Abstracts

The intracellular Ca2+ handling system in a cardiacmyocyte is of crucial importance. It regulates the contraction andrelaxation of the myocyte during the excitation-contraction (EC)coupling. A normal intracellular Ca2+ handling system keeps thecontraction of the heart orderly, which represents a powerful forceto pump blood to the whole body. However, disarrayed or remodelledcellular structure associated with the intracellular Ca2+ handlingsystem at the subcellular level, such as loss of T-tubule networkin diseased conditions, may promote abnormal cardiac EC coupling,leading to genesis of cardiac arrhythmias impairing cardiacmechanical functions. Up to date, it is still incompletelyunderstood how the intracellular Ca2+ handling system is altered bychanges in subcellular structures of Ca2+ handling systems. In thisthesis, biophysically detailed computational models for theintracellular Ca2+ handling system of a cardiac cell weredeveloped, providing a powerful platform to investigate thespatio-temporal complexity associated with the intracellular Ca2+handling, and its role in generating abnormal cardiac EC coupling.First, a well-validated single cell model was used to investigatehow the diastolic and systolic Ca2+ concentration responded toalterations in the model parameters related to the Ca2+ handlingsystem, from which the mechanisms underlying the rate-dependence ofEC coupling were analysed. Then, a novel single cell model, with a2D presentation of the spatial structures of subcellular Ca2+handling and membrane action potential, of a sheep atrial myocytewas developed for simulating the abnormal intracellular Ca2+regulation system due to the loss of T-tubules during atrialfibrillation. Variant scenarios of T-tubule loss were considered toinvestigate the role of the T-tubule in affecting the intracellularCa2+ regulation. Furthermore, membrane currents alterations due tothe electrical remodelling arising from atrial fibrillation wereconsidered together with the loss of T-tubule. Three typical typesof abnormal Ca2+ cycling phenomenon, namely intracellular Ca2+alternans, spontaneous Ca2+ sparks and intracellular Ca2+ waveswere observed in AF conditions. The relationship between T-tubuleloss, AF-remodelling and the genesis of delayedafterdepolarizations (DADs) was also investigated. It was shownthat the loss of T-tubule in AF condition played an important rolein disturbing the Ca2+ regulation system, which increases the riskfor a cell to generate impaired contraction.Advisors/Committee Members: LU, JIAN JR, Lu, Jian, Zhang, Henggui.