郑刚教授：靶向炎症的治疗策略——2型糖尿病合并心肌梗死管理新机遇_靶向炎症_2型糖尿病_心肌梗死

郑刚教授：靶向炎症的治疗策略——2型糖尿病合并心肌梗死管理新机遇

2025-04-15 来源：医脉通

关键词：靶向炎症 2型糖尿病心肌梗死

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郑刚

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在过去的30 年中，全球糖尿病（DM）的患病率显著增加，从1990年的2亿增加了一倍多，到2025年估计将超过5 亿^[1]。这对心肌梗死（MI）有重要的影响，而MI是DM患者最常见的死亡原因之一^[2]。不仅DM患者的MI发病率增加，而且MI后的结果一直更差。DM患者的短期和长期死亡率较高，MI后再梗死，心力衰竭（HF），心源性休克和心律失常发生率高^[3-8]。 MI治疗进展大大降低了院内死亡率，从 1960 年代的30%^[9]降至当代再灌注时代的< 7%^[10]。然而，尽管治疗和总体生存率有所改善，但DM患者的死亡率仍叫无DM患者增加 1.5~2 倍^[11]。

重要的是，尽管在治疗和总体生存方面取得了进展，但近几十年来这种差异一直保持一致。出现了一些假设来解释这种增加的风险，例如梗死面积或冠状动脉疾病严重程度的差异。本文回顾并重新评估MI后DM患者不良预后的证据，重点是如何针对炎症过程提供未探索的，但有价值的机会，以改善该脆弱患者群体的心血管预后。

流行病学

在保守治疗的时代，没有再灌注治疗相关尝试，MI后DM患者的院内死亡率为 60.8% ，是非DM患者的两倍^[12]。在冠状动脉监护病房（CCU）出现后，一项对832人的研究发现，在急性心肌梗死（AMI）后的第一个月，20.2% 的非DM患者和42.0%的DM患者死亡^[13]。在再灌注治疗中，GUSTO-1 研究发现，在ST段抬高型心肌梗死（STEMI）患者中，DM患者 30 天的死亡率为 10.5%，而无DM患者为6.2%^[14]。在GRACE 注册试验的患者中，DM 患者合并STEMI和非ST段抬高型心肌梗死（NSTEMI）患者的院内死亡率较高（分别为11.7% vs 6.4%和6.3% vs 5.1%）^[15]。

在当今常规侵入性冠脉造影和经皮冠状动脉介入治疗（PCI）时代，2005年至2013年对12270人（4388例DM患者）进行的一项单中心研究显示，DM患者的30天和1年死亡率显著增加（分别为13.5% vs 4.3%和25.7% vs 12.4%）^[16]。PROSPECT II试验的一个子研究显示，DM患者的主要不良心血管事件（MACE）增加了2倍^[17]。同样，HORIZONS-AMI 研究发现，在 30 天时，新诊断和确诊的DM患者的死亡率较高（4.5% vs 1.8%）^[18]。绝大多数DM患者患有2型糖尿病（T2DM），因此，大多数研究没有足够的效力来探究1型糖尿病（T1DM）对预后的影响。然而，Kerola 等^[19]对芬兰20家医院的调查显示，对于MI后患者，合并T1DM患者的30天和1年死亡率均较高（分别为12.8% vs 8.5%和24.3% vs 16.8%），这一趋势在不同亚组（有或无HF，有或无STEMI，有或无血运重建）中仍成立。因此，虽然潜在的病理生理学有所不同，但T1DM和T2DM似乎均对MI后患者的预后产生负面影响。

高血糖是T1DM和T2DM的主要特征，AMI患者入院时血糖水平升高与患者预后不良有关^[20]。在再灌注治疗之前，溶栓剂使用^[21]以及再灌注治疗时代，这一点已被充分证实^[22]。一项荟萃分析纳入了超过 20000名STEMI患者（23%为DM，但未指定类型)）接受直接PCI治疗，显示入院高血糖（AH）与30天和长期随访的死亡率较高有关。值得注意的是，AH在以前没有发现DM的人群中很常见，特别是对于那些既往有MI、多支血管冠状动脉疾病（CAD）和左前降支梗死的人群^[23]。尽管有这些长期的观察结果，但在回答围绕急性冠脉综合征（ACS）高血糖的关键问题方面进展甚微，其中最为重要的是高血糖是否为不良结果的介质或标志物^[24]。大多数关于MI预后的临床研究没有区分T1DM和 T2DM。从相对患病率推断，大多数研究主要包括 T2DM患者。在本文中除另行说明外，其他均指T2DM患者。

