房颤基质与消融治疗的研究进展

作者:赵鹏[1] 
单位:武警后勤学院附属医院[1]
  心房颤动(Atrial brillation,AF)是临床最常见的心律失常,不同种族人群均有较高的发病率,总体人群患病率约为0.4%,伴随人口老龄化、基础疾病增加以及及筛查方法改善,该病人群总体患病率呈现逐年上升的趋势[1-3]。房颤虽不常直接表现为恶性心律失常,但常常并发脑卒中、心力衰竭、外周血管栓塞,从而显著增加患者致死率和致残率,导致严重的公共健康问题和社会经济负担[4-6]。早年有关心动过速刺激诱发AF的实验[7]中,发现了电重构现象并得出一个重要的结论:房颤维持房颤自身。自此,房颤基质成为研究重点。但直至目前为止,房颤发生与维持的准确机制仍处于未知状态,探寻房颤基质的作用,及时辨明房颤基质的发展程度并进行早期干预,才有可能做到个体化治疗,提高房颤治疗的总体水平。本文将对房颤基质的研究情况作一综述。
一、心肌纤维化与房颤的关系
  临床实践中,我们经常可以看到,具有相同临床特征的房颤病人进行心房电解剖标测时,却出现完全不同的结果。阵发房颤患者反而可能出现更大面积的心房基质异常,这种情况单独用病程、上游疾病严重程度、心房大小、房颤类型等指标来解释,均不能获得满意答案。部分危险因素较少的患者房颤可能处于阵发状态几十年,同样的另一部分患者则可能首次发病就是持续房颤,用快速性心律失常引起的心肌电学重构并不能完美解释这些临床现象。简单的用肺静脉触发灶来解释房颤,将可能出现病理生理和临床特点的不统一,二尖瓣狭窄患者在没有触发灶的前提下,房颤能够长时间持续就是一个典型示例。越来越多证据[8,9]表明,即使是没有任何危险因素的所谓特发性房颤患者,房颤发作时心电持续紊乱的解剖基础来自于心肌纤维化。心房纤维化程度逐渐加重的病理改变解释了Framingham心脏研究[10]中,随着左房增大,房颤发生率增加的现象;也解释了心房在不同的纤维化阶段,出现房早、房速到房扑、房颤的病情演变过程;还解释了临床中常见的房颤与病态窦房结共同出现以及右房房扑消融后并不能避免后期房颤发生[11]的原因,这些临床中常见的现象均是由于心房处于不同的纤维化时期而出现的不同表象。
  心房肌细胞间质纤维化会导致细胞间连接出现异常,最终出现电传导的各方向不同步性,进而出现电学传导缓慢或者电位再次进入,从而触发或者维持包括房颤在内的折返性心律失常[12,13]。当心肌间传导缓慢时,折返只需要在极小的空间内即可形成。Kostin等[14]发现,纤维化的心房内仅需要0.6x2.6mm的空间即可形成一个折返。Boldt等[15]研究中,通过外科手术获得的心房标本中证实心肌纤维化的存在。该研究纳入56例特发房颤、46例房颤合并严重二尖瓣狭窄和16例窦性心律患者,通过获取的心房肌标本染色发现,窦律患者心房肌间胶原蛋白-1表达较少,而特发房颤与合并二尖瓣重度狭窄的患者心房肌间I型胶原蛋白表达量一致。I型胶原蛋白是心肌成纤维细胞的主要产物,换言之,特发房颤与合并二尖瓣狭窄的房颤,其纤维化程度一致。Stiles等[16]为26例恢复窦性心律至少7天的阵发房颤患者进行了电生理检查,发现相比无房颤对照者,心房内电传导减慢,不应期延长,心房内双极电压降低。该研究证实了房颤患者电学紊乱会随着心律变化在数日内出现逆转。Mahnkopf等[17]也通过MRI研究证实了特发房颤患者心房内同样存在纤维化的证据。心房纤维化,将导致心房结构重塑。心房结构重塑包括了心房腔扩大、心房肌间质改变、心房肌细胞超微结构改变等3个方面,其突出特点在于心房纤维化[18]。心房纤维化指异常胶原纤维沉积于正常心房肌细胞间质中,即胶原纤维含量在正常心房肌细胞间质中含量比例增高[19]。正常情况下,纤维组织占心房组织含量的2%-4%,心房纤维化定义为胶原纤维组织含量超过心房组织的10%。房颤患者心房纤维化与Ⅰ型胶原基因表达上调有关,与Ⅲ型胶原关系尚不明朗[20]。
二、房颤基质的本质--心房重构
