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通讯作者:

徐桂冬,E-mail: laosheng2006@163.com

中图分类号:R541.7

文献标识码:A

文章编号:1007-4368(2024)08-1161-09

DOI:10.7655/NYDXBNSN240074

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目录contents

    摘要

    心房颤动(atrial fibrillation,AF)是人群中常见的室上性心律失常,可引发缺血性卒中与心力衰竭等严重并发症,提高致残率与死亡率。AF的发生涉及多种电生理及病理生理学机制,而以左房(left atrial,LA)心肌纤维化为特征的心房重构是 AF发生、维持复发中的主要促进因素和预测因子。导管消融术(catheter ablation,CA)是有症状或药物难治性AF患者的一线治疗方案,但术后仍有一定的复发率。目前研究已证实,左房纤维化与CA术后AF的复发密切相关。因此,准确评估和量化 LA纤维化的程度对描述AF高危人群、制定个性化消融策略、预测CA术后AF的复发风险至关重要。文章就LA纤维化与AF 的关联性机制、影像学评价、血清学评价等方面作一综述,希望对AF的预防和管理具有指导意义。

    Abstract

    Atrial fibrillation(AF),a common supraventricular arrhythmia,is associated with severe complications,including ischemic stroke and heart failure,significantly increasing morbidity and mortality rates. Its pathogenesis encompasses a wide array of electrophysiological and pathophysiological mechanisms. Central to AF’s onset,persistence,and recurrence is atrial structural remodeling,notably characterized by left atrial(LA)myocardial fibrosis,which acts as a crucial predictive indicator. Catheter ablation (CA)is the preferred treatment for symptomatic or drug-resistant AF,despite a notable recurrence rate post-procedure. Contemporary research highlights a significant link between LA fibrosis and AF recurrence following CA. Thus,precise evaluation and quantification of LA fibrosis are imperative for identifying AF patients at high risk,formulating individualized ablation approaches,and estimating the likelihood of post-CA AF recurrence. This paper thoroughly reviews the interconnected mechanisms between LA fibrosis and AF, encompassing aspects such as imaging and serological evaluations,with the aim of informing AF prevention and management strategies.

  • 心房颤动(atrial fibrillation,AF)简称房颤,指心房丧失规律有序的电活动,代之以快速无序的颤动波,是严重的心房电活动紊乱[1-3]。AF可以无症状或表现为心悸、胸痛、头晕、呼吸困难、气促和疲乏等症状。近年来,AF患病率以大流行的方式上升,目前世界范围内AF患病率为2%~4%,约有6 000万例患者[4]。AF作为临床上最常见的心律失常之一,会明显增加患者卒中、痴呆、慢性肾脏病、心力衰竭甚至死亡的发生风险,为社会带来了巨大的医疗和经济负担[5]

  • 根据《心房颤动诊断和治疗中国指南 2023》及2023年美国心脏病协会发布的《心房颤动诊断与管理指南》[6-7],导管消融术(catheter ablation,CA)是阵发性房颤(paroxysmal atrial fibrillation,PAF)和持续性房颤(persistent atrial fibrillation,PeAF)患者的一线治疗方案。与传统药物治疗相比,CA在改善AF 患者症状、恢复窦律及提高患者长期生活质量等方面均表现出明显的优越性[8]。但目前研究表明,CA 尚不能根治AF。Kornej等[9] 发现,在5年随访中,长期PeAF患者CA后的复发率超过50%,PAF患者CA 后的复发率也高达 20%。预测 CA 后 AF 复发的因素众多,包括年龄、AF类型、病程、慢性肾功能不全以及其他心血管病危险因素,但这些因素对 AF 复发的预测价值尚存在争议[10-11]。相关研究已证实,左房结构重塑程度与 CA 的成功率呈显著负相关,可作为AF手术结局的预测指标[12-15]。左房结构重塑是指左房心肌细胞在应对机械、代谢或电应激源时发生的时间依赖性结构、功能和/或电改变,而左房纤维化是左房结构重塑的标志,也是 AF 永久存在的基础[16]。目前有多种技术检测方法可以对左房纤维化的存在及范围进行全面评估和量化,有利于更好地选择 CA 的候选者、规划消融策略以及预测术后复发风险[17]。基于此,文章就左房纤维化与 AF的关联性、CA技术的发展、左房纤维化检测技术的应用进展与局限性进行总结,为 AF 患者的管理提供新思路。

