No description available.

No description available.

Congenital Heart Defects (CHDs), structural heart defects that are present at birth, are prevalent in approximately 1% of live births. While, historically, the presence of such defects was associated with a heightened risk of mortality, advances in medicine have allowed nearly 85% of individuals with CHDs to live into adulthood. As such, many of these individuals are reaching reproductive age and are becoming pregnant. In order to understand the implications of pregnancy among women with CHDs, a literature review was undertaken in order to elucidate the conditions that may present to the mother, as a product of the underlying defect, as well as to discern the impact of a maternal CHD on the child. Pregnancy induces hemodynamic alterations, such as an increase in stroke volume and heart rate (and thus cardiac output), and brings about an increase in blood volume. In populations with CHD, these hemodynamic changes may induce particular risks to the mother, as her cardiac condition may obstruct her ability to cope to with the heightened stress on the heart. Moreover, given that the heart may not function in an ideal manner, a less than ideal environment is present in-utero. Women with CHD suffer from elevated cardiovascular and obstetric complications, with the risk of some cardiovascular events extending into the post-partum period. During pregnancy, approximately 11% of women with CHD will experience a cardiovascular complication; this risk is highest among those with complex forms of the defect. Arrhythmia, specifically, is the most common complication, and will occur in 4.5% of pregnancies. Heart failure is also frequent, occurring in 4% to 5% of pregnancies, with the highest risk presenting in those patients with Eisenmenger syndrome and those with cyanotic forms of CHD. Pulmonary edema and thrombolytic events are also present in this population with a higher prevalence than in a healthy pregnant population. In the 6-month period after delivery, 12% of women with CHD will experience a cardiac event, with arrhythmia and heart failure as the most common complications. Obstetric complications occur in approximately 5% of pregnancies among women with CHDs, with 11% experiencing premature labor, 8.4% experiencing post-partum hemorrhage and 5.5% experiencing pregnancy-induced hypertension. Miscarriage occurs in 15% of pregnancies, with a dose-response type relationship associated with the severity of the underlying defect, as miscarriage occurs in up to 66% of pregnancies in those with Fontan palliation. Premature rupture of membranes occurs in 3.5% of pregnancies, with half of these cases occurring to patients with transposition of the great arteries. Termination of pregnancy also occurs in 5% to 8% of pregnancies, given high risk of complications to both mother and fetus. While preeclampsia is expected to occur in approximately 2-3% of pregnancies, this risk does not exceed what occurs in a healthy population. With regard to the impact of maternal CHD on the fetus, events occurring to the fetus/neonate include preterm delivery, small for gestational age, respiratory distress syndrome, intraventricular hemorrhage, and neonatal death. Between 1.5% and 2% of pregnancies will terminate in fetal mortality. Premature birth is likely in 12% to 20% births, with of 8% of neonates born as small for gestational age. Moreover, 3.5% of children born to mothers with CHD will present with CHD, themselves. Long-term effects of maternal CHD are not well-described. Despite these complications, pregnancy among women with CHD is well-tolerated and only in very few cases of those presenting with severe defects, is pregnancy counter-indicated. However, in order to mitigate risks, pre-pregnancy counseling is recommended in all women with CHD, regardless of severity of the defect. Counseling should include an overview of the form of defect, any surgical or medicinal interventions undertaken in response to the defect, an echocardiography, an exercise stress test, among other evaluations. Monitoring of the pregnancy should continue throughout gestation and delivery should occur in a specialized care facility and the mother and fetus should be monitored by a consortium of cardiologists, obstetricians, anesthesiologists, midwives. Monitoring of the mother should extend into the post-partum period until any cardiovascular or hemodynamic pregnancy-related alterations have returned to normal.

