Yim Wai Yen, Xiong Tixiusi, Geng Bingchuan, Xu Li, Feng Yu, Chi Jiangyang, Guo Ruikang, Li Chenghao, Chen Yuqi, Shi Jiawei, Wang Yixuan, Dong Nianguo
Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277, Jiefang Avenue, Wuhan 430022, PRChina.
Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences, Wuhan, China.
Cardiovasc Res. 2023 Oct 16;119(12):2202-2212. doi: 10.1093/cvr/cvad114.
Circadian clocks play important role in immunoregulation. We aimed to investigate cardiac circadian clock specific pathways and compare cardiac grafts procured at different timing on survival after transplantation to explore novel criteria for donor selection.
In primate heart, phase set enrichment analysis (PSEA) showed rhythmic transcripts were enriched in antigen processing and presentation during activation of circadian rhythm. Digital sorting of immune cell composition and single-sample gene set enrichment analysis (ssGSEA) in unused donor transcriptomes showed the pathway, positive regulation of circadian rhythm significantly correlates with allograft rejection and antigen presentation pathways as well as with increased compositions of matured dendritic cell, CD4+ T cell, and naive B cell. Single-centre retrospective cohort of 390 adult heart transplants between 1 January 2015 and 31 December 2020 was used to generate a propensity score matching (PSM) cohort. Survival curve differed significantly showing inferior long-term survival when donor hearts were procured at activation group (12 pm to 12 am) compared to repression group (12 am to 12 pm) (6-year survival: 64.2% vs. 75.8%, P = 0.0065). Activation group was also associated with significantly higher rates of in-hospital death, cardiopulmonary resuscitation, and usage of mechanical circulatory support after heart transplantation compared to repression group. Furthermore, tendency for post-transplant free of rejection rates was higher in repression group compared to activation group (acute rejection, Gehan-Breslow P = 0.11 and 0.04; chronic rejection, Log rank P = 0.077 and 0.15, in full and PSM cohorts, respectively). Adjusted Cox regression analysis showed that activation group was associated with 2.20 times increased hazard of death (hazard ratio: 2.20; 95% confidence interval: 1.23-3.95; P = 0.008) compared to repression group.
Circadian immunity may represent donor-related risk factors for cardiac allograft rejection through activating genes related to antigen presentation pathway and immune cells oscillation at specific time of day. Molecular circadian clock should be considered during retrieval of cardiac allografts in order to maximize graft durability.
生物钟在免疫调节中发挥重要作用。我们旨在研究心脏生物钟的特定途径，并比较在不同时间获取的心脏移植物对移植后存活情况的影响，以探索供体选择的新标准。
在灵长类心脏中，相位集富集分析（PSEA）显示，在昼夜节律激活期间，节律性转录本在抗原加工和呈递过程中富集。对未使用的供体转录组进行免疫细胞组成的数字分选和单样本基因集富集分析（ssGSEA）显示，昼夜节律的正调控途径与同种异体移植排斥反应和抗原呈递途径显著相关，也与成熟树突状细胞、CD4 + T细胞和幼稚B细胞组成的增加相关。利用2015年1月1日至2020年12月31日期间390例成人心脏移植的单中心回顾性队列生成倾向评分匹配（PSM）队列。生存曲线存在显著差异，与抑制组（上午12点至下午12点）相比，激活组（下午12点至上午12点）获取供体心脏时长期生存率较低（6年生存率：64.2% 对75.8%，P = 0.0065）。与抑制组相比，激活组心脏移植后院内死亡、心肺复苏和使用机械循环支持的发生率也显著更高。此外，抑制组移植后无排斥率的趋势高于激活组（急性排斥反应，在完整队列和PSM队列中，Gehan - Breslow检验P分别为0.11和0.04；慢性排斥反应，Log rank检验P分别为0.077和0.15）。校正后的Cox回归分析显示，与抑制组相比，激活组死亡风险增加2.20倍（风险比：2.20；95%置信区间：1.23 - 3.95；P = 0.008）。
昼夜节律免疫可能通过在一天中的特定时间激活与抗原呈递途径和免疫细胞振荡相关的基因，代表心脏同种异体移植排斥反应中与供体相关的风险因素。在获取心脏同种异体移植物时应考虑分子生物钟，以最大化移植物的耐久性。
