医线心声丨中篇：促进心肌逆向重塑的机制
健康
健康
2024-10-18 17:25
北京
![]()
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。触发RR的干预措施取决于心肌损伤，包括免疫抑制治疗诱导心肌炎和炎症、遗传性心肌病、Takotsubo综合征、心动过速诱发心肌病等。可根据左心室质量（LVM）、射血分数（EF）和左室舒张末期（LVEDV）/收缩末期容积（LVESV）的正常化程度推断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、不完全RR和不良重塑（AR）的临床终点仍然有限且有争议。
首先，没有急性心肌梗死（AMI）的慢性冠状动脉综合征（CCS）会导致心肌冬眠（一个缺血但存活的心脏组织区域，其收缩长期受到抑制）[130]。根据存活节段的数量，心肌血运重建可以改善局部和整体左心室功能，逆转左心室扩张[4]，降低心脏事件的发生率[131]，并改善症状、左心室几何形状和EF。然而，研究缺血性冠心病患者血运重建后RR的试验得出了令人困惑的结果[132-134]。其次，AMI中的急性缺血会导致心肌坏死和顿抑[135]。存活心肌从缺血中缓慢恢复，其特征是可逆的收缩和生化功能障碍[130,136]。缺血再灌注损伤是AMI后发生的多方面病理生理过程。再灌注后，突然重新引入氧气会触发一系列事件，包括氧化应激、炎症、钙超载和线粒体功能障碍，导致短暂的机械功能障碍[130]，通常会自发缓解[137]。然而，与缺血相关的暂时性功能障碍可能导致危及生命的AMI后事件。因此，除了最快的血运重建外，各种药物还显示出加速、恢复或预防心肌顿抑的潜力。第三，AMI后存活心肌的大量丧失可导致AR，几乎总是进展为心房颤动（HF）[4]。AR涉及心肌细胞肥大、置换（瘢痕形成）、间质纤维化以及梗死区和偏远区不同程度的左心室扩张，导致功能障碍和预后不良[11,138]。一些研究已经评估了药物和装置（如左心室辅助装置[LVAD]）用于预防或逆转心肌梗死（MI）后不良重塑的有效性[18-57,139-158]。其中血管紧张素转化酶抑制剂和血管紧张素受体阻滞剂（ACEi/ARB）、β受体阻滞剂、盐皮质激素受体拮抗剂或钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂的联合疗法用于抑制左心室AR的疗效[4,24,53,139]已被证明或正在临床试验中研究。然而，这些药物对缺血后RR的作用机制没有特异性。随着病理情况的进展，瘢痕成熟和收缩为重塑铺平了道路，在重塑过程中，远程、存活的心肌必须适应改变的负荷条件以维持心输出量。这个过程的每个阶段都涉及不同的机制，有助于高度动态的重塑。因此，除了标准HF疗法外，靶向和阶段特异性疗法可能是必要的，例如早期抗炎症治疗[159-198]。透壁ST段抬高型心肌梗死（STEMI）、大面积梗死或心肌损伤、基线左心室扩张率较高、微血管阻塞、心肌内出血和高龄是随后左心室收缩容积较高和发生AR[10,200]的主要预测因素[199]，性别影响有限[138]。心肌应变分析对于预测经皮冠状动脉介入治疗（PCI）后RR/不良重塑特别有效，为评估左心室功能和存活率提供了一种更敏感的方法。例如，在左心室射血分数（LVEF）降低的患者中，基础整体纵向应变（GLS）＞ -11.3% 可预测PCI后8个月LVEF没有改善，而GLS＜ -12.5%可预测没有AR[201]。将GLS纳入基线模型，包括LVEF、梗死面积和微血管阻塞，可以改善4个月时AR的预测[202]。此外，心脏磁共振（CMR）衍生的参数，如梗死面积、微血管梗阻、LVEF和左心室整体功能指数，可以预测AR（LVEDV增加≥15%，AUC＞0.70），在多变量分析中，左心室整体功能指数仍然是一个重要的独立预测因素[203]。分子标记物，如血清可溶性白细胞介素（IL）-1受体样1、血浆半乳凝素-3和血浆miR-1254，也对MI患者6个月AR具有预测价值[204-206]。由于结果不同，PCI后RR/AR的识别至关重要。对PRESERVATION I试验的子分析表明PCI后1个月LVEF（RR）升高的STEMI患者在干预后1年的MI复发率、住院率和死亡率较低[96]。相比之下，PCI后AR（LVEDV增加≥20%）的STEMI患者有更高的HF住院率[97]。此外，PCI后主动脉瓣反流联合LVEF受损在76个月的中位随访中降低了生存率和无事件生存率[98]。此外，可溶性致瘤性抑制2（sST2）是一种阻断IL-33/ST2系统的诱饵受体，可消除包括减少心肌纤维化、心肌肥大和凋亡在内的心脏保护作用。事实上，sST2水平升高是预测AR的有力指标，预测RR和临床恢复的可能性较低[207-208]。相反，在稳定的缺血性心脏病患者中，在心绞痛负担和基础药物治疗的情况下，需要谨慎考虑有创治疗[132]。事实上，与保守治疗相比，对于患有稳定型冠状动脉疾病和严重或中度缺血的患者，初始有创策略并不能降低缺血性心血管事件或任何原因死亡的风险[209]。在ISCHEMIA试验中，有创策略组的患者在随访期间有更多的手术性梗死和更少的非手术性梗死，而各组之间因任何原因导致的死亡发生率相似[209]。然而，尽管这一证据不适用于当前/最近患有急性冠状动脉综合征（ACS）或症状严重、左主干狭窄或LVEF＜35%的患者，但HF/左心室功能障碍患者的侵入性治疗可能会改善获益[209]。相反，REVIVED-BCIS2试验未能证明多支PCI可提高严重缺血性心肌病患者的无事件生存率和LVEF[132]。以运动训练为中心的心脏再稳定计划是HF管理的第五个支柱，已经证明了可带来左心室RR，其特征是AMI后患者左心室容积减少，EF增加，从而阻止了HF的进展[210-212]。运动的影响因类型、持续时间和时间而异[213]。有氧训练可改善舒张功能和Ca2+处理[213]，通过AMPK-PGC-1α途径上调促进心脏线粒体生物合成和代谢重塑[214]。这支持有氧糖酵解和脂肪酸利用，减少脂质沉积和心脏乳酸积累[214]。高强度训练通过刺激循环祖干细胞、促进驻留心脏干细胞的增殖和分化、诱导新生血管生成、心肌细胞增生和减轻心肌壁应力来增强心脏功能[215]。然而，与中等强度连续训练相比，高强度间歇训练（HIIT）的效果仍有争议。虽然HIIT改善了超声心动图参数、心肌工作效率和应变测量[216]，但HIIT-EARLY随机对照试验观察到，急性STEMI后最佳治疗患者的GLS长期恶化，与中等强度连续训练相比，心脏RR没有显著差异[217]。相反，中等强度的运动训练产生了实质性的益处，增强了运动能力，而左心室舒张末期内径（LVEDD）没有波动，正如AMI后3个月的计划所证明的那样[218]。尽管左心室容积没有恢复，但在成功进行PCI后，MI后的中等强度踏车训练改善了左心室收缩功能、局部功能和运动能力[220]。此外，低强度训练减轻了接受PCI的AMI患者的LVEF下降，并显著降低了N-末端B型利钠肽前体（NT-proBNP）水平[221]。根据记录，高、中、低强度有氧运动导致心血管事件的风险较低[222]。然而，心脏康复后，MI患者左心室腔扩大和异常室壁运动百分比增加仍然是与左心室扩张相关的不良长期预后的预测因素[223]。
