Auerbach Scott R, Manlhiot Cedric, Reddy Sushma, Kinnear Caroline, Richmond Marc E, Gruber Dorota, McCrindle Brian W, Deng Liyong, Chen Jonathan M, Addonizio Linda J, Chung Wendy K, Mital Seema
Department of Pediatric Cardiology, Columbia University, Morgan Stanley Children's Hospital of New York-Presbyterian, New York, New York, USA.
J Am Coll Cardiol. 2009 May 19;53(20):1909-17. doi: 10.1016/j.jacc.2009.02.027.
This study sought to investigate the influence of recipient renin-angiotensin-aldosterone system (RAAS) genotype on cardiac function, rejection, and outcomes after heart transplantation.
The RAAS influences cardiac function and up-regulates inflammatory/immune pathways. Little is known about the effect of recipient RAAS polymorphisms in pediatric cardiac transplantation.
Patients <25 years of age, after cardiac transplantation, were enrolled (2003 to 2008) and genotyped for polymorphisms in genes associated with RAAS upregulation: AGT-G, ACE-D, AGTR1-C, CYP11B2-G, and CMA-A. Presence of at least 1 high-risk allele was defined as a high-risk genotype. Univariable and multivariable associations between genotypes and outcomes were assessed in time-dependent models using survival, logistic, or linear regression models. Biopsy samples were immunostained for interleukin (IL)-6, transforming growth factor (TGF)-beta, and tumor necrosis factor (TNF)-alpha during rejection and quiescence.
A total of 145 patients were studied, 103 primary cohort and 42 replication cohort; 81% had rejection, 51% had graft dysfunction, and 13% had vasculopathy, 7% died and 8% underwent re-transplantation. A higher number of homozygous high-risk RAAS genotypes was associated with a higher risk of graft dysfunction (hazard ratio [HR]: 1.5, p = 0.02) and a higher probability of death (HR: 2.5, p = 0.04). The number of heterozygous high-risk RAAS genotypes was associated with frequency of rejection (+0.096 events/year, p < 0.001) and rejection-associated graft dysfunction (+0.37 events/year, p = 0.002). IL-6 and TGF-beta were markedly upregulated during rejection in patients with >/=2 high-risk RAAS genotypes.
Recipient RAAS polymorphisms are associated with a higher risk of rejection, graft cytokine expression, graft dysfunction, and a higher mortality after cardiac transplantation. This may have implications for use of RAAS inhibitors in high-risk patients after transplantation.
本研究旨在调查心脏移植受者肾素 - 血管紧张素 - 醛固酮系统（RAAS）基因型对心脏功能、排斥反应及移植后结局的影响。
RAAS影响心脏功能并上调炎症/免疫途径。关于儿童心脏移植中受者RAAS多态性的影响知之甚少。
纳入2003年至2008年心脏移植术后年龄小于25岁的患者，并对与RAAS上调相关基因的多态性进行基因分型：AGT - G、ACE - D、AGTR1 - C、CYP11B2 - G和CMA - A。存在至少1个高危等位基因被定义为高危基因型。使用生存、逻辑或线性回归模型，在时间依赖性模型中评估基因型与结局之间的单变量和多变量关联。在排斥反应期和静止期，对活检样本进行白细胞介素（IL）-6、转化生长因子（TGF）-β和肿瘤坏死因子（TNF）-α的免疫染色。
共研究了145例患者，其中103例为原队列，42例为重复队列；81%发生排斥反应，51%出现移植物功能障碍，13%出现血管病变，7%死亡，8%接受再次移植。纯合高危RAAS基因型数量较多与移植物功能障碍风险较高（风险比[HR]：1.5，p = 0.02）和死亡概率较高（HR：2.5，p = 0.04）相关。杂合高危RAAS基因型数量与排斥反应频率（+0.096次事件/年，p < 0.001）和与排斥反应相关的移植物功能障碍（+0.37次事件/年，p = 0.002）相关。在具有≥2个高危RAAS基因型的患者中，排斥反应期间IL - 6和TGF - β明显上调。
心脏移植受者RAAS多态性与排斥反应风险较高、移植物细胞因子表达、移植物功能障碍及较高死亡率相关。这可能对移植后高危患者使用RAAS抑制剂有影响。
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