title: Mitochondrial oxidative stress during cardiac lipid overload causes intracellular calcium leak and arrhythmia.
abstract: Diabetes and obesity are associated with an increased risk of arrhythmia and sudden cardiac death. Abnormal lipid accumulation is observed in cardiomyocytes of obese and diabetic patients, which may contribute to arrhythmia, but the mechanisms are poorly understood. A transgenic mouse model of cardiac lipid overload, the peroxisome proliferator-activated receptor-γ (PPARg) cardiac overexpression mouse, has long QT and increased ventricular ectopy.
  
  
  
  The purpose of this study was to evaluate the hypothesis that the increase in ventricular ectopy during cardiac lipid overload is caused by abnormalities in calcium handling due to increased mitochondrial oxidative stress.
  
  
  
  Ventricular myocytes were isolated from adult mouse hearts to record sparks and calcium transients. Mice were implanted with heart rhythm monitors for in vivo recordings.
  
  
  
  PPARg cardiomyocytes have more frequent triggered activity and increased sparks compared to control. Sparks and triggered activity are reduced by mitotempo, a mitochondrial-targeted antioxidant. This is explained by a significant increase in oxidation of RyR2. Calcium transients are increased in amplitude, and sarcoplasmic reticulum (SR) calcium stores are increased in PPARg cardiomyocytes. Computer modeling of the cardiac action potential demonstrates that long QT contributes to increased SR calcium. Mitotempo decreased ventricular ectopy in vivo.
  
  
  
  During cardiac lipid overload, mitochondrial oxidative stress causes increased SR calcium leak by oxidizing RyR2 channels. This promotes ventricular ectopy, which is significantly reduced in vivo by a mitochondrial-targeted antioxidant. These results suggest a potential role for mitochondrial-targeted antioxidants in preventing arrhythmia and sudden cardiac death in obese and diabetic patients.
authors.affiliation: Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York.
authors.forename: Leroy C
authors.initials: LC
authors.lastname: Joseph
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons of Columbia University, New York, New York.
authors.forename: Prakash
authors.initials: P
authors.lastname: Subramanyam
authors.affiliation: Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York.
authors.forename: Christopher
authors.initials: C
authors.lastname: Radlicz
authors.affiliation: Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York.
authors.forename: Chad M
authors.initials: CM
authors.lastname: Trent
authors.affiliation: Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York.
authors.forename: Vivek
authors.initials: V
authors.lastname: Iyer
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons of Columbia University, New York, New York.
authors.forename: Henry M
authors.initials: HM
authors.lastname: Colecraft
authors.affiliation: Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York,. Electronic address: jpm46@cumc.columbia.edu.
authors.forename: John P
authors.initials: JP
authors.lastname: Morrow
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D004195:Disease Models, Animal; D007424:Intracellular Fluid / Q000378:metabolism; D050356:Lipid Metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D047495:PPAR gamma / Q000096:biosynthesis*
chemical_list: D047495:PPAR gamma; D002118:Calcium
keywords: Arrhythmia; Calcium; Lipid metabolism; Oxidative stress