医线心声丨下篇：促进心肌逆向重塑的措施和方法
健康
健康
2024-11-01 18:54
北京
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心脏逆向重塑（RR）被定义为心脏几何形状和功能的任何规范性改善，由治疗干预驱动，很少自发发生。虽然RR是大多数心血管疾病治疗的理想结果，但它们通常只会减缓/阻止其进展或改变风险因素，因此需要新的、更及时的RR方法。触发RR的干预措施取决于心肌损伤，包括药物（肾素-血管紧张素-醛固酮系统抑制剂、β受体阻滞剂、利尿剂和钠-葡萄糖协同转运蛋白2抑制剂）、装置（心脏再同步治疗、心室辅助装置）、手术（瓣膜置换术、冠状动脉旁路移植术）或生理学反应（解除条件、产后）。随后，根据左心室质量（LVM）、射血分数（EF）和舒张末期/收缩末期容积的正常化程度推断心脏RR，其程度通常与患者的预后相关。然而，旨在实现持续心脏改善的策略、评估RR程度的预测模型，甚至允许客观区分完全RR和不完全RR或不良重塑（AR）的临床终点仍然有限且有争议。
RR可由各种医疗器械的使用引起，其有效性在很大程度上取决于手术前的疾病进展阶段。本文回顾两种主要的治疗方式：心脏再同步治疗（CRT）和左心室辅助装置（LVAD）。这些方式用于不同的病理背景，服务于不同的目的和作用机制，它们可导致类似的RR模式。CRT通常用于实现轻度心力衰竭（HF）患者的RR，通常是那些EF降低、心电图不同步（如左束支传导阻滞[LBBB]）的HF患者。相比之下，LVAD用于终末期HF，通常用于心室严重扩张和功能障碍的患者，作为目标治疗、移植过渡或决策/候选过渡。因此，在这种情况下完全康复是罕见的[249]，心脏移植是首选[226]。在CRT诱导的RR中，心肌RR通常通过左心室容积的减少来评估。最大RR通常发生在前6个月内，一般会受到术前心肌状况的影响。例如，以左心室和/或左心房扩张为特征的晚期心肌AR降低了对CRT的“超反应”的可能性，这是由于NYHA分级降低和收缩功能保留的结合而导致的[250-251]。此外，HF病史较长可能会阻碍CRT后RR的达成。相反，如果心肌底物对电刺激有反应，并且整体收缩储备得到保留，则预期对CRT有反应，表现为左室射血分数(LVEF)改善和/或左心室收缩末期容积（LVESV）降低[252]。基线左心室舒张末期直径（LVEDD）≤71 mm和QRS≥170 ms可以预测CRT反应[253]。在一项较大的研究中，女性、非缺血性病因、较高的基线LVEF和较长的QRS都被确定为CRT超反应（随访时LVEF＞50%）的独立预测因素[254]。相反，先前的室性快速性心律失常发作、HF住院和非LBBB固有QRS模式被认为是不完全RR的预测因素[255]。与LVAD诱导的RR不同，年龄似乎不是CRT诱导RR的决定因素[256-257]。推广RR模型和预测装置植入后结果的局限性在于RR的程度（CRT的分数）。应答者和非应答者取决于RR评估的时间点。值得注意的是，超级反应患者的主要不良心脏事件（MACE）发生率较低，包括植入心脏复律除颤器、HF住院或心源性死亡[254]。其中，15%被归类为“短暂反应者”，在6个月时LVESV暂时降低（≥15%），但在1~2年的随访中没有。此外，根据PREDICT-CRT试验的回顾性分析，CRT后LVESV的降低与心血管或全因死亡风险的降低相关[102]，更大的降低对应于更低的死亡率[103]。整体纵向应变（GLS）的改善是CRT后RR的另一个特征，与收缩储备募集有关，与生存率的提高有关，特别是当与LVESV降低≥15%相结合时[104]。最后，纠正CRT后1年的机械不同步也与提高生存率有关[103]。