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The Role of Oxidative Stress on Calcium-Mediated Arrhythmia Substrates Following Myocardial Infarction

Plummer, Bradley N
http://rave.ohiolink.edu/etdc/view?acc_num=case1370388993

Abstract Details

2013, Doctor of Philosophy, Case Western Reserve University, Biomedical Engineering.
Sudden cardiac death due to arrhythmia following myocardial infarction (MI) is the most common cause of mortality from heart disease. In recent years, myocyte intracellular calcium dysregulation has been increasingly recognized as an important mechanism of cellular triggers and tissue substrates that are responsible for arrhythmias. However, the molecular mechanisms underlying such calcium dysregulation in MI have remained elusive. Oxidative stress is increased in MI and is known to cause calcium dysregulation and promote a broad range of arrhythmia triggers and substrates. Interestingly, however, chronic-MI patients do not see a reduction in cardiac events with general anti-oxidant therapy, suggesting that our understanding of oxidative stress-mediated arrhythmias is incomplete. Recent studies suggest that the location and source of reactive oxygen and nitrogen species is a key determinant of their action. This implies that oxidative stress local to the sarcoplasmic reticulum, where most calcium regulatory proteins reside, is an important mechanism of calcium dysregulation. Therefore, we hypothesize that increased oxidative stress local to the sarcoplasmic reticulum is a mechanism of calcium-mediated arrhythmias in chronic MI. The primary findings are that chronic MI is associated with calcium-mediated arrhythmia triggers in the form of PVCs and electrophysiologic substrates in the form of repolarization alternans. In addition, increased ROS was associated with redox modification of key calcium regulatory proteins. Specifically, increased xanthine oxidase activity that localizes to the SR was responsible for oxidation of SERCA2a and a resultant slowing of Ca2+ SR reuptake and shift in the pacing rate at which repolarization alternans. These results increase the growing body of evidence that arrhythmogenic oxidative stress is ubiquitous in cardiovascular disease, and targeted antioxidant therapies may be effective at preventing sudden cardiac death.
Kenneth Laurita (Advisor)
Kenneth Gustafson (Committee Chair)
Jonathan Stamler (Committee Member)
Xin Yu (Committee Member)
David van Wagoner (Committee Member)
79 p.
Biomedical Engineering; Medicine; Physiology
Myocardial Infarction; Oxidative Stress; Arrhythmia; SERCA2a; Allopurinol; Sudden Cardiac Death; Calcium Handling;

Recommended Citations

Citations

  • Plummer, B. N. (2013). The Role of Oxidative Stress on Calcium-Mediated Arrhythmia Substrates Following Myocardial Infarction [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1370388993

    APA Style (7th edition)

  • Plummer, Bradley. The Role of Oxidative Stress on Calcium-Mediated Arrhythmia Substrates Following Myocardial Infarction. 2013. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1370388993.

    MLA Style (8th edition)

  • Plummer, Bradley. "The Role of Oxidative Stress on Calcium-Mediated Arrhythmia Substrates Following Myocardial Infarction." Doctoral dissertation, Case Western Reserve University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=case1370388993

    Chicago Manual of Style (17th edition)

case1370388993
516
© 2013, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.