  • 1 左房纤维化与AF

  • AF的发生和维持机制包括“触发”和“基质”两种[518]。触发是指肺静脉肌袖处及上腔静脉、冠状窦口、左房后游离壁、左心耳等非肺静脉触发灶的异位放电,是一种快频率冲动,涉及钙稳态失调、自主激活、早期和延迟后去极化的触发活动等。这些异位放电通过过早的心房电激活引发AF,PAF主要依赖这种触发机制引发。然而,PeAF的维持尚需要心房基质的改变,基质也称为“易感底物”,其特征是心房结构重塑,包括纤维化形成、脂肪浸润和淀粉样沉积。心肌纤维化,指心肌细胞的细胞外基质胶原含量过度累积和/或胶原成分发生改变。这会影响心肌组织的传导特性,导致局部传导紊乱和阻滞,增加再进入环路的风险,成为AF持续存在的关键。

  • 实验动物模型研究表明,左房比右房的纤维化水平更高,局灶放电更频繁且有效不应期离散度更大[19]。此外,左房成纤维细胞具有更强的促纤维化细胞活性以及更高的促纤维化因子表达水平[20]

  • 因此,在AF发生发展过程中,左房纤维化具有重要作用。左房纤维化可分为反应性纤维化和修复性纤维化。反应性纤维化,包括间质性纤维化和血管周围纤维化两种,是心脏在面对容量或压力超负荷时,胶原蛋白和其他细胞外基质蛋白在心肌束和血管周围的间质中沉积增加,导致其扩张增厚。修复性纤维化,也称替代性纤维化,以纤维瘢痕组织替代坏死的心肌区域,常在心肌梗死后出现。当左房纤维化区域形成后,通过以下几种潜在机制参与 AF 的发生和维持:心肌细胞间质中细胞外基质的过度沉积使心肌束分离,扰乱其正常的连续性。同时,内插胶原链可以破坏心肌细胞间的正常连接,使横向波向前传导延迟。此外,纤维化屏障的存在可引发“之”字形传导和单向传导阻滞。并且,心肌细胞与成纤维细胞之间形成缝隙连接,二者发生电相互作用,引起自发的异位电活动和折返。最后,成纤维细胞可以通过旁分泌作用影响心肌细胞的电生物活性,具体表现为传导速度减慢、动作电位时程延长和静息膜电位的增加(图1)。因此,纤维化组织可通过破坏细胞结构、细胞间相互作用以及旁分泌效应等机制引发AF的发生和延续[21]。综上,左房纤维化在AF的发生和维持中起到了至关重要的作用,为AF的临床管理提供了病理生理基础。

  • 2 左房纤维化与CA后AF复发

  • 既往研究证实,左房纤维化的程度不仅是 AF 病情进展的标志,也是 AF 消融术后是否能够长期维持窦性心律的一个强有力的预测指标。Mar⁃ rouche等[22] 基于心脏磁共振成像检测的纤维化组织占左房壁总体积的百分比,提出Utah 分级,将左房纤维化程度分为4级,Ⅰ级<10%,10%≤Ⅱ级<20%, 20%≤Ⅲ级<30%,Ⅳ级≥30%。并且,此研究发现,左房纤维化程度每升高1%,AF消融术后复发风险增加6%,二者具有独立相关性。Assaf等[12] 报道左房纤维化区域的分布存在显著差异,左侧肺静脉窦通常表现出更高的纤维化倾向,并且左心耳区域的纤维化程度与 CA 后 AF 的复发密切相关。该研究提示临床医生在制定AF患者个性化消融策略时需考虑左房纤维化区域分布差异,这对 CA 的手术结局十分关键。此外,Yang等[23] 建立了基于左房功能参数和血BNP水平的联合预测模型,用于预测早期 PeAF 患者 PVI 联合线性消融术后 AF 的复发风险。其中,BNP 水平和左房功能参数与左房纤维化相关,可评估因纤维化引起的左房结构和功能改变。该研究结果发现,AF复发患者的最小左房容积指数和血BNP水平较高,而维持窦性心律患者的左房扩张指数和左心耳峰值排空速度较高。

