Dissertations / Theses on the topic 'Congenital heart diseases (CHD)'

Respiratory Syncytial Virus (RSV) infection is common among young children. Congenital Heart Disease (CHD) is a risk factor of severe illness and hospitalization. Palivizumab prophylaxis reduces the severity of RSV infection and reduces the risk of hospitalization for children at high risk of severe illness, such as children born premature or with CHD. The aim of this thesis was to evaluate compliance with national guidelines for prophylactic treatment and to study the Relative Risk (RR) of hospitalization due to RSV and unspecified Respiratory Tract Infection (RTI) for children with CHD. In a prospective study, questionnaires were sent to all paediatric cardiology centres in Sweden with questions about prophylactic treatment. Hospitalization rates were retrieved from the national inpatient registry. Heart defects were grouped according to type and the relative risk of hospitalization was calculated for each group and for summer and winter seasons. Half of the patients received prophylactic treatment later than recommended in the guidelines. The risk of hospitalization due to RSV infection was increased (RR=2.06 95% CI 1.6-2.6; p < 0.0001) for children with CHD compared to children without CHD. The RR of hospitalization was also increased for all CHD subgroups, and was further increased during summer for children with the more severe CHD. We conclude that guidelines for prophylactic treatment were not followed and that the risk of hospitalization due to RSV and unspecified RTI was increased for all subgroups of CHD. The risk was increased both during winter and summer and we therefore argue that information to health personnel and parents should include that the risk of severe RTI is present all year round for children with CHD.
Respiratoriskt syncytialvirus (RSV) är det vanligaste förkylningsviruset och de allra flesta barn drabbas före två års ålder. RSV kan leda till allvarlig luftvägsinfektion hos alla barn, men speciellt hos dem med medfött hjärtfel. Någon botande läkemedelsbehandling finns inte för RSV, utan de medicinska insatserna får inriktas mot att mildra sjukdomsförloppet och för svårt sjuka barn krävs sjukhusvård för att exempelvis erhålla syrgasbehandling. Det finns inget vaccin mot RSV, men barn som riskerar att bli svårt sjuka kan behandlas profylaktiskt med en monoklonal antikropp (Palivizumab) som ges som injektion en gång per månad under vintersäsong. Vissa barn med svårt hjärtfel får denna profylaktiska behandling enligt nationella riktlinjer. Vår första studie visade att ungefär hälften av barnen med medfött hjärtfel, aktuella för profylax mot RSV, fick behandlingen senare än vad de nationella riktlinjerna rekommenderade. Denna studie genomfördes via en enkät till alla landets barnkliniker under två vintersäsonger. Vi såg även att något fler barn än förväntat (4.6%) fick RSV-infektion trots profylaktisk behandling och för cirka en tredjedel av dessa barn fördröjdes tiden till hjärtoperation. Behovet av sjukhusvård kan användas som mått på hur svårt ett sjukdomsförlopp är, och baserat på Socialstyrelsens slutenvårdsregister studerade vi alla barn under två års ålder och fann att den relativa risken för sjukhusvård på grund av RSV var högre för barn med hjärtfel än för barn utan hjärtfel (RR=2.06 95% CI 1.6-2.6; p < 0.0001). I vår andra studie, baserad på slutenvårdsregistret, beräknade vi den relativa risken för sjukhusvård på grund av RSV, för barn med olika former av hjärtfel och uppdelat i sommar- och vintersäsong. Risken för sjukhusvård var ökad för alla barn oavsett typ av hjärtfel, och detta gällde såväl under vintern som under sommaren. Barn med de allvarligaste formerna av hjärtfel hade högre risk för sjukhusvård under sommaren jämfört med deras risk under vintern, medan barn med vad som anses vara lättare hjärtfel hade ökad risk för sjukhusvård under hela året, utan någon större skillnad i risk mellan vinter och sommar. Att barn med hjärtfel riskerar att bli svårt sjuka i RSV är väl känt, men våra resultat visar att denna risk även existerar under sommarhalvåret, då det inte är RSV-säsong och då profylax inte ges. Vi fann också att barn med vad som anses vara lättare hjärtfel löper lika stor risk att drabbas av svårare sjukdomsförlopp med sjukhusvård under vintern, som barn med svårare hjärtfel. Att denna information sprids till såväl sjukvårdspersonal som arbetar med denna patientgrupp som till föräldrar med hjärtsjuka barn är viktigt, för att belysa att även dessa barn behöver skyddas, och detta inte bara under vintern och RSV-säsongen.

