泰达国际心血管病医院 郑 刚

目前全球有5.4亿糖尿病患者，欧洲有6 100万糖尿病患者，其中90%患有2型糖尿病（T2DM）[1]。心血管疾病是T2DM患者发病率和死亡率居高不下的主要原因，心力衰竭（HF）是最常见的表现之一[2-3]。最近一项基于人群的研究包括190万患有和不患有T2DM、基线时没有心血管疾病的人，表明在5.5年的随访中，T2DM患者发生HF的频率高于心肌梗死或卒中[3]。校正后的HF发病相对风险明显更高（HR=1.56）[3]。多项纵向研究证实，T2DM是普通人群中新发HF的一个强有力的独立预测因子[3-5]。在同时患有T2DM和HF的患者中，每种疾病的存在都会对预后产生不利影响。另一方面，显著增加并发症、HF住院和死亡的风险[6-7]。

T2DM和HF之间密切关联已被认为可能患有糖尿病心肌疾病，以前称为“糖尿病心肌病”，这在一些专家文件中有不同的定义[8-12]。一种普遍的观点是，在没有冠状动脉疾病（CAD）、高血压、瓣膜病、肥胖或其他心脏代谢危险因素的情况下，低估了T2DM与导致HF的心肌结构和功能异常之间的关联。最近，根据HF分期的概念，没有心脏异常的T2DM患者被视为HF风险期（A期），而那些无症状的结构/功能性心脏异常和/或利钠肽升高的T2DM患者被视为HF前期（B期）。这样可以使T2DM患者发生HF诊断前移，从而可能提供预防或延缓HF发生的可能性[14-16]。

1型糖尿病（T1DM）患者也存在心脏结构和功能异常，以及发生HF的较高风险[17-18]。尽管可能与T2DM重叠，但T1DM患者的糖尿病心肌疾病的潜在机制和现象类型尚不清楚，有待进一步阐明[19]。本文将总结目前对T2DM和HF之间关联的理解，简要讨论了病理生理机制，并强调了在出现HF之前有充分记录的心脏异常，这可能与糖尿病心肌疾病有关。它强调了基于验证的风险模型对T2DM患者HF发展进行风险评估的重要性。

1 T2DM与HF的病理生理相关性

导致T2DM患者HF的结构/功能异常的发展涉及多种机制，这些机制尚未完全阐明[9]。广泛包括系统因素，如高血糖、胰岛素抵抗、高脂血症、晚期糖基化终末产物（AGEs）的过度产生、肾素-血管紧张素-醛固酮系统（RAS）的激活和自主神经失调[12,20-21]。这些是高血压、冠状动脉粥样硬化加速和微血管功能障碍的重要驱动因素，在很大一部分T2DM患者的HF发展中起着关键作用。全身因素还促进心肌中相关的病理细胞和分子过程，这些过程独立于或与上述机制共同导致HF的发展[22]。这些过程包括：1.1 心肌代谢变化、能量效率受损和收缩功能障碍 高胰岛素血症和胰岛素抵抗降低了心肌葡萄糖的摄取和能量生产利用[23]。同时，游离脂肪酸的输送和摄取也增加，导致对脂肪酸β-氧化的能量生产依赖性增加[24-25]。然而，这种代谢转变的代价是心肌耗氧量增加、心力效率降低和收缩功能障碍[26]。对脂肪酸代谢的依赖增加也会导致解偶联。线粒体蛋白和线粒体功能障碍，从而增加氧化应激[27]。1.2 葡萄糖毒性、脂肪毒性和氧化应激 慢性高血糖导致多元醇途径中醛糖还原酶活性增加，蛋白质O-GlcNA酰化增加，AGEs过度产生[22]。这些过程损害了细胞抗氧化机制，促进了线粒体功能障碍，进一步加剧氧化应激[22,28]。过度氧化应激导致内质网功能障碍[29]，钙离子处理受损和二碳肌丝功能低下[30]。O-GlcNA酰化增加还导致自噬受损，心肌细胞凋亡增加和微血管内皮功能障碍[31-33]。此外，心脏过度摄取未经β-氧化代谢的非酯化脂肪酸，导致心肌细胞脂质积累和脂质毒性[34-37]，进一步加重氧化应激并促进心肌细胞凋亡[38]。1.3 心肌纤维化、肥大和舒张功能障碍 由于基质金属蛋白酶的下调和胶原蛋白交联增加，AGEs过度堆积会降低细胞外基质周转[39-40]。脂质毒性还会促进促纤维化前途径（如己糖胺、多元醇、蛋白激酶B、蛋白激酶C/丝裂原活化蛋白激酶等）激活和胶原蛋白过度沉积[41-43]。间质纤维化会导致舒张功能障碍，这会因肌联蛋白表达的改变（转换为“更硬”的同工型）和翻译后修饰（低磷酸化）而进一步加重，肌联蛋白在被动心肌张力中起着至关重要作用[44-45]。此外，在T2DM患者中常会发现心肌肥大。由于DNA甲基化、非编码RNA（如microRNA）表达失调和组蛋白乙酰化引起表观遗传变化与心肌细胞过度营养的细胞途径激活有关[22,46]。RAS系统激活、AGEs过度产生和自主神经失调导致微血管功能障碍和一氧化氮生物利用率降低，也与刺激心肌肥大有关[47]。总的来说，这些过程会促进心脏重塑、收缩和舒张功能障碍以及微血管疾病的发生，并易患HF，而主要的病理生理机制可能导致糖尿病心肌疾病的不同表型[9,48-49]。关于这些过程的更详细讨论另文进行[22,41,45,50-55]。

