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Algoritmos para ecuaciones de reacci\u00f3n difusi\u00f3n aplicados a electrofisiolog\u00eda. Ph.D. Thesis. Universidad de Zaragoza. 2009. <ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/institutoi4.net\/wp-content\/uploads\/2017\/08\/TesisEAH.pdf\" xlink:type=\"simple\">https:\/\/institutoi4.net\/wp-content\/uploads\/2017\/08\/TesisEAH.pdf<\/ext-link>"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1007\/s10439-010-9997-2","article-title":"Adaptive Macro Finite Elements for the Numerical Solution of Monodomain Equations in Cardiac Electrophysiology","volume":"38","author":"EA Heidenreich","year":"2010","journal-title":"Ann Biomed Eng"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"H775","DOI":"10.1152\/ajpheart.00341.2009","article-title":"Cardiac alternans induced by fibroblast-myocyte coupling: mechanistic insights from computational models","volume":"297","author":"Y Xie","year":"2009","journal-title":"Am J Physiol Circ Physiol"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1161\/01.RES.68.6.1501","article-title":"A model of the ventricular cardiac action potential. 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