Proefschrift Universiteit Maastricht. / Omslagtitel: LQT-3 : novel insights in the congenital long QT-3 syndrome. Met bibliogr., index, lit. opg. - Met samenvatting in het Nederlands en Latijn.

This thesis deals with the issue of creating GIS type multitouch applications by using Qt library. Introductory part of this work discusses the current desktop and mobile solutions in the field of GIS with evaluations of user interfaces. It also contains a description of the available map services and options of the Qt library in the area of modern applications creation for touch screens. The following part is devoted to defining user and designing GIS with attention to userfriendly interface suitable for touch screens. The outcome of this work is the implementation of the proposed GIS having a modern multitouch user interface.

Ankyrin-B (Ank-B) is a crucial scaffolding protein regulating expression and localization of contractile machinery in the cardiac muscle. Recent genetic investigations in the First Nations Community, the Gitxsan of Northern BC, identified a mutation in Ank-B (p.S646F c.1937 C>T) associated with a cardiac arrhythmia, Long QT Syndrome Type 4 (LQTS4). Distinct from other LQTS4 subtypes, individuals harbouring the p.S646F variant exhibit development deficits including cardiomyopathies and accessory electrical pathways. How p.S646F interferes with the development of the heart is unknown due to a fundamental lack of understanding regarding Ank-B proteostasis and its role in cardiac differentiation. Initial in silico analyses predicted the p.S646F mutant to be deleterious to the Ank-B protein. Using in vitro techniques, I determined p.S646F mutant reduced levels of Ank-B in H9c2 rat ventricular cardiomyoblasts. Furthermore, haploinsufficiency in mice was previously shown to result in developmental cardiac deficits. I, therefore, hypothesized that p.S646F interferes with Ank-B proteostasis, thereby affecting cardiomyocyte development. I showed that p.S646F destabilized Ank-B in cardiomyoblasts, due to increased degradation via the proteasome. Furthermore, overexpression of p.S646F Ank-B had a significant impact on cellular behaviour including reduced cell viability, and altered expression of cellular differentiation markers. Together these data address critical knowledge gaps with regards to Ank-B protein homeostasis and the role of Ank-B in cardiomyocyte viability and development. These findings inform the diagnosis and treatment of patients with the p.S646F variant, creating potential targeted pathways of intervention, and furthering our understanding of the role of the Ank-B in the development of the heart. / Graduate / 2019-04-26

