2022, Vol. 29
2. 上海市心血管病研究所，上海 200032;
3. 复旦大学附属中山医院心内科，上海 200032
2. Shanghai Institute of Cardiovascular Disease, Fudan University, Shanghai 200032, China;
3. Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
扩张型心肌病（DCM）是一组表现为单侧或双侧心腔扩大伴收缩功能障碍的异质性疾病。其临床发病率约为1/250，多为散发，35%的患者有明确家族史，而约50%的患者病因不明确[1-3]。DCM患者临床表现个体差异性大，表现为不同程度的心腔扩大和心功能障碍，部分患者以恶性心律失常、传导阻滞为主，伴或不伴其他系统疾病，猝死率高。其主要病理表现为心肌细胞凋亡、自噬异常、线粒体功能异常、炎症反应等，组织学表现为心肌坏死和纤维化[4]。DCM可归因于遗传和非遗传因素，非遗传因素包括炎症、感染、心动过速、甲状腺功能亢进等。其临床病理表现的复杂性给临床医生对患者预后的评估及进展机制的阐明带来了重大挑战。
随着基因二代测序技术的发展，DCM基因组学被逐渐揭示，目前已有40多个致病基因被报道，如编码肌小节、细胞骨架蛋白、离子通道、线粒体、桥粒等的相关基因[5-6]。同时，随着对基因致病机制的研究，该疾病的遗传异质性（不同基因突变导致相同的临床表型或相同的基因突变导致不同的临床表型）以及表观遗传学在其进展过程中的调控作用也逐渐被发现。本文将DCM遗传学基础、发病机制及调控机制主要研究进展进行综述。
1 DCM的遗传学基础和发病机制DCM的遗传方式多种多样，以常染色体显性遗传为主，其他包括常染色体隐性遗传、X连锁遗传和线粒体遗传等。DCM致病基因编码一组心肌异质性成分，包括细胞骨架、肌小节、离子通道、线粒体及桥粒等（表 1）。目前最常见的致病基因依次为TTN、MYH7、LMNA、TNNT2、RBM20[5-6]。
| 基因 | 遗传咨询推荐 | 遗传方式 | 其他心肌病表型 |
| 肌小节 | |||
| MYH6 | 推荐 | AD | HCM |
| MYH7 | 推荐 | AD | HCM, LVNC |
| TPM1 | AD | HCM, LVNC | |
| ACTC1 | AD | HCM, RCM, LVNC | |
| TNNT2 | 推荐 | AD | HCM, RCM |
| TNNC1 | AD | HCM | |
| TNNI3 | AD, AR | HCM, RCM | |
| MYBPC3 | 推荐 | AD | HCM, RCM, LVNC |
| TTN | 推荐 | AD, AR | HCM, RCM, ARVC |
| 细胞骨架相关 | |||
| DES | 推荐 | AD, AR | HCM, RCM |
| FLNC | HCM, RCM, ARVC | ||
| VCL | HCM | ||
| 核表面 | |||
| LMNA | 推荐 | AD, AR | HCM |
| EMD | XLR | ||
| SYNE1 | AD, AR | ||
| Z带 | |||
| ACTN2 | AD | HCM | |
| BAG3 | AD | RCM | |
| CRYAB | AD, AR | RCM | |
| TCAP | AD, AR | HCM | |
| MYPN | 推荐 | AD, AR | HCM, RCM |
| CSRP3 | AD | HCM | |
| NEXN | AD | HCM | |
| ANKRD1 | 推荐 | AD | HCM |
| LDB3 | AD | HCM, LVNC | |
