郑刚教授：从纤维帽增厚到斑块消退——降脂治疗诱导冠状动脉斑块有利变化的演变进程（下）_郑刚_纤维帽增厚_斑块消退_降脂治疗冠状动脉斑块

郑刚教授：从纤维帽增厚到斑块消退——降脂治疗诱导冠状动脉斑块有利变化的演变进程（下）

2025-09-13 来源：医脉通

关键词：郑刚纤维帽增厚斑块消退降脂治疗冠状动脉斑块

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LLT启动后斑块表型变化的时间进程

既往CCTA研究表明，长期LLT会增加钙化斑块体积，图1显示了LLT 启动后斑块表型变化的时间进展，代表了对LLT 反应的有利变化，包括 PAV 回缩、maxLCBI4mm 减少和 FCT 增加[51]。

图1 PAV 回缩、maxLCBI4mm 减少和 FCT 增加的代表性图像

注：a,b：IVUS 中的 PAV回缩；c,d：NIRS 中的 maxLCBI4mm 减少；e,f：OCT 中的 FCT 增加

图2总结了随访期间 FCT、maxLCBI4mm 和 PAV 从基线到随访的绝对变化。多模态研究，包括PAV、maxLCBI4mm和FCT 的评估，对于理解斑块表型变化的顺序和临床意义至关重要，因为这些发现与临床结局相关。此外，同时采用灰阶IVUS、VH-IVUS 和 OCT 评估 FCT 与脂质成分的研究也具有重要参考意义。由于同时评估上述成像参数的研究数量有限，且随访周期多为人为设定（非基于生物学机制确定），因此难以完整呈现斑块表型变化的自然时间进程。然而，对随访周期相近的既往研究进行综合分析，仍可了解不同斑块成分对降脂治疗反应的速度与敏感性。

图2 与基线相比，不同随访周期的FCT、maxLCBI4mm 和 PAV 变化

斑块对降脂治疗的反应序列推测如下：首先是 OCT 检测到的 FCT 增厚 [25,26,28,30,31]，随后是 NIRS 和 OCT 检测到的脂质成分减少[27,30,37,38,45,50,51]，导致TCFA 发生率降低；同时，OCT显示的其他斑块易损性特征[38,45,50,51]（如巨噬细胞浸润的存在及程度）也会发生变化；最终则表现为 PAV 降低[34,47,53,55,57,58]。

总的来说，FCT是指示最早对 LLT 产生斑块反应的参数，具有高灵敏度，而斑块消退（以PAV减少为代表）则在后期观察到，通常在随访 9~12 个月后。然而，PAV 的绝对变化仅约1%~2%, 目前且对PAV减少的预后价值机制提出了疑问[62,63]。

PACMAN-AMI 研究中多模态冠状动脉成像与预后关系的分析为该问题提供了线索。Biccirè 等报道，在强化降脂治疗下，同时实现粥样硬化体积减少、脂质成分减少和 FCT 增厚的患者，其主要不良心血管事件（MACE，包括死亡、心肌梗死和缺血驱动的血运重建）发生率显著更低。在52 周随访期间，在所有成像血管均实现PAV降低的患者（约75%）中，67% 同时出现 maxLCBI4mm降低，63% 同时出现最小 FCT 增厚[63,64]。同样，既往一项基于多模态冠状动脉影像学评估的研究报道了PAV、maxLCBI4mm 和TCFA[65]之间的相关性。这些结果或解释为什么PAV仅有轻微变化也与更好的预后相关，即LLT引起的斑块消退，是斑块通过成分改变实现稳定的标志，而非单纯的管腔保留或扩大。

LLT的大部分预后价值可能并非来自斑块消退本身，而是来自FCT增厚和脂质成分减少所反映的斑块稳定。

关于FCT 增厚的临床意义，目前尚无研究评估FCT变化与预后之间的直接关系。然而，考虑到TCFA的预后价值，FCT增厚可能导致临床结果改善。尽管TCFA不一定直接导致硬终点的发生，但其或为MACE风险升高的预测因子[22-24]。

TCFA 相关 MACE 的一种可能机制是无症状血栓事件导致的管腔快速狭窄（这种情况有时会反复发生）。研究表明，斑块进展呈阶段性而非线性[66]（图 3），尤其是富脂斑块会以分阶段方式进展[67]。

图3 从基线到6 个月和 12 个月期间的斑块进展模式

注：在有进展的病灶中，三分之一呈现渐进模式，三分之二呈现快速阶段性进展模式。a.非进展, b.缓慢线性进展, c.早期快速阶段性进展和d晚期快速阶段性进展

血栓的临床表现取决于局部和全身性血栓形成与内源性抗血栓形成防御机制之间的平衡[69]；在斑块破裂或侵蚀之后会形成血栓，当血栓形成超过防御机制时，将形成闭塞性血栓，导致ACS或猝死。反之，强大的防御机制将导致非闭塞性血栓形成，随后血栓机化形成新的纤维层（层状斑块或愈合斑块），实现斑块稳定但伴随管腔丢失。

