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Repolarization in the Göttingen Minipig Heart

Morten Laursen

Summary

Despite the fact that minipigs are increasingly being used as a model animal incardiovascular research, knowledge regarding their cardiac electrophysiology isscarce. In this thesis, I focus on minipig cardiac electrophysiology (Chapter II) andpro-arrhythmic modeling (Chapter III).Chapter II: Cellular electrical repolarization is a fundamental part of cardiacphysiology and perturbations of its function are implicated in a myriad of inheritedand acquired dys-rhythmia syndromes with possible lethal outcome. As such, cardiacrepolarization has received widespread attention in both human and animals. As aresult, it is now known that many factors, such as heart rate, drugs, genetic factors andtemperature affects cardiac repolarization. Here, I report a series of experiment wherewe have for the first time characterized the minipig cardiac repolarization usingmethods ranging from mRNA quantification to in vivo studies. Cardiac mRNAquantification was performed using quantitative PCR methods. The results presentedshow that the expression profile of major cardiac ion channel proteins in both atriaand ventricle is very similar to what has been reported for humans. We also conductedelectrophysiological measurements on both ex vivo and in vivo preparations and showthat repolarization in minipig hearts is dependent on a) a subset of ion currents alsoimportant in other species; b) cycle length (i.e. heart rate) and c) temperature, whereduration of repolarization is inversely correlated to temperature. Overall, the resultspresented in Chapter II point toward the minipig being a promising species forcardiac safety research.Chapter III: Cardiac arrhythmia is a potentially lethal condition that can arisefollowing infarctions and ischemic heart disease, inherited mutations in genesregulating cardiac ion channels or pharmacological blockage of cardiac ion channels.A common denominator for these conditions is that they may constitute a substrate forpossible electrophysiological heterogeneity that predisposes to the development ofventricular tachy-arrhythmia which is associated with a high frequency of suddencardiac death. Therefore, there has been an extensive focus on this matter in bothacademia and the pharmaceutical industry leading to development of several proarrhythmicmodels. However, the ‘perfect’ model remains to be identified. In thispart, we hypothesize that minipig hearts could serve as a novel model of pro-arrhythmia. Using both whole-heart and multicellular preparations we show thatminipigs have significantly longer cardiac action potentials and QT intervals thandogs at comparable cycle lengths, a fact that may be important for the minipig as apro-arrhythmic model. In a variety of experimental settings, minipigs are relativelyresistant to arrhythmias – in fact, sustained arrhythmias are only observed in responseto programmed electrical S1-S2 stimulation after mechanical AV-ablation combinedwith pharmacological intervention. Correlating well with the absence of overtarrhythmia, several well-defined pro-arrhythmic biomarkers were not detected in theminipig. We also report that changes in frequency results in paradoxical transienteffects on repolarization. We discuss whether this may be involved in pro-arrhythmiaseen in other models. The evidence presented in Chapter III indicates thatLangendorff-perfused Göttingen minipig hearts are resistant to the development ofarrhythmias in experimental settings known to be pro-arrhythmic in other speciesincluding dogs.

Together, the results presented in Chapter II and Chapter III show that the minipig isindeed a valuable model in many aspects regarding cardiac repolarization andarrhythmia. However, certain aspects regarding the pro-arrhythmic propensityremains to be further quantified before the predictive value of the minipig heart as apro-arrhythmic model can be assessed.