  • 图1 左房纤维化参与AF的发生与维持

  • Figure1 Left atrial fibrosis involved in the occurrence and maintenance of atrial fibrillation

  • 目前,随着心肌纤维化无创评估技术的发展,左房纤维化程度逐渐成为AF消融术后复发的良好预测因素,准确评估左房纤维化对提高手术成功率、指导术式选择以及改善患者长期预后等方面具有重要指导意义。

  • 3 基于左房纤维化的CA

  • 1998年,Haissaguerre等[24] 观察到心房肌延伸至肺静脉产生的局灶激动对 AF 有触发作用,促进了环周肺静脉隔离(pulmonary vein isolation,PVI)射频消融术的诞生,标志着 CA 治疗 AF 新时代的开始。 PVI是AF消融技术的基石,主要作用是有效隔离起源于肺静脉的异常电冲动,2020年欧洲心脏病协会指南建议将其作为所有接受消融治疗患者的Ⅰ类推荐[1]。PVI 治疗 PAF 的成功率高达 70%,然而 PeAF 单纯行 PVI 术的成功率未达预期[25]。因此在 PVI的基础上,还需要心房基质改良的辅助策略来改善PeAF和长期PeAF患者的手术结局。

  • 随着消融策略的持续发展,AF消融术式不再局限于单纯的PVI术,通常在PVI基础上联合线性消融、碎裂电位消融、转子标测消融、神经节消融等[26-27]。近年来,基于左房纤维化的基质消融成为该领域的研究热点。Yamaguchi等[28] 对存在左房低电压区域 (low⁃voltage areas,LVA)的PeAF患者,在PVI的基础上行LVA区域消融,以达到均质化左房病变基质的目的。其中,LVA可以反映左房纤维化的程度。研究结果显示,与单独行PVI术相比,在PVI基础上联合 LVA 的消融术式显著降低了 PeAF 患者术后 AF 的复发率。Kottkamp 等[29] 提出了一种新的有前景的AF个体化消融方法,定义为“盒状隔离纤维化区域”。它是指 PVI 术后在窦性心律下电解剖标测 LVA确定消融范围,进而对严重纤维化受累区域进行点对点消融隔离,其消融线连接到肺静脉隔离线可防止致心律失常小通道的产生,这为 PeAF 患者提供了一种量身定制的基质改良策略。左房前间隔是左房心肌纤维化的常见部位,Bachmann束沿着两侧心房前壁走行,通过心外膜混入左房前间隔心肌可能致心律失常。Sun 等[30] 报道 PVI 联合 Bach⁃ mann束靶向消融可实现左房前壁纤维化区域的完全隔离,进而提高 PeAF 患者术后窦性心律的维持率。最近,多中心DECAAF Ⅱ研究发现[13],在PeAF 患者中,PVI结合心脏磁共振指导下的左房纤维化消融并不能提高手术成功率,但亚组分析显示,对于纤维化程度较轻的患者磁共振引导下的纤维化消融可改善手术结局。因此,针对不同的患者,制定个性化消融方案对降低 AF 患者 CA 后复发率具有重要意义。

  • 4 评估左房纤维化的技术手段

  • 4.1 经胸超声心动图(transthoracic echocardiogra⁃ phy,TTE)

  • TTE是评估心脏结构和功能最广泛、最成熟的方法。在 AF 患者中,左房心肌细胞变性和纤维化早期可导致左房主动收缩功能丧失、储存功能受损等功能改变,晚期可导致左房容积扩大等结构改变,TTE相关的左房结构和功能参数可间接反映左房纤维化程度[31-32]。Njoku等[33] 报道,与未复发患者相比,CA后AF复发患者的平均左房容积(left atrial volume,LAV)和 LAV 指数(left atrial volume index, LAVi)更大,并且 LAV/LAVi 的增加与CA后频繁的 AF复发独立相关,LAV/LAVi每增加1个单位,AF复发的概率就增加3%。此外,TTE还可以对左房功能进行量化,Chou等[34] 发现左房射血分数是CA术后 AF复发的独立预测因素,也是接受重复消融手术患者 AF 复发的预测因子。因此,左房的大小和功能可以作为一种风险评估指标,当与 AF 复发的其他预测因素相结合时,有助于优化CA候选者的选择。

