published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

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.

Thesis (M.A.)--Northern Kentucky University, 2007. / Made available through ProQuest. Publication number: AAT 1447123. ProQuest document ID: 1414126941. Includes bibliographical references (p. 30-31)

Thesis (M.Med.Sc.)--University of Hong Kong, 2002. / Includes bibliographical references (leaves 25-30). Also available in print.

OBJECTIVES: Congenital heart disease or CHD is a condition that affects 8 out of every 1,000 newborns. Every year more than 35,000 newborns are diagnosed with a congenital heart disease in the United States. Neonates and children with congenital heart disease are at increased risk for thrombotic events, especially those with a single ventricle physiology. The objective of this study was to assess the incidence and to identify the predictors of thrombosis in neonates and children with surgical and non-surgical heart diseases. METHODS: We performed a retrospective analysis of the Health Care and Cost Use Project Kid’s Inpatient Database. Neonates and children with a congenital heart disease were identified using the international classification of disease, 9th revision, clinical modification (ICD-9 CM) diagnostic codes, and grouped into two sub-categories of surgical heart and non-surgical heart diseases. These groups were further divided into four types of lesions: septal defects, single ventricle physiology, right ventricle outflow tract obstruction, and left ventricle outflow tract obstruction. Demographic characteristics, the presence of co-morbidities, the incidence of any thrombotic events, mortality rate, and the presence of additional complications such as acute kidney injury, sepsis, neurologic complications, the need for extracorporeal membrane oxygenation or ventricular assist device were also collected using ICD-9 CM codes. After propensity-matched analysis, neonates and children with a surgical congenital heart disease were compared with those with a non-surgical heart disease. We used uni- and multivariable logistic regression analysis to identify the predictors associated with the incidence of thrombotic events in both sub-group. RESULTS: In children with surgical heart disease, the incidence of thrombosis was 3.90%, compared with 2.13% in children with non-surgical heart disease. Furthermore, those with single ventricle physiology (surgical 2.13%; non-surgical 3.41%) or right ventricle outflow tract obstruction (surgical 1.54%; non-surgical 1.66) had the highest incidence of thrombosis. In addition to demographic characteristics (e.g. age) and the type of congenital heart disease, we observed that extracorporeal membrane oxygenation (ECMO) or ventricular assist device(VAD), the presence acute kidney injury, sepsis, and coagulopathy were strong predictors for the development of thrombotic events. CONCLUSIONS: Children with both surgical and non-surgical heart disease have an increased risk for thrombotic events, but those with a single ventricle physiology or a right ventricle outflow tract obstruction had a further increased risk.

Congenital heart disease (CHD) is characterized by structural defects of the heart and great vessels. It is the most common birth defect, affecting an estimated 1% of live births, and is the leading cause of mortality among birth defects. Despite recent progress in genetic research, more than 50% of CHD cases remain unexplained. An estimated 23% are due to aneuploidies and copy number variants and up to 30% has been attributed to de novo variation, though that number ranges between 3-30% depending on CHD complexity. The contribution of somatic mosaicism, or de novo genetic mutations arising after oocyte fertilization, to congenital heart disease (CHD) is not well understood due to limitations in sample size, detection method, and validation rate. Further, the relationship between mosaicism in blood and cardiovascular tissue has not been determined. We developed a computational method, Expectation-Maximization-based detection of Mosaicism (EM-mosaic), to analyze mosaicism in exome sequences of 2530 CHD proband-parent trios. EM-mosaic accurately detected 309 mosaic mutations in blood, with 85 of 94 (90%) candidates tested independently confirmed. We found twenty-five likely damaging mosaics in plausible CHD-risk genes, affecting 1% of our cohort. Variants in these genes predicted as damaging had higher variant allele fraction than benign variants, suggesting a role in CHD. The frequency of protein-coding mosaic variants detectable in blood was 0.122 or roughly 1 in 8 individuals. Analysis of 66 individuals with matched cardiac tissue available revealed both tissue-specific and shared mosaicism, with shared mosaics generally having higher allele fraction. CHD patients often present with comorbid cardiac and extracardiac anomalies that further their impact quality of life. Neurodevelopmental disorders (NDDs) are especially prevalent in CHD cases compared to the general population, yet the underlying genetic causes remain poorly explained. Further, patients with single ventricle defects undergoing surgery often later develop arrhythmias and experience worsening ventricular function. We used a statistical approach to dissect the association between de novo variation and these clinical outcomes and found that pleiotropic mutations contribute a large fraction of the risk of acquiring NDD and abnormal ventricular function phenotypes in CHD patients. We developed a proof-of-concept rare variant risk score that combines information from de novo, rare transmitted, and copy- number variants and show that prediction of outcomes such as NDD can be improved, especially in complex CHD cases.

A 36-year-old woman was seen with complaints of exertional chest pain and shortness of breath. Her medical history included atrial fibrillation and diabetes. Physical examination was unremarkable except for an irregular cardiac rhythm. Myocardial perfusion imaging revealed the presence of a large area of infarction involving the entire anterior and apical walls and part of the anteroseptal wall with minimal periinfarct ischemia. Computed tomography coronary angiogram revealed an anomalous left main coronary artery arising from the main pulmonary artery. Right and left heart catheterizations demonstrated moderate pulmonary hypertension with a slight step-up in oxygen saturation between the right ventricle and main pulmonary artery. Coronary angiography showed a large tortuous right coronary artery with collaterals to the left anterior descending artery that drained into the main pulmonary artery. She was referred for surgery. This case demonstrates a rare coronary artery anomaly in an adult where survival is dependent on collateral circulation.

No description available.

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)

The purpose of this literature review is to discuss the mechanisms of a cardiac arrest and how it contributes to the high-risk classification of congenital heart disease patients. While assessing the diagnoses process and types of treatments applied to cardiac arrest and congenital heart disease separately, we further explain this information’s significance by combining their incidence rates and analyzing their associations as it relates to surgical operations. A narrative review of studies is conducted in pediatrics and adults to reveal distinctions in lesion characteristics and interventions, as well as limitations that permit inconsistencies in data reports on health outcomes. There is not adequate research and data collection in reference to perioperative cardiac arrest in congenital heart disease patients and the aim of this paper is to highlight the need for further studies and to present current research that has been conducted to fill the gaps of this global health issue.