摘要：每年报告的心血管疾病新病例超过1200万例，导致欧美有1.13亿患者患病[1]。心脏病导致心肌重塑，这是病理生理刺激（缺血、血流动力学负荷、神经体液激活等）造成的几何和功能改变的组合[2-3]。考虑到该器官的再生能力有限，这些改变可能会损害这些患者的临床结果并
泰达国际心血管病医院 郑 刚
每年报告的心血管疾病新病例超过1200万例，导致欧美有1.13亿患者患病[1]。心脏病导致心肌重塑，这是病理生理刺激（缺血、血流动力学负荷、神经体液激活等）造成的几何和功能改变的组合[2-3]。考虑到该器官的再生能力有限，这些改变可能会损害这些患者的临床结果并导致心力衰竭（HF）。心脏重塑是一个多细胞过程，涉及不同的心肌细胞类型和细胞外基质（ECM），包括分子到器官水平的适应。随着心脏重塑，重要的细胞变化（如肥大、兴奋-收缩偶联、炎症、细胞存活信号和线粒体紊乱）和ECM改变（如纤维化）会影响重塑的进展和严重程度[2]。
1.心脏逆向重塑（RR）概念
逆向重塑一词被定义为心脏经历结构和功能变化，导致改善或恢复到更正常状态的过程。RR可由任何药物治疗[4]、介入/手术程序（如心室辅助装置、血运重建、再同步或瓣膜手术）[5]、或某些生理事件或生活方式改变（如分娩、体重明显减轻或戒酒）后引起[6]。RR的一个有趣方面是心室对干预的广泛反应。虽然一些患者表现出持续的心脏改善，但其他患者表现出不完全的RR（功能和结构恢复有限），或心脏功能进一步恶化，称为不良重塑（AR）。影响RR结果和预后的因素多种多样，包括高血压、冠状动脉疾病（CAD）、肥胖、糖尿病（DM）、年龄、性别、遗传风险、生活方式因素（如吸烟、过量饮酒和物质使用、营养和久坐行为），以及干预前心室收缩和/或舒张功能障碍、心肌肥大和纤维化的程度[7-8]。在临床实践中，射血分数（EF）、左心室（LV）舒张末期/收缩末期容积、质量和球度指数的变化通常可以替代重塑或RR[6,9-11]。“心肌恢复”代表了RR的理想结果，其特征是持续、有利的临床反应，与较低的长期死亡率、心脏生物标志物的正常化、运动耐受性的提高[5]和未来HF[7]风险的降低相关。
2.触发逆RR的因素
目前对心脏（逆向）重塑程度的了解主要依赖于成像技术，特别是超声心动图，以及心脏磁共振（CMR）。这些方法测量心腔大小、左心室质量（LVM）和功能参数，如LVEF和心肌应变。与超声心动图相比，CMR具有更高的准确性、可重复性、时空分辨率和组织特征。例如，T1标测通过量化细胞外体积分数评估间质纤维化，而晚期钆增强（LGE）的增强CMR测量局灶性纤维化（瘢痕心肌）[12-14]。至关重要的是，心脏成像参数可以单独或与其他基线变量（如心脏应激或心肌重塑的循环生物标志物）结合预测干预/手术后的RR/AR，从而提高预测模型的准确性[15-16]。
2.1 压力超负荷缓解引起的RR
压力超负荷可由多种原因引起，如高血压（原发性或继发性）、主动脉瓣狭窄（AS），在较小程度上，还可由瓣膜下（主动脉下）狭窄和主动脉缩窄引起[17]。高血压和AS是主要原因，许多药物显示出控制高血压的有效性[18-57]。在欧洲，AS仍是主要的瓣膜疾病，需通过经导管主动脉瓣置换术（TAVR）或主动脉瓣置换手术（SAVR）进行干预[58]。主动脉瓣开放受限增加左心室后负荷，促使心肌重塑，其特征是肥大、胎儿基因程序的重新激活和间质纤维化[59]。主动脉瓣置换术（AVR，包括TAVR/SAVR）可促进心肌RR，包括肥大减少、舒张功能正常化和分子重塑[60]。舒张功能障碍的改善取决于阻止间质纤维化（由基质金属蛋白酶[MMP]介导，压倒金属蛋白酶组织抑制剂[TIMP]的活性）、胶原亚型转换（从更硬的I型到更柔顺的III型）和主动舒张机制的恢复（肌浆/内质网钙ATP酶2A和其他钙处理蛋白的表达升高）的进展[61-63]。主动脉瓣置换术后RR的程度在很大程度上取决于瓣膜置换术前的重塑程度。瓣膜和动脉水平的左心室后负荷完全正常化势是RR的前提[64-65]。事实上，不受控制的高血压、心脏淀粉样变性或假体-患者不匹配会增加不完全RR/AR的风险[66-67]。即使在类似后负荷的情况下，高血压AS患者的RR也较差，这是通过瓣膜-动脉阻抗（累积瓣膜和动脉超负荷的一种测量方法）评估，强调了神经体液激活的扩散[67]，已知在心血管疾病的各个谱中都会使AR持续存在[68-69]。
