Thesis (M. Med. Sc.)--University of Hong Kong, 2005.

Tetralogy of Fallot (TOF) is the most common cyanotic congenital cardiac defect with a global annual incidence of 40,000 cases. Advances in surgery and perioperative care led to improvements in perioperative mortality and, thus, a growing number of survivors. TOF survivors often suffer from complications related to a failing right ventricle. Follow-up studies evaluating TOF repair strategies suggest an association between the type of surgical repair strategy and late right ventricular health. However, surgical practices remain unchanged and led by institution-level biases. The body of evidence addressing outcomes based on TOF surgical repair strategy is weak and controversies persists on the management of these patients.  This thesis comprises 6 chapters that form the foundation of a multi-centre research program on outcomes after TOF surgical repair. The program uses various methodologies to generate evidence with a vision to change surgical practices.  Chapter 1 is an introduction providing background on TOF and contemporary areas of controversy.  Chapter 2 presents the results of a retrospective analysis evaluating the use of early echocardiogram parameters in predicting late cardiac magnetic resonance imaging evaluation of the right ventricle.  Chapter 3 presents the results of a retrospective cohort exploring the association between TOF repair strategy and development of right bundle branch block.  Chapter 4 presents the results of a multinational survey aiming to explore contemporary biases in TOF surgical repair strategy selection.  Chapter 5 presents the background, rationale, design and baseline cohort characteristics of the Tetralogy of Fallot for Life (TOF LIFE) study. The study is a multi-centre inception cohort study with a follow-up period of 2 years.  Finally, Chapter 6 discusses the conclusion, limitations, and future implications of this research program. / Thesis / Doctor of Science (PhD)

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Introduction. Computational modelling has been used widely in biological and clinical applications, but relatively less in surgical design and optimization. Magnetic resonance image (MRI)-based right ventricle (RV) models were introduced for patients with repaired Tetralogy of Fallot (rTOF) to assess ventricle cardiac function, and to identify morphological and mechanical parameters which can be used to predict and optimize post-surgery cardiac outcome. Tetralogy of Fallot is a common congenital heart defect which includes a ventricular septal defect and severe right ventricular outflow obstruction, account for the majority of cases with late onset RV failure. The current surgical approach for the patients with repaired ToF including pulmonary valve replacement/insertion (PVR) has yielded mixed results. It is of great interest to identify parameters which may be used to predict surgical cardiac function outcome after PVR. Data, Model, and Methods. Cardiac Magnetic Resonance (CMR) data from 20 healthy volunteers (11 males, mean year : 22.8) and 56 TOF patients (37 males, mean year : 25.3) were provided by Children's Hospital - Boston, Harvard Medical School from our NIH-funded project (R01 HL089269). RV wall thickness (WT), circumferential and longitudinal curvature (C-cur and L-cur), surface area (SA) and surface to volume ratio (SVR) were obtained based on CMR data for morphological analysis. 6 healthy volunteers and 16 TOF patients were chosen to construct 3D computational models for mechanical analysis. The 3D CMR-based RV/LV/Patch combination models included a) isotropic and anisotropic material properties, b) myocardial fiber orientation, c) active contraction with two zero-load geometries, and d) fluid-structure interactions. The models were used to obtain the assessment for RV mechanical conditions, which might be helpful for PVR surgical outcome prediction. All the computational models were built and solved in a commercial finite element software ADINA. Statistical methods including Linear Mixed- effort Method and Logistical regression were used in the morphological and mechanical analysis to find out potential indicators for predicting PVR outcome from the morphological and mechanical parameters. Results. In morphological analysis, statistically significant differences were found in RV SA and SVR between better-outcome patient group (BPG) and worse-outcome patient group (WPG). At begin of ejection, mean RV SA of BPG was 13.6% lower than that from WPG (241.1 cm2 v.s. 279.0 cm2, p =0.0161). Mean RV SVR of BPG was 13.1% lower than that from WPG (1.26 cm2/ml v.s. 1.45 cm2/ml, p =0.0271). Similar results were also found in RV SA and SVR at begin of filling. Furthermore, RV EF change from pre- to post-PVR were found negatively correlated with RV SA and SVR. In mechanical analysis, 22 structure-only models with one zero-load geometry (1G) were constructed to obtain stress/strain distributions. Stress-P1 from BPG was found to be closer to that from HG, compared to Stress- P1 of WPG. At the beginning of ejection, mean Stress-P1 of BPG was only 6.8% higher than that from healthy group (p =0.6889), while average Stress-P1 of WPG was 84.1% higher than that of healthy group (p =0.0418). Similar results were also found at begin of filling. The results suggested that comparing patients' RV stress values with healthy RV stress values may help identify patients with possible better outcome. The models with two zero-load geometries (2G models) and FSI models were also constructed. Their numerical results indicated that 2G models can provide end-ejection and end-filling results which were not available in 1G models, and FSI models can provide flow velocity, pressure and shear stress information which lacked in structure-only models (1G and 2G models). Conclusion. In vivo image-based 3D patient- specific computational models could lead to considerable potential gain not only in surgical design and outcome prediction, but also in understanding the mechanisms of RV failure for patients with repaired TOF.

Background: Children with complex congenital heart disease (CHD) are exposed to cyanosis from birth until their surgical repair and are often not expected to participate in physical activities to the same extent as healthy peers because of a limited maximal exercise capacity (V̇O2max). Despite limitations in V̇O2max, these children may still have the capacity to perform most daily physical activity because it requires only a submaximal effort. The purpose of this research was to examine the relationships between submaximal exercise capacity, daily physical activity and cyanosis exposure, in children with complex CHD. Methods: Children with a single functioning ventricle (Fontan), tetralogy of Fallot or transposition of the great arteries, 10 to 17 years old were deemed eligible. The Bruce treadmill protocol with breath-by-breath analysis of oxygen consumption was used to assess submaximal exercise capacity. Five measures of submaximal exercise capacity were evaluated: energy consumption (V̇O2) at the ventilatory threshold, V̇O2 at a heart rate of 130 beats per minute (bpm), metabolic equivalents (METs) at ventilatory threshold, METs at 130 bpm and heart rate at stage 1 of the Bruce protocol. Moderate-to vigorous physical activity (MVPA) was measured (Actical accelerometer with 15 second epochs) for 7 consecutive days. Exposure to cyanosis was calculated by subtracting the child’s date of birth from the date of surgical repair. Results: Participants were children with a Fontan single ventricle (n=5), tetralogy of Fallot (n=4) or transposition of the great arteries (n=7). Daily physical activity was positively associated with V̇O2 at ventilatory threshold (r = 0.78, n = 16, p = < 0.01) and V̇O2 at a heart rate of 130 bpm (r = 0.61, n = 16, p = 0.01). Children who did more than 60 minutes of physical activity per day (n=4) achieved significantly higher energy expenditure before reaching ventilatory threshold, (95% CI of the difference [8.23, 24.85], t(14) = 4.27, p = < 0.01) and at a heart rate of 130 bpm (95% CI of the difference [1.61, 14.33], t(14) = 2.69, p = 0.02). Lastly, V̇O2 at ventilatory threshold was negatively associated with days spent in cyanosis (r = .55, n = 16, p = 0.03), Conclusion: Higher V̇O2 at ventilatory threshold and V̇O2 at a heart rate of 130 bpm was associated with more daily minutes spent in moderate-to-vigorous physical activity. These results suggest that children who meet the recommended 60 minutes of MVPA would have a higher submaximal exercise capacity (V̇O2 at ventilatory threshold or a heart rate of 130 bpm), than children who did not meet the MVPA guidelines. Lastly, children who were exposed to cyanosis for a longer period of time had a lower submaximal V̇O2 at ventilatory threshold, than children who were exposed to cyanosis for a shorter period of time.