  • TTE目前是临床心超检查中最重要、最基本的检查之一,但TTE易受左房不规则扩大、胸腔限制、依赖几何假设、观察者之间及内部差异等因素的影响而低估LAV,且在1个心动周期中对左房多次描绘费时费力,重复性欠佳。

  • 4.2 斑点追踪超声心动图(speckle tracking echocar⁃ diography,STE)

  • STE是一种新兴成像技术,通过分析左房应变 (left atrial strain,LAS)及应变率(left atrial strain rate,LASR)对心动周期中左房心肌的主动变形进行评估[35]。其中,LAS是指左房心肌发生形变的能力, LASR 指心肌发生形变的速度,二者可以反映左房储器、管道和泵的功能。已有研究表明,LAS可作为左房纤维化的间接标志物,能更早期发现左房功能变化,突破了传统心超仅能通过评估左房大小而反映重构的限制[36]

  • STE对预测AF患者CA后的复发具有重要的临床意义。有研究对 82 例非瓣膜性 PAF 患者用 STE 测定了左房3个功能时期的LAR和LASR。结果发现,反映左房顺应性的左房储器期应变(left atrial strain reservoir,LASr)和左房管道期应变(left atrial strain conduit,LAScd)是CA结局强而独立的预测因子,LASr每增加1%,CA成功的概率就增加135倍[37]

  • STE技术具有安全无创、可行性高和重复性好等特点,是评价心脏结构和功能的首选方法[38]。但是,STE对图像质量和时间分辨率过分依赖,需要清晰显示心内膜结构,对于肥胖、肺气肿、乳房假体患者的图像分析具有一定挑战。

  • 4.3 组织多普勒超声心动图(tissue doppler imaging, TDI)

  • 最近,有研究提出TDI测得的总心房传导时间 (total atrial conduction time,PA⁃TDI)可以作为心房重构的标志,PA⁃TDI是指左房总传导时间中,体表心电图中Ⅱ导联 P 波与组织多普勒成像中 A’波波峰(心房速度峰值)之间的时间差。该指标通过估计总心房传导时间,直接评估心房肌的电和解剖表现,可反映左房纤维化的程度,并与左房功能障碍密切相关。相关研究表明,PA⁃TDI能全面量化心房重构程度,在改善临床实践中的 AF 风险分层和管理方面具有潜在的作用[39]。Dons等[40] 报道应用TDI 获得的心肌做功指数增高与主要心血管不良事件的发生独立相关,可用来评估 AF 患者心律失常期间的心功能,为临床医生提供AF患者的预后信息。

  • TDI具有操作简便、应用广泛等特点,但它具有角度依赖性,易受心脏摆动和呼吸运动的影响,在反映心肌运动方向和评估心功能方面具有一定局限性。

  • 4.4 延迟钆增强核磁共振显像(late gadolinium enhancement magnetic resonance imaging,LGE⁃MRI)

  • 过去数年中,LGE⁃MRI已经成为容量分析的金标准,可以精确定位心内膜边界,完整测量左房容积。更重要的是,它可以识别、量化和表征心房纤维化。

  • LGE⁃MRI可以在术前帮助制定消融策略、术中引导消融以及术后评估残余病变。Siebermair等[41] 建议根据Utah分级来筛选CA的候选者,Ⅰ级、Ⅱ级和局限性Ⅲ级的AF患者首选PVI联合左房后壁及间隔部消融,而弥漫性Ⅲ级和Ⅳ级患者则首选药物治疗,这提示术前通过LGE⁃MRI评估左房纤维化程度有助于指导消融术式的选择。并且,在术中使用 LGE⁃MRI 可以对心房解剖结构、纤维化基底、导管位置和消融病灶进行实时评估,极大提高了手术效率,同时也减少医护人员及患者的辐射暴露时间[42]。此外,CA 后 LGE⁃MRI 检测到的左房残余纤维化也与AF复发高度相关。左房残余纤维化是由基线左房纤维化减去消融瘢痕所得,Akoum等[43] 发现术后未被永久性瘢痕组织覆盖的残余纤维化区域与房颤复发高度相关,残余纤维化的面积每增加1%,AF复发的风险就会增加8%。

