The onset of post-operative atrial fibrillation (POAF) after cardiac surgery continues to be the most common and costly post-operative complication. Despite rigorous investigation of POAF by physicians and scientists, significant gaps remain in our understanding as to why it occurs, and specifically why it only occurs in certain patients. Our laboratory has obtained exciting preliminary data showing that high activity of the enzyme monoamine oxidase (MAO), a mitochondrial outer membrane-bound enzyme and substantial generator of H2O2 in atrial myocardium, is strongly correlated with POAF independent of other known risk factors. So are, to a lesser extent, glutathione (GSH) and glutathione peroxidase (GPx), both critical for maintaining intracellular redox balance. These enzymes were all measured in discarded right atrial appendage (RAA) obtained during cardiac surgery. From a mechanistic perspective, these findings are compelling and scientifically plausible because they integrate catecholamine overload, mitochondrial dysfunction and redox imbalance in the atrial myocardium, all factors in the peri-operative period that are known to contribute to arrhythmogenesis. In the current proposal, by obtaining tissue and performing analyses using a much larger cohort of cardiac surgery patients, we will build on this highly promising data in order to establish a statistical model of POAF risk based on MAO as a predictive biomarker, and to elucidate mechanisms connecting elevated MAO activity in right atrium to POAF by focusing specifically on mitochondrial energetics in the atrial cardiomyocytes.
In Aim 1, we will validate MAO as a predictive biomarker of POAF, alone or in combination with other redox enzymes, by obtaining the RAA tissue intra-operatively from a large cohort (N=770) of adult patients undergoing cardiac surgery and immediately measuring activity of these enzymes. As an exploratory component of this Aim we will examine if MAO and/or GPx in platelets and RBC's, respectively, obtained pre- operatively from this same cohort of patients, can alternatively be used as predictive biomarkers of POAF.
In Aim 2, using a much smaller subset of the patient cohort recruited for Aim 1, we will begin to dissect mechanisms by which high MAO activity in atrium leads to POAF by focusing on the interaction between MAO and mitochondrial function in atrial myocardium. Thus, these studies will have both a practical, applied research component (Aim 1) as well as a basic research component (Aim 2). It is anticipated that the findings from the first Aim will have immediate and sustained clinical impact because they will provide clinicians the ability to predict with high probability which patients are predisposed and therefor at high risk to develop POAF. This would create a pathway to specifically target the 'high-risk' patients with prophylactic anti- arrhythmic medication in the near future. We expect the findings from our basic research on interactions between cardiac MAO and mitochondrial energetics to enhance our understanding of mechanisms connecting high levels of MAO activity in right atrium to POAF.

Public Health Relevance

Atrial fibrillation (irregular heartbeat) is the most common and costly complication after open heart surgery. It typically occurs within the first 5 post-operative days, increasing the patient's risk of stroke and infection, lengthening the hospital stay, and greatly increasing overall costs to the health care system. This project is directed towards validating a biochemical marker which could identify patients who are at high risk of developing this complication, so that clinicians would be able to aggressively treat these high-risk patients with certain drugs in order to prevent this complication from happening. Other studies directed at understanding how this complication develops in the first place will also be performed.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
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Schwartz, Lisa
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East Carolina University
Schools of Medicine
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Stein, Colleen S; Jadiya, Pooja; Zhang, Xiaoming et al. (2018) Mitoregulin: A lncRNA-Encoded Microprotein that Supports Mitochondrial Supercomplexes and Respiratory Efficiency. Cell Rep 23:3710-3720.e8
Nelson, Margaret-Ann M; Builta, Zachariah J; Monroe, T Blake et al. (2018) Biochemical characterization of the catecholaldehyde reactivity of L-carnosine and its therapeutic potential in human myocardium. Amino Acids :
Sullivan, E Madison; Pennington, Edward Ross; Sparagna, Genevieve C et al. (2018) Docosahexaenoic acid lowers cardiac mitochondrial enzyme activity by replacing linoleic acid in the phospholipidome. J Biol Chem 293:466-483
Efird, Jimmy T; Kiser, Andy C; Crane, Patricia B et al. (2017) Perioperative Inotrope Therapy and Atrial Fibrillation Following Coronary Artery Bypass Graft Surgery: Evidence of a Racial Disparity. Pharmacotherapy 37:297-304
Nelson, Margaret-Ann M; Baba, Shahid P; Anderson, Ethan J (2017) Biogenic Aldehydes as Therapeutic Targets for Cardiovascular Disease. Curr Opin Pharmacol 33:56-63
Wang, Qingtong; Liu, Yongming; Fu, Qin et al. (2017) Inhibiting Insulin-Mediated ?2-Adrenergic Receptor Activation Prevents Diabetes-Associated Cardiac Dysfunction. Circulation 135:73-88
Anderson, Ethan J; Efird, Jimmy T; Kiser, Andy C et al. (2017) Plasma Catecholamine Levels on the Morning of Surgery Predict Post-Operative Atrial Fibrillation. JACC Clin Electrophysiol 3:1456-1465
Taylor, David A; Theobald, Robert J; Abdel-Rahman, Abdel A et al. (2017) Editorial overview: Cardiovascular and renal: Putting the brake on heart-breaks: emerging targets and treatment strategies for cardiovascular and renal disorders. Curr Opin Pharmacol 33:iv-vi
Pereira, Renata Oliveira; Tadinada, Satya M; Zasadny, Frederick M et al. (2017) OPA1 deficiency promotes secretion of FGF21 from muscle that prevents obesity and insulin resistance. EMBO J 36:2126-2145
Anderson, Ethan J (2016) Cutting Calories and TXNIP From the Skeletal Muscle to Restore Insulin Sensitivity. Diabetes 65:16-8

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