泰达国际心血管病医院 郑 刚
瓣膜性心脏病（VHD），包括主动脉瓣、二尖瓣、三尖瓣或肺动脉瓣狭窄或反流，在全球范围内显著影响心血管发病率和死亡率。2017年，全球疾病负担研究报告称，主动脉瓣钙化性疾病（CAVD）估计有150万残疾调整后的生命年，退行性二尖瓣疾病估计有87万残疾调整生命年，其他非风湿性心脏瓣膜病估计有14万残疾调整生命年[1-2]。与其他常见心血管疾病相比，VHD导致的心血管死亡的相对比例很小：2019年VHD引起的心血管死亡比例为2.5%，而缺血性心脏病导致的心血管死亡率为49.2%，缺血性卒中导致的心血管死亡比例为17.7%，高血压心脏病造成的心血管死亡比例为6.2%[3]。然而，与动脉粥样硬化性心脏病相比，没有可用的医学疗法来预防或减缓VHD发展。相反，重度VHD通过手术或经导管瓣膜置换或修复解决。随人口老龄化，VHD和相关合并症导致的发病率和医疗保健相关成本持续上升，凸显了确定药物治疗分子靶点的紧迫性[4]。本文将概述对导致主动脉瓣疾病常见原因的分子和细胞机制的最新理解，找出我们对主动脉瓣疾病理解的差距，并讨论开发无创疗法所需的下一步措施。
1 发病机制的定义和范围
主动脉瓣叶的原发性疾病可导致主动脉狭窄（AS）和主动脉反流。主动脉瓣最常见的病理学是CAVD，包括瓣膜小叶的病理性纤维钙化重塑，导致钙化性AS。风湿性心脏病（RHD）仍是低收入国家最常见VHD[1]。RHD总是影响二尖瓣小叶，但20%~30%的病例也可见主动脉瓣受累。先天性主动脉瓣异常，如单叶主动脉瓣或双叶主动脉瓣（BAV），通常导致钙化性AS的早期发病，或主动脉瓣反流的发病率较低。
2 钙化性主动脉狭窄
2.1 分类和流行病学 AS是最常见的VHD，根据全球负担，估计每100 000人中有116.3例AS的年龄标准化患病率[3]。这一统计数字预计将随人口老龄化而上升；仅1990~2017年间，AS的全球患病率增加124%[1]。AS的其他危险因素包括年龄较大；男性、高血压、2型糖尿病、血脂异常，特别是脂蛋白（a）[Lp（a）]升高；吸烟、体重指数升高和终末期肾病[10,15]。关于饮食中的维生素D或钙是否会改变AS风险的数据不一致[16]，一些数据表明，补充钙会增加轻度至中度AS患者的死亡率[17]。CAVD的第一个病理迹象，即主动脉硬化症，表现为小叶增厚，代表局灶性脂质浸润和炎症，这可通过超声成像观察到。随小叶钙化区域的扩大，通过瓣膜的血流受阻，导致多普勒超声提高了通过瓣膜的流速。据估计，超过65岁的人群中有四分之一患有主动脉硬化症，大约1.8%的主动脉硬化症患者每年进展为AS。事实上，大多数主动脉硬化症患者在其一生中从未发生血液动力学显著的AS[18]。主动脉硬化或主动脉瓣钙化的临床风险因素与AS相似，包括血脂异常、代谢综合征、吸烟和体重指数升高。
然而，一旦主动脉硬化明显，目前尚不清楚哪些风险因素会促进更快地进展为AS，而包括Lp（a）在内的传统风险因素与主动脉瓣钙化的进展无明确关联[19-20]。这些数据表明，CAVD中的疾病发生和疾病进展可能是不同的过程，从而对药物治疗的时机和选择产生影响。
