20.500.12556/RUL-161593 Modeliranje vpliva elektroporacije na proženje akcijskih potencialov pri kardiomiocitih Modelling the effect of electroporation on the triggering of action potentials in cardiomyocytes Srčne aritmije so nepravilnosti srčnega ritma, ki lahko segajo od blagih in asimptomatskih do življenjsko ogrožajočih stanj. Zdravljenje srčnih aritmij je individualizirano in temelji na vrsti aritmije, resnosti, zdravstvenih razmerah posameznika ter tudi na starosti in življenjskem slogu bolnika. Atrijska fibrilacija (AF) je najpogostejša motnja srčnega ritma, ki jo zaznamuje neurejen in hiter srčni utrip. Pogosto povzroča simptome, kot so palpitacije, utrujenost in zasoplost, ter povečuje tveganje za možgansko kap in srčno popuščanje. V zadnjih letih je katetrska ablacija postala prednostna metoda za zdravljenje atrijske fibrilacije, kar odražajo tudi najnovejša priporočila. Postopek ablacije uniči določena območja srčnega tkiva, ki povzročajo aritmijo oz. ta območja električno izolira od preostalega dela srca. Klasični načini katetrske ablacije vključujejo radiofrekvenčno ablacijo (RFA) in krioablacijo, ki sta se izkazali za učinkoviti pri odpravljanju aritmičnih žarišč. Ireverzibilna elektroporacija je inovativna netermična ablacijska metoda v srčni elektrofiziologiji, ki temelji na uporabi visokonapetostnih električnih pulzov, ki povzročijo povečanje prepustnosti celičnih membran. Povečana prepustnost poruši celično homeostazo, kar lahko vodi v smrt tarčnih celic. Ta proces omogoča uničenje tarčnih celic, kar se je izkazalo učinkovito za zdravljenje srčnih aritmij. Ireverzibilna elektroporacija obeta manjše tveganje za poškodbe okoliških tkiv in boljšo varnost za bolnike v primerjavi s termičnimi metodami ablacije. Znano pa je, da se okrog ireverzibilno elektroporiranega tkiva vedno nahaja tudi regija reverzibilno elektroporiranega tkiva, v katerem celice preživijo izpostavitev električnim pulzom. Reverzibilna elektroporacija kardiomiocitov bi lahko vplivala njihovo sposobnost proženja akcijskih potencialov v teh regijah. Zato je potrebno bolje razumeti, kako elektroporacija vpliva na funkcijo kardiomiocitov. Cilj tega diplomskega dela je bil raziskati vpliv elektroporacije na funkcijo kardiomiocitov s poudarkom na modeliranju vpliva elektroporacije na proženje akcijskih potencialov pri izoliranih kardiomiocitih. Z modelom smo želeli razjasniti, kako povečanje prepustnosti membrane in neselektivnega toka ionov prek membrane vpliva na delovanje ionskih kanalov in prenašalcev v celični membrani ter na dinamiko akcijskih potencialov in časovnega poteka znotrajceličnega kalcija, ki je povezan s krčenjem kardiomiocita. Za dosego cilja raziskave smo uporabili dva matematičnega modela, ki opisujeta dinamiko akcijskih potencialov pri izoliranih kardiomiocitih s pomočjo nadomestnega električnega vezja. Izbrana modela smo nadgradili z vključitvijo opisa neselektivnega toka ionov prek por v membrani, nastalih zaradi elektroporacije. Model smo implementirali in simulirali v okolju Matlab, sistem diferencialnih enačb pa rešili s funkcijo ode15s. Naše simulacije so pokazale, da nastanek por v membrani močno vpliva na proženje akcijskih potencialov. Z višanjem števila por se akcijski potencial najprej podaljšuje, dokler se pri določenem številu por kardiomiociti ne morejo več repolarizirati in ostanejo depolarizirani ter niso več sposobni proženja akcijskih potencialov. Ko kardiomiociti postanejo depolarizirani, se možno poveča tudi koncentracija znotrajceličnega kalcija. Vse te spremembe opazimo že pri zelo majhnem številu ustvarjenih por (manj kot 20), kar pomeni, da že zelo šibka elektroporacija lahko močno vpliva na sposobnost proženja akcijskih potencialov. Rezultati raziskave bodo pripomogli k razumevanju sprememb v znotrajsrčnih elektrogramih, ki jih opazijo kardiologi po ablaciji srca z elektroporacijo, in potencialno k uporabi teh signalov za napovedovanje uspeha zdravljenja. Cardiac arrhythmias are irregularities in the heart's rhythm that can range from mild and asymptomatic to life-threatening conditions. The treatment of cardiac arrhythmias is individualized and based on the type of arrhythmia, its severity, the individual's health conditions, as well as the patient's age and lifestyle. Atrial fibrillation (AF) is the most common heart rhythm disorder, characterized by an irregular and rapid heartbeat. It often causes symptoms such as palpitations, fatigue, and shortness of breath