糖尿病持续时间的影响

在心血管风险评估中，通常考虑（以二元方式）给定患者是否患有DM。事实上，这种关注可能掩盖了包括：①DM的持续时间，②血糖控制质量和 ③治疗在内的重要因素的异质性。

在T2DM中，病程与死亡风险相关。在 2010 年1月至 2019 年12月期间，分析了意大利近14万名STEMI或NSTEMI住院患者的区域数据^[25]。研究者根据疾病持续时间将DM患者进一步分为三组：<5 年，5~10 年和 > 10年。在他们的分析（包括调整年龄）中，住院死亡率随着DM的持续时间而增加，与没有DM的人相比，受影响超过10年的人的风险最高（OR = 1.59）。这表明T2DM的不良结果可能不仅反映MI时的代谢状态，而且反映了随时间推移的病理特征的累积。同样，对糖化血红蛋白（HbA1c）相关研究的荟萃分析 (n = 25 项研究和> 30万名患者) 表明，即使并未确诊T2MD，长期血糖高水平也与ACS后患者的预后较差相关^[26]。

糖尿病治疗的影响

DM对MI后患者预后的影响也可通过特定的治疗来改变。在GRACE注册表中，与接受其他DM治疗的患者相比，需要胰岛素治疗的STEMI患者在急性住院期间死亡、HF、心源性休克和肾功能衰竭的风险增加^[15]。同样，对包括超过7000 名AMI和DM参与者在内的四项随机对照试验的汇总分析也显示，在随访2年期间，与没有DM的受试者相比，未接受胰岛素治疗的DM患者的心血管死亡风险增加（HR=1.25），但进行胰岛素治疗的DM患者的心血管风险增加幅度更高（HR=1.49）^[27]。在 SWEDEHEART 登记处，与单独饮食治疗的 DM 患者相比，接受胰岛素单药治疗的 DM 患者平均随访 3.4 年，死亡率、MI、卒中和HF综合评分的风险增加（HR=1.32）^[28]。然而，尽管这些研究显示了一致的模式，但这可能不一定是由于胰岛素治疗，而是可能反映了混杂因素，例如长期或控制不佳的DM对口服降血糖药物没有反应。

二甲双胍是T2D常用的一线口服降血糖药。在MI的实验模型中，有证据表明二甲双胍改善心血管功能并减少梗死面积^[29]。一项观察性研究显示，二甲双胍的使用与较低的肌酸激酶-肌钙蛋白水平有关^[30]，但这种相同的效果在其他地方没有显示出来^[^31]。在SWEDEHEART注册研究中，与单独进行饮食治疗的DM患者相比，使用二甲双胍单药治疗的患者有较低的MACE风险（HR=0.92）^[28]。然而，由于迄今为止没有大型随机对照试验，没有明确的证据表明二甲双胍在改善MI后的结局方面具有因果关系。同样，没有强效的证据表明磺脲类药物的使用有效以及其对MI预后的可能影响。在对 188 名MI和DM患者的观察性研究研究中，Garratt 等^[32]发现，经过多变量调整后，磺脲类药物的使用是早期死亡率的独立预测因子（HR=2.77）。然而，其他研究未能显示这种关联^[33-36]。

虽然没有明确的随机对照试验证实传统降糖药物对MI预后的影响，未来也不太可能进行相关试验，但近年来对新型降糖药物，特别是钠葡萄糖协同转运蛋白 2 （SGLT2）抑制剂对MI预后影响的兴趣越来越大。SGLT2抑制剂对T2DM患者的心血管预后有益。在EMPA-REG OUTOUT试验中，与安慰剂相比，每日一次恩格列净（empagliflozin）的使用与心血管原因死亡（HR=0.62）和因HF住院率（HR=0.68）降低显著相关，无论 HbA1c 降低如何^[37]。

随后，其他 SGLT2 抑制剂包括卡格列净（canagliflozin）^[38-39]，达格列净（dapagliflozin）^[40]和埃格列净（ertugliflozin）^[41]的随机临床试验都与T2DM患者HF住院风险降低有关，表现出一致的类效应。

