Decreased Catecholamine Degradation Associates with Shock and Kidney Injury after Cardiac Surgery

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, {"type":"clinical-trial","attrs":{"text":"NCT00334009","term_id":"NCT00334009"}}NCT00334009)Shock and acute kidney injury (AKI) are associated with increased mortality after cardiac surgery.^1,2 Cardiopulmonary bypass represents a common clinical setting of sympathetic nervous system activation and cardiovascular instability. Postoperative hypotension and vasodilation with increased requirements for catecholamines occur despite adequate intravascular filling, cardiac output, and increased plasma catecholamine concentrations.^1,3 High circulating catecholamine levels may contribute to persistent vasodilatation via α-adrenoceptor downregulation and desensitization,⁴ depression of vasopressin synthesis, and adenosine triphosphate-sensitive potassium channel activation in vascular smooth muscle cells.⁵ Circulating catecholamines are primarily catabolized through enzymatic pathways involving the enzyme catechol-O-methyltransferase (COMT).⁶ A functional G-to-A polymorphism in the fourth exon of the COMT gene results in a valine-to-methionine amino acid transition at codon 158 (COMT Val158Met polymorphism), leading to thermolability and lower (L), compared with higher (H) activity of the enzyme.^7,8 Genetically determined COMT activity, among others,^9,10 influences outcomes in patients with ischemic heart disease.^11,12 In the kidney, COMT is essential for catecholamine degradation along the distal parts of proximal tubules and thick ascending limb of loop of Henle.¹³ We hypothesized that the COMT LL genotype coding for low enzyme activity would shift metabolism toward increased plasma catecholamine concentrations and predispose to increased duration of vasodilatory shock and higher AKI incidence after cardiac surgery. To test this notion, we conducted a prospective observational cohort study in cardiac surgery patients.