心肌炎症可导致急性心肌炎和/或慢性炎症性心肌病（CIM），这是一个涉及易感性（如遗传和自身免疫性疾病）和各种触发因素的多因素过程，包括病原体、酒精、毒品等在内的心脏毒性物质都可导致组织炎症和损伤[224]。病原体如病毒可以直接感染心肌细胞（肠道病毒）或通过感染非心肌细胞间接诱导心肌功能障碍（例如细小病毒B19感染内皮细胞）[225]。以前的研究表明，急性心肌炎主要影响年轻患者（30~45岁）和男性（60~80%）[226]。急性和严重炎症导致心肌细胞损伤（如巨细胞或淋巴细胞性心肌炎）可根据达拉斯心肌炎标准进行组织学诊断。这些情况需要迅速有效的治疗，以实现快速康复，但如果不及时治疗，预后很差。CIM的发展较为缓慢，但对免疫抑制疗法的反应可能仍各不相同。路易斯湖标准已经过修订，包括成像（CMR与LGE和T1和T2标测）和心内膜心肌活检分析（组织学、免疫组织化学、病原体检测），以对患者进行分层，并选择合适的免疫抑制疗法人群。然而，即使是像CMR这样的金标准成像方法，在观察到明显的功能障碍或形态重塑之前，对早期检测的敏感性也有限，就像免疫检查点抑制剂诱导的心肌炎一样，超声心动图或CMR评估的EF可能是正常的，早期组织特征不明显[227]。在任何情况下，LVEF的改善都被用作药物治疗后炎症过程正常化的替代品[228]。例如，长期使用皮质激素（泼尼松）或其他免疫抑制剂（如硫唑嘌呤）治疗病毒阴性慢性心肌炎或CIM患者，LVEF明显改善[228]。EF降低、LGE/水肿、NYHA分级较高、心肌炎类型（如巨细胞、淋巴细胞、嗜酸性粒细胞）、遗传性组织学上的MI症状、易感性和体征通常被认为是不良重塑的独立预测因素。遗传性心肌病包括一组异质性的心肌疾病，是心脏功能障碍、HF和心源性猝死的常见原因。虽然扩张性心肌病（DCM）和肥厚型心肌病（HCM）是最常见的疾病（高达1:250~1:1000）[229]，但致心律失常性右心室心肌病、非扩张性左心室和限制性心肌病很少见[230]。针对心肌病的靶向治疗正在慢慢进入临床，但大多处于实验阶段。大多数患者接受标准的HF治疗，包括诱导RR的经典HF药物，如β受体阻滞剂，在一些患者中诱导RR，而另一些患者反应不佳，需要起搏器或植入式心脏复律除颤器。结缔组织蛋白和titin基因截短是分别与致心律失常性心肌病和DCM相关的最常见的致病性变体[231]。在尚未完全了解的结缔组织蛋白心肌病的“热期”，也可能发生高敏肌钙蛋白水平升高的心肌炎和心律失常，但LVEF正常[231]。除了经典的HF药物治疗外[232-233]，靶向肌球蛋白的药物在心肌病中显示出有希望的结果。肌球蛋白激活剂，如omecamtiv mecarbil已显示出增加DCM收缩性的潜力，尽管该化合物尚未获得临床批准。相反，肌球蛋白抑制剂，如玛伐凯泰（mavacamten）在梗阻性HCM中显示出有益作用[234]。其他策略仍处于实验阶段。例如，蛋白酶体抑制仍然是某些遗传性心肌病的潜在选择[2335-237]，但长期RR效应及其对症状前突变携带者的有效性尚未得到证实。最近的报告揭示了通过基因编辑纠正特定遗传变异从而预防/治疗心肌病的病理机制。CRISPR/Cas9或反义寡核苷酸可以靶向心脏功能（肌节基因突变诱导的HCM）[238-239]或线粒体代谢[229-240]，预防病理重塑或促进RR。4 、心尖气球样变综合征（Takotsubo综合征）
Takotsubo综合征是一种急性且可能致命的心脏急症，表现为突然严重的左心室功能障碍[241]。它主要影响中年（50~74岁）女性（90%），由情绪或身体压力引发。其症状与AMI难以区分，十分之一的人会在医院死亡。然而，Takotsubo综合征患者通常冠状动脉通畅，在没有任何MI或瘢痕的情况下，出现急性、严重的左心室功能障碍，心室腔“膨胀”。在过去的10年里，英国和北美的Takotsubo综合征发病率都上升了4~5倍[242]。急性发作后，RR的自然和自发过程开始，LVEF总是恢复正常或接近正常[243]。尽管有这种RR，但亚临床心脏功能障碍和疲劳、呼吸困难和胸痛等衰弱症状仍然存在[244]，很可能是由于轻度慢性炎症引起的[245]。这些症状的持续会引发Takotsubo综合征的复发，严重影响长期生存[246-247]。目前还没有循证治疗为这些患者提供症状或生存益处。心房扑动、AF、异位房性心动过速、房室心动过速，房室结性心动过快、室性心动过速度和起搏器介导的心动过速都与心肌病有关。通常，应考虑诊断平均心率＞100 bpm或心房颤动/异位负荷超过10%的患者。影像学检查通常会显示不同程度的左心室功能障碍，患者通常会出现新发或急性HF的体征和症状。心动过速诱导的心肌病的诊断需要恢复持续的窦性心律和左心室容积与EF的可逆性。诊断通常通过心脏成像来证实，其中超声心动图或CMR或两者均显示双心室扩张和中度至重度收缩功能障碍，壁厚和质量正常，没有相应的MI或纤维化。神经激素标志物，如利钠肽（BNP），通常会升高，并在心动过速消除后趋于降低[248]。治疗策略包括优化HF的药物治疗（β受体阻滞剂、肾素-血管紧张素抑制、利尿剂和SGLT2抑制剂），以促进RR并消除心动过速。然而，目前还没有关于LVEF恢复后医疗HF治疗持续时间的数据。在全球范围内，心血管病仍然是导致死亡的主要原因。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的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。先进的成像技术，特别是CMR，通过放射学提供了宝贵的见解。将经典和创新的分子生物标志物与CMR数据和应变超声心动图参数相结合，具有预测的潜力。
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
