Cellular and molecular mechanisms of arrhythmias in cardiac fibrosis and beyond : from symptoms to substrates towards solutions

Currently, treatment of arrhythmias is largely symptomatic and pro-arrhythmic mechanisms are incompletely understood. The research described in this thesis therefore investigates cellular and molecular pro-arrhythmic mechanisms in in vitro models of pro-arrhythmic substrates such as fibrosis and hypertrophy, to provide and expand upon a mechanistic basis for future, substrate-oriented anti-arrhythmic strategies. In the model of cardiac fibrosis, the prominent pro-arrhythmic role of myofibroblasts was apparent. In a quantity-dependent manner, these cells have a detrimental depolarizing and pro-arhythmic influence on cardiac tissue. A mechanism that appears to be responsible for this depolarization of cardiomyocytes is heterocellular coupling, a pro-arrhythmic mechanism that was also observed between mesenchymal stem cells and cardiomyocytes and may therefore also have cautionary implications for the future of cardiac stem cell therapy. Through the use of genetic modification, such mechanisms can be selectively targeted. In this thesis, control of selective transgene expression in myofibroblasts or cardiomyocytes was further refined by investigating the cellular tropism of several adeno-associated viral vectors and the use of celltype-specific promotors. By employing such genetic tools together with expanded knowledge of pro-arrhythmic mechanisms of cardiac fibrosis and other pro-arrhythmic substrates, future treatment modalities for arrhythmias may improve by becoming more mechanism- and substrate-oriented.Dutch Heart Foundation (2008/B119)for conducted studies. Scimedia and Greiner Bio-One for the publication of the thesisUBL - phd migration 201

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Development of a new model of cardiac hypertrophy with pro-arrhythmic features to study the role of hypertrophy in arrhythmogenesis

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Engraftment Patterns of Human Adult Mesenchymal Stem Cells Expose Electrotonic and Paracrine Proarrhythmic Mechanisms in Myocardial Cell Cultures

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Reduced repolarization reserve underlies calcium dependent early afterdepolarizations and consequent reentrant tachyarrhythmias in pathological hypertrophic cardiac tissue

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Optogenetic termination of ventricular tachyarrhythmias in fibrotic myocardial cultures

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Inward rectifier potassium channels determine cardioversion threshold and successrate by regulating post-shock refibrillation

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