Use of monoamine oxidase and redox enzymes in atrial tissue as novel predictors of postoperative atrial fibrillation

Postoperative atrial fibrillation (POAF) occurs in approximately 30% of cardiac surgery patients. The complication occurs despite advances in surgical procedures. It is associated with increased mortality, morbidity, and healthcare cost. The exact pathogenesis of this complication is unknown, but oxidative stress and inflammation are considered to be significant factors.   A precisely controlled balance between reactive oxygen species (ROS) generation and ROS scavenging influence the oxidative environment within cells and tissues. Increased activity of monoamine oxidase (MAO) activity, a ROS generating enzyme, can produce a more oxidative environment. A decrease in glutathione (GSH), a ROS scavenging molecule, can also yield an oxidative environment. The enzymes GSH-peroxidase (GPx) and GSH-reductase (GR) are responsible for maintaining the cellular redox environment within a range that is compatible with favorable homeostasis. Despite the well-characterized role that these enzymes play in maintaining redox environment, a comprehensive evaluation of these enzymes in human myocardium has never been attempted.  Furthermore, since reports have recently documented the association between oxidative stress in atrial tissue and the incidence of POAF, we tested the hypothesis that these enzymes are associated with POAF, in a cohort of patients undergoing cardiac surgery at Vidant Medical Center, East Carolina Heart Institute (ECHI).  Human right atrial appendage tissue were obtained from 244 patients undergoing elective coronary artery bypass graft surgery at ECHI between January, 2010, and December, 2012. The generation of ROS were determined using assays on MAO, NADPH oxidase (NOX), along with the activity of glutathione reductase (GR) and glutathione peroxidase (GPx). Patient outcomes, including POAF development, were analyzed in relation to the assays performed. A statistical model was then created to measure the association for risk of POAF development.   This was the first study to determine that MAO activity is a major source of ROS in human atrial tissue. MAO activity is significantly associated with POAF. Total glutathione (GSHt) activity is inversely related to POAF development. GPx is also significantly associated with POAF as well, but the trend is not a linear. GR activity is not correlated with POAF.   MAO, GSHt and GPx are enzymes that contribute to the atrial oxidative environment and increased risk of POAF development. Because this is a pilot study, further exploration is needed to validate our study and to determine if and where these enzymes fit in the etiology of POAF.  M.S

Monoamine Oxidase is a Major Determinant of Redox Balance in Human Atrial Myocardium and is Associated With Postoperative Atrial Fibrillation

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

Cyclodextrin Complexes of Reduced Bromonoscapine in Guar Gum Microspheres Enhance Colonic Drug Delivery

Here, we report improved solubility and enhanced colonic delivery of reduced bromonoscapine (Red-Br-Nos), a cyclic ether brominated analogue of noscapine, upon encapsulation of its cyclodextrin (CD) complexes in bioresponsive guar gum microspheres (GGM). Phase−solubility analysis suggested that Red-Br-Nos complexed with β-CD and methyl-β-CD in a 1:1 stoichiometry, with a stability constant (Kc) of 2.29 × 103 M−1 and 4.27 × 103 M−1. Fourier transforms infrared spectroscopy indicated entrance of an O−CH2 or OCH3−C6H4−OCH3 moiety of Red-Br-Nos in the β-CD or methyl-β- CD cavity. Furthermore, the cage complex of Red-Br-Nos with β-CD and methyl-β-CD was validated by several spectral techniques. Rotating frame Overhauser enhancement spectroscopy revealed that the Ha proton of the OCH3−C6H4−OCH3 moiety was closer to the H5 proton of β-CD and the H3 proton of the methyl-β-CD cavity. The solubility of Red-Br-Nos in phosphate buffer saline (PBS, pH ∼ 7.4) was improved by ∼10.7-fold and ∼21.2-fold when mixed with β-CD and methyl-β-CD, respectively. This increase in solubility led to a favorable decline in the IC50 by ∼2-fold and ∼3-fold for Red-Br-Nos−β-CD-GGM and Red-Br-Nos−methyl-β-CD-GGM formulations respectively, compared to free Red-Br-Nos−β-CD and Red-Br-Nos−methyl-β-CD in human colon HT-29 cells. GGM-bearing drug complex formulations were found to be highly cytotoxic to the HT-29 cell line and further effective with simultaneous continuous release of Red-Br-Nos from microspheres. This is the first study to showing the preparation of drug-complex loaded GGMS for colon delivery of Red-Br-Nos that warrants preclinical assessment for the effective management of colon cancer

Girls and Boys Born before 28 Weeks Gestation: Risks of Cognitive, Behavioral, and Neurologic Outcomes at Age 10 Years

To compare the prevalence of cognitive, neurological, and behavioral outcomes at 10 years of age in 428 girls and 446 boys who were born extremely preterm (EP)

Use of monoamine oxidase and redox enzymes in atrial tissue as novel predictors of postoperative atrial fibrillation

Postoperative atrial fibrillation (POAF) occurs in approximately 30% of cardiac surgery patients. The complication occurs despite advances in surgical procedures. It is associated with increased mortality, morbidity, and healthcare cost. The exact pathogenesis of this complication is unknown, but oxidative stress and inflammation are considered to be significant factors. A precisely controlled balance between reactive oxygen species (ROS) generation and ROS scavenging influence the oxidative environment within cells and tissues. Increased activity of monoamine oxidase (MAO) activity, a ROS generating enzyme, can produce a more oxidative environment. A decrease in glutathione (GSH), a ROS scavenging molecule, can also yield an oxidative environment. The enzymes GSH-peroxidase (GPx) and GSH-reductase (GR) are responsible for maintaining the cellular redox environment within a range that is compatible with favorable homeostasis. Despite the well-characterized role that these enzymes play in maintaining redox environment, a comprehensive evaluation of these enzymes in human myocardium has never been attempted. Furthermore, since reports have recently documented the association between oxidative stress in atrial tissue and the incidence of POAF, we tested the hypothesis that these enzymes are associated with POAF, in a cohort of patients undergoing cardiac surgery at Vidant Medical Center, East Carolina Heart Institute (ECHI). Human right atrial appendage tissue were obtained from 244 patients undergoing elective coronary artery bypass graft surgery at ECHI between January, 2010, and December, 2012. The generation of ROS were determined using assays on MAO, NADPH oxidase (NOX), along with the activity of glutathione reductase (GR) and glutathione peroxidase (GPx). Patient outcomes, including POAF development, were analyzed in relation to the assays performed. A statistical model was then created to measure the association for risk of POAF development. This was the first study to determine that MAO activity is a major source of ROS in human atrial tissue. MAO activity is significantly associated with POAF. Total glutathione (GSHt) activity is inversely related to POAF development. GPx is also significantly associated with POAF as well, but the trend is not a linear. GR activity is not correlated with POAF. MAO, GSHt and GPx are enzymes that contribute to the atrial oxidative environment and increased risk of POAF development. Because this is a pilot study, further exploration is needed to validate our study and to determine if and where these enzymes fit in the etiology of POAF