Introduction: La surcharge de pression ventriculaire augmente à l’exercice chez les patients avec une sténose de valve aortique (SVA). Lorsqu’il n’y a aucun symptôme apparent, il est cependant difficile d’indiquer l’intervention chirurgicale en utilisant seulement les indices de surcharge de pression ventriculaire. D’autres paramètres, tels que la dispersion de la repolarisation ventriculaire (d-QT), qui augmentent avec le gradient de pression transvalvulaire (GPT), n’ont pas été étudiés dans la SVA. L’objectif de l’étude était de déterminer le modèle de réponse du segment QT et de la d-QT à l’épreuve d’effort chez des enfants avec une SVA congénitale modérée afin d’évaluer l’impact de la surcharge de pression ventriculaire selon une perspective électrophysiologique. Matériel et méthodes: 15 patients SVA modérés ont été comparés à 15 sujets contrôles appariés pour l’âge (14.8±2.5 ans vs. 14.2±1.5 ans) et pour le sexe (66,7% de sujets mâles). Tous les sujets ont fait une épreuve d’effort avec enregistrement électrocardiographique à 12 dérivations. Le segment QT a été mesuré à partir du début du complexe QRS jusqu’à l’apex de l’onde T (QTa) au repos, à l’effort maximal ainsi qu’après 1 et 3 minutes de récupération. La longueur du segment QT a été corrigée selon l’équation de Fridericia et la d-QT a été calculée. Résultats: La longueur du segment QT corrigée (QTc) était similaire au repos entre les groupes d’étude, mais était significativement élevée chez les SVA en comparaison avec le groupe contrôle à l’effort maximal (p=0.004) ainsi qu’après 1 (p<0.001) et 3 (p<0.001) minutes de récupération. Une interaction significative a été identifiée entre les groupes pour la d-QT (p=0.034) et les tests post hoc ont révélé une différence significative seulement au repos (p=0.001). Conclusions: Les anomalies de repolarisation ventriculaire peuvent être révélées par l’évaluation de la repolarisation électrique lors de l’épreuve d’effort chez les SVA modérées asymptomatiques. L’utilisation de la réponse du QT à l’effort pourrait être bénéfique pour l’optimisation de la stratification du risque chez ces patients. / Introduction: Pressure overload increases in patients with moderate aortic valvular stenosis (AVS) during acute exercise. In the absence of symptoms, it remains difficult however, to discriminate patients for surgery based only on pressure overload. Other parameters, such as the dispersion of ventricular repolarisation (d-QT), which reportedly increases with the transvalvular pressure gradient, have not been fully studied in AVS. The aim of the study was to determine the pattern of QT and d-QT response to exercise testing in children with moderate AVS to evaluate the impact of pressure overload from an electrophysiological perspective. Materials and methods: 15 moderate AVS patients were compared to 15 controls paired for age (14.8±2.5 vs. 14.2±1.5 years old) and gender (66.7% male). All subjects underwent exercise stress testing with 12-lead ECG recording. QT was measured from the onset of QRS to the apex (QTa) at rest, peak exercise, 1 and 3 minutes of recovery. QT was corrected using the Fridericia equation and d-QT was calculated. Results: Resting QTc was similar among the study groups, but increased significantly in AVS in comparison to the control group at maximal effort (p=0.004) and after 1 (p<0.001) and 3 (p<0.001) minutes of recovery. A significant interaction was identified between groups for d-QT (p=0.034) and post-hoc tests revealed a significant difference only at rest (p=0.001). Conclusions: Ventricular repolarisation abnormalities can be unmasked and highlighted by the assessment of electrical repolarisation during exercise challenge in asymptomatic moderate AVS. Using QT response to exercise could be beneficial for better optimisation of risk stratification in these patients.

Class of 2016 Abstract / Objectives: This study assessed the feasibility of using a hand-held single lead ECG device to collect readable electrocardiograms (ECGs) in a community setting among the general population. Next, the goal was to determine if QT intervals could be measured from the collected ECGs. Additionally, this study was designed to examine if patients who had a prolonged QT interval were taking medications that are associated with an increased risk of prolonged QT interval. Methods: This prospective pilot study involved collecting ECGs via an AliveCor hand-held device at community health fairs. ECGs were evaluated for usefulness and QT intervals were measured if possible. Results: Forty-eight subjects participated in this pilot study. Forty-five viable ECGs were recorded using the hand-held device. Of the 45 ECGs, 38 were of sufficient quality to measure the QT interval and calculate QTc interval. There were no prolonged QT intervals observed in this study. Conclusions: The hand-held device recorded sufficient information to extract QT intervals for the majority of subjects. Due to the lack of prolonged QTc intervals, there was insufficient data to determine if this device could be utilized in the detection of QT prolongation due to medication use.

