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Integrative Studies on the Role of CaMKII in Cardiac Disease and Arrhythmias

Glynn, Patric Joseph

Abstract Details

2015, Doctor of Philosophy, Ohio State University, Biomedical Engineering.
Heart disease accounts for one of every three deaths in the United States annually. The majority of these deaths are caused by disturbances in normal cardiac electrical activity, known as arrhythmias. While progress has been made towards addressing this concern, recent advances have been limited. Mounting data indicate that Calcium/Calmodulin Protein Kinase II (CaMKII) plays a critical role in promoting arrhythmogenesis and dysfunction in cardiac disease. Overactivation of CaMKII has a proarrhythmic effect and impacts the ability of cells to maintain proper function. Additionally, CaMKII has been shown to be elevated in end-stage human heart failure. Despite the apparent importance of CaMKII in disease, however, the specific mechanisms and phosphorylation targets that CaMKII uses to impact cellular function, particularly in vivo, remain unresolved. In these studies, we utilized a combination of biochemistry, whole-animal, and mathematical simulation experiments to determine the role that CaMKII plays in cardiac arrhythmia and disease. Our studies have shown that CaMKII contributes to arrhythmias in a number of ways. Our major findings include: 1) CaMKII can induce structural changes that lead to heart disease, particularly in the sinus node; and 2) overactivation of CaMKII displays acute effects through its phosphorylation of ion channels, as we observed primarily in the sodium channel. Additionally, we developed new mathematical tools to analyze sinus node cell stability that demonstrated how CaMKII dysregulation can contribute to arrhythmias by altering subcellular structures. In summary, these experiments support an important role for CaMKII in the setting of heart disease. In the sinus node, we identified CaMKII as a contributor toward increased mortality in the setting of myocardial infarction in diabetes. Outside of the sinus node, our studies revealed CaMKII as a critical regulator of the late sodium current in disease, identified a site of singular control over this late current (S571 on Nav1.5), and clearly demonstrated that the late sodium current plays an important in vivo role in cardiac dysfunction.
Thomas Hund, Ph.D. (Advisor)
Peter Mohler, Ph.D. (Committee Member)
Samir Ghadiali, Ph.D. (Committee Member)
193 p.

Recommended Citations

Citations

  • Glynn, P. J. (2015). Integrative Studies on the Role of CaMKII in Cardiac Disease and Arrhythmias [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1429132697

    APA Style (7th edition)

  • Glynn, Patric. Integrative Studies on the Role of CaMKII in Cardiac Disease and Arrhythmias. 2015. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1429132697.

    MLA Style (8th edition)

  • Glynn, Patric. "Integrative Studies on the Role of CaMKII in Cardiac Disease and Arrhythmias." Doctoral dissertation, Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1429132697

    Chicago Manual of Style (17th edition)