Ion Channel Regulation in the Pathophysiology of Atrial Fibrillation: Using Mathematical Modeling as a Predictive Tool for Cardiac Disease
Başlık:
Ion Channel Regulation in the Pathophysiology of Atrial Fibrillation: Using Mathematical Modeling as a Predictive Tool for Cardiac Disease
Yazar:
Onal, Birce, author.
ISBN:
9780438097056
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (162 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-11(E), Section: B.
Advisors: Thomas Hund Committee members: Samir Ghadiali; Peter Mohler.
Özet:
Atrial fibrillation (AF) affects 2.5 million people per year in the U.S., and is associated with high morbidity and mortality. Both electrical and structural remodeling on the cardiac cell- and tissue-level contribute to AF, but the precise molecular pathways that lead to atrial fibrillation pathogenesis are not well understood. Mathematical modelling is ideally suited to understand the molecular basis of cardiac arrhythmias by allowing simulation of complex biological systems based on integrated data from individual populations of ion channels. A cross-platform multi-threaded graphical user interface LongQt was developed for advanced computational cardiac electrophysiology studies in sinoatrial, atrial, and ventricular cells to help bridge the gap between experimental and theoretical techniques in cardiac electrophysiology. A method of parameter sensitivity analysis is discussed to help define the contribution of individual ion channels to cell membrane excitability and action potential properties. Finally, a computational model of the human atrial cell was used to determine the mechanism for increased susceptibility to arrhythmogenic events in patients with defects in Ca2+/calmodulin-dependent protein kinase signaling pathways. An atrial computational model was extended to explore CaMKII activation of late sodium current (I Na,L) and phosphorylation of downstream targets (L-type Ca2+ channel, phospholamban, ryanodine receptor). Both LongQt and the method of parameter sensitivity analysis were used to help identify the cellular pathway responsible for disrupted ion homeostasis and afterdepolarizations in atrial cells. Intracellular Ca2+ and Na+ accumulation, increased phosphorylation of RyR2 by CaMKII, and abnormal Ca2+ dynamics [e.g. beat-to-beat alteration (alternans)], and afterdepolarizations (early and late phase) was observed in mathematical models of the atrial cell with constitutive increase in INa,L, compared to wildtype control. These simulations define roles for previously unexplored ion channel regulation of CaMKII-mediated INa,L in the context of atrial fibrillation. Although INa,L is < ~1% of peak sodium current at baseline in atrial myocytes, CaMKII-dependent increase in the current was sufficient to cause intracellular ion accumulation, disrupted Ca2+ homeostasis, and pro-arrhythmic dynamics. Most importantly, mathematical modelling tools including a novel software with extended action potential models were used to understand the molecular basis for atrial fibrillation. These efforts will help identify new mechanisms of atrial regulation with direct relevance for human atrial fibrillation.
Notlar:
School code: 0168
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(696377.1) | 696377-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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