The recently identified genetic short QT syndrome is characterised by abbreviated QT intervals on the electrocardiogram, an increased risk of atrial and ventricular arrhythmias, and an increased risk of sudden death. Although the short QT syndrome has been suggested to provide a paradigm for increasing understanding of the role of potassium channels in ventricular fibrillation, the basis for arrhythmogenesis in the short QT syndrome is incompletely understood. There are no animal models that accurately reproduce a short QT phenotype, and whilst in vitro electrophysiology of short QT mutant channels provides a route to greater understanding of the effects of short QT mutants on action potential repolarisation, on its own, this approach is insufficient to explain how arrhythmias arise and are maintained at the tissue level. Consequently, this thesis is concerned with the use of the viable alternative; in silico (computational) modelling to elucidate how the short QT syndrome facilitates the genesis and maintenance of ventricular arrhythmias and its effects on ventricular contraction. Using extant biophysical data on changes induced by the short QT mutations and data from BHF-funded in vitro electrophysiology, three novel mathematical models of the first three variants of the short QT syndrome were developed; a Markov chain model for short QT variant 1, a Markov chain model for short QT variant 2 and a Hodgkin-Huxley model for short QT variant 3. These models were incorporated into single cell and anatomically detailed tissue and organ computer models to elucidate how these variants lead to ventricular arrhythmias. The developed short QT models were then incorporated into electromechanically coupled single cell and tissue models to investigate the effects of the short QT mutants on ventricular contraction. It was found that each short QT variant uniquely increased the transmural dispersion of action potential duration across the ventricular wall, increased the temporal window of tissue vulnerability to premature excitation stimulus, leading to increased susceptibility to re-entrant arrhythmia.

This project solves teoretical design of digital reproductor system and controlling GUI software. This digital system is composed of one master unit, which digitalize different audio sources and stream them by ethernet to slave units. The controlling software is be able to set and monitor the audio system.

This thesis deals with the creation of wireless sensor networks consisting of components Arduino. The work includes introduction to the Arduino platform and its capabilities in combination with the wireless XBee modules. The important part is design a wireless network from these components and applications for the display of measured values from sensor nodes. The goal is to create sensor network with a dynamic topology and examine its behavior in real environment and the creation of applications for saving and displaying measured data from individual sensor nodes.

This thesis presents a method to develop a visualization software for time-varying and geographic-based data. The machine learning team at Ericsson has collected data from their machine learning algorithms. The data set contains timestamped and geographic information. To have a better understanding of the result made by the machine learning algorithms, it is important to understand the pattern of the data. It is hard to see the pattern of the data by only looking at the raw data set, and data visualization software will help the users to have a more intuitive view of the data.  To choose a suitable GUI library, three common GUI libraries were compared. The Qt framework was chosen as the GUI library and development framework because of its wide-range support to user interface design. Animation is the main method to visualize the data set. The performance evaluation of the software shows that it handles the back-end data efficiently, renders fast in the front-end and has low memory and CPU usage. The usability testing indicates that the software is easy to use. In the end, the thesis compares its method to a previous method, developed in R. The comparison shows that even though the old method is easier to develop, it has worse performance.

Background Long QT syndrome (LQTS) is characterized by a prolonged QT interval on the electrocardiogram (ECG), a risk for sudden cardiac death. A simple 'rule of thumb' method states that if a patient's heart rate is between 60-100 bpm, the QT interval should not be more than half the R-R interval. The clinical accuracy of this method has not been tested in the elderly. Objectives To determine if the 'rule of thumb' to calculate QT interval prolongation, is accurate, compared to the corrected QT interval calculated using Bazett's formula. Secondary objectives include the prevalence of long QT and risk factors for QT prolongation. Methods The QT interval was calculated using Bazett's formula, and the 'rule of thumb' method, from ECG's collected from patients over 60 years old, on their first visit to a geriatric clinical service. Only data from patients with heart rates in the range 60-100 were analyzed. Medications and electrolyte levels were recorded. Results A total of 1000 ECGs were collected. 776 ECGs were included in the study. Prevalence of prolonged QT interval was 37.8% using Bazett's formula. Compared to Bazett's formula, the 'rule of thumb' method had a sensitivity of 65.2% and a specificity of 96.9%. ECG computer analysis calculated QTc was available for 42.5% of the cases and had a sensitivity of 58.1% and specificity of 95.3% compared to Bazett's formula. Of the 23.3% of patients taking medications known to prolong the QT interval only 38.6% had a prolonged QT interval. There was a significant association between QT interval prolongation and hypokalaemia. Conclusion The 'rule of thumb' method to determine QT interval prolongation, has high specificity but low sensitivity. This bedside measure is similar in accuracy to QT determination using an ECG computer analysis calculation in this population of older persons. / MT 2019