  • 相比超声心动图和电解剖标测,LGE⁃MRI不会受到壁追踪错误或缺乏组织接触的影响,被认为是评估左房结构和功能的金标准。然而,LGE⁃MRI对左房纤维化的量化受以下因素的影响:钆造影剂的剂量、图像采集时间、薄壁的复杂分割以及患者肾功能、血细胞比容、体重指数、潜在心率等。并且, LGE⁃MRI在临床暂未大规模普及,未来还需要进一步的研究和技术支持来扩大应用。

  • 4.5 多层螺旋心脏计算机断层扫描(multidetector computed tomography,MDCT)

  • MDCT可通过评估心外膜脂肪组织(epieardial⁃ adipose tissue,EAT)预测 CA 后 AF 的复发率。EAT 是位于心肌与心外膜间的脂肪组织,紧邻左房后壁,通过直接浸润心肌或分泌纤维化因子、脂肪因子、炎症介质等参与左房纤维化的形成。Shao等[44] 发现MDCT测得的左房EAT体积和密度衰减值与电解剖标测的左房LVA具有明确的相关性,可间接评价左房纤维化的程度。另外,Huber 等[45] 报道左房增强 EAT 体积分数是 CA 术后 AF 复发的独立预测指标,其中增强EAT体积分数>33%与AF高复发风险相关。

  • 与 MRI 和 TTE 相比,MDCT 具有更高的空间分辨率和更短的图像采集时间,但存在时间分辨率低、辐射暴露以及肾功能不全和对碘造影剂过敏者禁忌使用等缺点。随着综合评估参数的使用和新型成像生物标志物的出现,MDCT 逐渐成为 LGE⁃ MRI的一个有吸引力的替代选择,特别是对后者有禁忌证的患者[46]

  • 4.6 心电图(electrocardiogram,ECG)

  • ECG 是临床实践中常见且便于操作的工具。其中,P波持续时间可以间接反映左房纤维化的程度并预测AF术后复发的潜在倾向。房间传导阻滞 (interatrial block,IAB)反映左房和右房之间的传导延迟,ECG 上表现为 P 波增宽,持续时间≥120 ms。根据P波形态分为两种类型:Ⅱ、Ⅲ、aVF导联P波为正向且伴有双峰或切迹为部分性 IAB;Ⅱ、Ⅲ、aVF 导联的P波正负双向为进展性IAB。Phrommintikul 等[47] 的研究表明 IAB 与 LGE⁃MRI 测得的左房纤维化区域具有明确的相关性。Ciuffo 等[48] 也报道,进展性IAB患者左房容积更大、排空分数更低且纤维化程度更严重。此外,Wu等[49] 发现,与部分性IAB 患者相比,进展性IAB患者在PVI术后AF复发的风险增加,并且该研究提示进展性IAB联合左房直径可以独立预测CA术后AF的复发风险。因此,临床医生在解读ECG时应更加关注IAB患者,尤其是进展性患者,及时干预已存在的危险因素以达到 AF 的二级预防。

  • 随着技术发展,基于人工智能的12导联ECG逐渐在临床上广泛应用,这对心脏电生理学产生了重大影响,也为临床医生的深度学习提供了机会[50-51]

  • 4.7 电解剖标测(electroanatomical mapping,EAM)

  • 在接受消融治疗的AF患者中,心内EAM 通过检测LVA 来识别左房纤维化的存在、位置和程度。该方法利用了纤维化区域由于存在潜在的传导异常而显示分段电图的原理。目前,LVA已经被证明与 LGE⁃MRI鉴别出的纤维化区域具有良好的一致性。