预测患者对CRT的反应可以加强HF管理。此外，CRT中的创新模式可能会改善结果，例如多点左心室起搏，与双心室CRT相比，这对心容量恢复和LVEF增加的影响更大[258-259]。此外，His优化的CRT和其他传导系统起搏方法可能会导致LBBB显著变窄并经常正常化，改善LVEF和NYHA分级，并在装置植入后长达12个月内显著减少左室容积[260-262]。左心室辅助装置诱导的RR只有少数晚期心力衰竭患者在LVAD植入后实现了持续的心脏改善，导致成功的移植，而大多数患者表现出不完全的RR，并依赖于持续的LVAD支持或心脏移植[253]。目前，尽管LVEF与LVAD 密切相关，但完全（恢复）和不完全RR之间的临床区别主要基于LVEF的变化。尽管如此，有研究已经报道了各种细胞和结构变化[155,263]。虽然在LVAD诱导的RR期间发现钙处理有所改善，但心肌细胞肥大和细胞外基质（ECM）周转的消退并没有一致的报道[264]。胶原周转和ECM体积在LVAD支持下表现出缓慢的双相模式[265]。例如，Klotz等[266]观察到，即使在LVAD植入后4~6个月，I型和III型胶原以及I/III比值也会增加，有利于心肌硬化。此外，MMP-1/TIMP-1和MMP-1和MMP-9水平的降低，加上血管紧张素I和II的增加，表明LVAD治疗后ECM得以保留。与其他干预措施相比，LVAD后RR对患者预后的影响研究较少。LVAD支持的持续时间或类型、年龄和HF病因（缺血性或特发性心肌病）等因素都会影响RR过程[150]。机械支持持续时间较短且RR最大的患者HF复发概率较低，而长期机械支持可能导致心功能恶化[267-269]。HF病史的持续时间及其病因被确定为心肌恢复的主要预测因素[155]。INTERMACS心脏恢复评分（I-CARS）来自一项纳入了14 000多名患者的研究，可以根据六个独立变量预测心肌恢复（LVAD移植）：年龄＜50岁、非缺血性病因、最近诊断（＜2年）、没有植入式心脏复律除颤器、肌酐≤1.2 mg/dl和LVEDD＜6.5 cm，预测表现优异（AUC=0.94）[269]。基于分子标记的模型，如双细胞因子模型（干扰素-γ和肿瘤坏死因子-α），也被提出用于准确预测LVAD“反应者”[270]。预测LVAD反应可能有助于预测不良事件和辅助治疗的需求。植入后2年内LVEF改善≥40%的患者复合终点的发生率较低，包括HF驱动的住院和死亡[99]。在心肺运动测试中，峰值耗氧量为12~14 mL/min/kg 且分钟通气/二氧化碳产生斜率＜35的LVAD患者的生存率也更高[100]。此外，LVAD后1个月，不完全左心卸载和右心室功能障碍与较差的中期结局（NYHA分级≥III，HF住院，死亡）有关[101]。指南推荐的药物 几种指南推荐的药品可以在各种病理生理条件下诱导RR。包括β受体阻滞剂、肾素-血管紧张素抑制、利尿剂和SGLT2抑制剂。针对RR的新疗法的临床前/早期临床证据 最近的进展集中在解决AR的特征和可能在临床前动物模型中诱导RR，这包括基于RNA、抗炎症、肌纤维或线粒体的靶向药物。运动对心血管系统的影响取决于各种因素，包括频率、强度、持续时间、方式和调节量[311]。长时间、有规律和高强度的运动会引起生理性心肌肥大，增强心肌收缩力和每搏输出量。由于运动时间和静脉回流的增加，运动员通常会出现心率下降和舒张功能改善的情况[312]。耐力和阻力训练与偏心重塑和向心性肥大有关[312-313]。性别因素影响了这种重塑，女运动员表现出更大的左心室腔扩大，而男运动员则表现出更高的左心室壁厚度和质量[314]。