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The Role of Reactive Oxygen Species in Arrhythmogenicity of Cardiac Glycoside

Ho, Hsiang-Ting
http://rave.ohiolink.edu/etdc/view?acc_num=osu1373401702

Abstract Details

2013, Doctor of Philosophy, Ohio State University, Biophysics.
Digoxin, a cardiac glycoside (CGs), is an important agent in the treatment of heart failure. Heart failure affects more than 5 million Americans and contributes to the deaths of 300,000 people annually in the US. More than 1 million patients receive digoxin, which is among the top 150 most prescribed drugs. The beneficial effects of digoxin are ascribed to improved calcium handling and increased contractility of the failing myocardium. Although it improves quality of life, digoxin fails to appreciably reduce mortality of patients with heart failure due to adverse side effects including vulnerability to lethal arrhythmias. These adverse side effects of digoxin have been attributed to ionic imbalances due to inhibition of Na+/K+- ATPase (NKA). Recent studies performed in our laboratory using cardiac cells obtained from laboratory rats (Chapter 2) and mice (Chapter 3) demonstrated that CGs, rather than acting by this orthodox mechanism, contribute to arrhythmogenesis by elevating reactive oxygen species (ROS) with subsequent redox-dependent alterations in intracellular calcium handling. Specifically our studies showed that exposure of cardiomyocytes to CGs leads to an elevation of ROS via the engagement of myocardial NADPH oxidase and mitochondria. This elevated ROS then leads to modification of the intracellular calcium release channel, the ryanodine receptor, in turn causing proarrhythmic alterations in calcium cycling. Our studies also showed that pharmacological or genetic interventions that target the release of ROS by NADPH oxidase and mitochondria inhibit the arrhythmic effects of CGs while preserving their positive inotropic effects. These new findings about the molecular and cellular mechanisms of the arrhythmic side effects of CGs provide a rational strategy for optimization of digoxin therapy for heart failure.
Sándor Györke (Advisor)
Mark Angelos (Committee Member)
Cynthia Carnes (Committee Member)
Mark Ziolo (Committee Member)
114 p.
Biology; Biomedical Research; Biophysics; Physiology
Calcium, myocytes, heart failure, NADPH oxidase, reactive oxygen species, mitochondria, cardiac glycoside, digitalis, arrhythmia

Recommended Citations

Citations

  • Ho, H.-T. (2013). The Role of Reactive Oxygen Species in Arrhythmogenicity of Cardiac Glycoside [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1373401702

    APA Style (7th edition)

  • Ho, Hsiang-Ting. The Role of Reactive Oxygen Species in Arrhythmogenicity of Cardiac Glycoside. 2013. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1373401702.

    MLA Style (8th edition)

  • Ho, Hsiang-Ting. "The Role of Reactive Oxygen Species in Arrhythmogenicity of Cardiac Glycoside." Doctoral dissertation, Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1373401702

    Chicago Manual of Style (17th edition)

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© 2013, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.