2.2 分子机制 CAVD中表现出的独特病理可能是由与跨瓣血流相关的剪切应力和与主动脉与左心室压差以及瓣膜打开和关闭相关的机械应力的组合引起。这些过程导致瓣膜内皮细胞（VEC）层的破坏，VEC层是小叶内疾病启动机制的巢穴，包括炎症、脂质浸润、氧化应激、纤维化和成骨转录程序的最终激活，以及原钙化细胞外小泡（EV）的释放，这些协同促进瓣膜间质细胞（VIC）周围细胞外基质（ECM）的病理矿化。矿化通常始于纤维瘤，但会扩展到侵犯所有3层，主动脉瓣尖通常是最先发生不良重塑[9,21]。无论是机械/剪切应力还是细胞特异性机制导致的固有ECM成分的破坏，都会影响主动脉瓣细胞的表型和功能，从而进一步促进ECM重塑以及随之而来的纤维钙化变化和硬化[9,22-24]。碎裂的ECM纤维还可作为钙和磷酸盐成核以及EVs积累和聚集的位点。
在早期病理性瓣膜标本中观察到脂质沉积，由此产生的炎症反应被认为是CAVD的早期疾病始发事件[25-26]。强有力的流行病学和遗传学证据表明，许多不同的载脂蛋白B-胆固醇颗粒在CAVD中起因果作用，包括低密度脂蛋白胆固醇（LDL-C）[27-28]、残余胆固醇[29]和Lp（a）[26,30]。这些载脂蛋白B颗粒的多变量孟德尔随机化表明，LDL-C和Lp与AS密切相关。当考虑到其他脂质时，甘油三酯和AS之间的关联变得无关紧要[27]。假设Lp（a）促进AS疾病的机制是通过氧化磷脂的作用发生，氧化磷脂与Lp（a）共价连接并促进基因表达程序，导致VIC的钙化转化。ATX基因在CAVD 的VICs中表达升高；自毒素（autotaxin）与循环Lp（a）有关[31]；尽管这些数据有力地支持脂质和脂质代谢在CAVD早期发病机制中的作用，但迄今为止，他汀类药物等脂质调节疗法尚未显示出在减轻CAVD进展方面的益处[32]。
多项证据表明，炎症以及瓣膜脂质沉积引起的炎症也是CAVD的早期启动事件。炎症被认为会破坏VIC和VEC的稳态，促使这些细胞获得成骨细胞样特征并钙化[9,33-38]。钙化AS常见遗传变异的先前全基因组关联研究（GWAS）涉及白介素-6（IL-6）基因的内含子单核苷酸多态性，编码促炎细胞因子IL-6[27,28,39]，这是NLRP3炎症小体复合体的下游细胞因子。进一步的支持性证据与以下观察结果有关，即造血干细胞中的某些体细胞变异，一种称为潜能不确定的克隆性造血的情况，在CAVD中频繁发生，并预示主动脉瓣置换术后预后更差[40-41]。潜能不定的克隆性血细胞通过增强NLRP3炎症小体介导的基因原，增加心血管风险[42]。CAVD中的炎症也延伸到先天免疫。干扰素病是一类导致1型干扰素系统性升高的遗传疾病，其模拟与分子模式信号相关的组成型活性损伤[43]。几种干扰素病，包括辛格尔顿-默顿综合征和ADAR相关的1型干扰素病，与早期和主动脉瓣钙化表型相关[44-48]。
EVs参与生理和病理过程，是CAVD病原体发生的新兴介质，尤其是钙化的起始和进展。根据大小和类型，EVs分为外泌体、微粒或凋亡体。它们从各种细胞类型中释放，包括驻留在瓣膜小叶中的细胞（如VECs、VICs、巨噬细胞）。EVs的外膜保护其货物，由生物活性分子、蛋白质、酶、微小RNA和亲代细胞的其他成分组成。
EVs可参与细胞间通信，并作为信使到达远处组织，以控制体内平衡和系统反应。EV钙化涉及多种途径。首先，选蛋白（sortilin）是一种多配体分选受体，也与LDL-C代谢密切相关[49]，也是AS的多个GWAS中的全基因组显著风险位点[27-28,50]，已被证明通过细胞内运输机制与钙化酶组织非特异性碱性磷酸酶（TNAP，ALPL基因）的EV负载有关[51]。当从细胞中释放时，含有TNAP的EV可被捕获在胶原纤维和其他ECM成分中，并通过膜联蛋白1[52]，由TNAP活性产生的最小外周体成核形成羟基磷灰石的微钙化[53-54]，其合并并发展为更大的大钙化，可通过临床成像模式进行可视化[55]。EVs在VHD和CAVD中的作用在很大程度上研究不足；此外，移植的生物人工心脏瓣膜还没有被检查是否存在EV。