此外，在 DAPA-HF试验^[42]中，对于左室射血分数（LVEF）≤40%的心衰患者，达格列净与 HF恶化风险降低（HR=0.70）和心血管死亡风险降低（HR=0.82）相关。DELIVER-TRIAL试验还表明，达格列净的有益作用已经延伸到了射血分数轻度降低或保留的心衰患者^[43]。重要的是，在两项试验中，这些益处均与是否合并DM无关。SGLT2 抑制剂发挥其心血管作用的机制尚不清楚，但其潜在机制已在相关文章中阐述^[44-45]，SGLT2抑制剂可能影响炎症过程和动脉粥样硬化斑块。一项观察性研究纳入了接受PCI的T2DM和多支非阻塞性冠状动脉病变患者，研究发现使用SGLT2 抑制剂与较高的最薄纤维帽厚度（FCT）（斑块易损性的测量）和较低的炎症临床测量值[如白细胞计数、高敏感性C反应蛋白（hs-CRP）、白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）]相关^[46]。

大量研究中一致的心血管获益提示SGLT2抑制剂或可使MI后早期患者获益^[47]。在纳入377名接受PCI的T2DM和AMI患者的观察性研究中，无论患者的血糖状况如何，SGLT2抑制剂使用均与改善预后相关^[48]。也有证据表明，在 T2D 患者中，使用 SGLT2 抑制剂与 MI 后新发心律失常的风险较低有关。

最近的一项随机对照试验探究了SGLT2 抑制剂在 MI 后急性期的作用^[49]。在该试验中，476 名AMI患者（包括13%的 T2D 患者）被随机分配到每日一次的恩格列净或安慰剂中，在 PCI术后72小时内服用 26 周。研究显示，恩格列净使用与平均 N 末端 B 型利钠肽前体（NT-proBNP）水平和LVEF显著改善有关，且这些变化在几周内就很明显^[50]。EMMY 试验的事后分析显示，与安慰剂相比，恩格列净没有显著降低全身炎症标志物，如IL-6、hs-CRP、嗜中性粒细胞计数、白细胞计数和嗜中性粒细胞/淋巴细胞比率^[51]。在DAPA-MI试验^[52]探究了达格列净对心血管死亡率或心衰发生的影响，但该研究的事件发生率较低、除外了高危人群，且随访时间较短，效力或不足。EMPACT-MI平均随访17.9个月显示，与安慰剂相比，恩格列净治疗并没有显著降低首次住院或因任何原因死亡的风险^[53]。

尽管总体死亡率已经下降，但与T2DM相关的风险仍持续增加^[3]，提示对T2DM认识的必要性和紧迫性。首先，为什么进行了当代T2DM治疗，但AMI的预后更差预后；其次，该如何改变这些结局。

下文将重新分析相关风险的潜在机制，并评估最新数据，以探索针对这一人群风险的新机会。

早期死亡率增加的潜在原因

在考虑早期死亡率增加的潜在原因时，探究造成DM患者MI后死亡的机制是有用的。据我们所知，还没有研究专门调查DM患者MI后的死亡机制，也没有研究询问与没有DM的人相比，是否存在不同分布的特定致命表现。

虽然死亡率是一个明确的终点，但确定MI后人们死亡的确切机制是具有挑战性的；且仅有少数人进行尸检，因此死亡证明的数据是常常不准确^[54] ，似乎不太可能对了解DM的不良风险有启发作用。

1.梗死面积及LVEF

梗死面积的大小与不良预后具有一定的相关性^[55,56]。DM患者往往有不太严重或非典型的MI症状^[57] ，或导致寻求护理、诊断和治疗的延迟，从而导致梗死面积增大。梗死面积与死亡率密切相关^[58] ，限制心肌损伤已成为推动有效再灌注治疗的关键临床优先事项。

然而，对梗死面积的量化并不能明确支持DM有助于梗死面积的增大。心肌磁共振（CMR）是心肌组织非侵入性评估的金标准，包括MI后确定梗死面积^[59]。对92名MI患者（包括22名DM患者）进行的CMR研究表明，DM患者的晚期钆增强（平均左室瘢痕百分比，25.6% vs 15.8%）测量的梗死面积较大^[55] ，然而本研究为观察性，样本量较小，效力或不足。

随后的 CMR研究未能显示类似的关联^[60-61]。Eitel 等^[60]研究了 411 名接受直接PCI的 STEMI 患者的 DM 与梗死面积之间的关系。研究显示，DM患者的MACE风险增加了3倍，即使梗死面积相似（左室瘢痕百分比 18.2 vs 18.2%)。有趣的是，预后不良与较大的梗死面积有关，但在DM患者中这种关联性较弱。Reinstadler等^[61]的一项研究（792例STEMI患者）发现，有或无 DM 患者的梗死面积或心肌挽救指数没有显着差异。