  • 从临床角度看,EAM测得的 LVA不仅可以预测 AF患者的不良临床结局,也可以协助CA的术式选择。一项观察性研究显示,与未复发者相比,AF复发者具有较低的左房总传导速度和较高数量的左房 LVA,并且AF 复发率随着左房LVA 数量的增加而增加[52]。Kircher 等[53] 证实与传统的根据 AF 类型选择线性消融的方法相比,利用 EAM 标测的电压图个体化制定 AF 基质改良的消融方法,可使 AF 患者从CA中获益更多。相同地,Vlachos等[54] 发现 <0.4 mV的LVA占左房总表面积超过10%时,可强烈预测PAF患者肺静脉隔离术后AF的复发。同时该研究提示,PAF患者在进行左房精细的高密度标测后,使用基质修饰和靶向低电压区域的消融术式可显著改善手术结局。另外,我国陈明龙教授团队原创的“STABLE⁃SR术”式,也是基于EAM标测的结果,该技术在PVI基础上进行个体化基质改良及碎裂电位消融,极大降低了PeAF患者CA术后的复发率,该方法在国际上称为“南京方法”[55]。最近,其团队开展的多中心随机对照研究“STABLE⁃SRⅡ”发现,在PeAF患者的队列中,约一半患者的左房LVA 基质是正常的,额外的LVA消融并没有提高PVI的成功率。根据该研究结果,对于电压图识别的左房基质正常的 PeAF 患者,单独使用 PVI 可以实现良好的节律控制,进而避免了过度消融[56]。然而, “STABLE⁃SRⅢ”研究显示,对于65~80岁的PAF患者,在PVI术后进行额外的LVA消融可显著降低术后AF复发率,极大改善了患者的预后[57]

  • EAM是AF行CA中重要的检测手段,可确定左房纤维化区域的存在而进行靶向消融,明显提高了手术效率。但EAM易受到电极类型、电极间距、导管方向和组织接触等因素的影响。并且,目前尚无标准化的低电压阈值来定义异常心房组织,传统的 LVA 定义为双极电压幅值≤0.5 mV,瘢痕组织定义为双极电压幅值≤0.05 mV,这尚未得到组织学验证。特别是,EAM具有侵入性,不能作为临床常规的检测手段,限制了诊断性的随访调查。

  • 4.8 生物标志物

  • 4.8.1 胶原肽

  • 在人类心房中,Ⅰ型和Ⅲ型胶原是最重要的两种纤维胶原类型。其中,前Ⅰ型胶原羧基末端肽 (C ⁃terminal propeptide of procollagen typeⅠ,PICP) 和前Ⅲ型胶原氨基末端肽(procollagen typeⅢamino⁃ terminal propeptide,PIIINP)是二者合成过程中的产物。Swartz 等[20] 发现血清 PICP 和 PIIINP 水平与 LA 纤维化程度密切相关,可作为心脏术后AF发生的独立预测因子。Ravassa等[58] 研究证明,Ⅰ型心肌胶原过量的交联及沉积与 CA 后 AF 复发风险明显增加相关。

  • 4.8.2 微小RNA(microRNA,miRNA)

  • miRNA是一种小型非编码核糖核酸,参与转录后基因表达的调控。目前已发现多种miRNA 参与左房纤维化的发生发展。研究表明,miR29可促进 Ⅰ型和Ⅲ型胶原蛋白的大量沉积,miR21通过多种机制诱导心肌纤维化的形成[59]。此外,miRNA也可作为 CA 后 AF 复发的预测指标。Lage 等[60] 发现左房血浆中miRNA⁃451a的浓度可以预测PVI术后AF 的复发风险。miRNA 种类众多,敏感性、稳定性以及组织特异性均较强,可以进行检测和定量,未来临床应用前景广泛。

  • 4.8.3 基质金属蛋白酶(matrix metalloproteinase, MMP)和金属蛋白酶抑制剂(tissue inhibitor of metal⁃ loproteinase,TIMP)

