切换至 "中华医学电子期刊资源库"

中华移植杂志(电子版) ›› 2021, Vol. 15 ›› Issue (04) : 250 -256. doi: 10.3877/cma.j.issn.1674-3903.2021.04.013

综述

哺乳动物雷帕霉素靶蛋白抑制剂在心脏移植中的应用研究进展
左一凡1, 吴琪1, 王志维1,()   
  1. 1. 430060 武汉大学人民医院心血管外科
  • 收稿日期:2021-01-06 出版日期:2021-08-25
  • 通信作者: 王志维
  • 基金资助:
    国家自然科学基金(82070481)

Research progress of mTOR inhibitors in heart transplantation

Yifan Zuo1, Qi Wu1, Zhiwei Wang1,()   

  1. 1. Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China
  • Received:2021-01-06 Published:2021-08-25
  • Corresponding author: Zhiwei Wang
引用本文:

左一凡, 吴琪, 王志维. 哺乳动物雷帕霉素靶蛋白抑制剂在心脏移植中的应用研究进展[J]. 中华移植杂志(电子版), 2021, 15(04): 250-256.

Yifan Zuo, Qi Wu, Zhiwei Wang. Research progress of mTOR inhibitors in heart transplantation[J]. Chinese Journal of Transplantation(Electronic Edition), 2021, 15(04): 250-256.

心脏移植是目前终末期心脏病的标准治疗方案。近年来哺乳动物雷帕霉素靶蛋白(mTOR)抑制剂在心脏移植中的应用逐渐增多,越来越多的研究证实其在心脏移植受者的维持治疗中具有延缓移植物血管病进展、改善肾功能、减少CMV感染和恶性肿瘤发生风险的作用。但mTOR抑制剂不良反应较多,如高血脂、高血糖、蛋白尿、急性排斥反应、水肿、增加血栓事件风险和肺毒性等。本文综述mTOR抑制剂在心脏移植中的应用研究进展。

Currently heart transplantation is the standard treatment for end-stage heart disease. Mammalian target of rapamycin (mTOR) inhibitors are increasingly used in heart transplantation recently. Numerous studies have demonstrated the efficacy of mTOR in attenuating cardiac allograft vasculopathy progression, improving renal function, and reducing cytomegalovirus infections and risks of malignancy. However, mTOR inhibitors have many adverse effects, such as hyperlipidemia, hyperglycemia, proteinuria, acute rejection, edema, risk of thrombotic events, and pulmonary toxicity. This review briefly discusses recent research progress of mTOR inhibitors in heart transplantation.