2.3 潜在的治疗靶点 CAVD和动脉粥样硬化在临床危险因素、流行病学和病理生物学方面有显著重叠。然而，包括他汀类药物在内的心血管疾病传统预防疗法的多项临床试验在应用于AS时失败了[32,56]，并且没有医学有效的治疗方法。既往对CAVD进行的强有力的遗传和实验研究已经产生了许多分子靶标和途径[1-3,,6,13,21,23,26,35,38,42-46,52,56-64,67-70,72-95]，我们希望这可能为靶向药物开发提供机会。少数正在进行的药物治疗试验针对AS的进展。也许最令人兴奋的是最近Lp（a）修饰疗法的成功，如siRNA分子olpasiran，它在2期临床试验中有效地降低了血浆Lp（a）[97]。积极的长期研究将评估Lp（a）修饰疗法对AS进展和结果的影响。药物开发的额外机会存在于与动脉粥样硬化中明显的靶向途径正交的靶向通路中。其中包括矿物质成核[98]、NOTCH途径信号传导[57]、肾素-血管紧张素-醛固酮信号传导途径[99]和二肽基肽酶4[100]等。在一个关于人类DNA、RNA和蛋白质的大型多组学CAVD数据集的时代[101]，工作可能会优先研究瓣膜中表达的途径和分子，这些途径和分子几乎没有假定的脱靶效应。
3 先天性双主动脉瓣和单主动脉瓣
3.1 分类和流行病学 先天性主动脉瓣畸形可导致双叶主动脉瓣（BAV），这是最常见的瓣膜畸形，发病率约为1.5%，或单叶瓣，这种情况不太常见，但可能诊断不足，因为与BAV的区别可能很困难[102]。BAV的两个小叶是由发育过程中瓣叶祖细胞融合或缺失引起，并且根据小叶的方向有不同分类[103]。BAV通常在成年时被诊断为BAV，因为先天性畸形的主动脉瓣通常功能正常，直到小叶开口受到叠加的纤维性变化的限制。然而，先天性BAV患者比三叶主动脉瓣患者更容易在年轻时发生主动脉瓣功能障碍，几乎所有患者在其一生中都需要进行瓣膜干预[104]。总体而言，大约一半接受AS瓣膜置换术的患者患有BAV，<60岁的患者患BAV的患病率更高[1]。
3.2 分子机制 BAV在高达89%的病例中具有稳定性[75,105]，但在大多数病例中，遗传基础尚未确定，这表明了复杂的病理学。遗传性BAV与Turner、Marfan和Loeys-Dietz综合征有关，在NOTCH1、GATA4/5/6和SMAD6以及与原发纤毛和内皮-间质转变相关的基因中发现了罕见的单基因变异[74-75]。无论最初的病因如何，BAV疾病包括瓣膜小叶的结构异常，有时与主动脉扩张有关，导致瓣膜小叶的异常流动模式和异常应力应变。与三叶主动脉瓣相比，这些瓣叶结构和生物力学应力的改变可能会加速二尖瓣患者的瓣叶退化和钙化[74,106-107]。
4 我们理解的差距
原发性CAVD病理生物学方面的许多知识差距仍存在，这可能是未来重新研究的重点。特别令人感兴趣的是对早期CAVD或主动脉硬化症的研究。尽管尚未在临床上可行，但≥65岁的患者中约有25%和≥80岁的患者有主动脉硬化症[18]。新出现的数据表明，主动脉硬化症是一种生物活性疾病。18F-氟化钠（18F-NaF）PET成像是早期钙化的标志，显示与正常瓣膜相比，主动脉硬化患者的瓣膜摄取增加[108]和新钙化。