  • MMP和TIMP通过参与细胞外基质的合成与降解、诱导心肌细胞连接蛋白消失等作用参与心房重构,二者协同参与了 AF 的发生发展过程。研究证实,MMP⁃9、TIMP⁃1、TIMP⁃2、TIMP⁃3、TIMP⁃4参与左房纤维化的形成[61]。另外,Mukherjee 等[62] 研究发现,MMP⁃9、MMP⁃3、TIMP⁃4 可独立预测 AF 术后复发,并且三者联合可提高预测率,对指导AF的分层和治疗具有重要意义。

  • 4.8.4 转化生长因子β(transforming growth factor⁃β, TGF⁃β)

  • TGF⁃β是目前研究最广泛的致纤维化因子,分为TGF⁃β1、TGF⁃β2和TGF⁃β3,其中TGF⁃β1是其致纤维化作用最强的亚型之一。Kim等[63] 报道AF患者血清 TGF⁃β水平与左房容积和左房 LVA 呈正相关,间接反映左房纤维化程度。Tian等[64] 发现TGF⁃ β1是AF复发的独立预测因子,且与左房直径相比有递增的预测价值,PAF患者消融前血浆TGF⁃β1浓度和左房直径相结合可能更有助于识别CA的获益人群。

  • 4.8.5 晚期糖基化终末产物(advanced glycation end product,AGE)

  • 在血糖过高、氧化应激、炎症等情况下,蛋白质和脂质分子通过发生非酶糖基化反应,形成AGE。它的特异性受体(receptor for advanced glycation end product,RAGE)属于免疫球蛋白受体超家族的模式识别家族,二者协同参与了 AF 的发病机制。研究发现,AEG促使胶原蛋白相互交联,使其弹性丧失,心肌顺应性下降,进而导致心肌纤维化[65]。此外, AGE⁃RAGE 可通过激活致纤维化细胞因子以及介导炎症反应参与左房纤维化的形成。

  • 4.8.6 可溶性生长刺激表达基因 2 蛋白(soluble suppression of tumorigenicity⁃2,sST2)

  • 近几年,sST2被鉴定为心肌纤维化的新型标志物,参与以心肌纤维化为特征的心房重构,进而介导 AF 的进展及消融术后复发。Wang 等[66] 证实血清 sST2 浓度与左房 LVA 具有明显相关性,并且该指标可以独立预测 AF 射频消融术后的复发风险。 Tan 等[67] 发现,在PeAF患者中,血清sST2 水平升高是CA术后AF复发的标志,并且术前血清sST2浓度≥ 39.25 ng/mL的患者更有可能在术后1年内复发。

  • 在过去的 10 年中,生物标志物不仅可以作为 AF治疗的潜在靶点,也可用于预测CA术后AF的复发风险。值得注意的是,如果存在其他与纤维化相关的合并症,胶原转换生物标志物的水平与经组织学证实的心房纤维化之间的关系可能会受到影响。并且,血浆中纤维化标志物水平可能因采样时的心脏潜在节律而发生变化,尤其是在 AF 发生的情况下,某些生物标志物水平往往比窦性心律时更高。因此,目前更多具有特异性和指导性的新型生物标志物正在被挖掘,以望为 AF 患者的管理带来益处。

  • 5 总结与展望

  • 左房纤维化与 AF 的发生和维持密不可分,它参与AF的结构重塑,反之,AF本身可以促进左房纤维化的形成,进而导致恶性循环。当前医学技术的进步使得左房纤维化的临床评估手段愈发精准,LGE⁃MRI、STE、MDCT、EAM、ECG 等可视化检测方法可以准确量化左房纤维化的程度和模式。此外,血清生物标志物作为一种简单经济的检测方式,对左房纤维化和 AF 复发风险的评估亦具有重要作用。虽然已有许多研究将评估左房纤维化的影像学检查技术与血清学指标联合应用,建立 AF 术后复发的预测模型,但尚无最佳评价标准。目前仍需更多的研究进一步探索左房纤维化与AF消融术后复发间的关系,以期为临床医生早期发现 AF 高危人群,选择CA治疗候选者,调整术中干预策略以及判断预后带来帮助。

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