既往糖尿病独立预测主动脉瓣置换术后1年僵硬和肥大增加[67,70]。糖尿病AS患者表现出左心室质量恢复不足、心肌被动力较高和间质纤维化[71]。此外，肥胖增加主动脉瓣置换术后左心室肥大的风险，这可能是由于心脏脂肪变性[72]。然而，关于肥胖之间关联的研究主动脉瓣置换术后的生存率得出了令人困惑的结果，一些人认为重度肥胖患者的生存率更高（“肥胖悖论”） [73]，而另一些人则认为仅对超重而非肥胖患者有保护作用[74]，还有一些人反驳了任何保护作用[75]。患有中度CAD的非血运重建AS患者在主动脉瓣置换术后3年的RR较差，LVM和LV大小的减小较慢[76]。除了左心室质量恢复较慢外。根据CMR追踪的心肌内周向应变评估，同时患有AS和CAD的亚群机械性能较仅患有AS的个体低约50%[77]。年龄和性别对RR的影响存在争议。虽然一项系统研究发现性别对LVM恢复没有影响[78]，但证据表明，女性肥大恢复可能更快[79]，老年患者主动脉瓣置换术后生存率较低[80]。
与AS类似，长期暴露于动脉高血压引起的血流动力学应激导致左心室形状、大小或功能的变化[81-82]，最终导致HF[81,83-84]。当与其他风险因素结合时，这些改变更为显著，通常导致额外的肥大效应[85-86]。特定药物在三个层面上影响高血压患者的长期RR和预后：预防心肌细胞肥大和死亡，逆转间质改变（炎症和纤维化）以减少僵硬，促进冠状动脉血管生成以增强氧气和营养供应[82,87-88]。例如，β受体阻滞剂在高血压患者中的抗纤维化作用仍存在争议[33,89]，部分原因是β受体阻滞剂类型的差异[90]，而血管紧张素转换酶抑制剂（ACEi）和血管紧张素受体阻滞剂（ARB）已经确立了抗纤维化作用[91-92]。对于AS或全身性高血压，LVM恢复是评估RR的主要终点[9,93-104]。较高的基线左心室质量始终预测主动脉瓣置换术后LVM的独立恢复[67,105-106]，尽管存在已知RR阴性预测因素的合并症，但具有更大的逆转肥大的潜力[67,72,107]。在AS中，主动脉瓣置换术前纤维化和瓣膜动脉阻抗与LVM恢复相关，并可预测LVM的恢复[64-65]。返流更多的患者表现出左心室几何形状的正常化较慢和舒张功能较差[108]，返流较少（无LGE）时观察到LVM恢复较大[109]。
舒张功能障碍引发左心房（LA）重塑，导致腔内压力升高，被认为是主动脉瓣置换术后收缩功能障碍[110]和更严重的整体收缩功能障碍的独立预测因素。主动脉瓣置换术后3个月心房纵向应变峰值[111]。相反，基线心房张力降低可能会损害舒张功能正常化，导致主动脉瓣置换术后左心房压力升高[112]。值得注意的是，任何方向（径向、周向和纵向全局）的心肌应变都可以预测主动脉瓣置换术后LVM的恢复[113]。分子标记物，如血浆miR-133a，已被证明可以预测左心室肥大的可逆性[114]。早期识别主动脉瓣置换术后RR受限的患者，其特征是明显的残余肥大、左心房扩大和舒张功能障碍，这至关重要，因为他们的预后较差，包括住院和死亡。主动脉瓣置换术后残余肥大与非致命性HF相关住院、瓣膜再介入、心肌梗死（MI）、完全性房室传导阻滞和左心室流出道梗阻有关[9,93]。术后1年左心室肥大，加上左心房扩张，与主要的心脑血管不良事件和3年死亡率增加有关[94]。一项使用日本注册J-PROVE-Retro的大型长期研究（>9年随访）证实，主动脉瓣置换术后1年肥大和左心房扩张增加的患者更有可能因HF住院或心脏死亡风险更高[95]。
