The Role of Oxidative Stress on Calcium-Mediated Arrhythmia Substrates Following Myocardial Infarction
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Case Western Reserve University School of Graduate Studies / OhioLINK
2013
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| Online Access: | http://rave.ohiolink.edu/etdc/view?acc_num=case1370388993 |
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ndltd-OhioLink-oai-etd.ohiolink.edu-case13703889932021-08-03T05:24:02Z The Role of Oxidative Stress on Calcium-Mediated Arrhythmia Substrates Following Myocardial Infarction Plummer, Bradley N. Biomedical Engineering Physiology Medicine Myocardial Infarction Oxidative Stress Arrhythmia SERCA2a Allopurinol Sudden Cardiac Death Calcium Handling 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. 2013-08-23 English text Case Western Reserve University School of Graduate Studies / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=case1370388993 http://rave.ohiolink.edu/etdc/view?acc_num=case1370388993 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
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NDLTD |
| language |
English |
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NDLTD |
| topic |
Biomedical Engineering Physiology Medicine Myocardial Infarction Oxidative Stress Arrhythmia SERCA2a Allopurinol Sudden Cardiac Death Calcium Handling |
| spellingShingle |
Biomedical Engineering Physiology Medicine Myocardial Infarction Oxidative Stress Arrhythmia SERCA2a Allopurinol Sudden Cardiac Death Calcium Handling Plummer, Bradley N. The Role of Oxidative Stress on Calcium-Mediated Arrhythmia Substrates Following Myocardial Infarction |
| author |
Plummer, Bradley N. |
| author_facet |
Plummer, Bradley N. |
| author_sort |
Plummer, Bradley N. |
| title |
The Role of Oxidative Stress on Calcium-Mediated Arrhythmia Substrates Following Myocardial Infarction |
| title_short |
The Role of Oxidative Stress on Calcium-Mediated Arrhythmia Substrates Following Myocardial Infarction |
| title_full |
The Role of Oxidative Stress on Calcium-Mediated Arrhythmia Substrates Following Myocardial Infarction |
| title_fullStr |
The Role of Oxidative Stress on Calcium-Mediated Arrhythmia Substrates Following Myocardial Infarction |
| title_full_unstemmed |
The Role of Oxidative Stress on Calcium-Mediated Arrhythmia Substrates Following Myocardial Infarction |
| title_sort |
role of oxidative stress on calcium-mediated arrhythmia substrates following myocardial infarction |
| publisher |
Case Western Reserve University School of Graduate Studies / OhioLINK |
| publishDate |
2013 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=case1370388993 |
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AT plummerbradleyn theroleofoxidativestressoncalciummediatedarrhythmiasubstratesfollowingmyocardialinfarction AT plummerbradleyn roleofoxidativestressoncalciummediatedarrhythmiasubstratesfollowingmyocardialinfarction |
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