and increases the risk of stroke and heart failure. In recent years, catheter ablation has become the preferred method for treating atrial fibrillation, as reflected in the latest recommendations. The ablation procedure destroys specific areas of heart tissue that cause the arrhythmia or electrically isolates these areas from the rest of the heart. Traditional methods of catheter ablation include radiofrequency ablation (RFA) and cryoablation, which have proven effective in eliminating arrhythmic foci. Irreversible electroporation is an innovative non-thermal ablation method in cardiac electrophysiology that uses high-voltage electric pulses to increase the permeability of cell membranes. The increased permeability disrupts cellular homeostasis, which can lead to the death of target cells. This process allows the destruction of target cells and has been shown to be effective in treating cardiac arrhythmias. Irreversible electroporation promises a lower risk of damage to surrounding tissues and better safety for patients compared to thermal ablation methods. However, it is known that around the irreversibly electroporated tissue, there is always a region of reversibly electroporated tissue, in which cells survive exposure to the electric pulses. Reversible electroporation of cardiomyocytes could affect their ability to trigger action potentials in these regions. Therefore, it is necessary to better understand how electroporation affects the function of cardiomyocytes. The aim of this thesis was to investigate the impact of electroporation on the function of cardiomyocytes, with a focus on modeling the impact of electroporation on the triggering of action potentials in isolated cardiomyocytes. The model aimed to clarify how increased membrane permeability and non-selective ionic current across the membrane affect the functioning of ion channels and transporters in the cell membrane, as well as the dynamics of action potentials and the time course of intracellular calcium associated with cardiomyocyte contraction. To achieve the research goal, we used two mathematical models that describe the dynamics of action potentials in isolated cardiomyocytes using an equivalent electrical circuit. The selected models were upgraded by including a description of the non-selective ionic current through pores in the membrane created due to electroporation. The model was implemented and simulated in the Matlab environment, and the system of differential equations was solved using the ode15s function. Our simulations showed that the formation of pores in the membrane significantly affects the triggering of action potentials. As the number of pores increases, the action potential starts to prolong until, at a certain number of pores, cardiomyocytes can no longer repolarize and remain depolarized, becoming incapable of triggering action potentials. When cardiomyocytes become depolarized, the concentration of intracellular calcium also increases. These changes are observed already with a very small number of created pores (less than 20), indicating that even very weak electroporation can significantly affect the ability of cardiomyocytes to trigger action potentials. The results of this research will contribute to better understanding of the changes in intracardiac electrograms that are observed by cardiologists following cardiac ablation with electroporation,and potentially to the use of these signals for improving the treatment outcome. srčne aritmije elektroporacija matematični model nadomestno vezje akcijski potencial regulacija znotrajceličnega kalcija ionski kanali ionski prenašalci cardiac arrhythmias electroporation mathematical model equivalent circuit action potential intracellular calcium handling mechanisms ion channels ion transporters true false false Slovenski jezik Angleški jezik Diplomsko delo/naloga 2024-09-12 13:11:10 2024-09-12 13:11:21 2024-09-14 03:38:21 0000-00-00 00:00:00 2024 0 0 0000-00-00 NiDoloceno NiDoloceno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 62492 207341315 Bogicevic_Bojana_-_Modeliranje_vpliva_elektroporacije_na_prozenje_akcijskih_potencialov_pri_kard.pdf Bogicevic_Bojana_-_Modeliranje_vpliva_elektroporacije_na_prozenje_akcijskih_potencialov_pri_kard.pdf 1 117426A20F8C2FAC2C50426BF75EADDC 24e0ef339a1251db000550e86ef58a67f9db170814c2cca30645fbcf7df470e0 afd7a5cf-70f7-11ef-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=190554 Fakulteta za elektrotehniko 0 0 0