| Dstrophin复合体 | |||
| DMD | 推荐 | XLR | |
| SGCD | AD, AR | ||
| 桥粒 | |||
| DSC2 | AD, AR | ARVC | |
| DSP | 推荐 | AD, AR | ARVC |
| DSG2 | AD | ARVC | |
| PKP2 | AD | ARVC | |
| 离子稳态相关 | |||
| PLN | AD | HCM | |
| RYR2 | AD | ARVC | |
| DOLK | AD | ||
| SCN5A | 推荐 | AD，AR | ARVC |
| KCNQ1 | AD | ||
| 线粒体 | |||
| CPT2 | AD, AR | ||
| DNAJC19 | AR | ||
| SDHA | AD, AR | ||
| TAZ | XLR | ||
| CTF1 | AD, AR | ||
| 其他 | |||
| RBM20 | 推荐 | AD | |
| RAF1 | 推荐 | AD | |
| EYA4 | AD | ||
| LAMP2 | XLD | HCM | |
| AR：常染色体隐性遗传；AD：常染色体显性遗传；XLR：X染色体隐性遗传；HCM：肥厚型心肌病；ARVC；致心律失常型右室心肌病；RCM；限制型心肌病；LVNC：左室致密化不全。 | |||
TTN基因编码已知在心脏中表达的最大蛋白（达35 000个氨基酸），即肌联蛋白。该蛋白从Z盘到M带跨越了肌节长度的一半，与细丝和粗丝一起组成肌节，被称为“第三丝”。TTN能调节肌节收缩和信号传递，并通过其弹性结构域（PEVK结构域）影响心脏的舒张功能。在心脏中，TTN基因通过可变剪切编码多个异构体。其中，N2A异构体占比越高，心脏顺应性越好; 而N2B异构体比例增高，心脏的顺应性变差。TTN基因突变是DCM最常见的基因突变，在家族性和散发患者中的突变率分别是25%和18%[7]。其突变以截断突变为主，目前只有小部分的错义突变被报道[8]。在纯合突变小鼠中，TTN缺失会导致肌小节发育异常，导致小鼠在胚胎早期即死亡，而杂合小鼠的表现不尽相同; 蛋白组学分析提示TTN突变后会上调野生型小鼠TTN的表达，使小鼠在正常情况下没有明显的心脏结构及功能异常表现，而在面对应激时，会出现心脏扩大、收缩功能异常及纤维化等表现[9]。因此，携带TTN突变的DCM患者临床表现常不明显，大部分患者表型较轻，只有少数患者表现为恶性心律失常、明显纤维化和线粒体功能异常[7, 8, 10]。另外，编码肌小节其他基因，如MYH7、TNNT2、TNNI3、MYH6、MYBPC3、TNNC1也可以导致DCM[11-12]。肌小节基因突变常导致肌小节收缩和钙离子循环失衡，导致患者出现心功能异常，而因其对钙离子的敏感性不同，会导致心肌向扩张或肥厚两个不同方向发展，其中DCM患者对钙离子的敏感性多降低[13]。
1.2 细胞骨架相关致病基因LMNA编码层纤维蛋白A/C，该蛋白是一种广泛表达的核内膜蛋白，参与多种细胞活动，包括调节基因表达、维持正常核结构的作用。LMNA突变是一种常染色体显性遗传，在DCM患者中占6%~8%。LMNA突变可发生在编码区任何位置，主要以错义和框架突变为主[14-16]，且伴随高心律失常风险，包括窦房结、房室结功能障碍、房颤、室速、室颤等[17]。LMNA编码的核纤层蛋白可以通过网蛋白和钙调蛋白与细胞骨架（中间丝、肌动蛋白）相连，对维持细胞结构有重要作用。LMNA基因敲除小鼠的心肌细胞结构明显紊乱[18]。除维持细胞结构的稳定性外，LMNA还参与调控基因转录，LMNA突变会导致相关基因转录水平改变。在小鼠模型中发现，LMNA N195K突变可导致HF1b/Sp4（参与心脏传导系统发育）表达减少，导致小鼠心肌组织电流信号减弱，该现象也为LMNA突变携带者易出现房室传导阻滞提供了依据; 同时，在LMNA突变的iPSC细胞上发现存在钙离子水平失衡，这为心律失常发生提供了基础[19]。
