吸烟;糖尿病患者的血糖水平应谨慎控制;应对诸如高血压等并存疾病的药物进行优化,以防止疾病进展。这本身将导致房颤和心衰的住院率和发病率下降 [60]。

6. 心脏植入电子设备房颤的治疗总结与展望

在植入心脏装置的患者中,亚临床心房颤动较为常见。这些患者常为高龄、合并高血压病史、冠状动脉粥样硬化心脏病病史、心力衰竭病史等危险因素。亚临床房颤,尽管不同于临床房颤,但是它对临床房颤有很强的预测作用,并与卒中风险升高、心力衰竭加重相关。目前对于SCAF的治疗管理尚未明确。无症状、长期负担的房颤应考虑早期干预,改善生活方式如减轻体重、增加身体活动、避免过量饮酒等生活方式干预措施,改善高血压、心衰等危险因素。目前关于SCAF是否进行抗凝仍存在争议。根据目前不完全的证据,对于没有卒中危险因素的患者或那些只有非常短暂的心房高频率事件的患者,延迟抗凝似乎是合理的,但对于有卒中、TIA或其他卒中危险因素的患者,如何治疗目前尚无充分的临床证据。2个正在进行的研究ARTESiA和NOAH,将有助于阐明SCAF的临床相关性,并指导短期发作患者的治疗决策。

文章引用

卢江婷,沈智达,杨 莹. 心脏植入式电子设备相关心房颤动最新研究进展
The Research Progress of Cardiac Implantable Electronic Device-Identified Atrial Fibrillation[J]. 临床医学进展, 2020, 10(03): 222-231. https://doi.org/10.12677/ACM.2020.103036

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