Modelling pathological effects in intracellular calcium dynamics leading to atrial fibrillation

dc.contributor
Universitat Politècnica de Catalunya. Departament de Física
dc.contributor.author
Marchena Angos, Miquel
dc.date.accessioned
2020-07-28T09:05:54Z
dc.date.available
2020-07-28T09:05:54Z
dc.date.issued
2020-07-23
dc.identifier.uri
http://hdl.handle.net/10803/669289
dc.description.abstract
The heart beating is produced by the synchronization of the cardiac cells' contraction. A dysregulation in this mechanism may produce episodes of abnormal heart contraction. The origin of these abnormalities often lies at the subcellular level where calcium is the most important ion that controls the cell contraction. The regulation of calcium concentration is determined by the ryanodine receptors (RyR), the calcium channels that connect the cytosol and the sarcoplasmic reticulum. RyRs open and close stochastically with calcium-dependent rates. The fundamental calcium release event is known as calcium spark, which refers to a local release of calcium through one or more RyRs. Thus, a deep knowledge on both the spatio-temporal characteristics of the calcium patterns and the role of the RyRs is crucial to understand the transition between healthy to unhealthy cells. The aim of this Thesis has been to figure out these changes at the submicron scale, which may induce the transition to Atrial Fibrillation (AF) in advanced stages. To address this issue, I have developed, and validated, a subcellular mathematical model of an atrial myocyte which includes the electro-physiological currents as well as the fundamental intracellular structures. The high resolution of the model has allowed me to study the spatio-temporal calcium features that arise from both the cell stimulation and the resting conditions. Simulations show the relevance of the assembly of RyRs into clusters, leading to the formation of macro-sparks for heterogeneous distributions. These macro-sparks may produce ectopic beats under pathophysiological conditions. The incorporation of RyR-modulators into the model produces a nonuniform spatial distribution of calcium sparks, a situation observed during AF. In this sense, calsequestrin (CSQ) has emerged as a key calcium buffer that modifies the calcium handling. The lack of CSQ produces an increase in the spark frequency and, during calcium overload, it also promotes the appearance of global calcium oscillations. Finally, I have also characterized the effect of detubulation, a common issue in cells with AF and heart failure. Thus, the present work represents a step forward in the understanding of the mechanisms leading to AF, with the development of computational models that, in the future, can be used to complement in vitro or in vivo studies, helping find therapeutic targets for this disease.
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dc.format.extent
189 p.
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dc.format.mimetype
application/pdf
dc.language.iso
eng
en_US
dc.publisher
Universitat Politècnica de Catalunya
dc.rights.license
L'accés als continguts d'aquesta tesi queda condicionat a l'acceptació de les condicions d'ús establertes per la següent llicència Creative Commons: http://creativecommons.org/licenses/by/4.0/
dc.rights.uri
http://creativecommons.org/licenses/by/4.0/
*
dc.source
TDX (Tesis Doctorals en Xarxa)
dc.subject
Calcium modeling
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dc.subject
Atrial cells
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dc.subject
Intracellular calcium signaling
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dc.subject
Calcium release unit
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dc.subject
Ryanodine receptor
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dc.subject
Atrial fibrillation
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dc.subject.other
Àrees temàtiques de la UPC::Física
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dc.title
Modelling pathological effects in intracellular calcium dynamics leading to atrial fibrillation
en_US
dc.type
info:eu-repo/semantics/doctoralThesis
dc.type
info:eu-repo/semantics/publishedVersion
dc.subject.udc
53
en_US
dc.subject.udc
61
en_US
dc.contributor.director
Echebarría, Blas
dc.embargo.terms
cap
en_US
dc.rights.accessLevel
info:eu-repo/semantics/openAccess


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