Browsing by Author "Behradfar, Elham"

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    Contribution of the Purkinje System in Initiation and Maintenance of Arrhythmias
    (2016) Behradfar, Elham; Vigmond, Edward J.; Nygren, Anders; Fear, Elise C.; Berenfeld, Omer; Davidsen, Jörn
    The Purkinje system is the conduction network of the heart that facilitates coordinated ventricular contraction and couples to the myocardium at discrete sites called Purkinje-Myocyte Junctions (PMJs). Fine and intricate geometry of the Purkinje system have confined experimental observations, therefore density and distribution of PMJs and Purkinje system contribution during cardiac arrhythmia are unclear. This thesis presents a detailed computer simulation study that highlights the role of the Purkinje system and its interaction with ventricles in arrhythmogenesis and maintenance. Firstly, simulations were performed on a model of rabbit ventricles to explore Purkinje system contributions during ventricular fibrillation. A fractal method for growing the Purkinje system was implemented to allow construction of anatomically realistic Purkinje network and investigation of PMJ density. The role of the Purkinje system in maintaining the arrhythmia was assessed by analyzing reentry dynamics. Results showed that the activation pattern at PMJs had little consistency over time during functional reentry, and a Purkinje system with a higher PMJ density contributed more to reentrant arrhythmia; however, the overall dynamics of sustained reentry did not appear to be significantly affected by Purkinje system complexity and coupling strengths at PMJs. Secondly, the realistic model of the Purkinje system was used to investigate mechanisms through which reduced myocardial coupling, induced by ischemia, modify the interaction between the Purkinje system and ventricular tissue, and affect ventricular excitation pattern. Experimental and modeling results suggest that ischemia-induced closing of gap junctions activates normally quiescent PMJs due to reduced source-sink mismatch and as a result, increased the complexity of activation. Modeling results indicated that a higher number of functional PMJs can speed activation of tissue and compensate for effects of uncoupling in slowing activation of the ventricles. Finally, effects of a potential antiarrhythmic drug, dantrolene, on suppressing delayed afterdepolarizations (DADs) due to Calcium overload were modeled. In ventricular model, rapid pacing promoted triggered activity but only those arising in the Purkinje fibers could generate action potential that propagated throughout the myocardium. According to modeling results, dantrolene could eliminate DAD at the Purkinje level by blocking channels that are only present in the Purkinje system.