There is relatively little epidemiologic information about Ebstein anomaly (EA) ─ a rare congenital heart defect. Thus, we analyzed characteristics of EA in a geographically and ethnically diverse population. Data from the National Birth Defects Prevention Study were used to study infants born from 1997-2007 with EA. Birth prevalence and prevalence ratio (PR) estimates were derived from the number of affected infants per 10,000 live births in the catchment area. Case characteristics were examined, stratified by the presence of other cardiac and extracardiac defects. Predictive modeling using logistic regression was conducted to understand infant mortality risk factors. There were 249 cases with EA, for a birth prevalence of 0.55/10,000 live births. Other cardiac defects were present in 41.0% and extracardiac defects in 10% of cases. Prevalence was higher among multiple births compared to singletons (PR 2.41, 95% confidence interval (CI) 1.46-3.92) and preterm compared to term infants (PR 1.84, 95% CI 1.27-2.64). Compared to EA cases without other defects, those with additional defects were more likely to die (crude Odds Ratio (cOR) 4.07, 95% CI 1.71-9.93) or undergo cardiac surgery (cOR 6.06, 95% CI 2.78-13.49). Risk for death during infancy was increased by being small for gestational age (adjusted (a) OR 2.97, 95% CI 1.13-7.76) and having extracardiac defects (aOR 6.31, 95% CI 2.28-17.52). Some findings are consistent with previous work, but further studies of EA could clarify risk factors for occurrence and mortality. Knowing population characteristics could guide development of prevention strategies and may improve clinical care.

No description available.

Children with Down Syndrome (DS) experience cognitive delays with language being one of the most impaired domains. Exploring the effects of congenital heart defects (CHD), hospitalization, hearing impairment, and parental concern can provide a more precise view of factors affecting language development. Participants were 49 children with DS, 22 to 54 months of age. Expressive and receptive vocabulary size was obtained using a word count with the MacArthur Communication Development Inventory (MCDI). Medical information was obtained from the child’s medical file. Results showed expressive vocabulary was marginally significantly different between children with DS and no CHD, a CHD that did not require surgery, and a CHD that did require surgery, such that children with a CHD requiring surgery had the smallest vocabulary. Children had significantly more health problems when they had a CHD that required surgery. Expressive and receptive vocabularies were significantly smaller for children with hearing impairment.

Congenital heart defects (CHD) are structural anomalies affecting the heart, are found in 1% of the population and arise during early stages of embryo development. Without surgical and medical interventions, most of the severe CHD cases would not survive after the first year of life. The improved health care for CHD patients has increased CHD prevalence significantly, and it has been estimated that the population of adults with CHD is growing ~5% per year. Understanding the causes of CHD would greatly help improve our knowledge of the pathophysiology, family counseling and planning and possibly prevention and treatment in the future. The aim of my thesis was to identify novel or known CHD genes enriched for rare coding genetic variants in isolated CHD cases and learn about the relative performance of different study designs. High-throughput next generation sequencing (NGS) was used to sequence all coding genes (whole exome) coupled with various analytical pipelines and tools to identify candidate genes in different family-based study designs. Since there is no general consensus on the underlying genetic model of isolated CHD, I developed a suite of software tools to enable different family-based exome analyses of de novo and inherited variants (chapter 2) and then piloted these tools in several gene discovery projects where the mode of inheritance was already known to identify previously described and novel pathogenic genes, before applying them to an analysis of families with two or more siblings with CHD. Based on the tools developed in chapter 2, I designed a two-stage study to investigate isolated parent-offspring trios with Tetralogy of Fallot (chapter 3). In the first stage, I used whole exome sequence data from 30 trios to identify genes with de novo coding variants. This