<p>This phenomenological study of John Banville’s fiction exhibits the way in which <i>Doctor Copernicus</i>, <i>Kepler, The Newton Letter</i>, and <i>Mefisto</i> persistently present air as a constituting factor. Air occurs as a phenomenological oasis permitting constitution to effectuate disclosure <i>ex nihilo</i>. As a self-constituting field of forms rather than as a system or arrangement of signs, <i>Doctor Copernicus</i> promotes a vision of reality that bypasses a world of scientific or aesthetic representation where objective or subjective deciphering has precedence over immediate revelation as immanent showing. In <i>Kepler</i>, air’s <i>aseity </i>marks a process of constitution intense enough to erase any sense of separation between the flight-paths of discovery and the thing discovered—thus producing the impression of an intriguing parity between the constituting and the constituted. Phenomena of aviation outline the experience of air’s constituting capacity as a prehuman directedness with no source outside itself. The scientist is drawn into an airborn or airborne allure recasting his life in more profound ways than those made available in cosmological inquiry. By means of the slightness of its constituting touch, air is shown as giving birth to apparently insignificant phenomena highlighting an explorability that cannot be defined in terms of mathematical models or logical postulations. In <i>The Newton Letter</i> penurious phenomena gain ascendancy over the scientist through a process defined as <i>autochthonous substantiation</i>. As in <i>Mefisto</i>, the destructive power of accidental fire reduces material and immaterial worlds to an empirical nothing where air, almost indistinguishable from that emptiness, becomes a form of saying facilitating recovery, or the semblance thereof. Finally the study elucidates the phenomenon of <i>monozygotic gemination</i> in <i>Mefisto,</i> a constituting force that allows a phantom brother or phantom limb to function as a regenerating resource rather than as a missing entity.</p>

This phenomenological study of John Banville’s fiction exhibits the way in which Doctor Copernicus, Kepler, The Newton Letter, and Mefisto persistently present air as a constituting factor. Air occurs as a phenomenological oasis permitting constitution to effectuate disclosure ex nihilo. As a self-constituting field of forms rather than as a system or arrangement of signs, Doctor Copernicus promotes a vision of reality that bypasses a world of scientific or aesthetic representation where objective or subjective deciphering has precedence over immediate revelation as immanent showing. In Kepler, air’s aseity marks a process of constitution intense enough to erase any sense of separation between the flight-paths of discovery and the thing discovered—thus producing the impression of an intriguing parity between the constituting and the constituted. Phenomena of aviation outline the experience of air’s constituting capacity as a prehuman directedness with no source outside itself. The scientist is drawn into an airborn or airborne allure recasting his life in more profound ways than those made available in cosmological inquiry. By means of the slightness of its constituting touch, air is shown as giving birth to apparently insignificant phenomena highlighting an explorability that cannot be defined in terms of mathematical models or logical postulations. In The Newton Letter penurious phenomena gain ascendancy over the scientist through a process defined as autochthonous substantiation. As in Mefisto, the destructive power of accidental fire reduces material and immaterial worlds to an empirical nothing where air, almost indistinguishable from that emptiness, becomes a form of saying facilitating recovery, or the semblance thereof. Finally the study elucidates the phenomenon of monozygotic gemination in Mefisto, a constituting force that allows a phantom brother or phantom limb to function as a regenerating resource rather than as a missing entity.

Magnetic resonance imaging nowadays supplies a noninvasive method in clinical applications. For tetralogy of Fallot (TOF) patients, after undergoing clinical operation, their cardiac anatomy still cannot supply sufficient blood flow in the pulmonary arteries with respect to the normal. In this study, we use phase contrast MR imaging to evaluate of regurgitation and turbulence of flow in pulmonary arteries after repair of TOF. We use parameters such as coefficient of variance (CV), regurgitant fraction (RF), and normalized area variation (NAV) to analyze the difference between repaired patients and normal controls. Our result also shows that CV and regurgitant fraction have loose relation. This study may provide more information to help doctors in clinical diagnosis. In the meanwhile, another three parameters were used to evaluate patients and normal persons. We use windkessel volume to see the difference of flow volume between inlet and outlet in the pulmonary arteries. We use pulse wave velocity (PWV) to discuss the propagating velocity of pressure wave on the vascular wall. We use pulmonary vascular resistance (PVR) to analyze the resistance of blood wall. PWV and PVR may lose information by means of insufficient points in a cardiac cycle, but the result may still be a kind of reference.

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease (CHD). The understanding of the genetics and inheritance of TOF is limited. Although about 15% of cases are associated with a 22q11.2 deletion, the majority have no known aetiology. Even in 22q11.2 Deletion Syndrome (22q11DS), factors that increase the likelihood of CHD expression are poorly understood. We aimed to determine the prevalence and phenotypes of CHD in relatives of adults with TOF. We also investigated the prevalence of CHD in relatives without a 22q11.2 deletion of individuals with 22q11DS. Offspring of patients with TOF had the greatest prevalence of CHD. Diverse cardiac phenotypes, including left heart obstructive lesions, were found in families. We also found that unaffected relatives of individuals with 22q11DS had a greater prevalence of complex CHD over population expectations, suggesting that modifier genetic factors may be involved in expression of CHD in 22q11DS.