表1 近3年有关mTOR抑制剂在心脏移植应用中的研究
研究时间 目的 研究类型 免疫抑制方案 随访时间 主要结果
2018年[7] 评价mTOR抑制剂在心脏移植儿童受者中伤口并发症的风险 回顾性 西罗莫司111例 90 d 1例在术后第17天出现切口起搏器感染、甲氧西林敏感金黄色葡萄球菌阳性。12例需要再次手术。西罗莫司在心脏移植儿童受者中伤口并发症的风险较低。
2018年[8] 西罗莫司在预防心脏移植后CAV进展和长期预后的安全性和有效性 回顾性 西罗莫司268例,CNI 134例 8.9年 西罗莫司组和CNI组经血管内超声检查的斑块体积分别为(2.8±2.3)和(0.46±1.8)mm3、斑块指数(斑块体积/血管体积)分别为(12.2±9.6)%和(1.1±7.9)%,差异均有统计学意义(P均<0.0001),且全因死亡率更低(HR=0.47,95%CI:0.31~0.70)。
2019年[11] 基于西罗莫司的免疫抑制方案能否降低心脏移植后恶性肿瘤的发病风险 RCT 西罗莫司307例,CNI 216例 10年 31%的CNI和13%的西罗莫司受者出现新发恶性肿瘤(调整后HR=0.34,95%CI:0.18~0.62)。西罗莫司和CNI组转换前非黑素瘤皮肤癌发病风险类似(HR=0.92,95%CI:0.66~1.28);转换后西罗莫司组新发非黑素瘤皮肤癌(HR=0.44,95%CI:0.28~0.69)和移植后淋巴增殖性疾病(HR=0.13,95%CI:0.03~0.59)的风险降低。
2019年[12] 比较mTOR抑制剂/无CNI方案和mTOR抑制剂/CNI减量方案的疗效 RCT 依维莫司/CNI减量74例,依维莫司/无CNI 71例 18个月 两种方案均有利于稳定肾功能,依维莫司/无CNI方案的肾脏益处至少与依维莫司/CNI减量方案相当,但会增加急性排斥反应的风险。
2021年[13] mTOR抑制剂相关蛋白尿对心脏移植后CAV的进展和长期预后的影响 回顾性 西罗莫斯137例 5.4年 转换为西罗莫司的受者蛋白尿(尿蛋白≥300 mg/24 h)发作更频繁(约26%),合并蛋白尿的受者全因死亡率(HR=3.8,95%CI:1.4~10.)和CAV事件风险(HR=1.3,95%CI:0.46~3.8)更高。
1
Stehlik J, Kobashigawa J, Hunt SA, et al. Honoring 50 years of clinical heart transplantation in circulation: In-depth state-of-the-art review[J]. Circulation, 2018, 137(1): 71-87.
2
Zaza G, Granata S, Caletti C, et al. mTOR inhibition role in cellular mechanisms[J]. Transplantation, 2018, 102(2S Suppl 1): S3-S16.
3
Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease[J]. Cell, 2017, 168(6): 960-976.
4
Xie A, Yan H, Fu J, et al. T follicular helper and memory cell responses and the mTOR pathway in murine heart transplantation[J]. J Heart Lung Transplant, 2020, 39(2): 134-144.
5
Fine NM, Kushwaha SS. Recent advances in mammalian target of rapamycin inhibitor use in heart and lung transplantation[J]. Transplantation, 2016, 100(12): 2558-2568.
6
Jennings DL, Lange N, Shullo M, et al. Outcomes associated with mammalian target of rapamycin (mTOR) inhibitors in heart transplant recipients: A meta-analysis[J]. Int J Cardiol, 2018, 265:71-76.
7
Heble A, Everitt MD, Gralla J, et al. Safety of mTOR inhibitor continuation in pediatric heart transplant recipients undergoing surgical procedures[J]. Pediatr Transplant, 2018, 22(1).
8
Asleh R, Briasoulis A, Kremers WK, et al. Long-term sirolimus for primary immunosuppression in heart transplant recipients[J]. J Am Coll Cardiol, 2018, 71(6): 636-650.
9
Ueyama H, Kuno T, Takagi H, et al. Maintenance immunosuppression in heart transplantation: insights from network meta-analysis of various immunosuppression regimens[J]. Heart Fail Rev, 2020.
10
Rossano JW, Jefferies JL, Pahl E, et al. Use of sirolimus in pediatric heart transplant patients: A multi-institutional study from the Pediatric Heart Transplant Study Group[J]. J Heart Lung Transplant, 2017, 36(4): 427-433.
11
Asleh R, Clavell AL, Pereira NL, et al. Incidence of malignancies in patients treated with sirolimus following heart transplantation[J]. J Am Coll Cardiol, 2019, 73(21): 2676-2688.
12