analysis identified six de novo loss-of-function and 13 de novo missense variants. Only one gene showed recurrent de novo mutations in NOTCH1, a well known CHD gene that has mostly been associated with left ventricle outflow tract malformations (LVOT). Besides NOTCH1, the de novo analysis identified several possibly pathogenic novel genes such as ZMYM2 and ARHGAP35, that harbor de novo loss-of-function variants (frameshift and stop gain, respectively). In the second stage of the study, I designed custom baits to capture 122 candidate genes for additional sequencing using NGS in a larger sample size of 250 parent-offspring trios with isolated Tetralogy of Fallot and identified six de novo variants in four genes, half of them are loss-of-function variants. Both of NOTCH1 and its ligand JAG1 harbor two additional de novo mutations (two stop gains in NOTCH1 and one missense and a splice donor in JAG1). The analysis showed a strongly significant over-representation of de novo loss-of-function variants in NOTCH1 (P=3.8 ×10-9). To assess alternative family-based study design in CHD, I combined the analysis from 13 isolated parent-offspring trios with 112 unrelated index cases of isolated atrioventricular septal defects (AVSD) in chapter 4. Initially, I started with a case/control analysis to test the burden of rare missense variants in cases compared with 5,194 ethnically matching controls and identified the gene NR2F2 (Fisher exact test P=7.7×10-07, odds ratio=54). The de novo analysis in the AVSD trios identified two de novo missense variants in the same gene. NR2F2 encodes a pleiotropic developmental transcription factor, and decreased dosage of NR2F2 in mice has been shown to result in abnormal development of atrioventricular septa. The results from luciferase assays show that all coding sequence variants observed in patients significantly alter the activity of NR2F2 target promoters. My work has identified both known and novel CHD genes enriched for rare coding variants using next-generation sequencing data. I was able to show how using single or combined family-based study designs is an effective approach to study the genetic causes of isolated CHD subtypes. Despite the extreme heterogeneity of CHD, combining NGS data with the proper study design has proved to be an effective approach to identify novel and known CHD genes. Future studies with considerably larger sample sizes are required to yield deeper insights into the genetic causes of isolated CHD.

INTRODUCTION: Congenital Heart Defects are the most common congenital defects in the United States. They affect a significant proportion of all births, and many babies with CCHDs are not expected to survive their first year. While diagnostic and surgical interventions have drastically improved mortality rates, a growing population of adolescent and adult CHD patients continue to face unique developmental, psychological and QoL issues. METHODS: Medical journal articles were utilized to determine the prevalence, mortality rates, survival rates, adverse psychological outcomes, and follow-up rates for CHD patients as they transitioned through adolescence. Most articles came from Pediatrics, The Journal of Pediatrics, and Circulation. RESULTS: From 1980-2005, the prevalence of CHDs in the United States increased, while CHD mortality decreased by nearly half. Over a similar time period, CHD patients were more likely to have poor psychological, behavioral, and QoL outcomes than their healthy peers. Specifically, CHD patients were likely to have developmental disorders, lower QoL, and loss to follow-up when transitioning to adult care providers. CHD patients also demonstrated a poor understanding of their condition, especially with respect to need for follow-up, identifying symptoms of deteriorating heart condition, and the negative effects of smoking, drugs, and alcohol. DISCUSSION: Diagnostic and surgical interventions for CHD patients have led to increased survival. However, many of these interventions occur in the early stages of life, leaving a gap in medical management of CHD patients as they transition through adolescence. This is represented by high attrition rates for those following-up with adult care providers, adverse psychosocial outcomes, and patients’ lack of knowledge about their condition. CHD patients may benefit from more comprehensive, coordinated and formal transition programs that incorporate good social support systems, self-efficacy, and education about their condition.