在2年以上的连续扫描中，发生在18F-NaF摄取增加的区域。目前尚不清楚为什么一些人从主动脉硬化症进展得更快，发展为具有血液动力学意义的AS。未来的研究可能侧重于预测主动脉硬化症和AS发病或进展的临床和遗传因素。尽管与AS相关的风险因素与一般心血管疾病的风险因素相似，但引发瓣膜细胞重新编程为钙化状态的急性初始事件尚不完全清楚。体外疾病建模表明，生物力学应力、炎症和氧化应激等刺激促进了VIC的成骨再编程[109-110]。进一步了解这些应力启动钙化程序的机制，并确定驱动健康瓣膜细胞向钙化细胞转变的新途径，可用于开发非侵入性疗法，以预防、停止甚至逆转瓣膜钙化。
AS在某些人群之间表现出显著的流行病学差异，但没有明确的生物学解释。患有CAVD的男性往往比女性更容易钙化，女性会发展出更大程度的瓣膜纤维化[111]。这一点在临床上表现为女性血液动力学AS更严重，主动脉瓣钙化更少[111]。我们不知道CAVD的发病机制在男性和女性之间是否因疾病的发作而不同，也不知道疾病的进展是否存在差异[112]。使用猪和人的VICs，研究人员发现X染色体失活导致性别差异，因此一些逃避X染色体失能的基因优先增加了女性的肌成纤维细胞活性。
男性婴儿（7.1/1000人）的患病率高于女性婴儿（1.9/1000人），这种3~4倍的患病率差异一直持续到成年。解释这种差异的基本生物学仍未知；然而，逃避X染色体失活的基因剂量的减少已被认为是一种促成机制[113]。此外，非白人个体的AS患病率低于白人个体[114]，尽管研究往往因非白人人群的VHD相关医疗保健相互作用的差异而有偏误[115]。迄今为止，大多数关于CAVD的大群体研究都集中在白人个体，GWAS没有足够的能力进行性别分层分析。未来的研究工作应该针对不同的人群，以便临床和生物学见解能够最好地代表普通人群。
对于我们理解CAVD的发病机制同样重要的是开发能概括人类状况的理想模型。谱系追踪小鼠模型表明，小鼠主动脉瓣小叶的钙化方式与人类小叶不同[116]。小鼠主动脉瓣含有产生色素的黑色素细胞[117]，它们很容易与阳性von Kossa染色（识别钙沉积物）混淆，因为两者均表现为棕色沉淀物。VIC中的黑色素细胞有助于产生小叶的弹性蛋白[118-119]；人类是否存在猿类种群尚不清楚。绵羊、猪和牛模型更好地再现了在人类中观察到的CAVD，但大型动物模型需要高成本和高空间要求[120]。生物工程领域已经很好地利用生物材料来再现瓣叶硬度，例如，通过三维生物打印，这能够评估机械敏感的细胞反应[121-122]，但我们还没有合适的工具体外模拟瓣膜疾病。
小结
尽管在识别VHD发展的潜在机制方面取得进展，但在几个关键领域仍存在重大知识差距。首先，确定VHD早期发展的主要驱动因素很必要，特别是在可以确定可进行预防性干预的因素的情况下。除本文强调的机制外，辐射诱发的瓣膜病等外源性因素还驱动了适应不良过程，导致瓣膜损伤。现有成像和诊断模式的改进可能允许更快速的临床实施潜在的药物治疗，终点由瓣膜叶病变进展缓慢的成像证据定义，因为死亡率和瓣膜置换等临床终点需要大样本量和长随访间隔。在主动脉瓣疾病中，研究强调了药物治疗减缓或阻止疾病进展的可能性，但还需继续努力，以确定新的分子靶点并将其转化为可行的药物。
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
参考文献
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