斑块中脂质成分的减少不仅有助于FCT增厚，还可能降低局部血栓形成。斑块内的脂质核心被认为是已知的最易致血栓形成的斑块成分[70]。因此，LLT所致FCT增厚和脂质成分减少，不仅可使ACS 发生率减少还可使 SAP发生率减少。

总之，IVUS测得的PAV 回缩的预后价值可以基于冠状动脉粥样硬化斑块的稳定。斑块消退是脂质成分减少和炎症减轻的晚期结果。在这个过程中，斑块随着FCT增厚趋于稳定。脂质成分的减少有助于FCT增厚，这一点得到了PACMAN-AMI 研究中FCT与maxLCBI4mm呈负相关结果的支持。

理论上，LLT启动后，FCT、脂质成分和斑块体积的微观变化可能同时开始，但变化幅度和诊断技术的敏感性或有所不同。在现有成像技术中，高分辨率 OCT 可最早检测到 FCT 变化，随后 NIRS 可检测到斑块内脂质减少，最后 IVUS 可检测到斑块体积变化。基于传统血管水平评估的 PAV 降低或为LLT效果的标志，且与更好的预后相关[62-63] 。相比之下，纤维帽厚度和TCFA消退反映了斑块表型的早期变化，并可以预测血管对LLT的反应以及可能的未来心脏事件。例如，心梗后6~10 周内LDL-C水平的大幅降低与有利预后相关[71], 这强调了早期脂质降低的重要性。FCT 可能反映了LLT在如此短时间内的功效，并支持预后相关机制。FCT有助于评估 LLT 在数周到数月内的影响，以及比较不同降脂策略对斑块特征的影响；这一见解将有助于设计未来关于 LLT 的研究。

总体而言，图4总结了LLT 提供的斑块表型变化的时间过程及其伴随的临床意义，这不仅提供了LLT 对CAD 预防作用的机制，还有助于我们更好地理解斑块稳定过程的发病机制。LLT 药物的多效性作用可能提供斑块表型的变化，超出 LDL-C降低的范围，这是未来研究的一个主题。

图4 血管内成像变化的时间过程及其对LLT 反应的临床影响

自最初确定LLT 预后价值的临床试验以来，已经进行了许多系列 IVUS、NIRS 和 OCT 试验。LLT 导致 FCT 增厚，随后脂质成分退化，最后整体斑块体积退化。FCT 是反映 LLT 疗效的早期和敏感指标。PAV 略微减少的影响是斑块稳定的晚期标志，而不是管腔扩张。然而，在既往研究中，随访成像的时间是任意的，需要未来具有预先设定随访期的多模态研究来揭示LLT 期间斑块表型变化的具体时间过程

然而，在临床实践和解释先前研究中应用这种建议的时间序列存在几个局限性：

①FCT 评估的可重复性可能存在问题[72]。

②在OCT下区分TCFA 和巨噬细胞侵润有时存在挑战性，因为巨噬细胞在斑块表面线性侵润形成高强度线，并伴随着后方衰减，类似于TCFA, 而误诊可能导致对 LLT 疗效的误解。人工智能算法可以解决这个问题[73], 而且用三维方法进行FCT测量，而不是测量单个截面中的单个点，可以提供更准确的FCT 评估[74]。

③尽管MaxLCBI4mm降低、VH-IVUS测得的坏死核心大小和OCT测得的脂质弧减少，均表明脂质成分的减少，但目前缺乏这些参数之间的直接比较，同一病灶中这三项指标可能存在差异，且各自的意义也可能不同。

④斑块特征的变化是动态和复杂的，目前尚不清楚在LLT 启动后，随着时间推移出现的所有有利变化是否会在任何时间点出现。

⑤成像参数变化的重要性受到样本量和参数检测敏感性的影响。

因此，未来需要进行具有不同随访周期的多模态大规模前瞻性研究，以揭示斑块表型变化的详细时间过程。

LLT 响应的成像特征和决定因素

本节从冠状动脉影像学的角度总结了LLT 对具有特定特征患者的疗效。

SATURN试验事后分析随访24个月（IVUS 评估）显示，与未使用ACS的患者相比，高强度他汀类药物治疗可提供了更大的斑块消退和MACE改善[75]。

在一项基于OCT成像的研究显示，ACS 是他汀类药物治疗后血管产生有利反应的独立预测因子[76]。此外，基线FCT 较薄的患者，在进行他汀类药物治疗后FCT增厚的幅度较大[35]。

FOURIER 研究的亚组分析显示，高危患者（近期心梗、既往≥2次心梗或多支血管冠脉疾病）接受治疗后的风险降低幅度大于低危患者[77]。

关于CAD 的临床表现与非罪犯病变的斑块特征之间的关联，已有多项研究。在一项三血管OCT 研究显示，ACS患者的非罪犯斑块较SAP患者的FCT更薄[78]。根据COMPLETE 研究显示，近50%的STEMI患者至少有一处TCFA 的狭窄病变[79]。对斑块侵蚀和斑块破裂的罪犯病灶进行对比发现，破裂病灶患者非罪犯病灶的TCFA发生率高于侵蚀病灶患者[80]。此外，已知未经治疗的非罪犯病变在 ACS 患者中的MACE 发生率高于SAP[81]患者。