  心房重构通常包括了结构重构与电重构。心房结构重构的特点是心房扩大和组织纤维化。在心房肌功能正常时,心房大小成为房颤维持的关键因素[21]。心房出现纤维化后,纤维组织打断了正常心肌细胞间的电传导,使电传导不连续,局部出现扰动[22]。心房成纤维细胞与心肌细胞之间互相作用可能导致异常电信号出现[23],纤维化则是房颤维持关键点,也是预测治疗效果的预测因子之一[24],同时,房颤本身也促进了纤维化形成[25],这也是长程持续房颤患者治疗效果不佳的原因[26]。目前研究[27]已经发现,转化生长因子-β1(Transforming growth factor-beta1,TGF-β1)是导致心肌纤维化的信号级联反应中心,可以引起并放大纤维化信号。TGF-β1的基因表达和合成不但可促进细胞外基质的积聚和心肌纤维化,更重要的是其出现先于细胞外基质的改变[28]。在慢性抑制一氧化氮合成的小鼠模型中,其TGF-β1的mRNA水平上调早于可观察到的心肌间质纤维化[29]。在另一项研究中发现TGF-β1水平高的转基因小鼠心房有明显的纤维化,而同样的小鼠心室却没有表现出纤维化迹象,提示TGF-β1对心房肌的影响不同于心室肌[30]。综合上述基础研究结果,可以推断TGF-β1在房颤的早期即起作用,并特异性地作用于心房肌细胞,诱发并促进了细胞外纤维基质积聚引起心房纤维化,进而发展为心房结构重构。
  心房电重构的概念最早由Wijffels 等[7]提出,该研究小组通过给正常山羊心房超速起搏2周后发现,心房有效不应期明显缩短,并由此提出了该概念。目前的研究已经证实,电重构的机制来自于包括:L型Ca离子通道表达降低、乙酰胆碱依赖的K离子通道异常、桥粒分布不均等心肌离子通道、离子泵、离子流等异常所造成。目前研究显示,细胞内钙超载在房颤发病机制中起到关键的作用[19]。心房肌细胞内钙循环主要包括肌质网钙释放、钙回摄、钙储存三个过程。细胞外的Ca2+通过分布于细胞膜上的L-型钙通道内流,形成钙电流作为诱导信号,诱导肌质网钙贮库中的钙被释放到胞质中,肌质网通过钙泵(Ca2+-ATPase,负责舒张期Ca2+回收)、磷酸受纳蛋白(PLB,负责调节钙泵)、兰尼碱受体(RyR2,主要负责收缩期Ca2+释放)、三磷酸肌醇受体(IP3R1,部分负责收缩期Ca2+释放)以及肌集钙蛋白(主要结合Ca2+)等调节心肌细胞内游离Ca2+浓度,维持细胞内钙稳态以协调高效地完成机械收缩全过程,其中任何一个过程异常都将使心肌细胞内钙稳态遭到破坏[32]。K离子流改变在房颤的电重构中也起到一定作用。内向K离子电流(IK1)是心肌细胞主要的内向背景离子流,决定了静息电位和3相复极水平。内向离子电流对于房颤时折返维持有至关重要的作用[33],房颤时,IK1水平上调[19],使静息电位升高,3相复极延长,导致心肌容易出现电学紊乱。另一个重要的内向整流电流是乙酰胆碱介导的K离子电流(IKACh),该电流使内流的K离子出现空间异质性,缩短心肌动作电位时程[34]。房颤发作时,心动过速和Ca超载导致蛋白激酶C构型改变,使IKACh活化[35],从而使房颤得以维持。
三、针对心房基质的射频消融治疗
  不同消融策略背后是对房颤机制的不同理解。多子波折返学说由Moe等[36]在1959年提出,后期通过动物实验[37]证实,该学说认为心房内存在多个独立存在、平等的折返波,这些电波围绕心房内某些传导障碍形成折返。这种障碍可以分布在心房内出现电学传导异常的任意部位,可以是疤痕、结构交错处、纤维化的岛状心肌等。然而,多子波折返假说不易解释为何房颤没有在心电向量和心动周期方面表现出一致的空间不均性[38-40],为何部分病例消融没有形成完整的消融线前房颤就终止[41],以及为何另一部分病例即使反复大面积消融后近期成功率仍然不高[42]的原因。另一方面,试验已经证实了转子[43]或局灶[44]的存在,由这些局部因素引发稳定存在的大折返环[45,46]是房颤发生的另一种机制。在房颤由阵发转变为持续的过程中,心房基质异常程度逐渐加重,对于房颤的维持起到了关键作用[47,48]。