运动诱导的肥大特征是心肌细胞生长、纤维化和凋亡减少、钙处理改善、心脏干细胞活化、一氧化氮产生增加、血管生成、内皮功能改善和抗氧化保护，保护心脏结构和功能[311-312,315]。胰岛素样生长因子-1-PI3K（p110α）-Akt通路在心脏重塑过程中起着关键作用[311,315]。运动训练还可以增加线粒体与肌纤维体积比，促进更节能的Frank-Starling机制[312]。Maron等[316]发现奥运会运动员在去调节期后可观察到左心室壁厚度和质量下降。此外，在马拉松完成后4周，LVM和壁厚恢复，体积卸载后腔室体积和功能不变[317]。然而，在马拉松比赛后8周，这种RR并不明显[317]。急性血容量减少和Frank-Starling适应之间的延迟可能是由于去调节后体重增加造成的[317]。运动员在大约5年的去调节期后，左心室腔尺寸减小，时间性增加[118]。先前运动练习的持续时间和水平也会调节长期RR，特别是在运动员超过生理性心肌肥大的心室形态上限的情况下[312]。例如，尽管室间隔厚度相似，但在38年的去适应期后，前职业自行车手的LVEDV和LVM指数略高于高尔夫球手[319]。肥胖和糖尿病主要导致血管并发症，促进心肌缺血和糖尿病心肌病[320]。这种类型的心肌病在女性中更为常见，其特征是明显的结构和功能损伤[321-322]。糖尿病患者表现出两种心脏表型：向心性左心室重塑伴舒张功能障碍导致HF，EF保持不变；偏心性左心室扩张伴收缩功能障碍导致HFrEF[323]。这两种表型都涉及间质和血管周围纤维化、心肌细胞肥大和细胞损失。心脏代谢失调，包括代谢不灵活、脂肪毒性、糖毒性、线粒体呼吸受损和胰岛素抵抗，在糖尿病心肌病的发展中起着至关重要的作用[324-325]。减肥手术后快速减肥与HF和非HF患者心血管死亡率的降低有关[326-327]。体重减轻导致左心室肥大的线性恢复，与年龄、性别和心脏代谢危险因素无关[328]。LVM的减少伴随着左心室几何形状和舒张功能的改善[329]，主要是由壁厚的减少而不是舒张末期容积的变化引起的[330]。然而，最近的研究表明，减肥手术后RR不完全，尽管左心室GLS增加，但LVEF略有下降，舒张功能恶化[330]。除了减肥手术外，热量限制和SGLT2抑制剂等药物疗法在促进糖尿病HF的RR方面显示出了希望，无论糖尿病状况如何[4,331]。另一个新出现的靶点是胰高血糖素样肽-1受体激动剂（GLP-1RA），其已被证明对心血管结局有益处，可能是通过改善脂质水平、血压和炎症生物标志物发挥作用[332-333]。GLP-1RA的作用可以通过靶向炎症和ECM来预防心肌梗死（MI）后的不良重塑，而与血糖控制无关[334]。正在进行的SURPAS-CVOT试验旨在进一步评估GLP-1RA对心血管结局的影响[335]。热量限制及其药理学模拟物可有效减轻代谢综合征动物模型的心脏重塑和舒张功能障碍，同时减少纤维化和氧化应激[166,336-337]。MI后开始热量限制可改善非糖尿病动物的心脏功能障碍和变力储备[338]。总体而言，这些临床、行为和药理学干预措施旨在缓解心脏过度供血，这可能导致胰岛素抵抗、代谢不灵活以及线粒体和收缩功能障碍，最终促进RR[339]。酒精性心肌病，被世界卫生组织认定为一种独特的临床实体，是由长期大量饮酒引起的，表现为扩张型心肌病[340-341]。其特征是在没有冠状动脉疾病和营养不良的情况下LVM增加、心室扩张和室壁变薄，类似于左心室偏心重构伴心室功能障碍[341-343]，其临床和组织学特征与特发性扩张型心肌病相似[341,344]。酒精性心肌病的治疗与其他非缺血性DCM的治疗类似，重点是完全或显著减少饮酒，以防止心脏功能和心力衰竭的进一步恶化[344-345]。