Single ventricle heart defects are present in two of every 1000 live births in the US. In this condition the systemic and pulmonary blood flow mix in the functioning ventricle, resulting in insufficient blood oxygenation to sustain life. As part of the palliation of these defects, the staged surgical procedure, known as the Fontan procedure, is performed. Here, the venous returns are directed to the pulmonary arteries, bypassing the right heart and forming the Total Cavopulmonary Connection (TCPC). Even though the palliation improves life expectancy, there are numerous long-term complications that become more prevalent as patients reach adulthood. Many of these complications have been related to the function of the single ventricle circulation, especially to the abnormal TCPC hemodynamics, for which this has been the focus of research throughout the years. Recent progress has been made with the availability of improved medical imaging techniques and computational modeling tools; however, there is limited information on how these evolve in time. In order to improve the Fontan palliation, image-based surgical planning has been used in the most complex cases to prospectively design the TCPC, aiming to improve the hemodynamics. Even though this paradigm has shown promising results, improvement is needed to provide more realistic predictions of the post-operative outcomes. To address this, in this thesis we have developed a novel surgical planning framework that allows us to: (i) model the interaction of the TCPC and global circulation hemodynamics, and (ii) assess the robustness of the surgical option proposed. Here, the single ventricle circulation is modeled using a lumped parameter model, coupled to a computational fluid solver to describe the local TCPC hemodynamics. With this framework, we can predict the immediate post-operative state, model various physiological scenarios, and assess the impact on the local hemodynamics and global circulation. This will allow us to provide information on the effect on the global hemodynamics to the clinical team. In addition to the surgical planning advancements obtained in this thesis, we have performed the largest longitudinal Fontan study to date in which we have evaluated the evolution of the Fontan physiology in time and the effect it has on the energy efficiency of the TCPC. In this thesis, we have studied the short and long-term effects that geometrical and physiological changes have on the Fontan hemodynamics. With this, we have improved the understanding of the Fontan physiology in terms of the short-term effects of Fontan palliation and the long-term deterioration of the changing single ventricle physiology.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / Estudos que abordem a acurÃcia das caracterÃsticas definidoras (CD) podem contribuir para o aprimoramento do raciocÃnio clÃnico, conduzindo, por conseguinte, a formulaÃÃo de diagnÃsticos de enfermagem mais condizentes com a situaÃÃo clÃnica do paciente. Diante do exposto, o estudo teve como objetivo determinar as medidas de acurÃcia das CD do diagnÃstico de enfermagem PadrÃo respiratÃrio ineficaz (PRI) em crianÃas e adolescentes com cardiopatias congÃnitas (CC). A amostra incluiu 61 crianÃas e adolescentes com idade de 5 a 17 anos, diagnosticados com CC. Estes indivÃduos foram examinados pela pesquisadora, que realizou um exame fÃsico, enfocando a avaliaÃÃo respiratÃria. Em seguida, o mÃdico que atendia o paciente foi consultado para autorizar a realizaÃÃo dos testes de funÃÃo pulmonar (espirometria e manovacuometria). As informaÃÃes obtidas a partir do exame fÃsico e realizaÃÃo dos testes foram analisadas pela pesquisadora para determinar a presenÃa ou ausÃncia das CD de PRI, com base em um protocolo previamente estabelecido. Ressalta-se que 30 crianÃas e adolescentes nÃo receberam anuÃncia mÃdica para realizar os testes de funÃÃo pulmonar. Apesar disto, estes sujeitos foram incluÃdos na amostra para determinaÃÃo do diagnÃstico apenas com base nas CD provenientes da entrevista e do exame fÃsico. Com isto, duas subamostras foram formadas, sendo a primeira composta por 30 crianÃas e adolescentes que nÃo realizaram os referidos testes, e a segunda por 31 indivÃduos que realizaram tais exames. O conjunto de CD para cada crianÃa e adolescente foi organizado em 92 planilhas. Nestas, foi assinalada a presenÃa ou ausÃncia da CD. Cada avaliaÃÃo dos indivÃduos da segunda subamostra deu origem a duas planilhas, uma apenas com as CD provenientes da entrevista e exame clÃnico, e outra com estes mesmos dados acrescidos Ãs informaÃÃes dos testes de funÃÃo pulmonar. Tais planilhas foram submetidas a dois enfermeiros diagnosticadores que determinaram a