  到目前为止,无论是阵发房颤还是持续房颤,肺静脉隔离消融(Pulmonary vein isolation,PVI)都是治疗的基石[49]。围绕肺静脉(Pulmonary vein,PV)前庭进行的环形隔离方式成功率高于对单个PV隔离的节段消融策略[50]。既往研究[51,52]认为,单纯PVI治疗持续性房颤通常效果欠佳,但近期研究却获得相反的结论。RASTA研究[53]显示,对于持续性房颤,在PVI基础上进行包括非PV触发灶、复杂碎裂电位(Complex fractionated atrial electrograms,CFAE)消融在内的强化消融策略,并没有提高单次手术成功率。PVI术后,无论是否出现房颤复发,PV传导恢复率较高,证明持续的PV隔离并非保持窦律所必需的,这一发现说明在PVI之后更重要的是房颤基质消融。CONFIRM研究[55]对持续性房颤患者采取大环隔离加房顶线性消融策略,发现碰巧有45%病例毁损了房颤源。该研究结果解释了为何PVI对部分持续性房颤有效,为何扩大消融面积可以提高消融成功率,为何部分病例即使PV恢复传导仍然能够保持窦律,为何不采用PVI术式为基础的消融策略同样部分有效。
  基于外科迷宫手术演变而来的包括了房顶、二尖瓣峡部在内的线性消融,同样可以达到部分基质改良的作用[56]。Willems等[57]证实了在PV前庭顶部进行线性消融,可以获得额外的受益。Valles等[58]则发现PV内部同样存在房颤的触发灶。Letsas等[59]在PVI的同时,对PV间的峡部进行连接前后的“θ”式消融,虽然长期效果不错,但并未获得统计学差异。
  心肌间质纤维化是房颤发生维持的重要病理生理改变。Marrouche等[60]研究发现,在房颤患者消融治疗前,采用MRI延迟钆增强扫描,将纤维化心房肌占左心房的范围分为4期:1期(<10%),2期(10%~20%),3期(20%~30%),4期(≥30%)。在475天的随访期内,患者房颤复发率随着纤维化程度增加而增加,纤维化程度每增加1%,房颤复发风险增加6%。心肌纤维化与心房电标测双极低电压存在一定关联。心室标测中,将双极电压<0.05mV定义为疤痕,电压<0.5mV定义为纤维组织已经有良好的对应关系[61],但在心房中尚无准确定义,通常在研究中沿用此标准。Kottkamp等[62]利用Carto-3系统对41例房颤患者进行心房电压标测。左房内点对点标测100-120点,标测集中于后壁、房顶、下壁和前壁。窦性心律下,当压力导管接触力为5-10g,局部电压<0.5mV处定义为低电压区(Low-voltage area, LVA),如患者标测到LVA,则将该区域盒式消融隔离。结果显示,10例房颤复发行再次消融的阵发房颤患者均发现了LVA,对该区域盒式消融后,9例患者均长期保持窦性心律。31例持续房颤患者中13例未发现LVA,仅进行了PVI消融;18例发现LVA者采取PVI+盒式消融。平均随访12.5月,单次手术成功率达72.2%。该研究认为,LVA代表着心房纤维化的区域,对每一例患者均应标测LVA并据此给予个体化治疗。
  复杂碎裂电位(CFAE)在所有类型的房颤患者心房标测时均可看到,对于CFAE电位的理解争议极大,有两种主要的假说来解释CFAE电位。一种是“转子”学说,认为当转子遇到传导异质性的心房基质,CFAE电位就是转子在其边界处产生的附属产物。左房后壁结构复杂,来自PV方向的转子传导到此后,由于传导受阻出现各向异性,表现为电位碎裂,出现CFAE电位[63]。在阵发房颤向持续房颤发展的过程中,由于心房纤维化和细胞微结构改变,来自局部转子的电位传导过程中互相碰撞、干扰、碎裂进而表现为CFAE电位[64]。另一种是“自主神经”学说,认为CFAE电位处是神经节的位置,Lin等[65]研究中,犬心肌局部给予乙酰胆碱可以出现CFAE样电位表现。研究[66]证实,心脏自主神经过度激活可以诱发心房CFAE电位,且主要集中在肺静脉、左房前壁、间隔部、冠状窦、左房顶部和左后间隔二尖瓣峡部等部位。因此目前大多学者认为CFAE电位是由于自主神经系统与心房组织之间复杂、精密的相互作用产生。CFAE在临床中最大的优势是可以指导消融的位点,但是其效果争议较大。对于CFAE的定义,Nademanee等[67]认为是:(1) 心房电位呈两个或两个以上曲折的碎裂波和/或基线在10s内持续曲折;(2) 心房电位在10s内平均周长≤ 0.12s。该团队在不进行PVI的前提下,仅针对CFAE消融,2次手术后1年内使92%的患者保持窦律。但该研究结果受到多方质疑。多中心的STAR AF 2研究[68]中,共入选589例持续房颤患者,按照1:4:4分为单纯PVI组、PVI+CFAE消融组和PVI+房顶+二尖瓣峡部线线性消融组,随访18个月。