Cardiac arrhythmias are one of the major causes of morbidity and mortality in the world. The clinical management of cardiac arrhythmias relies on several anti-arrhythmic therapies, e.g. drugs,... Show moreCardiac arrhythmias are one of the major causes of morbidity and mortality in the world. The clinical management of cardiac arrhythmias relies on several anti-arrhythmic therapies, e.g. drugs, ablation, and device implantation that, unfortunately, are often unspecific, irreversible and/or traumatizing, respectively. Recently, to overcome these side effects, gene therapy has been introduced as an alternative option to treat cardiac arrhythmias by specifically targeting the biological defect. However, gene therapy alone is lacking the possibility to gain precise spatiotemporal and quantitative control over a certain target. Interestingly, more recently, such precise control could be achieved with an innovative strategy, called optogenetics. Here, gene therapy is combined with optics allowing expression of light-activatable proteins that are specifically activate and deactivate by simply turning light on and off, respectively. This now opens new and unique possibilities for cardiac arrhythmias research based on optical modulation of excitability with superb spatiotemporal resolution. Therefore, in the studies presented in this thesis, the unique features of optogenetics were employed for investigating the underlying mechanism of arrhythmia initiation, maintenance, and termination in order to identify novel biological anti-arrhythmic strategies. Show less
Mazurek, M.; Huisman, M.V.; Rothman, K.J.; Paquette, M.; Teutsch, C.; Diener, H.C.; ... ; GLORIA-AF Investigators 2018
The results of this thesis acknowledge one of the major contemporary problems in AF treatment, which is to find the optimal balance between ablation efficacy and related potential complications.... Show moreThe results of this thesis acknowledge one of the major contemporary problems in AF treatment, which is to find the optimal balance between ablation efficacy and related potential complications. A higher efficacy may be obtained by a more invasive ablation strategy, while this type of procedure also seems to increase the risk for complications. On the other hand, simplifying the procedure with a so-called single-shot device can also lead to an increased complication rate. Therefore, optimization of procedures with currently available catheters may be the best strategy to achieve a highly effective procedure for patients with paroxysmal or even persistent AF, without leading to significant complications. A minimally invasive strategy may be suitable for patients with (longstanding) persistent AF, especially if these patients have no comorbidities that require open heart surgery. The studies described in this thesis contributed to further elucidating the feasibility and potential risks of performing new ablation procedures and catheters. This may contribute to optimize AF ablation procedures. Show less
Cardiac tachyarrhythmias are a vast contributor to morbidity and mortality worldwide. Still, the mechanisms underlying these arrhythmias are incompletely understood. As a result, many of the... Show moreCardiac tachyarrhythmias are a vast contributor to morbidity and mortality worldwide. Still, the mechanisms underlying these arrhythmias are incompletely understood. As a result, many of the treatment options available for these arrhythmias rely on sole alleviation of symptoms or prevention of complications secondary to the arrhythmia, or are associated with non-trivial adverse effects. An increased understanding of the mechanisms underlying cardiac tachyarrhythmias as well as the means to reverse them is a critical prerequisite if we are to shift towards more specific, more effective and less harmful arrhythmia treatment. Therefore, the research described in this thesis investigates the molecular and cellular determinants of cardiac tachyarrhythmias in ex vivo and in vitro models of cardiac hypertropfy/fibrosis, ventricular fibrillation and atrial fibrillation using state of the art electrophysiological and genetic tools. Show less
Skeletal and cardiac muscle disorders are associated with substantial morbidity and mortality. Despite many improvements in the medical and surgical management of these disorders, development of... Show moreSkeletal and cardiac muscle disorders are associated with substantial morbidity and mortality. Despite many improvements in the medical and surgical management of these disorders, development of effective treatments has proven to be challenging. This is because of the limited suitability of existing experimental models for acquiring a thorough understanding of the mechanisms underlying skeletal and cardiac muscle diseases and the lack of efficiency and specificity of many of the currently available therapeutic interventions. Therefore, the aim of this thesis was to establish and use dedicated cellular models in combination with genetic interventions to study the biology of skeletal and cardiac muscles in healthy and diseased states and thereby identify potential targets for future therapeutic interventions. The experiments described in this thesis indeed emphasized the importance of cellular models for (i) elucidating the mechanisms underlying skeletal and cardiac muscle diseases and (ii) identification of novel therapeutic targets. This thesis also underlined the usefulness of viral vector-mediated gene transfer technology for development of biological assays and the evaluation of therapeutic targets. In conclusion, application of in vitro models in combination with genetic interventions can improve our understanding of skeletal and cardiac muscle diseases and aid development of new therapies for these disorders. Show less
