Leroy C Joseph1, Prakash Subramanyam2, Christopher Radlicz1, Chad M Trent1, Vivek Iyer1, Henry M Colecraft2, John P Morrow3. 1. Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York. 2. Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons of Columbia University, New York, New York. 3. Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York,. Electronic address: jpm46@cumc.columbia.edu.
Abstract
BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
BACKGROUND: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 diabeticpatients, which may contribute to arrhythmia, but the mechanisms are poorly understood. A transgenicmouse model of cardiac lipid overload, the peroxisome proliferator-activated receptor-γ (PPARg) cardiac overexpression mouse, has long QT and increased ventricular ectopy. OBJECTIVE: 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. METHODS: 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. RESULTS: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. CONCLUSION: 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 diabeticpatients.
Authors: Michael Reppel; Bernd K Fleischmann; Hannes Reuter; Frank Pillekamp; Heribert Schunkert; Jürgen Hescheler Journal: Ann N Y Acad Sci Date: 2007-03 Impact factor: 5.691
Authors: Daniel C Andersson; Matthew J Betzenhauser; Steven Reiken; Albano C Meli; Alisa Umanskaya; Wenjun Xie; Takayuki Shiomi; Ran Zalk; Alain Lacampagne; Andrew R Marks Journal: Cell Metab Date: 2011-08-03 Impact factor: 27.287
Authors: Nian Liu; Marco Denegri; Yanfei Ruan; José Everardo Avelino-Cruz; Andrea Perissi; Sara Negri; Carlo Napolitano; William A Coetzee; Penelope A Boyden; Silvia G Priori Journal: Circ Res Date: 2011-06-16 Impact factor: 17.367
Authors: Tobias Eckle; Katherine Hartmann; Stephanie Bonney; Susan Reithel; Michel Mittelbronn; Lori A Walker; Brian D Lowes; Jun Han; Christoph H Borchers; Peter M Buttrick; Douglas J Kominsky; Sean P Colgan; Holger K Eltzschig Journal: Nat Med Date: 2012-04-15 Impact factor: 53.440
Authors: Shanna Hamilton; Radmila Terentyeva; Tae Yun Kim; Peter Bronk; Richard T Clements; Jin O-Uchi; György Csordás; Bum-Rak Choi; Dmitry Terentyev Journal: Front Physiol Date: 2018-12-21 Impact factor: 4.566