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

Raad, Nour

dc.contributor.advisor	Luther, Stefan Prof. Dr.
dc.contributor.author	Raad, Nour
dc.date.accessioned	2014-03-31T08:11:10Z
dc.date.available	2014-03-31T08:11:10Z
dc.date.issued	2014-03-31
dc.identifier.uri	http://hdl.handle.net/11858/00-1735-0000-0022-5E72-F
dc.identifier.uri	http://dx.doi.org/10.53846/goediss-4436
dc.language.iso	eng	de
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/3.0/
dc.subject.ddc	571.4	de
dc.title	NaV1.5 Modulation: From Ionic Channels to Cardiac Conduction and Substrate Heterogeneity	de
dc.type	doctoralThesis	de
dc.contributor.referee	Luther, Stefan Prof. Dr.
dc.date.examination	2014-01-16
dc.description.abstracteng	The 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 tissue.	de
dc.contributor.coReferee	Katschinski, Dörthe Prof. Dr.
dc.subject.eng	Antiarrhythmic drugs	de
dc.subject.eng	Optical Mapping	de
dc.subject.eng	Action potential duration	de
dc.subject.eng	Spatial dispersion of repolarization	de
dc.subject.eng	Cardiac depolarization	de
dc.subject.eng	Conduction velocity	de
dc.subject.eng	Anisotropy	de
dc.subject.eng	Duchenne muscular dystrophy	de
dc.subject.eng	mdx - mouse model	de
dc.subject.eng	Dystrophin	de
dc.subject.eng	ΔKPQ mouse model	de
dc.subject.eng	Long QT Syndrome 3	de
dc.subject.eng	Cardiac Sodium Channel (NaV1.5)	de
dc.subject.eng	Flecainide	de
dc.subject.eng	Maximum upstroke velocity	de
dc.subject.eng	Least Squares Ellipsis Fitting Method	de
dc.subject.eng	Area Fitting Method	de
dc.subject.eng	Plane Fitting Method	de
dc.subject.eng	Conduction abnormalities	de
dc.subject.eng	Voltage sensitive dyes	de
dc.subject.eng	Cardiac arrhythmia	de
dc.subject.eng	Functional heterogeneity	de
dc.subject.eng	Spatial-temporal heterogeneity	de
dc.subject.eng	Proarrhythmia	de
dc.subject.eng	Activation maps	de
dc.subject.eng	Symmetry breaking	de
dc.subject.eng	Intrinsic cardiac heterogeneity	de
dc.identifier.urn	urn:nbn:de:gbv:7-11858/00-1735-0000-0022-5E72-F-2
dc.affiliation.institute	Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB)	de
dc.subject.gokfull	Biologie (PPN619462639)	de
dc.identifier.ppn	781978009

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