Decreased Catecholamine Degradation Associates with Shock and Kidney Injury after Cardiac Surgery
Decreased Catecholamine Degradation Associates with Shock and Kidney Injury after Cardiac Surgery
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DOI：
10.1681/asn.2008080915
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发表时间：
2009-06-01
影响因子：
13.6
通讯作者：
Dragun, Duska
中科院分区：
文献类型：
--
作者：
Haase-Fielitz, Anja;Haase, Michael;Dragun, Duska
涉及儿茶酚- o -甲基转移酶（COMT）的酶途径分解循环儿茶酚胺。COMT基因第4外显子的G-to-A多态性导致密码子158处缬氨酸到蛋氨酸的氨基酸替换，从而导致耐热性和低（“L”）而不是高（“H”）的酶活性。我们招募了260例心脏搭桥术后患者，以验证COMT基因变异损害循环儿茶酚胺代谢，易导致心脏手术后休克和急性肾损伤（AKI）的假设。根据Hardy-Weinberg平衡，我们鉴定出64例（24.6%）纯合子（LL）， 123例（47.3%）杂合子（HL）和73例（28.1%）纯合子（HH）患者。纯合子LL患者术后儿茶酚胺含量高于杂合子HL和纯合子HH患者（P < 0.01）。在重症监护期间，LL患者发生血管扩张性休克的频率显著较高（LL: 69%, HL: 57%, HH: 47%; P = 0.033），中位休克持续时间显著较长（LL: 18.5 h, HL: 14.0 h, HH: 11.0 h; P = 0.013）。LL患者AKI的发生率也更高（LL: 31%, HL: 19.5%, HH: 13.7%; P = 0.038），并且他们的AKI更严重，需要肾脏替代治疗（LL: 7.8%, HL: 2.4%, HH: 0%; P = 0.026）。LL基因型与重症监护和住院时间相关（分别为P < 0.001和P = 0.002），我们观察到死亡率升高的趋势。交叉验证分析显示，不良结果与基因型之间存在类似的分级关系。总之，本研究确定COMT LL纯合性是心脏手术后休克、AKI和住院的独立危险因素。（ClinicalTrials.gov编号：NCT00334009）
Enzymatic pathways involving catechol-O-methyltransferase (COMT) catabolize circulating catecholamines. A G-to-A polymorphism in the fourth exon of the COMT gene results in a valine-to-methionine amino acid substitution at codon 158, which leads to thermolability and low ("L"), as opposed to high ("H"), enzymatic activity. We enrolled 260 patients postbypass surgery to test the hypothesis that COMT gene variants impair circulating catecholamine metabolism, predisposing to shock and acute kidney injury (AKI) after cardiac surgery. In accordance with the Hardy-Weinberg equilibrium, we identified 64 (24.6%) homozygous (LL), 123 (47.3%) heterozygous (HL), and 73 (28.1%) homozygous (HH) patients. Postoperative catecholamines were higher in homozygous LL patients compared with heterozygous HL and homozygous HH patients (P < 0.01). During their intensive care stay, LL patients had both a significantly greater frequency of vasodilatory shock (LL: 69%, HL: 57%, HH: 47%; P = 0.033) and a significantly longer median duration of shock (LL: 18.5 h, HL: 14.0 h, H H: 11.0 h; P = 0.013). LL patients also had a greater frequency of AKI (LL: 31%, H L: 19.5%, H H: 13.7%; P = 0.038) and their AKI was more severe as defined by a need for renal replacement therapy (LL: 7.8%, HL: 2.4%, HH: 0%; P = 0.026). The LL genotype associated with intensive care and hospital length of stay (P < 0.001 and P = 0.002, respectively), and we observed a trend for higher mortality. Cross-validation analysis revealed a similar graded relationship of adverse outcomes by genotype. In summary, this study identifies COMT LL homozygosity as an independent risk factor for shock, AKI, and hospital stay after cardiac surgery. (ClinicalTrials.gov number, NCT00334009)