Myocardial redox status, catecholamine metabolism and post-operative arrhythmia

East Carolina University, Greenville NC

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Abstract

DESCRIPTION (provided by applicant): 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.