总的来说，有全身性炎症升高的高危患者（如ACS 患者，特别是斑块破裂和多血管疾病患者），可能从LLT 中获益最大，治疗后斑块稳定的效果或更为显著。此外，仅凭患者特征、临床表型和缺血评估，难以可靠地预测斑块易损性。未来进行生物标志物（包括蛋白质组学、代谢组学、转录组学或多基因风险评分）相关研究，或有助于识别未来心脏事件高危患者。目前，在PCI 期间通过冠状动脉成像识别具有易损特征的非罪犯斑块，或有助于未来进行风险分层。

LLT 的启动时机及疗程

来自胆固醇治疗试验者协作组的荟萃分析显示，无论患者风险水平、CAD 病史或基线 LDL-C水平如何，心血管事件发生率均会随LDL-C水平的降低而呈比例地减少[2-4]。另一项荟萃分析显示，无论采用何种降脂药，LLT 均可使患者获益[82]。目前，欧美脂质管理指南[83-84]均建议高危人群使用高强度他汀类药物、依折麦布和PCSK9抑制剂进行LLT，以进行一级预防和CAD 二级预防，尤其推荐ACS患者在二级预防中尽早启动强化降脂治疗[85]。

SWEDEHERT注册研究中位随访3.2年显示，10.2%的首发心梗患者因再次心梗住院，且非罪犯病灶相关的再次心肌梗死风险是罪犯病灶的2 倍[86]。众所周知，ACS 患者在发病后早期发生ACS等复发性心血管事件的发生率较高[87-88]。结合前文所述斑块表型在数周至数月内即可改善的结论，ACS 后尽早启动高强度降脂治疗，可能有助于降低心血管风险。

MIRACL研究显示，与安慰剂相比，强化他汀治疗可降低16% 的MACE风险，且事件曲线在4 周时即开始出现分离[89]。

PROVE IT-TIMI 22 研究[22]表明，与使用普伐他汀（40 mg）的患者相比，进行阿托伐他汀（80 mg）治疗的ACS患者的MACE风险显著降低16%, 且早在3 个月时即存在差异[90]。有研究显示，他汀联合依折麦布治疗可改善ACS患者的预后[6]。

Odyssey Outcomes 研究随访2.8年显示，与在基线时便进行安慰剂联合他汀治疗的患者相比，在基线时进行阿利西尤单抗联合他汀治疗且中位8.3个月时转为安慰剂联合他汀治疗的患者的MACE发生率更低[91]。

FOURIER OLE 研究比较了 FOURIER 研究（随访 2.2 年）后启动依洛尤单抗治疗的患者与 FOURIER 研究期间持续接受依洛尤单抗治疗的患者，结果显示，从研究开始即接受依洛尤单抗治疗的患者，在中位5年随访期间的风险降低 15%[92]。

考虑到斑块表型变化的时间过程，这两项研究中的PCSK9 抑制剂应该分别在8.3个月和2.2年内为冠状动脉斑块提供了有利的变化。

一项回顾性研究表明，ACS后3个月内进行PCSK9 抑制剂治疗，可降低1年时的MACE发生率, 特别是1年时的血运重建率[93]。

这些研究表明，早期强化LLT 的有利斑块表型变化可能有助于患者后续的预后改善。

WOSCPOS试验探讨了他汀类药物治疗的长期（20 年）疗效，结果表明早期起始强化LLT对一级和二级预防均有益[94]。近日，累积LDL-C暴露水平升高被认为是冠心病的危险因素[95] ，而他汀治疗的结局获益被认为与冠状动脉斑块稳定相关。

结论

LLT 在冠状动脉疾病一级和二级预防中的预后价值得到了斑块特征有利变化的支持。从他汀类药物治疗到 PCSK9 抑制剂的出现，冠状动脉影像学的应用也已经从IVUS 的体积分析扩展到 NIRS 的脂质成分评估和 OCT易损斑块的评估。

总体而言，FCT 似乎是对LLT最早且最敏感的反应指标，其次是脂质成分的变化，最终实现斑块体积的消退。然而，斑块表型变化与临床结局改善的直接相关性仍需进一步研究证实；斑块表型改善是否能降低侵蚀性斑块所致ACS 的发生率（占ACS总数的40%-50%）也尚未可知。

本文旨在整合既往相关研究，但在全面呈现降脂治疗期间斑块表型变化的严谨时间进程方面仍存在局限性。未来需要开展采用多种血管内成像技术、设置不同随访周期的研究，以进一步明确这一过程。

专家简介

郑刚教授

•现任泰达国际心血管病医院特聘专家

•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

•《中华老年心脑血管病杂志》编委，《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》审稿专家，《华夏医学》杂志副主编，《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，《世界临床药物》杂志编委、《医学综述》杂志会编委、《中国医药导报》杂志编委、《中国现代医生》杂志编委、《心血管外科杂志（电子版）》审稿专家

•本人在专业期刊和心血管网发表文章948篇其中第一作者759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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