Post-operative atrial fibrillation (POAF) in patients following cardiac revascularization surgery is a significant health care burden and estimates of occurrence range from 15-65%. The mechanisms by which this occurs remain unknown, and a bio-marker for identifying those patients that are more vulnerable, or pre-disposed, to POAF would be highly valuable to clinicians. The studies proposed in this grant proposal will have a target cohort of 300 adult patients undergoing elective cardiac revascularization surgery via cardiopulmonary bypass. Samples of right atrial appendage will be obtained from these patients during surgery, and the following Specific Aims have been constructed to test the CENTRAL HYPOTHESIS that a diminished glutathione antioxidant capacity in myocardial tissue at the time of surgery pre-disposes a patient to developing POAF, and that this diminished antioxidant capacity is linked to increased mitochondrial oxidant emission.
Aim 1) : To determine if decreased glutathione content or glutathione-related enzyme activity in a patient's atrium at the time of surgery is linked to the development of POAF. The concentration of intracellular reduced (GSH) and oxidized (GSSG) glutathione will be assessed in samples of right atrial appendage obtained from patients directly prior to institution of cardiopulmonary bypass as outlined above. The specific activities of glutathione peroxidase (H2O2 scavenging) and glutathione reductase (regenerates GSH from GSSG) will also be assessed in each sample. Patients will then be continuously monitored with ECG post-operatively until discharge from hospital, and the glutathione data for each patient will then be compared with the post-operative ECG profile of that patient to determine whether there is a link between glutathione content and/or glutathione-related enzyme activity in a patient's atrium at the time of surgery and the development of POAF.
Aim 2) : To determine whether elevated rates of mitochondrial oxidant emission are linked to diminished glutathione antioxidant capacity in myocardial tissue of patients undergoing CABG surgery. Mitochondrial H2O2 emission supported by endogenous substrate oxidation at baseline and following exogenous Ca2+ uptake will be assessed in permeabilized atrial myofibers prepared from samples of right atrial appendage obtained from patients directly prior to institution of cardiopulmonary bypass. These data will then be analyzed together with the glutathione data, to establish whether high rates of mitochondrial H2O2 emission are associated with reduced glutathione content and/or enzyme activity in atrial tissue. CLINICAL SIGNIFICANCE: It is anticipated that the findings from this project will result in identification of biochemical markers that may be able to identify patients at higher risk for developing POAF, in addition to providing a first step towards elucidating a potential mechanism by which POAF occurs.

Public Health Relevance

Atrial fibrillation (irregular heartbeat) is one of the most common complications after open heart surgery. Its incidence ranges from 20% to 40% in most published series. Significant adverse effects include stroke, increased risk of death, and increased length of stay in hospital, resulting in a large financial burden to hospitals and clinics. Little is known about the mechanism for the development of this arrhythmia, and more importantly why it occurs in some patients and not in others. The studies proposed here are directed towards identifying a biochemical marker which could identify patients who are at increased risk of developing postoperative atrial fibrillation, and towards further understanding of the causative factors underlying its development.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL098780-02
Application #
8092793
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Schwartz, Lisa
Project Start
2010-06-17
Project End
2013-05-31
Budget Start
2011-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2011
Total Cost
$179,375
Indirect Cost
Name
East Carolina University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
607579018
City
Greenville
State
NC
Country
United States
Zip Code
27858
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Anderson, Ethan J; Thayne, Kathleen A; Harris, Mitchel et al. (2014) Do fish oil omega-3 fatty acids enhance antioxidant capacity and mitochondrial fatty acid oxidation in human atrial myocardium via PPAR? activation? Antioxid Redox Signal 21:1156-63
Virag, Jitka A I; Anderson, Ethan J; Kent, Susan D et al. (2013) Cardioprotection via preserved mitochondrial structure and function in the mPer2-mutant mouse myocardium. Am J Physiol Heart Circ Physiol 305:H477-83
Fisher-Wellman, Kelsey H; Mattox, Taylor A; Thayne, Kathleen et al. (2013) Novel role for thioredoxin reductase-2 in mitochondrial redox adaptations to obesogenic diet and exercise in heart and skeletal muscle. J Physiol 591:3471-86
Anderson, Ethan J; Katunga, Lalage A; Willis, Monte S (2012) Mitochondria as a source and target of lipid peroxidation products in healthy and diseased heart. Clin Exp Pharmacol Physiol 39:179-93
Anderson, Ethan J; Thayne, Kathleen; Harris, Mitchel et al. (2012) Aldehyde stress and up-regulation of Nrf2-mediated antioxidant systems accompany functional adaptations in cardiac mitochondria from mice fed n-3 polyunsaturated fatty acids. Biochem J 441:359-66
Anderson, Ethan J; Rodriguez, Evelio; Anderson, Curtis A et al. (2011) Increased propensity for cell death in diabetic human heart is mediated by mitochondrial-dependent pathways. Am J Physiol Heart Circ Physiol 300:H118-24