细丝蛋白C（FLNC）是细胞骨架重要组成部分，参与肌节与细胞膜及细胞间的连接，同时参与细胞内信号转导[20-21]。FLNC突变外显率较高且患者容易出现心肌纤维化及恶性心律失常[22]。在斑马鱼模型中，FLNC突变（I2160F）可导致心肌细胞Z盘和肌小节结构紊乱[23]; 而其纯合无义突变可导致青鳉鱼在胚胎晚期就出现心室破裂和骨骼肌退行性变[24]。另外，中间丝、肌营养不良蛋白复合体（DMD、SGCD等）、桥粒蛋白（DSG2、DSC2、DSP、PKP2）[25-27]、Z盘（MYPN、CSRP3、ACTN2、BAG3、ANKRD1等）[28-29]等细胞骨架相关基因的突变均可导致DCM。
1.3 离子稳态相关的致病基因PLN基因编码的受磷蛋白（跨膜蛋白，52个氨基酸）可通过自身磷酸化调节肌浆网Ca2+-ATP酶(SERCA)，在心肌细胞钙稳态的调节中起重要作用。目前，PLN中的几个显性突变已证实与DCM相关[30]，其中R14del突变最常见，该突变首先在新西兰和德国被报道[31-32]。R14del突变可以导致心肌舒张期肌浆网Ca2+ATP酶对钙离子再摄取减少，从而出现钙超载，导致心律失常的发生[33]。在PLN突变的iPSC细胞中，观察到在核周和细胞质中有大量异常的PLN蛋白聚集及其自噬降解异常[34]。
SCN5A基因编码跨膜钠离子通道，在维持心肌动作电位方面有重要作用。该基因既往在Brugada综合征、特发性室颤、家族性房颤患者中被发现[35-36]，也存在于DCM患者中[37]。携带SCN5A突变的DCM患者有较高的心律失常风险[37]。携带SCN5A突变基因的小鼠出现持续异常心房和心室钠电流，后期出现心脏收缩功能降低和房颤[38]。
1.4 其他致病基因RBM20是一种RNA结合蛋白，在心房和心室中均高表达。RBM20基因突变占DCM相关基因突变的1%~5%[39]。在心脏中，RBM20介导包括TTN蛋白在内的蛋白剪接，其突变可能与TTN截断突变有相似之处[40-41]。RBM20突变细胞肌节变薄，与TTN突变的iPSC心肌细胞有类似表现[42]; 另外，线粒体相关基因（CPT2、TAZ等）[43]、RAF1、EYA4、LAMP2等基因突变与DCM的相关性均有报道[44-45]。
临床中，偶有携带双突变的病例报道。相对于单基因突变携带者，多基因突变携带者往往临床表现更严重。如：LMNA突变的家系中，合并TTN截断突变者的临床表型更重[46]; MYBPC3多突变携带者表型出现时间早，甚至出现在新生儿时期[47]。部分突变携带者除心脏表现外，还合并全身其他系统疾病或表现为特殊的临床综合征，如LMNA、DES、DMD、SGCD突变携带者常合并骨骼肌营养不良[27, 48-49]; DSP上某些特定位点的突变会导致Carvajal综合征，患者临床表现为心脏扩张、羊毛状毛发和皮肤角化[50]。TAZ突变导致线粒体功能异常，携带者发生以骨骼肌病、中性粒细胞减少、生长迟缓以及心脏扩大为特征的Barth综合征[51]。
2 DCM基因型和表型的关系DCM患者有显著的遗传异质性。如PLN R14del突变在新西兰携带者中可引起严重的临床表型[32]，而在波兰人群中引起的表型较轻[52]; TNNI3、TTN、DES可导致DCM，也可导致心肌肥厚、限制型心肌病[53]。KCNQ1突变可导致离子通道疾病，但部分携带者临床表现以心衰为主，因此，其基因型和表型之间的关系仍未完全阐明[54]。鉴于DCM遗传学的复杂性，2019年《单基因遗传性心血管疾病基因诊断指南》仅推荐对有家系共分离证据支持的14个致病基因进行筛查[55]（表 1），并建议在基因筛查中严格按照国际标准解读基因变异的致病性[56]。
