title: Targeted antioxidant treatment decreases cardiac alternans associated with chronic myocardial infarction.
abstract: BACKGROUND
  In myocardial infarction (MI), repolarization alternans is a potent arrhythmia substrate that has been linked to Ca2+ cycling proteins, such as sarcoplasmic reticulum Ca2+ ATPase (SERCA2a), located in the sarcoplasmic reticulum. MI is also associated with oxidative stress and increased xanthine oxidase (XO) activity, an important source of reactive oxygen species (ROS) in the sarcoplasmic reticulum that may reduce SERCA2a function. We hypothesize that in chronic MI, XO-mediated oxidation of SERCA2a is a mechanism of cardiac alternans.
  
  
  RESULTS
  Male Lewis rats underwent ligation of the left anterior descending coronary artery (n=54) or sham procedure (n=24). At 4 weeks, optical mapping of intracellular Ca2+ and ROS was performed. ECG T-wave alternans (ECG ALT) and Ca2+ transient alternans (Ca2+ALT) were induced by rapid pacing (300-120 ms) before and after the XO inhibitor allopurinol (ALLO, 50 µmol/L). In MI, ECG ALT (2.32±0.41%) and Ca2+ ALT (22.3±4.5%) were significantly greater compared with sham (0.18±0.08%, P<0.001; 0.79±0.32%, P<0.01). Additionally, ROS was increased by 137% (P<0.01) and oxidation of SERCA2a by 30% (P<0.05) in MI compared with sham. Treatment with ALLO significantly decreased ECG ALT (-77±9%, P<0.05) and Ca2+ ALT (-56±7%, P<0.05) and, importantly, reduced ROS (-65%, P<0.01) and oxidation of SERCA2a (-38%, P<0.05). CaMKII inhibition and general antioxidant treatment had no effect on ECG ALT and Ca2+ ALT.
  
  
  CONCLUSIONS
  These results demonstrate, for the first time, that in MI, increased ROS from XO is a significant cause of repolarization alternans. This suggests that targeting XO ROS production may be effective at preventing arrhythmia substrates in chronic MI.
authors.affiliation: From The Heart and Vascular Research Center, Department of Medicine, MetroHealth Campus (B.N.P., H.L., X.W., I.D., K.R.L.), and Department of Biomedical Engineering (B.N.P., I.D., K.R.L.), Case Western Reserve University, Cleveland, OH.
authors.forename: Bradley N
authors.initials: BN
authors.lastname: Plummer
authors.affiliation: From The Heart and Vascular Research Center, Department of Medicine, MetroHealth Campus (B.N.P., H.L., X.W., I.D., K.R.L.), and Department of Biomedical Engineering (B.N.P., I.D., K.R.L.), Case Western Reserve University, Cleveland, OH.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Liu
authors.affiliation: From The Heart and Vascular Research Center, Department of Medicine, MetroHealth Campus (B.N.P., H.L., X.W., I.D., K.R.L.), and Department of Biomedical Engineering (B.N.P., I.D., K.R.L.), Case Western Reserve University, Cleveland, OH.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wan
authors.affiliation: From The Heart and Vascular Research Center, Department of Medicine, MetroHealth Campus (B.N.P., H.L., X.W., I.D., K.R.L.), and Department of Biomedical Engineering (B.N.P., I.D., K.R.L.), Case Western Reserve University, Cleveland, OH.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Deschênes
authors.affiliation: From The Heart and Vascular Research Center, Department of Medicine, MetroHealth Campus (B.N.P., H.L., X.W., I.D., K.R.L.), and Department of Biomedical Engineering (B.N.P., I.D., K.R.L.), Case Western Reserve University, Cleveland, OH. klaurita@metrohealth.org.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Laurita
mesh_terms: D000493:Allopurinol / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D020013:Calcium Signaling; D002304:Cardiac Pacing, Artificial; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D009203:Myocardial Infarction / Q000150:complications* / Q000201:enzymology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D011917:Rats, Inbred Lew; D017382:Reactive Oxygen Species / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D013997:Time Factors; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000889:Anti-Arrhythmia Agents; D000975:Antioxidants; C506948:Atp2a2 protein, rat; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D000493:Allopurinol; D014969:Xanthine Oxidase; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
keywords: SERCA2a; allopurinol; arrhythmia (mechanisms); myocardial infarction; oxidative stress