2.2 容量超负荷缓解诱导的RR
在慢性主动脉瓣反流中，容量超负荷引发心脏重塑，其特征是左心室扩张和偏心性肥大向更球形的方向发展[115]。主动脉瓣置换术后诱发RR成功的手术，改善了心室收缩和舒张功能，纽约心脏协会（NYHA）的等级和生活质量[116-117]。尽管主动脉瓣置换术后LVEF早期下降，但术后1年内出现显著改善，此后持续存在，其特征是左心室尺寸减小和LVM恢复趋势[117-119]。术前指数左心室收缩末期直径或容积和LVEF独立预测不完全RR[118-119]，而主动脉瓣置换前的限制性舒张充盈似乎会损害左心室RR[116]。术后左心室整体工作指数受损与左心室RR恶化显著相关，可能是由于心肌纤维化增加[120]。不完全RR与致命性室性心律失常、HF或心脏死亡导致的更多再住院有关[119,121]。在终末期肾病（ESRD）中，心脏结构的特征是左心室肥大和舒张功能障碍，随着疾病进展，这可能会发展为扩张表型[122-123]。这一进展主要归因于尿毒症毒素以及血流动力学因素，如通过水钠滞留导致的体积增加和与动静脉瘘和贫血相关的高血流量[122,124]。尿毒症毒素是心脏抑制剂，可引起钠钾ATP酶泵功能障碍[124]。
在接受血液透析的患有ESRD和非缺血性扩张型心肌病（DCM）的年轻男性中，通过减少干重和限制钠和水的摄入进行最佳的游离体容量管理，可导致心脏RR，其特征是LVEF的逐渐改善与左室和左房扩张的消退有关[122,125]。这种RR，也称为反向尿毒症心肌病，在肾移植（ESRD治疗的最有效形式[122-124,126]）后1个月内进一步增强，LVM减少是RR的重要预测因素[123,127]。据报道，肾移植后6个月LVM减少与整体纵向应变（GLS）改善之间存在显著相关性[128]。瓣膜性心脏病、CAD或HF、DM和血红蛋白变化史是肾移植后RR的预测因素[129]，并与长期心血管发病率和死亡率的降低有关[126-127]。
小结
在全球范围内，心血管疾病仍是发病率和死亡率的主要原因，导致压力超负荷、缺血或遗传变异等各种损伤引起的不同心脏重塑模式。干预措施旨在诱导心脏RR，并受到初始心脏应激和危险因素的影响。虽然LVM、LVEF、左室体积、QRS持续时间和心肌瘢痕等传统因素一直可以预测RR，但个性化的多尺度信息，包括遗传学、代谢、炎症和人工智能，为预测个体治疗反应和评估RR潜力提供了关键途径。
专家简介
郑刚 教授
现任泰达国际心血管病医院特聘专家，济兴医院副院长
中国高血压联盟理事，中国心力衰竭学会委员，中国老年医学会高血压分会天津工作组副组长，中国医疗保健国际交流促进会高血压分会委员
天津医学会心血管病专业委员会委员，天津医学会老年病专业委员会常委，天津市医师协会高血压专业委员会常委，天津市医师协会老年病专业委员会委员，天津市医师协会心力衰竭专业委员，天津市医师协会心血管内科医师分会双心专业委员会委员，天津市心脏学会理事，天津市心律学会第一届委员会委员，天津市房颤中心联盟常委，天津市医药学专家协会第一届心血管专业委员会委员，天津市药理学会临床心血管药理专业委员会常委，天津市中西医结合学会心血管疾病专业委员会常委
《中华临床医师杂志（电子版）》特邀审稿专家，《中华诊断学电子杂志》《心血管外科杂志（电子版）》审稿专家，《华夏医学》副主编，《中国心血管杂志》常务编委，《中国心血管病研究》杂志第四届编委，《中华老年心脑血管病杂志》《世界临床药物》《医学综述》《中国医药导报》《中国现代医生》编委
本人在专业期刊和心血管网发表文章979篇，其中第一作者790篇，参加著书11部。获天津市2005年度“五一劳动奖章和奖状”和“天津市卫生行业第二届人民满意的好医生”称号
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