此外，除梗死面积外，LVEF降低也是MI后死亡率的预测因子^[62]，但是LVEF在有/无DM患者之间是可比较的^[55,56,61]。因此，似乎梗死面积和LVEF的差异都不足以解释T2D对MI后不良预后的影响。

2.动脉粥样硬化负担

ACS患者通常接受侵入性冠状动脉造影，但冠状动脉造影为腔内检查，从而限制了动脉粥样硬化的定量分析和斑块组成的测定，这反过来影响斑块的生物学特性，尤其是侵蚀或破裂的倾向。更详细的斑块成分可以使用血管内成像光学相干断层扫描（OCT）和血管内超声（IVUS）获得。

DM患者冠心病的患病率较高^[63]，人们普遍认为DM与更严重和更广泛的冠心病有关。Niccoli 等^[64]的研究比较了伴或不伴DM的ACS患者的多支血管病变情况，提示合并DM组患者的多支血管疾病发生率更高（68% vs 42%）。

同样，PROSPECT I 试验的一项子研究（IVUS测量）显示，合并DM的ACS患者具有更长的冠状动脉病变（12.0 vs 10.7 mm）^[65]。另一项主要纳入稳定型冠心病患者的研究（CT测量）显示，与不合并DM的患者相比，合并DM患者的混合冠脉斑块数量更高（1.67 vs 1.23），但所有类型的斑块（钙化、非钙化和混合）数量在两组之间无显著差异^[66]。

然而，由于不同的研究采用的定量方法有所不同，因此不同研究中冠心病（CAD）患者的严重程度可能无法比较。此外，应用IVUS、OCT和/或其他侵入性冠脉测量方法的研究或包含对复杂和弥漫性狭窄CAD患者的固有选择偏倚。在 PROSPECT II试验中，有/无DM患者的平均SYNTAX评分也没有显著差异^[17]。因此，尽管CAD类型和严重程度或与DM患者的死亡率增加有关^[67]，但相关性或并不明显。

PROSPECT II试验^[68]显示，高脂质含量（OR=3.80）和高斑块负荷（OR=5.37）是非罪犯病变MACE（定义为心源性死亡、MI、不稳定型心绞痛或进行性心绞痛的复合事件）的独立预测因子。PROSPECT II的一项亚组分析试验显示，与无DM患者相比，尽管DM患者进行了支架和/或药物治疗，但其MACE发生率仍增加了1倍（OR=1.94），这主要是由非罪犯病变中的自发性MI以及罪犯病变的再狭窄所致^[68]。DM是非罪犯病变MACE的独立预测因子（OR=2.47），但似乎不影响罪犯病变的MACE。此外，在有无DM的人群中^[17]，罪犯和非罪犯病变的斑块特征（脂质含量和斑块负荷）是相似的，基线和残留SYNTAX评分没有差异。

Sugiyama等^[69]的报道（OCT检测）提示，在ACS时，DM患者具有更广泛的CAD和更 “脆弱”的斑块。然而，正如Ali等^[70]所强调的那样，OCT对“脆弱”斑块的确定受到观察者间对于帽厚度和脂质弧测量的适度一致性的限制，再加上TCFA患者的每个病变事件发生率极低。虽然MI时冠心病的负担在DM患者中可能更重，但这并无法说明DM对MI后患者预后的影响。

GUSTO血管造影试验^[71]比较了随机接受四种不同溶栓方案的2431例STEMI患者的基线血管造影差异，发现DM患者的多支血管病变频率更高，梗死相关动脉的参考直径明显更小，但在校正多支血管病变和90分钟MI溶栓（TIMI）后，DM 仍然是30 天死亡率的独立预测因子。然而，这项研究应用的衡量标准相对粗糙（有无多支血管病变），且未调查冠脉斑块的组成。

总体而言，这些研究表明，通过侵入性血管造影、血管内成像或心脏CT等方法定量描述斑块范围、形态和病变复杂性差异无法充分解释DM患者MACE风险增加的原因。

3.心肌灌注和冠状动脉微血管功能障碍

有效、及时的再灌注治疗是AMI预后的决定因素，主要与心外膜血管的通畅性和微血管系统的能力相关。即使进行PCI治疗改善了心外膜血管的通畅性，冠状动脉微血管功能障碍（CMD）也可能延迟或阻止再灌注导致的持续性缺血和梗死。

冠状动脉微循环由直径 <500μm 的微小动脉和小动脉组成，是调节心肌灌注的主要部位。虽然这些血管在目前的成像模式（包括侵入性动脉造影）下是不可见的，但它们的功能可以通过生理测量来评估^[72]。冠状动脉血流储备（CFR）异常或心肌血流储备（MFR）等指标，可测量应激或最大充血时心肌血流量与静息心肌血流量的比率，提供了在没有心外膜狭窄的情况下 CMD 的定量定义。