值得注意的是，戒酒或显著减少酒精摄入可能会导致6个月内的心脏RR[346]，从而改善左心室功能、HF症状和短期与长期预后[344-346]。由于在RR期间难以观测人类心肌组织的变化，动物模型对于理解其机制和预测因素至关重要。动物模型应模拟应激源诱导的心脏重塑和干预后的RR过程[347-348]。理论上，每只接受治疗的心脏损伤动物都是研究RR的合适模型。然而，在研究心肌肥大、纤维化、血管生成和氧化应激恢复时，通常使用手术模型，如主动脉结扎后去捆绑和左前降支（LAD）冠状动脉结扎后再灌注的小动物[349-350]和大动物[351-352]。主动脉束带模拟慢性压力过载，并阻碍随后情况的缓解，模仿了手术/治疗干预前后AS和高血压等疾病。异位心脏移植也可以在主动脉束带和其他动物模型中复制。LAD结扎及其切除模拟了心肌再灌注后的缺血事件[347]。这两个模型都代表了具有高翻译潜力的人类RR过程。结合这些模型可以复制临床相关的合并症，如缺血性心脏病和动脉压超负荷[353]。为了通过心动过速诱发心肌病，可以使用持续快速的心房或心室起搏。这会导致严重的双心室舒张和收缩功能障碍，伴有严重的心腔扩张和随后的球形重塑。然后可以通过停止持续快速起搏来诱导RR[354]，模仿控制时间性的效果。在动物模型中，纵向样本采集允许识别心脏病逆转的生物标志物，并利用遗传功能获得/丧失模型。复制影响RR的合并症具有挑战性，但可以纳入现有模型。衰老与细胞衰老有关，释放与衰老相关的分泌表型，导致包括HF在内的与年龄相关的心脏病[69,355]。衰老的心肌细胞促进心脏成纤维细胞活化，导致病理性心脏重塑[356-358]。在老年动物的实验中，β肾上腺素诱导的心肌病停止后，衰老会损害RR。老年雌性动物在异丙肾上腺素停药后表现出持续的心肌肥大、纤维化和功能障碍，而年轻雌性动物则从心脏重塑中恢复过来[357]。需要对老年动物进行进一步的机制研究，以了解衰老对RR的影响。考虑到其在维持微血管功能障碍和促炎信号传导中的作用，研究还应解决RR中的内皮-间充质转化问题[359-361]。此外，还需要进一步的研究来探索新的治疗方案。在心血管研究中，像小鼠这样的简单模型对临床翻译实验数据构成了重大障碍，特别是对于涉及许多遗传和环境因素的RR。大型动物模型（如猪、狗）更准确地模拟了人类的病理生理学，包括缺血后再灌注和主动脉条带的缓解[350-351]，增强了治疗干预和预后策略的转化潜力。在全球范围内，心血管疾病仍然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。新兴的抗糖尿病药物、新型肌力药和代谢干预措施显示出改善心血管结局的希望。RR程度模型、机器学习方法增强了RR预测，并可能很快超越既定的指导方针。虽然LVM、LVEF、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[362-363]。动物模型在理解RR的复杂机制和评估新靶点的临床潜力方面发挥着至关重要的作用。这些模型为操纵变量提供了一个受控的环境，允许详细探索RR中涉及的分子途径和生理反应。利用这些优势有助于验证新的靶点，并深入了解心脏RR新兴疗法的转化潜力，弥合临床前和临床应用之间的差距。这些进展有望改善RR预测，并确定患者药物和非药物干预的最佳时机。
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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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