Monoamine oxidase is a major determinant of redox balance in human atrial myocardium and is associated with postoperative atrial fibrillation

Abstract

Background: Onset of postoperative atrial fibrillation (POAF) is a common and costly complication of heart surgery despite major improvements in surgical technique and quality of patient care. The etiology of POAF, and the ability of clinicians to identify and therapeutically target high-risk patients, remains elusive.

Methods and results: Myocardial tissue dissected from right atrial appendage (RAA) was obtained from 244 patients undergoing cardiac surgery. Reactive oxygen species (ROS) generation from multiple sources was assessed in this tissue, along with total glutathione (GSHt) and its related enzymes GSH-peroxidase (GPx) and GSH-reductase (GR). Monoamine oxidase (MAO) and NADPH oxidase were observed to generate ROS at rates 10-fold greater than intact, coupled mitochondria. POAF risk was significantly associated with MAO activity (Quartile 1 [Q1]: adjusted relative risk [ARR]=1.0; Q2: ARR=1.8, 95% confidence interval [CI]=0.84 to 4.0; Q3: ARR=2.1, 95% CI=0.99 to 4.3; Q4: ARR=3.8, 95% CI=1.9 to 7.5; adjusted Ptrend=0.009). In contrast, myocardial GSHt was inversely associated with POAF (Quartile 1 [Q1]: adjusted relative risk [ARR]=1.0; Q2: ARR=0.93, 95% confidence interval [CI]=0.60 to 1.4; Q3: ARR=0.62, 95% CI=0.36 to 1.1; Q4: ARR=0.56, 95% CI=0.34 to 0.93; adjusted Ptrend=0.014). GPx also was significantly associated with POAF; however, a linear trend for risk was not observed across increasing levels of the enzyme. GR was not associated with POAF risk.

Conclusions: Our results show that MAO is an important determinant of redox balance in human atrial myocardium, and that this enzyme, in addition to GSHt and GPx, is associated with an increased risk for POAF. Further investigation is needed to validate MAO as a predictive biomarker for POAF, and to explore this enzyme's potential role in arrhythmogenesis.

Keywords: biomarkers; cardiopulmonary bypass; catecholamines; oxidative stress; post‐operative atrial fibrillation; redox; tachyarrhythmias.

Figure 1.

Comparative analysis of major ROS sources in human atrial myocardium. A, Representative H₂O₂ production traces from NADPH oxidase (blue), MAO (red), and mito‐ETS (black dash) in RAA tissue obtained from one individual patient. PmFBs were used for determining H₂O₂ from mito‐ETS, while homogenate was used for NADPH oxidase and MAO. Substrates were added to cuvette where indicated. Apocynin and Clorgyline are administered where indicated to confirm the source of H₂O₂ production to be NADPH oxidase and MAO, respectively. In (B) are the quantified rates from each of these 3 sources in RAA tissue obtained from 12 individual patients. MAO indicates monoamine oxidase; mito‐ETS, mitochondrial electron transport system; nadph, β‐Nicotinamide adenine dinucleotide phosphate hydrate; PmFBs, permeabilized myofibers; RAA, right atrial appendage; ROS, reactive oxygen species.

Figure 2.

MAO activity in atrial myocardium and incidence of POAF. All rates of MAO activity from entire cohort of patients recruited for this study are shown (1 circle=1 patient). Quartiles of pooled data were generated, and univariable analysis performed with POAF as the outcome variable using Poisson regression. Each quartile is delineated with color shading to illustrate the risk of POAF within that particular quartile (Green=<15%, Yellow=15% to 30%, Orange=30% to 40%, Red=>60%). Within each quartile, POAF incidence=number of patients in that particular quartile experiencing POAF. RR=relative risk, with 95% confidence interval (CI). MAO indicates monoamine oxidase; POAF, post‐operative atrial fibrillation.

Figure 3.

Total GSH (GSHt) in atrial myocardium and incidence of POAF. Data shown in this figure is GSHt for the entire cohort of patients recruited for this study. Quartiles of pooled data were generated, and univariable analysis performed with POAF as the outcome variable using Poisson regression. Each quartile is delineated with color shading to illustrate the risk of POAF within that particular quartile (Red=>40%, Yellow=15% to 30%, Orange=30% to 40%). Within each quartile, POAF incidence=number of patients in that particular quartile experiencing POAF. RR=relative risk, with 95% confidence interval (CI). GSHt indicates total glutathione; POAF, post‐operative atrial fibrillation.

Figure 4.

GPx‐GR activity in atrial myocardium and incidence of POAF. A, Simplified schematic of the redox cycle involving GSH and related enzymes GPx and GR (HOO‐Lipid=Lipid peroxide). Data shown in (B) is GPx activity and (C) GR activity for the entire cohort of patients recruited for this study. Quartiles of pooled data were generated, and univariable analysis performed with POAF as the outcome variable using Poisson regression. Each quartile is delineated with color shading to illustrate the risk of POAF within that particular quartile (Red=>40%, Yellow=15% to 30%, Orange=30% to 40%). Within each quartile, POAF incidence=number of patients in that particular quartile experiencing POAF. RR=relative risk, with 95% confidence interval (CI). GPx indicates GSH‐peroxidase; GR, GSH‐reductase; GSH, glutathione; GSSG, oxidized glutathione; POAF, post‐operative atrial fibrillation.