重要的是，CMD影响MI后的预后，Kelshiker等^[7^3]在他们的CFR和心血管预后系统综述中表明，在急性和慢性冠状动脉综合征中，CFR异常是MACE的预测因子。专门比较DM和非DM患者的研究很少，而且大多数是在症状稳定而非AMI患者的情况下进行的。

在一项单中心研究显示，与非DM患者相比，DM患者的MFR异常更为普遍，且DM和MFR均为MACE的独立预测因子^[74]。同样，另一项研究显示，CFR < 2是DM患者MACE风险的预测指标^[75]。这些数据已经在侵入性血管造影测量中得到复制，以确定CFR以及微循环阻力特异性指标，如微循环阻力指数，充血性微血管阻力和微血管阻力储备^[76-79]，表明DM患者（主要在稳定型心绞痛的情况下）更可能具有较低的 CFR（<2），尽管不一致，但微循环阻力指数较高。

一项纳入144名T2DM患者的研究^[80]显示， DM 患者的微血管阻塞（MVO）更为普遍，或导致死亡率过高。对7项纳入直接PCI的STEMI患者的随机对照试验进行的汇总分析发现，在急性事件发生7天内测量的MVO与HF的死亡率和住院率密切相关^[81]。介入治疗后，糖尿病患者 ST 段抬高不完全，CMR 测量的心肌红斑分级降低^[82]，MVO 降低^[83]。可以预期MVO通过增加梗死面积影响预后，但 MVO 是不良结局的独立预测因子，即使在调整梗死面积后也是如此^[81]。

总体而言，无论侵入性和非侵入性方法均表明，DM患者倾向于患有CMD，CFR是MACE的独立预测因子，且STEMI后更易发生MVO。在MI后DM患者预后较差的情况下，这些发现可以反映：①损害再灌注或修复的冠脉微血管疾病和/或②加重AMI期间功能性微血管功能障碍或阻塞损害心肌再灌注。

4.糖尿病心肌病

DM 使HF^[85-86]的风险增加 2 ~4 倍，这通常归因于 “糖尿病心肌病”，这是指在没有CAD，高血压和DM个体中没有显著的瓣膜疾病的情况下心肌结构和功能异常。MI后HF的风险增加也很明显，例如在 SWEDEHEART注册研究中，DM使MI后HF的风险增加了30%^[87-88] 。糖尿病患者的心脏结构改变包括心肌纤维化、心肌肥厚/重塑和微血管功能障碍^[89]。一项 CMR相关研究显示，28%的既往无MI临床证据的DM患者有心肌瘢痕，且研究中大多数患者或为T2DM^[90]。在该队列中，心肌瘢痕的高发生率提示T2DM患者有无症状性梗死，或T2DM引起的纤维化。包括成纤维细胞增殖、神经体液激活、促炎细胞因子产生、氧化应激、心肌转化生长因子-β表达增加和晚期糖基化终产物（AGE）/AGE受体（RAGE）轴的激活在内的多种机制或导致DM患者发生纤维化^[91]。在DM患者中经常观察到心脏重塑^[92-93]，且由于仅少数患者进行CMR检查，因此心脏重塑很可能未被检测到。

总体而言，糖尿病心肌病的潜在不同表现或可解释DM患者为什么更容易受到MI的影响，如通过影响梗死区域或损伤远端心肌等。

5.性别对预后的影响

多项研究表明，MI后，女性的预后往往比男性更差，包括住院率^[94]、因HF住院^[88,95]、短期^[96-100]和长期死亡率^[101-102]更高。然而，当校正年龄，风险因素和合并症等混杂因素时，这种预后差距往往会减少或消失^{[96,99,102-103]}。此外，女性在MI后更不可能及时接受指南推荐的药物治疗^[98-100]，提示这种预后差距并不完全由生物学性别差异解释。

女性DM患者或为一个极其脆弱的群体。一项观察性研究探究了17154名PCI后患者的1年死亡率和MI发生率，提示女性DM患者的死亡和MI风险最高^[104]。值得注意的是，女性非DM患者与男性DM患者的不良事件风险相似^[101,105]。对于短期死亡率，既往一项纳入48878名AMI患者的研究提示，在校正混杂因素后，18 ~45岁之间的女性DM患者的住院死亡风险并不高于男性^[106]。