Barten MJ, Hirt SW, Garbade J, et al. Comparing everolimus-based immunosuppression with reduction or withdrawal of calcineurin inhibitor reduction from six months after heart transplantation: the randomized MANDELA study[J]. Am J Transplant, 2019.
13
Asleh R, Alnsasra H, Lerman A, et al. Effects of mTOR inhibitor-related proteinuria on progression of cardiac allograft vasculopathy and outcomes among heart transplant recipients[J]. Am J Transplant, 2021, 21(2): 626-635.
14
Mallah SI, Atallah B, Moustafa F, et al. Evidence-based pharmacotherapy for prevention and management of cardiac allograft vasculopathy[J]. Prog Cardiovasc Dis, 2020, 63(3): 194-209.
15
Lee MS, Tadwalkar RV, Fearon WF, et al. Cardiac allograft vasculopathy: A review[J]. Catheter Cardiovasc Interv, 2018, 92(7): E527-E536.
16
Lund LH, Edwards LB, Dipchand AI, et al. The Registry of the International Society for Heart and Lung Transplantation: Thirty-third adult heart transplantation report-2016; Focus theme: Primary diagnostic indications for transplant[J]. J Heart Lung Transplant, 2016, 35(10): 1158-1169.
17
Chih S, Chong AY, Mielniczuk LM, et al. Allograft vasculopathy: The achilles′ heel of heart transplantation[J]. J Am Coll Cardiol, 2016, 68(1): 80-91.
18
Nikolova AP, Kobashigawa JA. Cardiac allograft vasculopathy[J]. Transplantation, 2019, 103(7): 1338-1348.
19
Sobieszczanska-Malek M, Korewicki J, Komuda K, et al. Heart transplantation and risk of cardiac vasculopathy development: What factors are important?[J]. Ann Transplant, 2017, 22:682-688.
20
Johansson I, Andersson R, Friman V, et al. Cytomegalovirus infection and disease reduce 10-year cardiac allograft vasculopathy-free survival in heart transplant recipients[J]. BMC Infect Dis, 2015, 15:582.
21
Klimczak-Tomaniak D, Roest S, Brugts JJ, et al. The association between cytomegalovirus infection and cardiac allograft vasculopathy in the era of antiviral valganciclovir prophylaxis[J]. Transplantation, 2020, 104(7):1508-1518.
22
Andreassen AK, Andersson B, Gustafsson F, et al. Everolimus initiation with early calcineurin inhibitor withdrawal in de novo heart transplant recipients: Three-year results from the randomized SCHEDULE study[J]. Am J Transplant, 2016, 16(4): 1238-1247.
23
Gustafsson F, Andreassen AK, Andersson B, et al. Everolimus initiation with early calcineurin inhibitor withdrawal in de novo heart transplant recipients: Long-term follow-up from the randomized SCHEDULE study[J]. Transplantation, 2020, 104(1): 154-164.
24
Topilsky Y, Hasin T, Raichlin E, et al. Sirolimus as primary immunosuppression attenuates allograft vasculopathy with improved late survival and decreased cardiac events after cardiac transplantation[J]. Circulation, 2012, 125(5): 708-720.
25
Sousa JE, Costa MA, Abizaid A, et al. Lack of neointimal proliferation after implantation of sirolimus-coated stents in human coronary arteries: a quantitative coronary angiography and three-dimensional intravascular ultrasound study[J]. Circulation, 2001, 103(2): 192-195.
26
Zeng H, Chi H. mTOR signaling in the differentiation and function of regulatory and effector T cells[J]. Curr Opin Immunol, 2017, 46:103-111.