虽然DCM与多基因相关，且有明显的遗传异质性，但基因型在疾病诊断和临床决策制定上仍有不可替代的价值。对于临床表现不典型或病因不明确的患者，基因型阳性可以协助疾病确诊和病因诊断，并为其临床预后预测提供一定参考。携带某些突变基因型的DCM患者可有特定的临床表现和预后。对194例LMNA突变携带者的为期57个月的前瞻性随访研究发现，其容易出现恶性心律失常、传导阻滞、终末期心衰，且心源性猝死（SCD）事件明显增加[57]。LMNA突变可表现为单独心肌受累或同时合并骨骼肌营养不良（如Emery-Dreifuss型肌营养不良、肢带型肌营养不良），往往需要早期进行起搏器干预[58]。针对LMNA突变的大规模随访研究[47]得出类似结论，尤其是LMNA截断突变患者恶性心律失常风险更高。因此，对于DCM合并进行性房室传导阻滞或恶性心律失常的患者，应警惕合并LMNA突变，合并时应早期进行起搏器干预，避免不良临床事件的发生。另外，有研究发现PLN[30]、FLNC[22]、DES[59]、和SCN5A[37]与DCM的恶性程度相关，这些基因的突变会导致房室传导阻滞、恶性室性心律失常等心脏节律的紊乱。而且，多个突变携带者往往临床表型更重、预后更差。因此，在制定DCM治疗决策是应充分考虑其基因型。
另外，基因型能为DCM精准治疗提供潜在的靶点，例如：Lee等[60]发现，与对照组相比，在LMNA K117fs突变的iPSC细胞中，PDGF信号通路被激活，且PDGF受体的过度激活与其心律失常表型密切相关，为特异性药物治疗提供了潜在靶点; 在LMNA基因敲除小鼠病变组织（心肌和骨骼肌）中检测到了mTORC1通路的激活，应用雷帕霉素抑制mTORC1通路能明显改善DCM表型[61]; Nair等[62]的研究发现，SCN5A R222Q突变能增强患者心脏钠通道兴奋性，予以钠离子拮抗剂（利多卡因）后可明显改善其心律失常。因此，对基因突变机制的揭示，能为未来DCM的精准治疗提供潜在靶点。
3 DCM基因-获得性因素/环境-表型随着对DCM异质性的认知，近年来研究重点逐渐从对单纯基因型的探讨转变为对基因、获得性因素/环境、表观遗传调控、表型之间关系的探讨（图 1）。基因和获得性因素/环境相互作用影响DCM患者的预后。表观遗传调控对基因表达进行调控，同时受获得性因素、环境等因素影响，作用于细胞内相关通路，从而影响患者的表型和预后，形成复杂的调控网络。
|
| 图 1 扩张型心肌病基因型和表型之间的关系 |
多种获得性因素/环境，如心肌毒性药物、感染、应激、体质量指数（BMI）、妊娠等能影响DCM的发生和发展。酒精和蒽环类抗肿瘤药物是常见的细胞毒性药物，可导致一系列心脏损害，甚至导致严重的心力衰竭。大量酒精摄入会导致氧化应激、交感神经过度激活、血脂异常以及自噬激活。上述多因素协同作用可引起心脏的线粒体功能障碍、能量代谢异常、炎症、心肌细胞凋亡和心律失常等，从而导致酒精性DCM[63]。蒽环类心肌毒性药物会导致心肌活性氧的产生和消除失衡、激活NF-κB通路和炎症免疫系统，导致心肌损害，诱发DCM[64]。体质量、空气质量等亦能影响DCM的发生和发展。一项对1 393 346例受试者进行的为期33年的前瞻性随访研究[65]发现，不考虑基因突变的遗传学背景情况时，在年轻女性中，BMI升高将会导致其DCM发生风险增高，尤其是过度肥胖会增加5倍以上的风险。另一项研究[66]证实，在健康人群和DCM患者中，肥胖均使心脏重构加重，继而引起心室腔扩大。此外，在小鼠DCM模型中，相比对照组，长期暴露于PM2.5的心衰小鼠左右心收缩功能均下降，肺动脉压力升高，且纤维化程度加重（Ⅱ型胶原和TGF-α基因表达增多）[67]。
