Targeted Antioxidant Treatment Decreases Cardiac Alternans Associated With Chronic Myocardial Infarction. (February 2015)

• Record Type: Journal Article
• Authors: Plummer, Bradley N.; Liu, Haiyan; Wan, Xiaoping; Deschênes, Isabelle; Laurita, Kenneth R.
• Is Part Of: Circulation. Volume 8:Number 1(2015)
• Publication Date: 2015-02
• Subjects: allopurinol -- arrhythmia (mechanisms) -- myocardial infarction -- oxidative stress -- SERCA2a; Arrhythmia -- Periodicals; Heart -- Electric properties -- Periodicals; 616.128
• DOI: 10.1161/CIRCEP.114.001789
• Languages: English
• ISSNs: 1941-3149

Abstract

Abstract : Background—: In myocardial infarction (MI), repolarization alternans is a potent arrhythmia substrate that has been linked to Ca 2+ cycling proteins, such as sarcoplasmic reticulum Ca 2+ 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. Methods and 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 Ca 2+ and ROS was performed. ECG T-wave alternans (ECG ALT) and Ca 2+ transient alternans (Ca 2+ 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 Ca 2+ 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 Ca 2+ 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 Ca 2+ 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.