27
Bellumkonda L, Patel J. Recent advances in the role of mammalian target of rapamycin inhibitors on cardiac allograft vasculopathy[J]. Clin Transplant, 2020, 34(1): e13769.
28
Norum HM, Michelsen AE, Lekva T, et al. Circulating delta-like Notch ligand 1 is correlated with cardiac allograft vasculopathy and suppressed in heart transplant recipients on everolimus-based immunosuppression[J]. Am J Transplant, 2019, 19(4): 1050-1060.
29
Mociornita AG, Adamson MB, Tumiati LC, et al. Effects of everolimus and HLA-G on cellular proliferation and neutrophil adhesion in an in vitro model of cardiac allograft vasculopathy[J]. Am J Transplant, 2018, 18(12): 3038-3044.
30
Asleh R, Prasad M, Briasoulis A, et al. Uric acid is an independent predictor of cardiac allograft vasculopathy after heart transplantation[J]. J Heart Lung Transplant, 2018, 37(9): 1083-1092.
31
Masetti M, Potena L, Nardozza M, et al. Differential effect of everolimus on progression of early and late cardiac allograft vasculopathy in current clinical practice[J]. Am J Transplant, 2013, 13(5):1217-1226.
32
Puttarajappa CM, Bernardo JF, Kellum JA. Renal complications following lung transplantation and heart transplantation[J]. Crit Care Clin, 2019, 35(1): 61-73.
33
Ma MKM, Yung S, Chan TM. mTOR inhibition and kidney diseases[J]. Transplantation, 2018, 102(2S Suppl 1):S32-S40.
34
Tholking G, Gillhaus NH, Schutte-Nutgen K, et al. Conversion to everolimus was beneficial and safe for fast and slow tacrolimus metabolizers after renal transplantation [J]. J Clin Med, 2020, 9(2): 328
35
Kelsh SE, Girgis R, Dickinson M, et al. Everolimus use for intolerance or failure of baseline immunosuppression in adult heart and lung transplantation[J]. Annals of Transplantation, 2018, 23:744-750.
36
Groetzner J, Kaczmarek I, Schulz U, et al. Mycophenolate and sirolimus as calcineurin inhibitor-free immunosuppression improves renal function better than calcineurin inhibitor-reduction in late cardiac transplant recipients with chronic renal failure[J]. Transplantation, 2009, 87(5): 726-733.
37
Gonzalez-Vilchez F, Vazquez De Prada JA, Paniagua MJ, et al. Use of mTOR inhibitors in chronic heart transplant recipients with renal failure: calcineurin-inhibitors conversion or minimization?[J]. Int J Cardiol, 2014, 171(1): 15-23.
38
Gleissner CA, Doesch A, Ehlermann P, et al. Cyclosporine withdrawal improves renal function in heart transplant patients on reduced-dose cyclosporine therapy[J]. Am J Transplant, 2006, 6(11): 2750-2758.
39
Gude E, Gullestad L, Andreassen AK. Everolimus immunosuppression for renal protection, reduction of allograft vasculopathy and prevention of allograft rejection in de-novo heart transplant recipients: could we have it all?[J]. Curr Opin Organ Transplant, 2017, 22(3): 198-206.
40
Tan L, Sato N, Shiraki A, et al. Everolimus delayed and suppressed cytomegalovirus DNA synthesis, spread of the infection, and alleviated cytomegalovirus infection[J]. Antiviral Res, 2019, 162:30-38.
31