2 T2DM患者HF前无症状的结构和功能异常

许多研究报告了T2DM患者心脏结构和功能无症状异常的高负担，这是通过不同的成像方式评估的。在一组没有已知HF的T2DM（≥60岁）老年患者中，荷兰一项基于社区的横断面调查显示，25.8%的患者有无症状左心室功能障碍的超声心动图证据，其中大多数患者有舒张功能障碍（占总队列的25.1%）[56]。即使在没有高血压或冠心病的患者中，左心室舒张和收缩功能也报告了超声心动图异常[如左心室肥大、左心室射血分数降低（LVEF）和二尖瓣环平面收缩偏移、二尖瓣流入峰值早期舒张速度与组织多普勒二尖瓣环早期舒张速度的异常比率]，以及心肌应变受损（整体纵向应变降低）和左心房扩大[57-60]。心脏磁共振（CMR）成像证实，在3984名社区样本中，患有T2DM、无已知心血管疾病且LVEF保持≥50%的患者的左心室和右心室体积和功能早期发生了变化[61]。此外，对患有和不患有2型T2DM（无冠心病）的无症状高血压患者的CMR研究表明，存在更严重的左心室向心性肥大，与单纯高血压患者相比，T2DM患者的心肌应变更差，置换和间质纤维化负担更大[62]。尽管T2DM的左心室质量和血压与单纯高血压患者相似，但这些早期不良心脏异常发生在T2DM患者身上，并且与不同的促炎和促纤维化生物标志物谱有关（即血清蛋白通路分析中炎症反应和免疫细胞贩运活性增加，以及生长分化因子15与细胞外基质置换纤维化/扩张之间的关联）[48,62]。几项研究观察到，即使在没有冠心病或高血压的情况下，T2DM患者的无症状心脏功能障碍与更高的HF发病风险之间存在关联[63-64]。最近对美国三项队列研究的汇总分析，由10208名没有已知心血管疾病或HF（有和没有T2DM）的人组成，显示T2DM患者超声心动图结构和功能异常的患病率很高（即左心房扩大、左心室肥大、舒张功能障碍），并表明其与5年随访中HF事件的预后相关性[64]。患有T2DM和一种或多种超声心动图异常的患者被认为患有“T2DM伴心肌病”，其患病率从67.0%（基于单次超声心动图异常）到11.7%（基于多次超声心动图畸形和利钠肽水平升高）不等[64]。心脏异常的存在预示着在5年的随访中，HF的发病率逐渐上升（HR范围从1.65~1.75）[64]。同样，最近对包括842名T2DM患者在内的两个前瞻性队列的分析也表明，与无症状超声心动图异常复杂性增加相关的不良心血管事件（包括HF事件）的风险也在增加，预后最差的是左心室肥大、轻度收缩功能障碍和心肌应变受损[65]。