128. Barbosa MF, Contti MM, de Andrade LGM, Mauricio A, Ribeiro SM, Szarf G.Feature-tracking cardiac magnetic resonance left ventricular global longitudinal strain improves 6 months after kidney transplantation associated with reverse remodeling, not myocardial tissue characteristics. Int J Cardiovasc Imaging 2021;37:3027–3037.
129. Kobayashi M, Huttin O, Schikowski J, Bozec E, Zohra L, Frimat L, et al. Cardiovascular comorbidities are the main predictors of cardiac reverse remodeling following kidney transplantation. Cardiology 2020;145:71–76.
130. Heusch G. Myocardial stunning and hibernation revisited. Nat Rev Cardiol 2021;18:522–536.
131. Howlett JG, Stebbins A, Petrie MC, Jhund PS, Castelvecchio S, Cherniavsky A,et al.; STICH Trial Investigators. CABG improves outcomes in patients with ischemic cardiomyopathy: 10-year follow-up of the STICH trial. JACC Heart Fail 2019;7:878–887.
132. Perera D, Clayton T, O’Kane PD, Greenwood JP,Weerackody R, Ryan M, et al.;REVIVED-BCIS2 Investigators. Percutaneous revascularization for ischemic left ventricular dysfunction. N Engl J Med 2022;387:1351–1360.
133. Velazquez EJ, Lee KL, Deja MA, Jain A, Sopko G, Marchenko A, et al.; STICH Investigators. Coronary-artery bypass surgery in patients with left ventricular dysfunction. N Engl J Med 2011;364:1607–1616.
134. Rohde LE, McMurray JJV. REVIV(E)ing the ischaemic paradigm in heart failure:STICHes are needed. Eur Heart J 2023;44:3652–3654.
135. Kloner RA. Stunned and hibernating myocardium: Where are we nearly 4 decades later? J Am Heart Assoc 2020;9:e015502.
136. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al.;ESC Scientific Document Group. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation:The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2018;39:119–177.
137. Bax JJ, Visser FC, Poldermans D, Elhendy A, Cornel JH, Boersma E, et al.Time course of functional recovery of stunned and hibernating segments after surgical revascularization. Circulation 2001;104:I314–I318.
138. van der Bijl P, Abou R, Goedemans L, Gersh BJ, Holmes DR Jr, Ajmone Marsan N, et al. Left ventricular remodelling after ST-segment elevation myocardial infarction: Sex differences and prognosis. ESC Heart Fail 2020;7:474–481.
139. Hashimoto H, Olson EN, Bassel-Duby R. Therapeutic approaches for cardiac regeneration and repair. Nat Rev Cardiol 2018;15:585–600.
140. Gabrielli L, Sitges M, Mont L. Assessing reverse remodeling in heart failure patients treated with cardiac resynchronization therapy and its impact on prognosis. Expert Rev Cardiovasc Ther 2012;10:1437–1448.
141. McAloon CJ, Theodoreson MD, Hayat S, Osman F. Cardiac resynchronization therapy and its role in the management of heart failure. Br J Hosp Med (Lond) 2017;78:312–319.
