This investigation was undertaken to explore biochemical changes which may occur in heart tissue with age. In this connection, the cellular enzymes were of special interest.

The heart is a muscular organ which acts as a biomechanical pump. Electrical impulses are generated in specialized cells and flow through the heart myocardium by the ion changes on the cell membrane which is the beginning of both the electrical and the mechanical activity. Both the electrical and the mechanical states of the organ will directly affect the pumping activity. The main motivation of this thesis is to better understand physiological and pathological properties of the heart muscle via studying the electro-mechanics of the heart. This model could be used to gain better solutions of the ill-posed inverse problem of ECG and Body Surface Potential Maps (BSPM) or to estimate the electrical propagation and mechanical response on patient specific heart geometry models which can be obtained by using MRI technique. Cellular automaton technique will be used to simulate the physiological function of the left ventricle to estimate the cardiac functions. To model the heart tissue firstly the anatomical knowledge of the heart will be used such as properties of the myocardium, fiber orientations, etc. to simulate the three dimensional electrical propagation. Then the mechanical activity consisting of contraction and relaxation will be simulated according to the material properties of the heart. Using this simulation, the effects of the cardiac arrhythmias such as reentry will be generated. In this study, electrical and mechanical properties of the heart tissue are modeled for normal heart beat and heart beat in case of ischemic heart tissue. Contraction of the tissue via electrical activation has also been considered in terms of time synchronization. &ldquo / Cellular automaton&rdquo / method is used for modeling the electromechanical interactions in the heart tissue. A simplified left ventricle model is used to observe the electrical and the mechanical behavior. Using this method, both the normal heart beat&rsquo / s electrical activation and the arrhythmia excitation could be taken on, without using complex differential equations. To consider the anisotropy of the heart tissue, fiber orientations have also been added to the model. In this thesis work, electro-mechanic models at cellular, macroscopic and heart left ventricle level are presented. The electro-mechanical adaptation is performed by cellular electrophysiology and cellular force development due to intercellular excitation propagation. Varying densities of transmembrane proteins, changes on concentration of calcium, metabolic and hormonal effects are neglected. Also in simplified ventricular model the fluid mechanics and mechanoelectrical feed-back is not taken into-account.

Congenital heart defects are the number one cause of birth defect-related deaths. Cardiovascular diseases are the most common cause of death worldwide. Layered cellular sheet constructs offer one very valuable option for cardiac patch implantation during surgical treatment of both pediatric and adult patients with cardiac defects or damage. A very exciting, relatively unexplored, autologous, available cell source for making patches are placenta-derived mesenchymal stem cells (pMSCs). In this study, pMSCs were assessed as a potential cell source for cardiac repair and regeneration by evaluating their differentiation capacity into cardiomyocytes, their effects on cardiac cell migration and proliferation, and their ability to be grown into cell sheets. It was found that pMSC cardiac protein content was enhanced by differentiation media treatment, but no beating cells were produced. Undifferentiated pMSCs improved migration and proliferation of a cardiac cell population and formed intact, aligned cell sheets. However, like many new cell sources for cardiac repair, pMSCs should still be functionally characterized to understand how compatible they will be with resident heart tissue. Implanting non-autologous, potentially pluripotent, non-myocyte (non-beating) cells presents concerns regarding electromechanical mismatch and implant rejection. The characterization of non-traditional cell sources such as pMSCs motivated the design of a bio-MEMS device that assesses contractile force and conduction velocity in response to electrical and mechanical stimulation of a cell source as it is grown and once it forms a cellular sheet. This ideally creates the ability for patient specific cell sheets to be cultured, characterized, and conditioned to be compatible with the patient’s cardiac environment in vitro, prior to implantation. In this work, the device was designed to achieve the following: cellular alignment, electrical stimulation, mechanical stimulation, conduction velocity readout, contraction force readout, and upon characterization, cell sheet release. The platform is based on a set of comb electrical contacts which are three dimensional wall contacts made of polydimethylsiloxane and coated with electrically conductive metals. Device fabrication and initial validation experiments were completed as part of this study; ultimately the device will allow for the complete functional characterization and conditioning of variable cell source cell sheet implants for myocardial implantation. / 2019-07-02T00:00:00Z

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20978号 / 医博第4324号 / 新制||医||1026(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 井上 治久, 教授 木村 剛, 教授 瀬原 淳子 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM