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published_or_final_version / abstract / Paediatrics and Adolescent Medicine / Doctoral / Doctor of Philosophy

Mothers who have an infant with severe congenital heart disease (CHD) face an uncertain and emotionally challenging postpartum period as their baby is hospitalised and undergoes life-saving cardiac surgical treatment. There are many potential risk factors to mother-infant bonding, that is, the emotional tie a mother develops with her baby, in the context of infant illness. Having an infant with a diagnosis of severe CHD could be seen as a threat to the mother's experience of bonding. However, there is limited understanding about the maternal perception of bonding with an infant with severe CHD. This study aimed to explore mothers' bonding with their infant with severe CHD throughout antenatal, perinatal and postnatal periods and how they coped with any challenges to this bond. Interviews were conducted with eight mothers of infants aged between eight and fifteen months with severe CHD, who were recruited from a children's hospital and who were diagnosed either antenatally or postnatally. Interpretative Phenomenological Analysis was used to identify themes across the mothers' accounts. Four superordinant themes were identified: ‘An Emotional Start to Motherhood and the Mother-Infant Bond', ‘Losing Control in the Context of CHD', ‘Keeping Connected to the Baby' and ‘Moving on Together'. The findings identify mother-infant bonding as a process that can withstand challenges such as maternal-infant separation, potential loss of the infant and maternal feelings of disconnection from the baby. Practical strategies were used by mothers to maintain their bond with their infant following diagnosis and during hospitalisation. These included being close to their infant and taking over caregiving duties from the nurses. Mothers described strength and resilience from the experience and a process of increasingly feeling closer to their infant. Several potential research implications and clinical recommendations for healthcare professionals are suggested.

M.Sc. (Med. (Paediatric Cardiology)), Faculty of Health Sciences, University of the Witwatersrand, 2008 / Left ventricular (LV) noncompaction is characterized by the presence of an extensive trabecular myocardial layer within the luminal aspect of the compact myocardium of the ventricular wall. The trabeculae are both excessive in number and more prominent than normal. Noncompaction may occur in isolation usually with clinical features of dilated cardiomyopathy, or it may be associated with congenital or acquired heart diseases. Echocardiography is the reference standard for diagnosis, where a ratio of thickness of trabecular-to-compact myocardium (compaction ratio) of >2 is a major diagnostic criterion. Noncompaction is usually considered to result from persistence of the highly trabeculated myocardium found in early cardiogenesis of the human embryo. If persistence of excess trabeculae is the only determinant of the compaction ratio it would be expected that it would remain a consistent measurement in postnatal life. However, temporal changes in the degree of noncompaction in individual case reports have raised the question as to whether the compaction ratio might be sensitive to haemodynamic or other factors. In the present dissertation, I assessed echocardiographically whether the compaction ratio is associated with increases in indices of LV volume preload in 100 children or adolescents with ventricular septal defects (VSD), and 36 with chronic rheumatic heart disease (RHD). Compared to 79 normal controls (compaction ratio=1.4±0.07), patients with VSDs (compaction ratio=2.0±0.2, p<0.0001) and RHD (compaction ratio = 2.0±0.3, p< 0.0001) had a marked increase in the compaction ratio. A compaction ratio>2 was found in 42% of patients with VSDs and 47% with RHD. In VSDs, independent of age and gender, the compaction ratio was positively associated with LV mass index (LVMI) (partial r=0.44, p<0.0001), VSD size (partial r=0.4, p<0.0001), LV end diastolic diameter indexed (LVEDD) (partial r=0.24, p= 0.01), and the presence of additional shunts (partial r=0.21, p=0.02). In RHD, independent of age and gender, the compaction ratio was positively associated with LVEDD (partial r=0.62, p=0.0001), and LVMI (partial r=0.48, p=0.005), and negatively with LV ejection fraction (partial r=0.31, p=0.03). The strong association of indices of LV volume load and the compaction ratio would suggest that haemodynamic influences are contributing to the compaction ratio both in congenital and acquired cardiac disease in childhood. Thus an increased compaction ratio may be the consequence of an increased volume preload, and therefore may not necessarily occur only as a result of persistence of embryonic patterns.

Aim: To describe innovative uses of catheter based treatment in a variety of native and post surgical stenoses in children and young adults with congenital heart disease. Background: Cardiac catheterization in man was first described 1929 and since then there has been a drive to develop endovascular techniques to investigate and treat both congenital and acquired heart disease. Many of the advances are being made in congenital heart disease. Methods: A number of congenital cardiac stenotic lesions were studied including baffle obstruction after atrial switch for transposition of the great arteries, aortic stenosis in infants, coarctation of the aorta, peripheral pulmonary artery stenosis and superior vena caval obstruction. The use of angioplasty balloons, cutting balloons, stents and alternative catheter approaches were investigated for these lesions. Results: Following atrial redirection surgery for transposition of the great arteries balloon angioplasty improved baffle haemodynamics. The technique of anterograde balloon dilation of the aortic valve was developed and had superior outcomes in terms of aortic insufficiency compared to a retrograde approach in neonates with severe aortic valve stenosis. In an animal model of peripheral pulmonary arterial stenosis, the application of cutting balloon angioplasty produced effective relief in a controlled fashion. Balloon mounted stents were used in patients with native and post surgical coarctation of the aorta with significant relief of stenosis and relief of hypertension. Finally, a group of patients with superior vena obstruction syndrome after surgical repair of partial anomalous pulmonary venous drainage had successful treatment using balloon mounted stents. Conclusions: Catheter based treatment of congenital and post surgical vascular stenoses of the heart and great arteries using angioplasty balloons, cutting balloons and balloon mounted stents is safe and appears to be effective in the short and medium term. It may represent a useful alternative to surgery and will reduce the number of surgical procedures required over a lifetime. Future directions will include bio-absorbable stents and hybrid techniques involving surgery.

The development and function of the heart is governed by a conserved set of transcription factors (TFs) that regulate gene expression in a cell-type, time point and stimulus driven manner. Of these core cardiac TFs, the most ubiquitously expressed is the zinc finger protein GATA4. In cardiomyocytes, GATA4 is central to proliferation, differentiation, hypertrophy and induction of pro-survival pathways. In cardiac endothelial cells, it is required for valve and septal development, although the exact mechanisms remain unclear. To regulate such a wide array of functions in a spatially and temporally controlled manner, GATA4 interacts with specific protein partners, the majority of whom have been identified in cardiomyocytes. However, a complete understanding of the protein interactome of GATA4, particularly in cardiac endothelial cells, has not yet been achieved. Using a mass spectrometry-based approach, we have identified a series of novel GATA4 interacting partners in cardiac endothelial cells. 3xFlag GATA4 was stably overexpressed via retroviral transduction in the TC13 cardiac endothelial precursor cell line, immunoprecipitated from nuclear protein extracts and sent for HPLC-ESI-MS/MS. Several novel GATA4 interacting partners were identified including the chaperone protein Heat Shock Protein 70 (HSP70), the inducible orphan nuclear receptor Nerve Growth Factor 1β (NGFIβ, NUR77) and the Drosophila-Binding/Human Splicing protein family members Non-POU Domain Containing Octamer Binding Protein (NONO) and Paraspeckle 1 (PSPC1). Chapter 1 discusses the interaction between GATA4 and HSP70 and its role in cardiomyocyte survival upon exposure to chemotherapeutic agent Doxorubicin (DOX). HSP70 binds directly to GATA4, preventing DOX-mediated cleavage and degradation by Caspase-1, cardiomyocyte cell death and heart failure. Chapter 2 focuses on the cooperative interaction between GATA4 and NUR77 in cardiac microvascular endothelial cells and its central role in myocardial angiogenesis in response to pressure overload. The GATA4-NUR77 complex transactivates the promoter of Angiopoietin-Like 7 (ANGPTL7), a secreted pro-angiogenic chemotactic factor, triggering endothelial cell proliferation and tube formation in cultured cardiac endothelial cells and increasing myocardial capillary density in vivo. Chapter 3 discusses the interaction between GATA4 and the DBHS proteins NONO and PSPC1 in the regulation of cardiac development. These proteins play opposing roles when bound to GATA4 as PSPC1 enhances GATA4 activation of critical cardiac promoter targets and NONO acts as a rheostat to repress GATA4 activity. In vivo, loss of NONO results in left ventricular non-compaction consistent with humans with loss-of-function mutations. However, simultaneous Gata4 haploinsufficiency partially rescues this phenotype. Together, this data identifies multiple novel cell type and time point specific GATA4 protein partners and sheds light on GATA4 regulatory mechanisms in cardiac development and disease.

Resumo: O objetivo geral deste estudo foi avaliar a presença, a sintomatologia predominante e as fases do estresse, identificar estratégias de enfrentamento de problemas utilizadas por mães de crianças cardiopatas submetidas a cirurgia cardíaca, e os objetivos específicos associar as variáveis tais como estratégia de enfrentamento e cardiopatia, fase de estresse e cardiopatia, fase de estresse e faixa etária da mãe, estratégia de enfrentamento e idade da mãe, fase de estresse e estratégia de enfrentamento, classe sócio-econômica e estratégia de enfrentamento. A amostra da pesquisa constituiu-se de 60 mães de crianças cardiopatas. Foram incluídas no estudo somente as mães biológicas, as quais vivenciavam a experiência da primeira cirurgia cardíaca do filho logo após a revelação do diagnóstico. Foi um estudo epidemiológico de prevalência do tipo transversal. Os resultados indicaram que a maioria das mães apresentou estresse na fase de resistênci , fase caracterizada por demasiado estresse e vulnerabilidade a doenças, com predominância de sintomas psicológicos, a estratégia de enfrentamento prioritária foi a busca de práticas religiosas. Para a análise estatística foi utilizado o teste Qui-quadrado, que mostrou não haver associação entre as variáveis tipo de cardiopatia com as estratégias de enfrentamento P= 0,840, cardiopatia com a fase de estresse P= 0,675, fase de estresse com estratégia de enfrentamento P= 0,375, fase de estresse com faixa etária, estratégia de enfrentamento com faixa etária e classe social com estratégia de enfrentamento P= 0,444, pois os valores de P foram > 0,05. Com base nos resultados obtidos concluiu-se que é necessário uma intervenção profissional com o objetivo de acolher, orientar e disponibilizar recursos de auxílio as mães desde o diagnóstico à alta hospitalar da criança para favorecer a um enfrentamento e adaptação... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Study general objectives: to assess stress and coping in mothers of children with congenital heart disease who had undergone surgery; and specifics objectives to associate coping style, stress, mothers age, heart disease and social class. Methods: Sixty mothers whose children had undergone surgery for congenital heart disease filled the Lipp Stress Symptoms Inventory for Adults, and the Ways of Coping Scale. Results: most mothers were in the resistance stage of stress. Psychological symptoms of stress were predominant and the most used coping strategy was religion. Chi-square test showed no association (p≤0.05) between heart disease and coping style (p = 0,840), heart disease and stress stage (p = 0,675), stress stage and coping (p = 0,375), stress and age, coping and age and social class and age and social class and coping (P = 0,444). The presence of and age stress in the resistance stage in most participants indicates the need for professional intervention from diagnosis until the discharge after surgery, to favor positive coping strategies and a better quality of life for mother and child. / Orientador: Antonio Sergio Martins / Coorientador: Ulisses Alexandre Croti / Banca: Marcos Augusto de Moraes Silva / Banca: Reinaldo Ayer de Oliveira / Mestre

Congenital heart disease is the most common form of birth defect, affecting approximately 1% of liveborn babies. Secundum atrial septal defect (ASD) is the second most common form of congenital heart disease (CHD). Most cases have no known cause. Chromosomal, syndromal and teratogenic causes account for a minority of cases. The hypothesis that mutations in the ASD genes NKX2-5 and GATA4 may cause apparently sporadic ASD was tested by sequencing them in unrelated probands with ASD. In this study, 1/102 individuals with ASD had an NKX2-5 mutation, and 1/129 had a deletion of the GATA4 gene. The cardiac transcription factor TBX20 interacts with other ASD genes but had not previously been associated with human disease. Of 352 individuals with CHD, including 175 with ASD, 2 individuals, each with a family history of CHD, had pathogenic mutations in TBX20. Phenotypes included ASD, VSD, valvular abnormalities and dilated cardiomyopathy. These studies of NKX2-5, GATA4 and TBX20 indicate that dominant ASD genes account for a small minority of cases of ASD, and emphasize the considerable genetic heterogeneity in dominant ASD (also caused by mutations in MYH6 and ACTC). A new syndrome of dominant ASD and the Marcus Gunn jaw winking phenomenon is reported. Linkage to known loci was excluded, extending this heterogeneity, but a whole genome scan did not identify a candidate locus for this disorder. Previous studies of inbred laboratory mice showed an association between patent foramen ovale (PFO) and measures of atrial septal morphology, particularly septum primum length (???flap valve length??? or FVL). In humans, PFO is associated with cryptogenic stroke and migraine, and is regarded as being in a pathological contiuum with ASD. Twelve inbred strains, including 129T2/SvEms and QSi5, were studied, with generation of [129T2/SvEms x QSi5] F1, F2 and F14 mice. Studies of atrial morphology in 3017 mice confirmed the relationship between FVL and PFO but revealed considerable complexity. An F2 mapping study identified 7 significant and 6 suggestive quantitative trait loci (QTL), affecting FVL and two other traits, foramen ovale width (FOW) and crescent width (CRW). Binary analysis of PFO supported four of these.