142. Daubert C, Behar N, Martins RP, Mabo P, Leclercq C. Avoiding non-responders to cardiac resynchronization therapy: A practical guide. Eur Heart J 2017;38:1463–1472.
143. Young JB, Abraham WT, Smith AL, Leon AR, Lieberman R, Wilkoff B, et al.;Multicenter InSync ICD Randomized Clinical Evaluation (MIRACLE ICD) Trial Investigators. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: The MIRACLE ICD trial.JAMA 2003;289:2685–2694.
144. Higgins SL, Hummel JD, Niazi IK, Giudici MC, Worley SJ, Saxon LA, et al. Cardiac resynchronization therapy for the treatment of heart failure in patients with intraventricular conduction delay and malignant ventricular tachyarrhythmias.J Am Coll Cardiol 2003;42:1454–1459.
145. St John Sutton MG, Plappert T, Abraham WT, Smith AL, DeLurgio DB, Leon AR, et al.; Multicenter InSync Randomized Clinical Evaluation (MIRACLE) Study Group. Effect of cardiac resynchronization therapy on left ventricular size and function in chronic heart failure. Circulation 2003;107:1985–1990.
146. Sutton MG, Plappert T, Hilpisch KE, Abraham WT, Hayes DL, Chinchoy E.Sustained reverse left ventricular structural remodeling with cardiac resynchronization at one year is a function of etiology: Quantitative Doppler echocardiographic evidence from the Multicenter InSync Randomized Clinical Evaluation (MIRACLE). Circulation 2006;113:266–272.
147. Cimino S, Maestrini V, Cantisani D, Petronilli V, Filomena D, Gatto MC,et al. 2D/3D echocardiographic features of patients with reverse remodeling after cardiac resynchronization therapy. Echocardiography 2019;36:1475–1481.
148. Chen Z, Hanson B, Sohal M, Sammut E, Jackson T, Child N, et al. Coupling of ventricular action potential duration and local strain patterns during reverse remodeling in responders and nonresponders to cardiac resynchronization therapy. Heart Rhythm 2016;13:1898–1904.
149. Martens P, Nijst P, Verbrugge FH, Dupont M, Tang WHW, Mullens W. Profound differences in prognostic impact of left ventricular reverse remodeling after cardiac resynchronization therapy relate to heart failure etiology. Heart Rhythm 2018;15:130–136.
150. Miyagawa S, Toda K, Nakamura T, Yoshikawa Y, Fukushima S, Saito S, et al.Building a bridge to recovery: The pathophysiology of LVAD-induced reverse modeling in heart failure. Surg Today 2016;46:149–154.
151. Klotz S, Jan Danser AH, Burkhoff D. Impact of left ventricular assist device (LVAD) support on the cardiac reverse remodeling process. Prog Biophys Mol Biol 2008;97:479–496.
152. Birks EJ, Tansley PD, Hardy J, George RS, Bowles CT, Burke M, et al. Left ventricular assist device and drug therapy for the reversal of heart failure. N Engl J Med 2006;355:1873–1884.
153. Birks EJ, George RS. Molecular changes occurring during reverse remodeling following left ventricular assist device support. J Cardiovasc Transl Res 2010;3:635–642.
154. Radovancevic B, Vrtovec B, Frazier OH. Left ventricular assist devices: An alternative to medical therapy for end-stage heart failure. Curr Opin Cardiol 2003;18:210–214.
155. Drakos SG, Mehra MR. Clinical myocardial recovery during long-term mechanical support in advanced heart failure: Insights into moving the field forward.J Heart Lung Transplant 2016;35:413–420.
156. Muthiah K, Humphreys DT, Robson D, Dhital K, Spratt P, Jansz P, et al.Longitudinal structural, functional, and cellular myocardial alterations with chronic centrifugal continuous-flow left ventricular assist device support. J Heart Lung Transplant 2017;36:722–731.
157. Imamura T, Kinugawa K, Nitta D, Hatano M, Kinoshita O, Nawata K, et al.Advantage of pulsatility in left ventricular reverse remodeling and aortic insufficiency prevention during left ventricular assist device treatment. Circ J 2015;79:1994–1999.
158. Haft J, Armstrong W, Dyke DB, Aaronson KD, Koelling TM, Farrar DJ, et al.Hemodynamic and exercise performance with pulsatile and continuous-flow left ventricular assist devices. Circulation 2007;116:I8–I15.
159. Kanellakis P, Dinh TN, Agrotis A, Bobik A. CD4+CD25+Foxp3+ regulatory T cells suppress cardiac fibrosis in the hypertensive heart. J Hypertens 2011;29:1820–1828.
160. Matrougui K, Abd Elmageed Z, Kassan M, Choi S, Nair D, Gonzalez-Villalobos RA, et al. Natural regulatory T cells control coronary arteriolar endothelial dysfunction in hypertensive mice. Am J Pathol 2011;178:434–441.
161. Rieckmann M, Delgobo M, Gaal C, Buchner L, Steinau P, Reshef D, et al. Myocardial infarction triggers cardioprotective antigen-specific T helper cell responses.J Clin Invest 2019;129:4922–4936.
162. Lee DI, Zhu G, Sasaki T, Cho GS, Hamdani N, Holewinski R, et al. Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease. Nature 2015;519:472–476.
163. Gargalovic P, Wong P, Onorato J, Finlay H, Wang T, Yan M, et al. In vitro and in vivo evaluation of a small-molecule APJ (apelin receptor) agonist, BMS-986224,as a potential treatment for heart failure. Circ Heart Fail 2021;14:e007351.
164. Kim GJ, Jung H, Lee E, Chung SW. Histone deacetylase inhibitor, mocetinostat,regulates cardiac remodelling and renin-angiotensin system activity in rats with transverse aortic constriction-induced pressure overload cardiac hypertrophy. Rev Cardiovasc Med 2021;22:1037–1045.