结果显示,成功率PVI组59%,PVI+CFAE组49%,PVI+线性消融组46%(p=0.15%),该研究显示额外的CFAE消融对成功率并无影响。Narayan等[69]采用多电极导管外加单相动作电位(Monophasic action potentials,MAP)的方法重新定义了CFAE电位,发现了4种CFAE形式,其中仅有8%的CFAE呈现为低电压且具有缩短心动周期的作用,被认为与房颤密切相关,其他CFAE则认为更多来自于远场信号。Jadidi等[70]发现,CFAE的定位点变化很大,窦律或起搏下出现的CFAE更多来自于电波碰撞所致,房颤时CFAE固定出现而窦律下电压正常的区域则是结构性疤痕所在处,该研究小组还发现,CFAE与心房纤维化程度呈现反比关系[71]。
  主频标测是另一种基质探索方法,其目标在于房颤发作时发现频率最高的位点[72],在主频最高的区域通常都是转子出现的位点[73]。高主频位点通常表现为频率极快且没有明显的碎裂波[74]。阵发房颤患者高主频区常位于PV内,持续房颤则位于左房内[72]。回顾性分析[75,76]显示,对于高主频区消融可以减慢或终止房颤,证明了该区域对于房颤维持的重要性。高主频区通常比毗邻区域频率快20%以上,通过快速傅里叶转换方式计算获得[76]。如果高主频区是房颤发生的局灶,则碎裂电位可能在其传播边界处出现。Lin等[77]发现,最碎裂的电位出现在主频最高的位点或其位点的边缘。但遗憾的是,二者同时出现的概率很低。Kumagai等[78]研究显示,PVI后再次进行电标测,仅有高主频区与持续CFAE区仅有14%的重叠率。如何确定高主频区并采取何种方式消融仍然需要进一步探索。
  法国波尔多中心在2005年报道了使用递进式消融策略[79],该策略既考虑了PV隔离,又同时兼顾了上述几种消融方式,是一种相对个体化且更兼顾房颤基质的术式。Haissaguerre[80]对60例持续性房颤患者按照上述步骤进行递进式消融,术中终止了87%的房颤,再次消融后随访11±6个月,成功率高达95%。然而,该术式操作十分复杂且风险较高,平均手术时间长达5~7小时,限制了该术式的临床推广应用,迄今为止的其他中心的类似研究并未表现出与该中心接近的结果。
  对房颤患者进行心脏神经节治疗是另一种思路。心脏受交感与副交感神经双重支配,神经丛(Ganglionated plexi,GP)主要位于心外膜侧,自主神经活性增强可通过影响心肌动作电位时程而促进房颤发生。Schauerte等[81]发现肺静脉开口处有丰富的迷走神经分布,刺激该处神经节可诱发房颤,对这些神经丛密集的脂肪垫进行消融后房颤变得不易诱发。Jackmans实验室[82]在PVI基础上,进一步消融肺静脉开口周围的自主神经丛,随访6个月窦性心律维持率84%,表明肺静脉隔离消融后附加去神经化消融可以提高手术成功率。Pappone等[83]发现在左心房环肺静脉线性消融后, 同时实现迷走神经去神经化可以降低房颤复发,术中无迷走反射发生且不能确定神经消融位点的患者房颤复发率为15%, 发现迷走神经并成功消融的患者复发率仅1%。Platt等[84]单纯采用神经节消融策略治疗房颤,采用超高频刺激确定GP位置(刺激时心率下降50%区域为迷走反射位点) 并进行消融,术中接近90%的患者房颤终止,随访6个月成功率达96% 。但以后其他多个中心GP消融的结果却与此有很大差异,主要争议在于是消融过程中否实现了真正的去迷走神经化以及GP的定位是否准确。由此可见,自主神经在房颤的发生和维持中更倾向于协同作用,自主神经消融可以作为房颤消融的补充,但不推荐作为独立的术消融术式。
  综上所诉,房颤基质目前仍然是一种较为模糊的认识,针对其本质认识还有大量的研究工作需要开展。现阶段对于房颤基质消融的策略也尚无定论,过分强调完全自主的个体化策略不利于规范手术流程和评价手术终点,固定的手术程序又容易以偏概全。综合考量,如果能够结合MRI、超声指标、房颤类型等参数,将房颤患者按照纤维化程度进行简单分层,按照层次不同消融策略各异,同一层次内采取固定消融术式,则是一种既考虑临床实际,又可能进一步提高成功率的思路,在目前的房颤治疗中具有重要的现实意义。
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