Poglitsch M, Weichhart T, Hecking M, et al. CMV late phase-induced mTOR activation is essential for efficient virus replication in polarized human macrophages[J]. Am J Transplant, 2012, 12(6): 1458-1468.
42
Bak S, Tischer S, Dragon A, et al. Selective effects of mTOR inhibitor sirolimus on naive and CMV-specific T cells extending its applicable range beyond immunosuppression[J]. Front Immunol, 2018, 9:2953.
43
Tian T, Li X, Zhang J. mTOR signaling in cancer and mTOR inhibitors in solid tumor targeting therapy[J]. Int J Mol Sci, 2019, 20(3): 755.
44
Zuckermann A, Osorio-Jaramillo E, Aliabadi-Zuckermann AZ. mTOR inhibition and clinical transplantation: Heart[J]. Transplantation, 2018, 102(2S Suppl 1): S27-S29.
45
Ventura-Aguiar P, Campistol JM, Diekmann F. Safety of mTOR inhibitors in adult solid organ transplantation[J]. Expert Opin Drug Saf, 2016, 15(3): 303-319.
46
Peterson TR, Sengupta SS, Harris TE, et al. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway[J]. Cell, 2011, 146(3): 408-420.
47
Cybulski N, Polak P, Auwerx J, et al. mTOR complex 2 in adipose tissue negatively controls whole-body growth[J]. Proc Natl Acad Sci U S A, 2009, 106(24): 9902-9907.
48
Asleh R, Briasoulis A, Pereira NL, et al. Hypercholesterolemia after conversion to sirolimus as primary immunosuppression and cardiac allograft vasculopathy in heart transplant recipients[J]. J Heart Lung Transplant, 2018, 37(11): 1372-1380.
49
Verges B. mTOR and cardiovascular diseases: Diabetes mellitus[J]. Transplantation, 2018, 102(2S Suppl 1): S47-S49.
50
Kezic A, Popovic L, Lalic K. mTOR inhibitor therapy and metabolic consequences: where do we stand?[J]. Oxid Med Cell Longev, 2018:2640342.
51
Arriola Apelo SI, Neuman JC, Baar EL, et al. Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system[J]. Aging Cell, 2016, 15(1): 28-38.
52
Asleh R, Alnsasra H, Lerman A, et al. Effects of mTOR inhibitor-related proteinuria on progression of cardiac allograft vasculopathy and outcomes among heart transplant recipients[J]. Am J Transplant, 2021, 21(2):626-635.
53
Anglicheau D, Pallet N, Rabant M, et al. Role of P-glycoprotein in cyclosporine cytotoxicity in the cyclosporine-sirolimus interaction[J]. Kidney Int, 2006, 70(6): 1019-1025.
54
Grahammer F, Wanner N, Huber TB. mTOR controls kidney epithelia in health and disease[J]. Nephrol Dial Transplant, 2014, 29(Suppl 1): i9-i18.
55
Witkowsky O, Teuteberg J, Althouse AD, et al. Thrombotic events with proliferation signal inhibitorbased immunosuppression in cardiac transplantation[J]. J Heart Lung Transplant, 2019, 38(6): 619-626.
56
Steffel J, Latini RA, Akhmedov A, et al. Rapamycin, but not FK-506, increases endothelial tissue factor expression: implications for drug-eluting stent design[J]. Circulation, 2005, 112(13): 2002-2011.
57
Willemsen AE, Grutters JC, Gerritsen WR, et al. mTOR inhibitor-induced interstitial lung disease in cancer patients: Comprehensive review and a practical management algorithm[J]. Int J Cancer, 2016, 138(10): 2312-2321.
58