Congenital Heart Disease (CHD) is one of the most common birth defects. It is the single most modifiable cause of infant mortality under one year of age. Therefore, the causes of CHD have been extensively researched in the past but the etiology remains largely unknown. Environmental risks, particularly maternal risk factors for congenital cardiac malformation have been evaluated in the original BWIS previously. However, in this research we examined one of the additional risk factors. We sought to determine whether maternal headache during six months prior to conception and throughout gestation until birth is a risk factor for CHD in the BWIS dataset. Among 3274 singleton cases and 3519 controls, a maternal report of headache was found to be associated with a nearly 20% increase in the risk of a congenital heart defect (OR= 1.2 p=0.001). Moreover, any medications use for headache 1-6 months prior to conception increased the risk of abnormal cardiac development by 1.3 fold (OR = 1.3, p=0.0004). Aspirin or aspirin containing analgesics were found to increase the risk for CHD at the defined risk period. According to subgroup analysis, aspirin or aspirin containing analgesics and acetaminophen or acetaminophen containing analgesics were found to be the risk factor for CTD i.e. Conotruncal defects. Furthermore, aspirin or aspirin containing analgesics increased the risk for PVSD i.e. Peri-membranous Ventricular Defect in offspring when the mother uses these drugs 1-6 months prior to conception. Additionally, the risk for CVD i.e. critical valve disease were found to be increased when women were exposed to aspirin or aspirin containing analgesics during third trimester after pregnancy. In conclusion, maternal headache increased the risk for CHD by 20% and the use of headache medications specifically pain relievers during 1-6 months prior to conception modulated type of defect was observed.

Background: Approximately 1000 children with a congenital heart disease are born in Sweden each year. Congenital heart diseases include malformations of the heart which comprise various anatomical differences. Progresses in diagnostics and treatment of the cardiac diseases have contributed to the survival of these young adults which makes a new and growing group of patients. Aim: The aim of this study was to describe young adults' between the ages of 13-40 experiences of living with congenital heart disease. Method: A literature study based on qualitative studies from Cinahl and PubMed was performed. Ten articles were analyzed by content analysis. Results: The results of the study present two main categories "accept one's heart disease" and "challenge to accept one's heart disease" with a total of ten subcategories. Conclusion: Individuals with congenital heart disease may experience their situation in various ways and they may or may not have accepted their congenital heart disease. Some individuals feel that the disease contributes to personal strength, while others are living with a constant presence of anxiety over the fact that life can change for the worse at any time.

