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NaV1.5 Modulation: From Ionic Channels to Cardiac Conduction and Substrate Heterogeneity

dc.contributor.advisorLuther, Stefan Prof. Dr.
dc.contributor.authorRaad, Nour
dc.titleNaV1.5 Modulation: From Ionic Channels to Cardiac Conduction and Substrate Heterogeneityde
dc.contributor.refereeLuther, Stefan Prof. Dr.
dc.description.abstractengThe work presented in this thesis is centered on characterizing macroscopic electrophysiological instabilities observed at the tissue level that emanate from perturbations affecting essentially the NaV1.5 channel in the murine heart. We tried to approach this question by directly targeting NaV1.5, either through genetically modified mouse models that mirror fatal pathologies observed in man, or through the use of antiarrhythmic drugs that principally modify the channel’s function in its respective environment. The hallmark of an unstable tissue is that excitability is spatially heterogeneous; hence characterizing these instabilities in excitability and conduction will require a technical tool that provides the spatial-temporal resolution necessary to map the electrical activity from the epicardial surface of the in-vitro perfused heart. Optical mapping has provided us with the capacity to measure the propagation of the electrical wave on the surface of the intact heart, with a spatial resolution down to a few epicardial cardiac cells in one pixel and a temporal resolution more than ten times faster than the time it takes the actual electrical wave to travel across the epicardium. Using this technique, our aim was to measure more accurately a set of biophysical parameters and to elucidate the fundamental relationships between them. To fulfill this aim, we investigated two genetically modified mouse models: the mdx-mouse model of Duchenne muscular dystrophy and the ΔKPQ mouse model of LQTS3, each compared to their respective WT control. We adopted a generic approach to these models, by focusing on one denominator: the NaV1.5 channel and its modulation by antiarrhythmic drugs (Flecainide). Although, we appreciate the entanglement of the molecular pathways underlying the different pathologies, we aimed in our optical mapping investigations at describing the translational axis that connects the ion channel on one side to macroscopic electrical instabilities on the other side. The results of this thesis have tried to answer the questions proposed by: 1. Characterizing electrical instabilities in conduction in a model where NaV1.5 is lost exclusively from the LM of the cardiomyocyte. 2. Implementing and validating different analytical strategies to evaluate conduction velocity in a medium with anisotropic and atypical spatial-temporal patterns of activation. 3. Investigating a circumstantiated proarrhythmic mechanism of Flecainide in normal heart tissues using clinically valid concentrations. 4. Providing adminicular evidence that a model harboring a LQTS3 mutation is exceedingly destabilized in the presence of Flecainide. This multidisciplinary approach in integrative cardiology allowed us to study how genetic mutations and pharmacological interventions could possibly lead to destabilizations of the normal electrical propagation in the cardiac
dc.contributor.coRefereeKatschinski, Dörthe Prof. Dr.
dc.subject.engAntiarrhythmic drugsde
dc.subject.engOptical Mappingde
dc.subject.engAction potential durationde
dc.subject.engSpatial dispersion of repolarizationde
dc.subject.engCardiac depolarizationde
dc.subject.engConduction velocityde
dc.subject.engDuchenne muscular dystrophyde
dc.subject.engmdx - mouse modelde
dc.subject.engΔKPQ mouse modelde
dc.subject.engLong QT Syndrome 3de
dc.subject.engCardiac Sodium Channel (NaV1.5)de
dc.subject.engMaximum upstroke velocityde
dc.subject.engLeast Squares Ellipsis Fitting Methodde
dc.subject.engArea Fitting Methodde
dc.subject.engPlane Fitting Methodde
dc.subject.engConduction abnormalitiesde
dc.subject.engVoltage sensitive dyesde
dc.subject.engCardiac arrhythmiade
dc.subject.engFunctional heterogeneityde
dc.subject.engSpatial-temporal heterogeneityde
dc.subject.engActivation mapsde
dc.subject.engSymmetry breakingde
dc.subject.engIntrinsic cardiac heterogeneityde
dc.affiliation.instituteGöttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB)de
dc.subject.gokfullBiologie (PPN619462639)de

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