ocorrÃncia de PRI. A anÃlise das inferÃncias e as informaÃÃes sobre a ocorrÃncia das CD possibilitaram a estimativa das medidas de acurÃcia. Para a primeira subamostra, a caracterÃstica que evidenciou melhores medidas de acurÃcia foi taquipneia. As inferÃncias realizadas para a segunda subamostra, com base nos dados clÃnicos e de entrevista, apresentaram como principais CD: ortopneia e uso da musculatura acessÃria para respirar. Quando os resultados dos testes de funÃÃo pulmonar foram acrescidos, as inferÃncias dos diagnosticadores nÃo evidenciaram medidas de acurÃcia com significÃncia estatÃstica para nenhuma das CD. Com isto, os resultados do presente estudo levantam questionamentos acerca da importÃncia dos testes de funÃÃo pulmonar para a inferÃncia do diagnÃstico PRI. Ademais, algumas caracterÃsticas nÃo mostraram legitimidade para PRI, a saber: assumir uma posiÃÃo de trÃs pontos, bradipneia, diÃmetro Ãntero-posterior aumentado, capacidade vital diminuÃda, pressÃo expiratÃria diminuÃda e ventilaÃÃo-minuto diminuÃda. Assim, acredita-se que novas pesquisas sÃo necessÃrias tanto para confirmar estes achados, como para esclarecer a relaÃÃo de tais CD com o diagnÃstico em questÃo. As medidas de acurÃcia obtidas ajudaram a identificar quais CD sÃo mais representativas de PRI. AlÃm disto, os resultados possibilitaram reconhecer quais caracterÃsticas sÃo menos utilizadas durante a inferÃncia deste diagnÃstico em crianÃas e adolescentes com cardiopatias congÃnitas. / Studies which address the accuracy of the defining characteristics (DC) may contribute to the improvement of diagnostic reasoning, leading to the formulation of nursing diagnoses which are more consistent with the clinical situation of the patient. Thus, the study aimed to estimate the measures of accuracy of the DC of the nursing diagnosis Ineffective breathing pattern (IBP) in children and adolescents with congenital heart disease (CHD). The sample included 61 children and adolescents aged 5-17 years, diagnosed with CHD. These patients were examined by the researcher, who conducted a physical examination, focusing on the respiratory evaluation. Then the doctor who attended the patient was consulted to authorize the performance of pulmonary function tests (spirometry and manovacuometry). The information obtained from physical examination and from the tests were analyzed by the researcher to determine the presence or absence of DC of IBP, based on a previously established protocol. It is highlighted that 30 children and adolescents have not received medical approval to perform the pulmonary function tests. Despite this, these patients were sampled to determine the diagnosis just based on the DC from the interview and physical examination. Thus, two subsamples were formed, the first with 30 children and adolescents who did not perform such tests, and the second with 31 individuals who carried out such tests. The set of DC for each child and teenager was organized into 92 spreadsheets. In these, it was indicated the presence or absence of the DC. Each evaluation of the patients in the second subsample resulted in two spreadsheets, one only with the DC from the interview and clinical examination, and another with these same data added information from the pulmonary function tests. These spreadsheets were submitted to two nurses diagnosticians which determined the occurrence of IBP. The analysis of the inferences and the information on the occurrence of DC allowed the estimation of measures of accuracy. For the first subsample, the DC that showed better measures of accuracy was tachypnea. The inferences made for the second subsample, based on clinical data and interviews, presented as main DC: orthopnea and use of accessory muscles to breathe. When the results of pulmonary function tests were added, the inferences of the diagnosticians showed accuracy measures without statistical significance for all DC. With this, the results of this study raise questions about the importance of pulmonary function tests for the inference of the nursing diagnosis IBP. Furthermore, some DC showed no legitimacy for IBP, as follows: assumption of three point position, bradypnea, increased anterior-posterior diameter, decreased vital capacity, decreased expiratory pressure, and decreased minute ventilation. Thus, it is believed that further research is needed to confirm these findings, as well as to clarify the relationship of such DC with the diagnosis IBP. The measures of accuracy obtained helped identify which DC is more representative of IBP. Moreover, the results allowed to recognize which features are less used during the inference of this diagnosis in children and adolescents with congenital heart disease.