165. Dey S, DeMazumder D, Sidor A, Foster DB, O’Rourke B. Mitochondrial ROS drive sudden cardiac death and chronic proteome remodeling in heart failure. Circ Res 2018;123:356–371.
166. Abdellatif M, Trummer-Herbst V, Koser F, Durand S, Adao R, Vasques-Novoa F,et al. Nicotinamide for the treatment of heart failure with preserved ejection fraction. Sci Transl Med 2021;13:eabd7064.
167. Duan Q, McMahon S, Anand P, Shah H, Thomas S, Salunga HT, et al. BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure. Sci Transl Med 2017;9:eaah5084.
168. Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR, Gustafsson E,et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med 2007;13:952–961.
169. Seropian IM, Cerliani JP, Toldo S, Van Tassell BW, Ilarregui JM, Gonzalez GE,et al. Galectin-1 controls cardiac inflammation and ventricular remodeling during acute myocardial infarction. Am J Pathol 2013;182:29–40.
170. Rech L, Abdellatif M, Pottler M, Stangl V, Mabotuwana N, Hardy S, et al. Small molecule STING inhibition improves myocardial infarction remodeling. Life Sci 2022;291:120263.
171. Marchetti C, Toldo S, Chojnacki J, Mezzaroma E, Liu K, Salloum FN, et al.Pharmacologic inhibition of the NLRP3 inflammasome preserves cardiac function after ischemic and nonischemic injury in the mouse. J Cardiovasc Pharmacol 2015;66:1–8.
172. Li J, Cai SX, He Q, Zhang H, Friedberg D, Wang F, et al. Intravenous miR-144 reduces left ventricular remodeling after myocardial infarction. Basic Res Cardiol 2018;113:36.
173. Traverse JH, Swingen CM, Henry TD, Fox J, Wang YL, Chavez IJ, et al.NHLBI-sponsored randomized trial of postconditioning during primary percutaneous coronary intervention for ST-elevation myocardial infarction. Circ Res 2019;124:769–778.
174. Luz A, Santos M, Magalhaes R, Silveira J, Cabral S, Dias V, et al. Lack of benefit of ischemic postconditioning after routine thrombus aspiration during reperfusion:Immediate and midterm results. J Cardiovasc Pharmacol Ther 2015;20:523–531.
175. Stiermaier T, Jensen JO, Rommel KP, de Waha-Thiele S, Fuernau G, Desch S,et al. Combined intrahospital remote ischemic perconditioning and postconditioning improves clinical outcome in ST-elevation myocardial infarction. Circ Res 2019;124:1482–1491.
176. Garcia S, Henry TD, Wang YL, Chavez IJ, Pedersen WR, Lesser JR, et al.Long-term follow-up of patients undergoing postconditioning during ST-elevation myocardial infarction. J Cardiovasc Transl Res 2011;4:92–98.
177. Engstrom T, Kelbak H, Helqvist S, Hofsten DE, Klovgaard L, Clemmensen P,et al.; Third Danish Study of Optimal Acute Treatment of Patients With ST Elevation Myocardial Infarction–Ischemic Postconditioning (DANAMI-3–iPOST) Investigators. Effect of ischemic postconditioning during primary percutaneous coronary intervention for patients with ST-segment elevation myocardial infarction:A randomized clinical trial. JAMA Cardiol 2017;2:490–497.
178. Lonborg J, Holmvang L, Kelbak H, Vejlstrup N, Jorgensen E, Helqvist S, et al.ST-segment resolution and clinical outcome with ischemic postconditioning and comparison to magnetic resonance. Am Heart J 2010;160:1085–1091.
179. Thuny F, Lairez O, Roubille F, Mewton N, Rioufol G, Sportouch C, et al.Post-conditioning reduces infarct size and edema in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol 2012;59:2175–2181.
180. Ma X, Zhang X, Li C, Luo M. Effect of postconditioning on coronary blood flow velocity and endothelial function and LV recovery after myocardial infarction.J Interv Cardiol 2006;19:367–375.
181. Micheletti R, Plaisance I, Abraham BJ, Sarre A, Ting CC, Alexanian M, et al. The long noncoding RNA Wisper controls cardiac fibrosis and remodeling. Sci Transl Med 2017;9:eaai9118.
182. Batkai S, Genschel C, Viereck J, Rump S, Bar C, Borchert T, et al. CDR132L improves systolic and diastolic function in a large animal model of chronic heart failure. Eur Heart J 2021;42:192–201.
183. Taubel J, Hauke W, Rump S, Viereck J, Batkai S, Poetzsch J, et al. Novel antisense therapy targeting microRNA-132 in patients with heart failure: Results of a first-in-human Phase 1b randomized, double-blind, placebo-controlled study.
Eur Heart J 2021;42:178–188.
184. Foinquinos A, Batkai S, Genschel C, Viereck J, Rump S, Gyongyosi M, et al.Preclinical development of a miR-132 inhibitor for heart failure treatment. Nat Commun 2020;11:633.
185. Gao R, Zhang J, Cheng L,Wu X, Dong W, Yang X, et al. A Phase II, randomized,double-blind, multicenter, based on standard therapy, placebo-controlled study of the efficacy and safety of recombinant human neuregulin-1 in patients with chronic heart failure. J Am Coll Cardiol 2010;55:1907–1914.
186. Cacciapuoti M, Johnson B, Kapdia A, Powell S, Gallicano GI. The role of neuregulin and stem cells as therapy post-myocardial infarction. Stem Cells Dev 2020;29:1266–1274.