3.2 表观遗传调控表观遗传通过调控DCM相关基因的表达影响患者的临床预后。其中，非编码RNA和DNA甲基化是近年来的研究热点。
非编码RNA如miRNA（约22个核苷酸）、lncRNA（＞200个核苷酸）参与DCM基因表达的调控。miRNA可与多个特定mRNA结合从而抑制其表达[68]。不同基因突变DCM患者的miRNA水平及其介导的信号通路不同。与对照组相比，TTN突变的DCM患者miR-208b表达上调，而miR-208b是介导心肌重构的重要因子[69]。LMNA突变的DCM患者血清中的let-7a-5p、miR-142-3p、miR-145-5p、miR-454-3p上调; 生物信息学分析发现这些miRNA与转化生长因子β（TGF-β）、Wnt等信号通路相关，可能参与介导心肌纤维化及心肌重构[70]。Verjans等[71]发现，高负荷诱导DCM动物模型miR-221/222明显升高，且参与上调TGF-β介导的SMAD2通路或非SMAD通路活性，从而加重心肌纤维化。而在心肌炎发展为DCM的过程中，不同感染阶段出现不同的miRNA上调和下调，导致下游SIRT1/AMPK/NF-κB、AMPK、RAS通路等相继发生激活或下调，继而影响心肌重构，导致DCM的发生[72-73]。在酒精性DCM中，MiR-1865-p通过调节XIAP基因的表达，诱导心肌细胞凋亡[74]。近年来多项研究[75-80]表明，miRNA对心肌细胞自噬、增殖、纤维化、免疫等过程有重要调控作用，是DCM病理生理过程中的重要调控因子。与miRNA相同，lncRNA在心衰过程中差异性表达[81]，且其表达随血流动力学变化而变化[82]。lncRNA可以通过调节邻近基因转录或特异性吸附miRNA，负向调控其功能，形成lncRNA-miRNA-mRNA的调控网络[83-84]。在小鼠中，上调lncRNA CRNDE可抑制经典纤维化通路中重要因子SMAD3的转录，从而减轻DCM小鼠心肌纤维化的程度[85]。降低lncRNA DCRF的表达可以抑制miR-155b-5p和PCDH17，从而降低心肌细胞自噬，改善心功能[86]。
另外，在DCM发展过程中，DNA甲基化也起重要的调控作用[87-89]。DNA甲基化可使基因组中相应区域染色质结构变化，使染色质高度螺旋化，凝缩成团，失去转录活性。LMNA编码的层纤维蛋白与数百个大型染色质结构域相互作用，调控相关基因表达[90]。该过程主要是通过募集DNA甲基转移酶对CpG岛进行甲基化，从而下调多个细胞代谢、生存相关基因的表达，这也是LMNA心肌病的重要发病机制[91]。另外，Haas等[92]在DCM患者中发现，DNA甲基化可导致LY75等基因表达水平改变，从而诱导心肌的适应性和非适应性重构。在DCM终末期，心肌供能逐渐从脂类供能转化为糖分解，而这一改变是心肌重构的重要过程。Pepin等[93]发现，DNA甲基化修饰参与这一转换过程，在终末期心衰患者中，参与氧化代谢的基因是高甲基化的，而参与糖代谢的基因是低甲基化的。
4 小结近20年来对DCM基因型的探讨，使临床对DCM的遗传学基础有了初步的了解。基因突变者DCM的易感性增加，特定的基因型可为患者的临床诊断、危险分层提供关键信息，从而为精准药物治疗提供靶点。而近年来，对DCM获得性因素/环境、基因对其表型共同影响的探讨及表观遗传学调控的进展进一步提高了临床对于DCM异质性的理解。在DCM发生和进展过程中，基因型-环境-表型模式的作用，及这些因素之间的相互关系仍需进一步研究。
利益冲突：所有作者声明不存在利益冲突。
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