尽管如此，女性在临床研究中代表性不足，在了解性别对MI预后的影响，包括其与DM的相互作用方面仍然存在许多知识差距。

识别和靶向炎症的新兴可能性

大量证据表明，在DM状态下，细胞和分子反应发生改变。其中，氧化应激、血管生成和细胞能量改变已经被很好的描述了。

MI后，过量产生的活性氧类（ROS）可通过直接损伤DNA、脂质、蛋白质和线粒体，导致心肌细胞死亡增加，在介导缺血/再灌注损伤中起着至关重要的作用^[107]。ROS 也可以触发炎症过程，例如激活核苷酸结合寡聚化结构域，含有富亮氨酸重复结构域的蛋白 3 （NLRP3）炎性体^[108]，Janus 激酶/信号传导和转录激活因子（JAK-STAT）途径^[109]和核因子kappa B（NF-κB）途径等。

DM患者表现出高NADPH氧化酶活性^[110]和血管内皮一氧化氮合酶功能受损，导致活性氧的产生升高^[111]。在DM患者的心肌中也观察到活性氧水平升高^[112]。通过提供氧气和营养物质来限制缺血，血管生成在促进受损心肌的修复中也起着至关重要的作用^[113]。白细胞的募集需要新的血管形成，白细胞是损伤和修复的重要介质^[113]。缺氧诱导因子1-α（HIF1-α）是血管生成的关键调节因子，心肌细胞中HIF1-α的表达增加，可增强心脏功能并减少MI小鼠模型中的梗死面积^[114]。众所周知，高血糖会损害内皮细胞中HIF1-α的稳定性^[115]。既往研究也显示，与无DM者相比，T2DM患者的HIF1-α和血管内皮生长因子表达下降^[116]。此外，与新型血管生成蛋白相关的其他途径^[117]，缺陷内皮祖细胞^[118]和血管一氧化氮抵抗^[119]都可能损害T2DM后MI患者的血管生成^[120,121]。

改变心肌能量学，可能影响MI后患者的预后。通常情况下，心脏使用多种底物，包括游离脂肪酸、葡萄糖、氨基酸和酮来产生三磷酸腺苷。然而，在T2DM患者中，心脏代谢的灵活性降低。高胰岛素血症和胰岛素抵抗降低了葡萄糖利用率，增加了心肌的游离脂肪酸摄入量，导致毒性脂质代谢物和活性氧的积累，最终导致心肌功能障碍^[122]。

然而，其他先前被忽视的与炎症过程有关的因素，似乎越来越相关和合理。循环炎症标志物，特别是高敏C反应蛋白（hs-CRP），与各种临床情况下的不良结果有关^[123-126]。在CARE试验中，通过升高的CRP和血清淀粉样蛋白 A （SAA）^[127]测量的全身炎症证据与MI后复发冠状动脉事件的风险增加有关，但在T2DM患者中事件的比例较高。事实上，通常认为CRP和SAA在T2DM患者中更高。近期Ridker等^[12^8]对三项随机临床试验的荟萃分析显示，hs-CRP 升高与未来事件的相关性较 “治疗” LDL-C更强^[129]。重要的是，该分析中的大多数人（76%）合并 T2DM。

总体而言，炎症过程或导致DM患者的预后恶化。然而，“炎症” 这个笼统的术语或无法提供足够的信息。由肝脏合成和释放的CRP代表了几种梗死后相关炎症过程的综合下游作用，并且不足以描述复杂的分子和细胞炎症过程^[130]。关于特定分子途径激活，互补（或竞争）细胞类型参与阶段的功能相关信息，急性炎症状态与分辨率，甚至炎症的精确位点目前在MI中没有明确定义。因此，针对潜在易处理的炎症过程的干预措施的最佳时机和性质上是未知的。此外，针对炎症过程需要考虑对MI的免疫反应中的性别差异^[131]。因此，我们将把重点放在机制上重要的，治疗上易处理的炎症过程上，并受到DM患者潜在干扰。

心梗后炎症相关过程

MI引发局部和全身炎症反应。在心肌中，梗死后的炎症反应可分为三个阶段：报警阶段、白细胞动员阶段和消退阶段^[122]。

在报警阶段，死亡的心肌细胞和其他细胞释放被称为损伤相关分子模式（DAMPs）的信号，包括高迁移率组蛋白 B1^[133]、热休克蛋白^[134]、S100A8/A9^[135]和纤连蛋白^[136]。DAMP与模式识别受体，如Toll 样受体、核苷酸寡聚化结构域样受体和RAGE结合，激活先天性免疫通路^[137]。可以在先天性免疫细胞内激活的促炎信号传导途径，包括但不限于 (NLRP3)/IL-1β^[138]、NFκB^[139]和 JAK-STAT 信号传导途径^[140]。