187. Chen L, Chen CX, Gan XT, Beier N, Scholz W, Karmazyn M. Inhibition and reversal of myocardial infarction-induced hypertrophy and heart failure by NHE-1 inhibition. Am J Physiol Heart Circ Physiol 2004;286:H381–H387.
188. Raake PW, Schlegel P, Ksienzyk J, Reinkober J, Barthelmes J, Schinkel S, et al.AAV6.β ARKct cardiac gene therapy ameliorates cardiac function and normalizes the catecholaminergic axis in a clinically relevant large animal heart failure model.Eur Heart J 2013;34:1437–1447.
189. Pleger ST, Shan C, Ksienzyk J, Bekeredjian R, Boekstegers P, Hinkel R, et al.Cardiac AAV9-S100A1 gene therapy rescues post-ischemic heart failure in a preclinical large animal model. Sci Transl Med 2011;3:92ra64.
190. Fraccarollo D, Galuppo P, Motschenbacher S, Ruetten H, Schafer A, Bauersachs J. Soluble guanylyl cyclase activation improves progressive cardiac remodeling and failure after myocardial infarction. Cardioprotection over ACE inhibition.
Basic Res Cardiol 2014;109:421.
191. Malik FI, Hartman JJ, Elias KA, Morgan BP, Rodriguez H, Brejc K, et al. Cardiac myosin activation: A potential therapeutic approach for systolic heart failure.Science 2011;331:1439–1443.
192. Teerlink JR, Felker GM, McMurray JJ, Solomon SD, Adams KF, Cleland JG, et al.;COSMIC-HF Investigators. Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF): A phase 2, pharmacokinetic,randomised, placebo-controlled trial. Lancet 2016;388:2895–2903.
193. Voors AA, Tamby JF, Cleland JG, Koren M, Forgosh LB, Gupta D, et al. Effects of danicamtiv, a novel cardiac myosin activator, in heart failure with reduced ejection fraction: Experimental data and clinical results from a phase 2a trial. Eur
J Heart Fail 2020;22:1649–1658.
194. Green EM, Wakimoto H, Anderson RL, Evanchik MJ, Gorham JM, Harrison BC, et al. A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice. Science 2016;351:617–621.
195. Sharpe AN, Oldach MS, Kaplan JL, Rivas V, Kovacs SL, Hwee DT, et al.Pharmacokinetics of a single dose of aficamten (CK-274) on cardiac contractility in a A31P MYBPC3 hypertrophic cardiomyopathy cat model. J Vet Pharmacol Ther 2023;46:52–61.
196. Maron MS, Masri A, Choudhury L, Olivotto I, Saberi S, Wang A, et al.;REDWOOD-HCM Steering Committee and Investigators. Phase 2 study of aficamten in patients with obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2023;81:34–45.
197. Gramlich M, Pane LS, Zhou Q, Chen Z, Murgia M, Schotterl S, et al.Antisense-mediated exon skipping: A therapeutic strategy for titin-based dilated cardiomyopathy. EMBO Mol Med 2015;7:562–576.
198. Kraft L, Erdenesukh T, Sauter M, Tschope C, Klingel K. Blocking the IL-1β signalling pathway prevents chronic viral myocarditis and cardiac remodeling.Basic Res Cardiol 2019;114:11.
199. Castelvecchio S, Careri G, Ambrogi F, Camporeale A, Menicanti L, Secchi F,et al. Myocardial scar location as detected by cardiac magnetic resonance is associated with the outcome in heart failure patients undergoing surgical
ventricular reconstruction. Eur J Cardiothorac Surg 2018;53:143–149.
200. Garber L, McAndrew TC, Chung ES, Stancak B, Svendsen JH, Monteiro J, et al.Predictors of left ventricular remodeling after myocardial infarction in patients with a patent infarct related coronary artery after percutaneous coronary intervention
(from the Post-Myocardial Infarction Remodeling Prevention Therapy [PRomPT] trial). Am J Cardiol 2018;121:1293–1298.
201. Ben Driss A, Ben Driss Lepage C, Sfaxi A, Hakim M, Elhadad S, Tabet JY,et al. Strain predicts left ventricular functional recovery after acute myocardial infarction with systolic dysfunction. Int J Cardiol 2020;307:1–7.
202. Reindl M, Tiller C, Holzknecht M, Lechner I, Eisner D, Riepl L, et al. Global longitudinal strain by feature tracking for optimized prediction of adverse remodeling after ST-elevation myocardial infarction. Clin Res Cardiol 2021;110:61–71.
203. Pezel T, Besseyre des Horts T, Schaaf M, Croisille P, Biere L, Garcia-Dorado D,et al. Predictive value of early cardiac magnetic resonance imaging functional and geometric indexes for adverse left ventricular remodelling in patients with
anterior ST-segment elevation myocardial infarction: A report from the CIRCUS study. Arch Cardiovasc Dis 2020;113:710–720.
204. Minana G, Nunez J, Bayes-Genis A, Revuelta-Lopez E, Rios-Navarro C, Nunez E,et al. ST2 and left ventricular remodeling after ST-segment elevation myocardial infarction: A cardiac magnetic resonance study. Int J Cardiol 2018;270:336–342.
205. Andrejic OM, Vucic RM, Pavlovic M, McClements L, Stokanovic D,Jevtovic-Stoimenov T, et al. Association between galectin-3 levels within central and peripheral venous blood, and adverse left ventricular remodeling after first acute myocardial infarction. Sci Rep 2019;9:13145.
206. de Gonzalo-Calvo D, Cediel G, Bar C, Nunez J, Revuelta-Lopez E, Gavara J,et al. Circulating miR-1254 predicts ventricular remodeling in patients with ST-segment-elevation myocardial infarction: A cardiovascular magnetic resonance study. Sci Rep 2018;8:15115.
