Background: Sudden arrhythmia death syndrome (SADS) is a genotypically and phenotypically heterogeneous condition that might produce fatal ventricular arrhythmia in otherwise healthy individuals. Congenital long QT syndrome (LQTS) is the most common type of SADS with a frequency of 1 in 2500 individuals. Up to 13 genes have been shown to be associated with LQTS and genetic testing has a role in disease diagnosis, prognostication, treatment guidance, cascade testing, and reproductive counseling. Interdisciplinary care is the standard but such service is unavailable in Hong Kong. Objectives: In this study, we aim to evaluate the clinical characteristics of a local cohort of pediatric patients with LQTS, establish the practicability of a model on interdisciplinary delivery of care for SADS, and explore the process of genetic counseling in Chinese families with LQTS from the perspective of discourse analysis. Method: Pediatric patients with LQTS and their families were recruited from the Department of Paediatric Cardiology, Queen Mary Hospital between 1 January 2011 and 31 December 2012. With informed consent, patients underwent genetic testing for 6 LQTS genes (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, KCNJ2). Clinical characteristics were documented and the process of pre-test and post-test counseling was videotaped and transcribed. Data was mapped and analyzed for discourse strategies in the focal themes of uncertainty management in risk communication. Results: 19 patients were identified, 9 were male, with the corrected QT interval (QTc) ranging from 460-619ms. Mode of presentation included syncope (n=9), ventricular tachycardia (n=2), convulsion (n=1) and as incidental finding (n=7). Pathogenic mutations were identified in 9 patients (LQT1=3, LQT2=4, LQT3=1, LQT5=1), likely pathogenic mutations in 2 (LQT2), unclassified variants in 2, and no mutation in 6. Patients with pathogenic and likely pathogenic mutations had significantly longer mean QTc than those without such mutations (p=0.046). Three mutations, all in the LQT2 genes, represented novel mutations. All 3 patients with mutations in the pore-looping forming domains of the KCNH2 (LQT2) channel had personal or family histories of malignant arrhythmia or sudden cardiac death compatible with previously reported genotype-phenotype correlation. Eight families involving 18 family members underwent cascade testing, and family mutations were identified in 10 individuals from 6 families. Autosomal dominant transmission was the likely mode of inheritance in these 6 families. Counseling sessions involved the joint input from clinical geneticist, genetic counsellor and pediatric cardiologist. Discourse analysis on 2 counseling sessions of a selected family with unclassified variants revealed increased uncertainty after genetic testing in the index patient and family members. Strategies used to mitigate uncertainty included abstraction, generalization and categorization. Conclusion: Genetic testing was crucial in the comprehensive assessment of patients with congenital LQTS, and we demonstrated a feasible model to delivery interdisciplinary care for patients with SADS in Hong Kong. The process of genetic counseling is highly complex and deserves further examination. / published_or_final_version / Paediatrics and Adolescent Medicine / Master / Master of Medical Sciences

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The management and prevention of Sudden Cardiac Death remains a great challenge in modern Cardiology. Implantable Cardioverter Defibrillators (ICDs) have been shown to reduce mortality. Despite decades of research, the mechanisms are not fully understood and ICD treatment is crude, palliative and expensive. Nonetheless, outcome studies have helped to inform national and international guidance in the implantation of these devices. Patient selection is crucial to ensure correct patients are identified and appropriately treated. More refined and stringent risk stratification is needed to identify patients at high risk. This thesis examines non-invasive, readily measureable markers to see whether they can be used to assess the risk of ventricular arrhythmia in patients with cardiomyopathy who have indications for ICD implantation. Baseline data in the form of 12 lead electrocardiograms, echocardiography, 24 hour Holter monitoring and venous blood were obtained to analyse QT dispersion, Heart Rate Variability (HRV), QT Variability Index (QTVI), ECG restitution measures and NTproBNP levels in these patients. Patients were followed up for a two year period through the ICD clinic and appropriate therapy was recorded as a surrogate marker for ventricular arrhythmia. Patients with and without appropriate therapy were then compared to look for significant differences in the examined markers. The percentage of beats with a QT/TQ ratio>1 was associated with appropriate shocks when compared with no therapy (p=0.04). However, the result was not significant when all appropriate ICD therapy was compared with no therapy (p=0.06). This possibly reflects the period of time the heart spends on the more ‘unstable portion’ of the restitution slope in patients at highest risk. Median BNP was non-significantly higher in patients with arrhythmia compared to those who were shock free. None of the other examined markers were predictive of appropriate therapy. There is thus promise in the use of some non-invasive markers in the refinement of patient selection with LVSD being considered for ICD therapy.

Experiments were performed to elucidate the mechanisms contributing to the hyperbaric bradycardia. Ethical approval was obtained and all subjects gave written and informed consent. Heart rate, arterial blood pressure, respiratory activity and carotid sinus baroreceptor reflexes were monitored non-invasively. Four healthy male saturation divers were compressed to 46ATA. Significant reductions in resting heart rate, mean arterial pressure, systolic blood pressure and diastolic blood pressure were observed. Baroreceptor sensitivity was significantly increased at 46ATA. A separate series of investigations determined the effects of breathing an increased gas density and an increased partial pressure of oxygen (<I>P</I>₀₂) on arterial blood pressure, heart rate and baroreceptor sensitivity at 1ATA. Two groups of 6 healthy male subjects participated in the experiments. No significant changes in resting heart rate, arterial blood pressure, respiratory rate, tidal volume or baroreceptor sensitivity were observed breathing an increased gas density up to 5.47gl^-1. Raising the inspired <I>P</I>₀₂ to 0.5bar at 1ATA resulted in a significant reduction in resting heart rate and a significant increase in carotid sinus baroreceptor sensitivity. Respiratory sinus arrhythmia (RSA) was used as a non-invasive estimate of vagal tone to determine whether the hyperbaric bradycardia is associated with changes in vagal autonomic control. No changes in the overall magnitude of RSA were observed over a range of respiratory rates at high pressure compared to controls at 1ATA. These results suggest that increased gas density is not a contributing factor but increased <I>P</I>₀₂ may play a role in the development of hyperbaric bradycardia.

国立情報学研究所で電子化したコンテンツを使用している。

国立情報学研究所で電子化したコンテンツを使用している。

国立情報学研究所で電子化したコンテンツを使用している。

Thesis (M. P. H.)--University of Hong Kong, 200. / Also available in print.

Thesis (M.S.)--University of Wisconsin--Madison, 1982. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaf 23).

Thesis (Ph. D.)--University of Hong Kong, 2002. / Includes bibliographical references.