在白细胞动员阶段，白细胞迅速浸润缺血心肌。中性粒细胞是第一个有反应的细胞^[141-142]，其次是促炎性单核细胞^[143]（随后分化成巨噬细胞），以清除死亡的心肌细胞和其他坏死组织。既往资料已表明内皮细胞衍生的细胞外囊泡如何将嗜中性粒细胞和单核细胞动员到梗死心肌^[144-145]，以及这些细胞的转录组在募集到受损心肌之前如何在血液中改变。AMI也将白细胞动员到远离缺血区域的心肌。

在消退阶段，促炎症过程被抑制。在这个阶段，巨噬细胞功能从吞噬作用，蛋白水解和细胞外间质降解转变为血管生成和肉芽组织形成。系统地，MI 增加促炎细胞因子TNF-α^[150]和 IL-6^[151] 的血浆浓度。值得注意的是，实验性MI通过增加骨髓细胞向斑块的募集来加速动脉粥样硬化^[152]。

潜在治疗目标

炎症过程是潜在的治疗靶点。在MI实验模型中，抑制促炎性单核细胞向受损心肌的募集减少了梗死面积 ^[153-15^5]。这导致了夸大或延长的促炎反应加剧损伤并使修复最小化，从而导致不良的心室重塑^[149,156]。然而，MI后的非靶向抑制可能是有害的。既往已经显示皮质类固醇和非甾体抗炎药与MI后的心室壁破裂有关^[157,158]。如前所述，巨噬细胞转变成愈合剂，并且可以理解非靶向抑制损害愈合/修复。

近年来，针对性地抑制CAD中的炎症通路已经显示出有希望的结果。2017 年的CANTOS试验表明，针对炎症途径的概念或有益，即使用单克隆抗体卡那单抗（canakinumab）的IL-1β可改善hs-CRP≥2 mg/L的已知CAD的预后，尽管效应大小是适度的^[159]。

随后，IL-6，一种更下游的细胞因子，目前正在作为一个潜在的治疗靶点进行研究。在ASSAIL-MI 中，对199名个体进行的2期随机临床试验中，用托珠单抗（tocilizumab）靶向 IL-6 显著增加了胸痛6 h内进行直接PCI的STEMI患者的心肌挽救指数^[160]。RESCUE 2 期随机临床试验显示，在肾功能受损的人群中，针对 IL-6 的单克隆抗体Ziltivekimab，可在不影响胆固醇水平的情况下，显著降低CRP 水平^[161]。ZEUS 3 期临床试验近期已完成患者招募。一项更相关的3期 ARTEMIS试验将在侵入性操作后尽早探究Ziltivekimab的疗效，STEMI患者在住院36小时内起始，NSTEMI患者在住院48小时内起始。

IL-1β和IL-6都是活性细胞因子，与冠心病及其并发症的因果途径有关，因此是潜在的治疗靶点。这与CRP相反，后者是一种在肝脏中产生的对 IL-6 有反应的急性期蛋白质，但其仅仅为一种生物标注物，对发病机制物影响。重要的是，对因果途径的有针对性的抑制应该提供对驱动动脉粥样硬化进展的炎症过程的更好的理解，并帮助描述和定义可能受益最大的患者组。

糖尿病和炎症过程

DM等代谢性疾病如何影响免疫细胞功能，人们对此越来越感兴趣。还有很多东西有待理解，但是现有证据表明了DM病如何加重MI后的炎症过程，以及如何介导不良结局的潜在可能性。在动物模型中，高血糖驱动骨髓生成^[162]，这似乎由于短暂间歇性高血糖的模式而加剧^[163,164]。最近，发现了高血糖诱导的训练免疫（HITI）的新现象，其中高血糖加剧经典炎症并抑制修复。高血糖导致造血干细胞的表观遗传学改变，使其后代远离M2修复表型，转向M1促炎症表型。

