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).

Figure 1.

Flow diagram of patient enrollment into the study.

Figure 2.

Mean pre- and postoperative concentrations of catecholamines and metabolites in plasma of COMT^LL (♦), COMT^HL (▪), and COMT^HH (▴) genotype carriers. (A) Epinephrine concentration with the following standard deviations (pg/mL) applying at 0, 6, and 24 hours in LL (87, 209, and 234), n = 64; HL (60, 202, and 194), n = 123 and HH (56, 175, and 116), n = 73 groups. (B) Norepinephrine concentration in patients not receiving any norepinephrine infusion with the following standard deviations (pg/mL) applying at 0, 6, and 24 hours in LL (117, 41, and 123), n = 16, HL (270, 96, and 289), n = 74, and HH (233, 171, and 449), n = 39 groups. (C) 3,4-dihydroxyphenylglycol (DHPG) concentrations with the following standard deviations (pg/mL) applying at 0, 6, and 24 hours in LL (281, 285, and 288), n = 64 HL (259, 158, and 235), n = 123; and HH (157, 116, and 227), n = 73 groups. (D) 3,4-dihydroxyphenylalanine (l-DOPA) concentration with the following standard deviations (pg/mL) applying at 0, 6, and 24 hours in LL (1471, 1264, and 1126), n = 64, HL (1246, 1133, and 988), n = 123; and HH (1242, 542, and 911), n = 73 groups.

Figure 3.

Duration of vasodilatory shock (median with 25th and 75th percentiles) according to catechol-O-methyltransferase (COMT) genotype. Black circles indicate medians and black lines indicate 25th and 75th percentiles, *P = 0.013.

Figure 4.

Influence of the catechol-O-methyltransferase (COMT) genotype on acute kidney injury (AKI). (A) Incidence of postoperative AKI in patients with different COMT genotypes; *P = 0.038. (B) Absolute increase in serum creatinine from baseline to peak value during the first five postoperative days (mean and SEM) according to COMT genotype. Circles indicate mean and lines indicate SEM, *P = 0.016. (C) Relative increase in serum creatinine from baseline to peak value within the first five postoperative days (mean and SEM), *P = 0.008.