3 T2DM患者并发HF的风险评估

T2DM患者发生HF的风险存在相当大的异质性，特别是在那些没有HF的患者中。这强调了风险评估的重要性，以识别可能从预防策略中获得更大益处的高风险个体。最近，已经开发了几个风险评分来预测T2DM患者未来患HF的风险[66-73]。其中几个评分的预测值已在其他人群中得到证实[73-74]，而其他评分则等待外部验证。大多数评分基于现成的临床、心电图和实验室变量，但尚未考虑可能的无症状心脏结构和/或功能异常（由于其在基于人群的研究中的可用性有限）。这些评分已被证明可以可靠地区分具有不同基线风险的队列中的中期（即5年）HF风险[74-75]。此外，基于生物标志物的评分，包括慢性心肌损伤、神经体液应激、全身炎症和心电图左心室肥大的生物标志物，已经证明了良好的预测有效性，可以将T2DM患者5年和10年HF风险与三种基于社区的疾病进行分层[71]。尽管基线时所有患者中<10%存在高生物标志物评分（≥3），但在5年的随访中，它占所有HF事件的35%[71]。T2DM的持续时间是评估未来HF风险的另一个方面，尽管糖尿病前期患者的HF发病率已经很高，即糖耐量受损[76]。在美国的一项基于社区的研究中，包括9734名没有基线HF（有和没有T2DM）的参与者，在控制并发冠心病和其他风险因素后，T2DM持续时间每5年HF发病风险增加17%，在持续时间≥15年的T2DM患者中观察到的相对风险最高（相对于没有T2DM的患者的HR=2.82）[76]。这种关联尤其在年轻（≤65岁）和肥胖患者、女性、自我认同的非裔美国人以及没有足够的血糖控制（糖化血红蛋白水平≥7%）的人中，这种情况很严重[77]。在考虑T2DM的持续时间进行风险评估时，需要认识到一个警告，因为一些患者的T2DM诊断可能会延迟，而T2DM持续时间的延长通常与年龄较大有关[78]。2023年糖尿病患者心血管疾病管理ESC指南建议对所有糖尿病患者的HF症状和/或体征进行系统调查，并在疑似HF的情况下测量利钠肽[79]。使用既定的风险评分（如WATCH-DM）筛查T2DM患者的风险[79]。WATCH-DM评分显示出良好的预测特性，特别是在中等风险患者中，与TRS-HFDM评分相比，在中度和高危患者中表现略好[74]。它可以从日常临床实践中可读的数据中计算出来，这可以促进其更广泛应用。SCORE2-糖尿病也是评估T2DM患者10年内致命和非致命心血管事件（心肌梗死和卒中）风险的评分工具，但不包括HF[79]。

小结

T2DM与HF密切相关，但糖尿病心肌病的定义仍有争议。近日，欧洲心脏协会（ESC）HF协会联合心肌和心包疾病工作组发表共识，建议糖尿病心肌病定义为在糖尿病存在的情况下出现心肌收缩和（或）舒张功能障碍。糖尿病性心肌病最初被描述为在无冠心病、高血压和/或肥胖的情况下，出现与T2DM相关的心肌结构/功能异常。但这种说法证据不足，因为按此标准仅有少数2型糖尿病患者确诊，临床无法使用。从HF进展角度来看，T2DM患者存在无症状的结构性/功能性心脏异常可认为是HF前期。声明还强调，糖尿病很少是心功能障碍的唯一原因，通常与肥胖、高血压、慢性肾脏疾病和/或冠脉疾病相关，协同造成心肌损害。

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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