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Modulation of the Arrhythmia Substrate in Cardiovascular Disease

Long, Victor P, III
http://rave.ohiolink.edu/etdc/view?acc_num=osu1459777728

Abstract Details

2016, Doctor of Philosophy, Ohio State University, Pharmacy.
Heart failure remains a leading cause of morbidity and mortality in the United States. Many of the deaths attributed to heart failure are sudden, presumably due to lethal arrhythmia. It is a combination of structural and electrical remodeling within the failing heart that promotes the abnormalities of normal rhythm that lead to arrhythmia. This remodeling can occur in the ventricle, resulting in tachyarrhythmia or the sinus node, where it can cause either brady- or tachyarrhythmias. Potassium currents mediate the repolarization phase of ventricular action potential, as well as the diastolic phase of the sinoatrial node action potential. One of the purposes of the research described in this dissertation is to understand, from the standpoint of cellular electrophysiology, how alterations of potassium currents play a role in heart-failure induced arrhythmia. The second purpose is to determine if management of serum potassium levels by pharmacists is an effective strategy in patients to minimize proarrhythmia risk in patients taking antiarrhythmic medications. We found that heart failure duration is very important in the progressive reduction of the repolarization reserve of K+ currents in the ventricle. Our results differ from other models, as we were able to identify IKr reduction in chronic heart failure compared to short-term duration heart failure. As a consequence of depleted repolarization reserve, chronic heart failure resulted in a high frequency of early afterdepolarizations (cellular arrhythmia). We also found increased ventricular tissue fibrosis in chronic heart failure, a hallmark of human end stage heart failure which is often absent in short-term pacing models. Our chronic heart failure model was also used to investigate the role of adenosine-induced sinus node dysfunction in heart failure. Failing sinoatrial node cells had slower intrinsic firing rates versus normal control cells. We were able to demonstrate an increase in the sensitivity of the rate slowing effects of adenosine in failing sinoatrial node cells. These results are due to an increase in adenosine A1 receptor (A1R) and G-coupled inward rectifier (GIRK) signaling. The negative chronotropic effects of adenosine were abolished through the use of A1R and GIRK inhibitors. Finally, we tested the performance of an algorithm designed to allow pharmacists to manage patient serum potassium levels in patients taking antiarrhytmic medications. Due to the high risk of proarrhythmia among this population, we established a conservative range of serum potassium to prevent low potassium from affecting patient therapy. Patients undergoing the protocol reached desired potassium levels more quickly than standard of therapy, and were able to maintain these levels upon a follow up visit occurring months later. We propose that these studies provide insights into the cellular bases for the development of heart failure-induced arrhythmias, as well as optimizing management of arrhythmia in a clinical setting.
Cynthia Carnes, PharmD/PhD (Advisor)
Sandor Gyorke, PhD (Committee Member)
Peter Mohler, PhD (Committee Member)
Kari Hoyt, PhD (Committee Member)
136 p.
Pharmacy Sciences
heart failure; sinus node; adenosine; potassium current; arrhythmia; hypokalemia; pharmacist; cellular electrophysiology;

Recommended Citations

Citations

  • Long, III, V. P. (2016). Modulation of the Arrhythmia Substrate in Cardiovascular Disease [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1459777728

    APA Style (7th edition)

  • Long, III, Victor. Modulation of the Arrhythmia Substrate in Cardiovascular Disease. 2016. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1459777728.

    MLA Style (8th edition)

  • Long, III, Victor. "Modulation of the Arrhythmia Substrate in Cardiovascular Disease." Doctoral dissertation, Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1459777728

    Chicago Manual of Style (17th edition)

osu1459777728
426
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This open access ETD is published by The Ohio State University and OhioLINK.