Lopez P, Kohler S, Dimri S. Interstitial lung disease associated with mTOR inhibitors in solid organ transplant recipients: Results from a large phase III clinical trial program of everolimus and review of the literature[J]. J Transplant, 2014:305931.
59
Budde K, Lehner F, Sommerer C, et al. Five-year outcomes in kidney transplant patients converted from cyclosporine to everolimus: the randomized ZEUS study[J]. Am J Transplant, 2015, 15(1): 119-128.
60
Oroszlan M, Bieri M, Ligeti N, et al. Proliferation signal inhibitor-induced decrease of vascular endothelial cadherin expression and increase of endothelial permeability in vitro are prevented by an anti-oxidant[J]. J Heart Lung Transplant, 2008, 27(12): 1311-1318.
61
Gonzalez-Vilchez F, Vazquez De Prada JA, Almenar L, et al. Withdrawal of proliferation signal inhibitors due to adverse events in the maintenance phase of heart transplantation[J]. J Heart Lung Transplant, 2012, 31(3): 288-295.
62
Pascual J, Marcen R, Ortuno J. Clinical experience with everolimus (Certican): optimizing dose and tolerability[J]. Transplantation, 2005, 79(9 Suppl): S80-S84.
63
Guba M, Pratschke J, Hugo C, et al. Early conversion to a sirolimus-based, calcineurin-inhibitor-free immunosuppression in the SMART trial: observational results at 24 and 36months after transplantation[J]. Transpl Int, 2012, 25(4): 416-423.
64
Lo Muzio L, Arena C, Troiano G, et al. Oral stomatitis and mTOR inhibitors: A review of current evidence in 20,915 patients[J]. Oral Dis, 2018, 24(1-2): 144-171.
65
Karpe KM, Talaulikar GS, Walters GD. Calcineurin inhibitor withdrawal or tapering for kidney transplant recipients[J]. Cochrane Database Syst Rev, 2017, 7(7):CD006750.
[1] 王青青, 耿翠芝, 苏晓雨, 彭玉晓, 秦明祎, 刘风侠. 乳腺癌芳香化酶抑制剂相关肌肉骨骼不良反应的研究进展[J]. 中华乳腺病杂志(电子版), 2023, 17(04): 243-249.
[2] 马敏榕, 李聪, 周勤. 宫颈癌治疗研究现状[J]. 中华妇幼临床医学杂志(电子版), 2023, 19(05): 497-504.
[3] 陈滔, 罗洪, 周进军. 老年食管癌单纯放疗及同期放化疗患者急性不良反应影响因素分析[J]. 中华普外科手术学杂志(电子版), 2023, 17(04): 405-407.
[4] 陈瑜, 尤良顺, 孟海涛, 杨敏. 嵌合抗原受体T细胞治疗多发性骨髓瘤新进展[J]. 中华移植杂志(电子版), 2023, 17(05): 313-320.
[5] 季媛, 魏巴金. NLRP3炎性小体在器官移植不良反应发病机制中的研究进展[J]. 中华移植杂志(电子版), 2023, 17(05): 308-312.
[6] 巨春蓉, 何建行, 钟南山. 咪唑立宾在器官移植领域的应用及展望[J]. 中华移植杂志(电子版), 2023, 17(04): 227-231.
[7] 中国康复医学会器官移植康复专业委员会. 成人实体器官移植后糖尿病管理专家共识[J]. 中华移植杂志(电子版), 2023, 17(04): 205-220.
[8] 蒋春艳, 赵刚, 诸国萍, 付庆辉, 卫建华. 等待心脏移植患者术前行右心漂浮导管检查临床应用及护理策略分析[J]. 中华移植杂志(电子版), 2023, 17(03): 164-168.
[9] 姜里蛟, 张峰, 周玉萍. 多学科诊疗模式救治老年急性非静脉曲张性上消化道大出血患者的临床观察[J]. 中华消化病与影像杂志(电子版), 2023, 13(06): 520-524.
[10] 张政赢, 鞠阳, 刘晓宁. 二甲双胍对2型糖尿病患者大肠腺瘤术后复发的影响[J]. 中华消化病与影像杂志(电子版), 2023, 13(06): 485-488.
[11] 盛静, 梅勇, 夏佩, 王晓林. 乌苯美司联合伊立替康二线治疗晚期胃癌的临床研究[J]. 中华消化病与影像杂志(电子版), 2023, 13(05): 317-321.
[12] 徐洪宇, 何亚爽. 羟考酮与氢吗啡酮用于胃癌根治术后镇痛的疗效[J]. 中华消化病与影像杂志(电子版), 2023, 13(05): 312-316.
[13] 董骏, 吴芳芳. mFOLFOX6与FOLFOX4化疗方案治疗直肠癌的临床疗效及安全性分析[J]. 中华消化病与影像杂志(电子版), 2023, 13(04): 236-240.
[14] 于晓东, 李德华, 高山, 徐鑫. 理中汤加味联合美沙拉嗪治疗轻度活动期克罗恩病的临床观察[J]. 中华消化病与影像杂志(电子版), 2023, 13(04): 199-202.
[15] 王昊, 明倩文, 王斌, 卢太坤, 张海宁. 利奈唑胺致黑毛舌的临床诊断学特征[J]. 中华诊断学电子杂志, 2023, 11(04): 254-260.
阅读次数
全文


摘要