Les cardiopathies congénitales (CC) sont les plus fréquentes des malformations congénitales et concernent près de 1% des naissances. Grâce aux progrès considérables de la cardiologie pédiatrique et de la chirurgie cardiaque, 90% des enfants nés avec une CC atteignent désormais l'âge adulte. Mais ces « survivants » ne sont pas guéris. Un certain nombre de complications, cardiaques et extracardiaques, attendues ou non, et de problématiques spécifiques émergent, justifiant une consommation de soins grandissante. Le besoin d’études en population a motivé l’analyse secondaire de données médico-administratives dans diverses régions du globe. L’objectif de cette thèse était d’étudier les conditions d’utilisation des bases de données médico-administratives (BDMA) et leurs applications possibles pour mieux comprendre les enjeux émergents de cette population nouvelle d’adultes avec CC (ACC). La première partie de ce travail a été de décrire de manière systématique toutes les études ayant utilisé des BDMA pour explorer spécifiquement les problématiques des patients ACC. Cette revue a montré l’intérêt de ces bases de données dans le domaine des ACC, les effectifs importants permettant d’étudier des maladies relativement rares et la disponibilité de données exhaustives sur de longues périodes d’observation autorisant l’étude de certaines complications cardiaques ou extracardiaques de survenue parfois différée chez ces patients. En France, les bases de données administratives de remboursement utilisent la Classification internationale des Maladies, dixième révision (CIM-10) dont la fiabilité pour repérer les ACC et les pathologies qui leur sont associées est inconnue dans ce contexte. La deuxième partie de ce travail avait donc pour objectif d’étudier la performance de la CIM-10 pour identifier et classer des patients ACC au sein de l’entrepôt de données de l’hôpital Européen Georges Pompidou disposant d'une unité dédiée aux ACC. La troisième partie de cette thèse rapporte un exemple concret de l’utilisation des BDMA. A partir des données de la Québec Congenital Heart Disease Database issue des BDMA du Québec, notre objectif était d’évaluer l’association entre l’exposition aux rayonnements ionisants provenant de procédures cardiaques et la survenue de cancer chez les ACC. En effet, l’amélioration de l’espérance de vie des patients avec CC et l’augmentation du recours aux modalités d’imagerie cardiaque irradiante, font craindre un effet carcinogène potentiel à long terme. Bien qu’elles n’aient pas été conçues à des fins de recherche, ce travail de thèse montre que les BDMA sont un outil particulièrement pertinent pour générer de nouvelles connaissances sur les patients ACC de par l’exhaustivité des informations disponibles, la possibilité de produire de grands échantillons et de permettre un suivi longitudinal sur de longues périodes d'observation. L’exploitation des dossiers médicaux électroniques par des méthodes de fouilles de texte pourrait alors permettre de développer et valider des algorithmes pour identifier les cas de CC dans les BDMA. En France, bien que des efforts aient été déployés pour créer un programme de collaboration multicentrique efficace, il n’existe à l’heure actuelle aucune donnée épidémiologique d’envergure concernant l’ensemble des ACC. L’analyse secondaire de ressources existantes, telles que le Système National des Données de Santé, permettrait d’établir la cohorte nationale d’ACC et d’analyser leur parcours de soins afin d’orienter au mieux l’allocation des ressources
Congenital heart diseases (CHD) are the most common types of birth defects and affect approximately 1% of births. Ninety percent of children born with CHD reach now adulthood thanks to improvements of pediatric cardiology and cardiac surgery. These "survivors" are not definitively cured. They are prone to cardiac or extra cardiac complications and specific issues that justify an increase in consumption of healthcare. The need for population-based studies worldwide has led to secondary analyses of administrative medical databases (AMD). The objective of this thesis was to study the conditions of use of the AMD and their possible applications, specifically to understand the emerging issues of this new adult population with CHD (ACHD). The first part of this work was to systematically describe all the studies that had used AMD to specifically explore the issues of ACHD patients. This review showed the value of these databases in the field of ACHD: the large numbers of patients allows studying relatively rare diseases and the availability of comprehensive data over long periods of follow-up enables to study cardiac and extra cardiac complications even when the occurrence is delayed. In France, claim databases use the International Classification of Diseases, 10th revision (ICD-10), the reliability of which is still largely unknown in this context. The second part of this work was therefore to study the performances of ICD-10 to identify and classify ACHD patients in the data warehouse of the Georges Pompidou European Hospital which has a dedicated specialized ACHD Unit. The third part of this thesis reported a concrete example of the use of AMD. Based on the Quebec Congenital Heart Disease Database derived from Quebec’s AMD, our goal was to evaluate the association between exposure to ionizing radiation from cardiac procedures and the risk of cancer in ACHD. Indeed, the improvement in the life expectancy of patients with CHD and the increasing use of cardiac imaging modalities using ionizing radiations may have a carcinogenic effect in the long term. Although not designed for research purposes, this thesis showed that AMD are a particularly relevant tool for generating new knowledge about ACHD patients through the comprehensiveness of information, the possibility of extracting large samples of patients with a longitudinal follow-up over long periods of observation. The exploitation of electronic medical records through text mining methods could then be used to develop and validate algorithms to identify CHD patients in AMD. In France, although efforts have been made to create an effective multi-center collaborative program, there is currently no significant epidemiological data for all ACHDs. Secondary analysis of existing resources, such as the National Health Data System, would establish the national ACHD cohort and analyze their care pathway in order to guide healthcare resources allocation

Congenital heart defects (CHD) are the largest class of birth defects in humans and are a major cause of infant mortality and morbidity. Deciphering the molecular and genetic etiologies central for heart development and the pathogenesis of congenital heart diseases (CHD) is a challenging puzzle. We have previously demonstrated that the zinc-finger kruppel-like transcription factor KLF13, expressed predominantly in the atria, binds evolutionarily conserved regulatory elements known as CACC-boxes and transcriptionally activates several cardiac promoters. KLF13 loss of function in Xenopus embryos was associated with cardiac developmental defects underscoring its critical role in the heart. In the current study, using in vivo and in vitro approaches, we examined KLF13’s mechanisms of action and its interaction with other cardiac regulators. To test the evolutionary conserved role in the mammalian heart, we deleted the Klf13 gene in transgenic mice using homologous recombination. Mice with homozygote deletion of Klf13 were born at reduced frequency owing to severe heart defects. We also report the existence of a novel isoform of KLF13, referred to here as KLF13b. Furthermore, we report that KLF13 interacts biochemically and genetically with the T-box transcription factor TBX5 which is a key regulator of heart development. Our data provide novel insight into the role of KLF13 in cardiac transcription and suggest that KLF13 maybe a genetic modifier of congenital heart disease. Furthering our knowledge of protein-protein interactions and gene transcription will enhance genotype-phenotype correlation and contribute to better understanding of the etiology of CHD.