207. Dudek M, Kału˙zna-Oleksy M, Migaj J, Sawczak F, Krysztofiak H, Lesiak M, et al.sST2 and heart failure-clinical utility and prognosis. J Clin Med 2023;12:3136.
208. Lupon J, Gaggin HK, de Antonio M, Domingo M, Galan A, Zamora E, et al.Biomarker-assist score for reverse remodeling prediction in heart failure: The ST2-R2 score. Int J Cardiol 2015;184:337–343.
209. Maron DJ, Hochman JS, Reynolds HR, Bangalore S, O’Brien SM, Boden WE,et al.; ISCHEMIA Research Group. Initial invasive or conservative strategy for stable coronary disease. N Engl J Med 2020;382:1395–1407.
210. Giallauria F, Cirillo P, Lucci R, Pacileo M, De Lorenzo A, D’Agostino M, et al.Left ventricular remodelling in patients with moderate systolic dysfunction after myocardial infarction: Favourable effects of exercise training and predictive role of N-terminal pro-brain natriuretic peptide. Eur J Cardiovasc Prev Rehabil 2008;15:113–118.
211. McGregor G, Gaze D, Oxborough D, O’Driscoll J, Shave R. Reverse left ventricular remodeling: Effect of cardiac rehabilitation exercise training in myocardial infarction patients with preserved ejection fraction. Eur J Phys Rehabil
Med 2016;52:370–378. PMID: 26530212.
212. Taylor RS, Dalal HM, Zwisler AD. Cardiac rehabilitation for heart failure:‘Cinderella’ or evidence-based pillar of care? Eur Heart J 2023;44:1511–1518.
213. Haykowsky M, Scott J, Esch B, Schopflocher D, Myers J, Paterson I, et al. A meta-analysis of the effects of exercise training on left ventricular remodeling following myocardial infarction: Start early and go longer for greatest exercise benefits on remodeling. Trials 2011;12:92.
214. Wang L, Gao K, Wang D. Exercise training has restorative potential on myocardial energy metabolism in rats with chronic heart failure. Iran J Basic Med Sci 2018;21:818–823.
215. Godfrey R, Theologou T, Dellegrottaglie S, Binukrishnan S, Wright J, Whyte G,et al. The effect of high-intensity aerobic interval training on postinfarction left ventricular remodelling. BMJ Case Rep 2013;2013:bcr2012007668.
216. D’Andrea A, Carbone A, Ilardi F, Pacileo M, Savarese C, Sperlongano S, et al.Effects of high intensity interval training rehabilitation protocol after an acute coronary syndrome on myocardial work and atrial strain. Medicina (Kaunas) 2022;58:453.
217. Eser P, Trachsel LD, Marcin T, Herzig D, Freiburghaus I, De Marchi S, et al. Shortand long-term effects of high-intensity interval training vs. moderate-intensity continuous training on left ventricular remodeling in patients early after ST-segment elevation myocardial infarction – the HIIT-EARLY randomized controlled trial. Front Cardiovasc Med 2022;9:869501.
218. Otsuka Y, Takaki H, Okano Y, Satoh T, Aihara N, Matsumoto T, et al. Exercise training without ventricular remodeling in patients with moderate to severe left ventricular dysfunction early after acute myocardial infarction. Int J Cardiol 2003;87:237–244.
219. Dubach P, Myers J, Dziekan G, Goebbels U, Reinhart W, Vogt P, et al.Effect of exercise training on myocardial remodeling in patients with reduced left ventricular function after myocardial infarction: Application of magnetic resonance imaging. Circulation 1997;95:2060–2067.
220. Elshazly A, Hasan RL, Saleh MA, Ibrahim AS, Khorshid H. Impact of exercise training on myocardial contractile functions assessed by cardiac magnetic resonance in post-myocardial infarction patients. Egypt Heart J 2022;74:51.
221. Chen MG, Liang X, Kong L, Wang J, Wang F, Hu X, et al. Effect of Baduanjin sequential therapy on the quality of life and cardiac function in patients with AMI after PCI: A randomized controlled trial. Evid Based Complement Alternat Med 2020;2020:8171549.
222. Rognmo O, Moholdt T, Bakken H, Hole T, Molstad P, Myhr NE, et al.Cardiovascular risk of high- versus moderate-intensity aerobic exercise in coronary heart disease patients. Circulation 2012;126:1436–1440.
223. Cannistra LB, Davidoff R, Picard MH, Balady GJ. Moderate-high intensity exercise training after myocardial infarction: Effect on left ventricular remodeling.J Cardiopulm Rehabil 1999;19:373–380.
224. Gil-Cruz C, Perez-Shibayama C, De Martin A, Ronchi F, van der Borght K,Niederer R, et al. Microbiota-derived peptide mimics drive lethal inflammatory cardiomyopathy. Science 2019;366:881–886.
225. Tschope C, Ammirati E, Bozkurt B, Caforio ALP, Cooper LT, Felix SB, et al.Myocarditis and inflammatory cardiomyopathy: Current evidence and future directions. Nat Rev Cardiol 2021;18:169–193.
226. Ammirati E, Frigerio M, Adler ED, Basso C, Birnie DH, Brambatti M, et al.Management of acute myocarditis and chronic inflammatory cardiomyopathy:An expert consensus document. Circ Heart Fail 2020;13:e007405.
227. Zhang L, Awadalla M, Mahmood SS, Nohria A, Hassan MZO, Thuny F, et al.Cardiovascular magnetic resonance in immune checkpoint inhibitor-associated myocarditis. Eur Heart J 2020;41:1733–1743.
