title: Decreased catecholamine degradation associates with shock and kidney injury after cardiac surgery.
abstract: 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, HH: 11.0 h; P = 0.013). LL patients also had a greater frequency of AKI (LL: 31%, HL: 19.5%, HH: 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).
authors.affiliation: Department of Intensive Care, Austin Health, Melbourne, Australia.
authors.forename: Anja
authors.initials: A
authors.lastname: Haase-Fielitz
authors.forename: Michael
authors.initials: M
authors.lastname: Haase
authors.forename: Rinaldo
authors.initials: R
authors.lastname: Bellomo
authors.forename: Gavin
authors.initials: G
authors.lastname: Lambert
authors.forename: George
authors.initials: G
authors.lastname: Matalanis
authors.forename: David
authors.initials: D
authors.lastname: Story
authors.forename: Laurie
authors.initials: L
authors.lastname: Doolan
authors.forename: Brian
authors.initials: B
authors.lastname: Buxton
authors.forename: Geoff
authors.initials: G
authors.lastname: Gutteridge
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.forename: Wolf-Hagen
authors.initials: WH
authors.lastname: Schunck
authors.forename: Duska
authors.initials: D
authors.lastname: Dragun
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology*; D000368:Aged; D006348:Cardiac Surgical Procedures / Q000009:adverse effects* / Q000401:mortality; D002394:Catechol O-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D002395:Catecholamines / Q000097:blood* / Q000378:metabolism; D003422:Critical Care; D005260:Female; D006801:Humans; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012769:Shock / Q000209:etiology*; D014664:Vasodilation
chemical_list: D002395:Catecholamines; D002394:Catechol O-Methyltransferase