尽管恢复了葡萄糖的生理水平，但这些修饰仍然存在^[165]。虽然这种（M1/M2）二分法是过于简单化的，但研究结果表明，HITI 或影响 MI后的炎症过程，并导致不能通过降低葡萄糖来纠正的变化。DM或影响MI后巨噬细胞的炎症过程。与创面愈合相关，DM和HITI可能会损害MI。有效的伤口愈合需要炎症期的促炎性单核细胞的顺序浸润，然后是修复期的抗炎性单核细胞。然而，在DM小鼠的伤口中，Ly6Chi单核细胞可表现出 “第二次内流” 并浸润，从而延迟其向 Ly6CLo单核细胞的转变^[166]。一种类似，但尚未探索的过程可能在心脏中发生。如前所述，高血糖导致偏离M2修复表型。促炎性单核细胞浸润缺血心肌可损害炎症的消退，加重损伤程度。如果这些是病理学上重要的过程，人们可能预期 DM患者的梗死面积会更大，但是在上述CMR研究中并不明显（在急性期测量的梗死面积没有显著差异）^[60,61]，尽管已知梗死面积仅在大约30天后达到其最终大小^[167]。因此，研究者或过早测量梗死面积，尤其是如果HITI可延迟梗死愈合和炎症消退时。此外，目前的成像技术无法检测梗死愈合过程中潜在的重要组织学差异。

DM对造血和白细胞功能的影响似乎可能影响招募到远端心肌的白细胞的性质。在人类心脏中，CCR2 +巨噬细胞（来源于循环单核细胞）的存在与心室功能恶化和不良重塑有关^[168]。偏向于促炎症过程的单核细胞可能不仅被招募到梗死区，而且被招募到远端心肌，这可以部分解释为什么DM患者在MI后更可能发生 HF^[169-170]。此外，最近的证据表明，炎症细胞可能是MI后心律失常的决定因素^[171]。全身而言，高血糖增加炎性细胞因子（TNF-α，IL-6 和 IL-18）^[172]和急性期蛋白的产生^[173]。如前所述，hs-CRP 与心血管事件的残余风险密切相关，特别是在 DM 患者中^[129]。CANTOS试验的亚组分析显示，对于T2DM患者进行抗炎治疗没有选择性益处^[175-176]。

综上所述，DM的存在或不足以确定DM患者或受益于靶向活动性炎症。在细胞水平上，高血糖驱动糖酵解反过来导致特定组蛋白的翻译后修饰。这些组蛋白修饰显著的改变了IL-6 启动子处的染色质可及性，这是 HITI 的主要特征^[165,177]。启动子 “保持开放”，从而有效的启动活性转录的 IL-6 基因。因此，T2D M导致HITI患者具有更高的IL-6 和 hs-CRP水平，且可能对IL-6抑制显示出特殊的治疗益处。

结论和未来影响

T2DM的全球流行正在迅速增加对心血管疾病的不利影响。尽管MI后预后总体上有所改善，但T2DM患者的预后持续恶化，并发症、再梗死和死亡率较高。影响因素是复杂和多重的，远远超出了血管造影表现的冠心病和/或MI大小的 “解剖学” 考虑范围。特别是，新出现的一系列证据指出了炎症过程和炎症消退受损在 T2DM中的作用。流行病学研究表明，在T2DM患者中，hs-CRP是预测结局的优越指标（与LDL-C相比）；以及近期数据提示的高血糖对先天性免疫功能的影响。这些先天免疫功能的改变可能与动脉粥样硬化的进展和AMI的反应有关，且所有名义上DM患者均会受到不同程度的影响。

另外，新出现强效证据表明，在未来，人们将受益于对疾病过程的描述，而不仅仅是名义上诊断的DM。特别是，对炎症过程和体内平衡紊乱结局的更好理解和角色塑造可能为针对并发症和改善DM患者的心血管预后开辟新的机会。

专家简介

教授.jpg

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

参考文献

                                                                
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                                    65.Marso SP, Mercado N, Maehara A, Weisz G, Mintz GS, McPherson J, Schiele F, Dudek D, Fahy M, Xu K, Lansky A, Templin B, Zhang Z, de Bruyne B, Serruys PW, Stone GW. Plaque composition and clinical outcomes in acute coronary syndrome patients with metabolic syndrome or diabetes. JACC Cardiovasc Imaging 2012;5(Suppl.):S42–S52.                                
                                                            
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                                                                68.Erlinge D, Maehara A, Ben-Yehuda O, Bøtker HE, Maeng M, Kjøller-Hansen L, Engstrøm T, Matsumura M, Crowley A, Dressler O, Mintz GS, Fröbert O, Persson J, Wiseth R, Larsen AI, Okkels JL, Nordrehaug JE, Bleie Ø, Omerovic E, Held C, James SK, Ali ZA, Muller JE, Stone GW; PROSPECT II Investigators. Identification of vulnerable plaques and patients by intracoronary near-infrared spectroscopy and ultrasound (PROSPECT II): a prospective natural history study. Lancet 2021;397:985–995.                                                            

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