228. Escher F, Kuhl U, Lassner D, Poller W, Westermann D, Pieske B, et al.Long-term outcome of patients with virus-negative chronic myocarditis or inflammatory cardiomyopathy after immunosuppressive therapy. Clin Res Cardiol 2016;105:1011–1020.
229. de Boer RA, Heymans S, Backs J, Carrier L, Coats AJS, Dimmeler S, et al.Targeted therapies in genetic dilated and hypertrophic cardiomyopathies: From molecular mechanisms to therapeutic targets. A position paper from the Heart Failure Association (HFA) and the Working Group on Myocardial Function of the European Society of Cardiology (ESC). Eur J Heart Fail 2022;24:406–420.
230. Yogasundaram H, Alhumaid W, Dzwiniel T, Christian S, Oudit GY. Cardiomyopathies and genetic testing in heart failure: Role in defining phenotype-targeted approaches and management. Can J Cardiol 2021;37:547–559.
231. Smith ED, Lakdawala NK, Papoutsidakis N, Aubert G, Mazzanti A, McCanta AC, et al. Desmoplakin cardiomyopathy, a fibrotic and inflammatory form of cardiomyopathy distinct from typical dilated or arrhythmogenic right ventricular cardiomyopathy. Circulation 2020;141:1872–1884.
232. Ho CY, Day SM, Axelsson A, Russell MW, Zahka K, Lever HM, et al.Valsartan in early-stage hypertrophic cardiomyopathy: A randomized phase 2 trial. Nat Med 2021;27:1818–1824.
233. Ho CY, Lakdawala NK, Cirino AL, Lipshultz SE, Sparks E, Abbasi SA, et al.Diltiazem treatment for pre-clinical hypertrophic cardiomyopathy sarcomere mutation carriers: A pilot randomized trial to modify disease expression. JACC Heart Fail 2015;3:180–188.
234. Olivotto I, Oreziak A, Barriales-Villa R, Abraham TP, Masri A, Garcia-Pavia P,et al.; EXPLORER-HCM Study Investigators. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM):A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2020;396:759–769.
235. Helms AS, Thompson AD, Day SM. Translation of new and emerging therapies for genetic cardiomyopathies. JACC Basic Transl Sci 2022;7:70–83.
236. Schlossarek S, Mearini G, Carrier L. Cardiac myosin-binding protein C in hypertrophic cardiomyopathy: Mechanisms and therapeutic opportunities. J Mol Cell Cardiol 2011;50:613–620.
237. Fomin A, Gartner A, Cyganek L, Tiburcy M, Tuleta I, Wellers L, et al.Truncated titin proteins and titin haploinsufficiency are targets for functional recovery in human cardiomyopathy due to TTN mutations. Sci Transl Med 2021;13:eabd3079.
238. Crilley JG, Boehm EA, Blair E, Rajagopalan B, Blamire AM, Styles P, et al. Hypertrophic cardiomyopathy due to sarcomeric gene mutations is characterized by impaired energy metabolism irrespective of the degree of hypertrophy. J Am Coll
Cardiol 2003;41:1776–1782.
239. Witjas-Paalberends ER, Guclu A, Germans T, Knaapen P, Harms HJ, Vermeer AM, et al. Gene-specific increase in the energetic cost of contraction in hypertrophic cardiomyopathy caused by thick filament mutations. Cardiovasc Res 2014;103:248–257.
240. Lehman SJ, Crocini C, Leinwand LA. Targeting the sarcomere in inherited cardiomyopathies. Nat Rev Cardiol 2022;19:353–363.
241. Singh T, Khan H, Gamble DT, Scally C, Newby DE, Dawson D. Takotsubo syndrome: Pathophysiology, emerging concepts, and clinical implications. Circulation 2022;145:1002–1019.
242. Pattisapu VK, Hao H, Liu Y, Nguyen TT, Hoang A, Bairey Merz CN, et al. Sexand age-based temporal trends in takotsubo syndrome incidence in the United States. J Am Heart Assoc 2021;10:e019583.
243. Eitel I, von Knobelsdorff-Brenkenhoff F, Bernhardt P, Carbone I, Muellerleile K,Aldrovandi A, et al. Clinical characteristics and cardiovascular magnetic resonance findings in stress (takotsubo) cardiomyopathy. JAMA 2011;306:277–286.
244. Scally C, Rudd A, Mezincescu A,Wilson H, Srivanasan J, Horgan G, et al. Persistent long-term structural, functional, and metabolic changes after stress-induced (takotsubo) cardiomyopathy. Circulation 2018;137:1039–1048.
245. Scally C, Abbas H, Ahearn T, Srinivasan J, Mezincescu A, Rudd A, et al. Myocardial and systemic inflammation in acute stress-induced (takotsubo) cardiomyopathy.Circulation 2019;139:1581–1592.
246. Templin C, Ghadri JR, Diekmann J, Napp LC, Bataiosu DR, Jaguszewski M, et al.Clinical features and outcomes of takotsubo (stress) cardiomyopathy. N Engl J Med 2015;373:929–938.
247. Tornvall P, Collste O, Ehrenborg E, Jarnbert-Petterson H. A case-control study of risk markers and mortality in takotsubo stress cardiomyopathy. J Am Coll Cardiol 2016;67:1931–1936.
248. O’Brien PJ, Ianuzzo CD, Moe GW, Stopps TP, Armstrong PW. Rapid ventricular pacing of dogs to heart failure: Biochemical and physiological studies. Can J Physiol Pharmacol 1990;68:34–39. ![]()
声明：本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。
凡原创文章版权属《国际循环》所有。欢迎个人转发分享。其他任何媒体、网站如需转载或引用本网版权所有之内容须在醒目位置处注明“转自《国际循环》”
![]()