Background: Advance in cardiac intervention improved the survival of patients with congenital heart diseases (CHD). However, they may have propensity of thromboembolism and the use of antithrombotic agents was generally based on small studies and consensus opinion. Objective: To systematically review the current literature on the efficacy and safety of various antithrombotic agents in patients with CHD. Methods: Studies published in English during the period 1990 – 2012 were identified using keyword search from PubMed, Medline, EMBase, and Cochrane Library. Additional search from reference sections of the articles and clinical trial registry was performed. Data extracted included: type of studies, number of patients, follow-up period during which the patients were on the antithrombotic agents, number of thromboembolic (TE) events, and all, major and minor bleeding events. Event rate as the proportion of events of the patients and event per 100 patients-year were obtained for respective antithrombotic agent in each study. Composite event rate and event per 100 patients-year were estimated after weighting. Results: Forty studies consisted of 5144 patients were reviewed. Observation period of 8916.6 years was available in 25 studies. Diagnostic categories included: Fontan operation 15, systemic-to-pulmonary artery shunt 7, mechanical valve 8, atrial septal defect occlusion device 2, cyanotic heart 1, mixed 7. Antithrombotic prophylaxis was not used in 13 studies, warfarin in 26, aspirin alone in 22, combined aspirin and dipyridamole in 2. Clopidogrel with concomitant antithrombotic agents was reported in 5 studies. Overall composite TE event rate was 3.9% (95% CI 2.3 – 5.4%) and that of all bleeding rate was 2.8% (95% CI 0 – 5.5%), with 1.4% (95% CI 0.0 – 2.6%) for major and 2.2% (95% CI 0.0 – 4.3%) for minor bleeding. Composite TE rate for no prophylaxis (9.6%; 05% CI 3.7 – 15.5%) was significantly greater than that of warfarin (1.7%; 95% CI 0.1 – 3.3%) and aspirin (1.3%; 95% CI 0.0 – 3.0%). Both TE and all bleeding rate showed no difference between warfarin and aspirin, while major bleeding tended to be higher in warfarin than aspirin(0.9% vs 0.0%, p=0.06). Fontan patients had overall TE rate of 2.7% (95% CI 0.1 – 5.4%). Patients with no prophylaxis (10.2%; 95% CI 9.2 – 18%) had significantly greater TE rate than warfarin (1.4%; 95% CI 0.0 – 0.4%) or aspirin (1.2%; 95% CI 0.0 – 3.0%). All bleeding rate in Fontan patients was 0.5% (95% CI 0.0 – 4.3%). Both TE ad bleeding rates showed no difference between warfarin and aspirin. Overall TE rate for shunt was 7.2% (95% CI 3.7 – 14.3%), being similar between aspirin group and no antithrombotic group. Patients with mechanical valves had TE rate of 7.3% (95% CI 2.9 – 11.6%) and all bleeding rate of 7.2% (95% CI 4.2 – 10.2%). There was no statistical difference between warfarin and APA group. Patients with ASD occlusion device has TE rate of 0.1% (95% CI 0.0 – 0.2%). No bleeding event was reported in the studies. Conclusion: Patients with congenital heart diseases were at risk of developing thromboembolism which justified the use of anti-thrombotic prophylaxis. Further studies relating the thromboembolic risk profile of patients with CHD to the efficacy of anti-thrombotic agents might help in selection of anti-thrombotic agents.
published_or_final_version
Community Medicine
Master
Master of Public Health

The population of adolescent and adults with congenital heart disease (CHD) has grown rapidly. Right ventricular (RV) dysfunction remains an important issue of concern in the long-term follow up of these patients. While circulating biomarkers have shown promise in the assessment and monitoring of adult patients with left heart diseases, little is known of the role of biomarkers in reflecting RV performance in CHD patients. Emerging circulating biomarkers that reflect underlying pathophysiologic processes have gained increasing attention. These include inflammatory cytokines namely tumour necrosis factor (TNF)-α, a biomarker of apoptosis annexin A5 (AnxA5), carboxy-terminal propeptide of type I procollagen (PICP) and amino-terminal propeptide of type III procollagen (PIIINP) that reflects collagen synthesis and turnover, low circulating levels of cardiac troponin T as detected by highly sensitive assay (hs-cTnT) that may reflect subclinical myocardial injury, and microRNAs found to be involved in cardiac remodeling. The studies in this thesis aimed to test the hypothesis that circulating biomarkers may be altered in patients with volume-overloaded right ventricles after repair of tetralogy (TOF) and pressure-overloaded right ventricles after atrial switch operation for complete transposition of the great arteries (TGA), and are related to indices of RV function. In patients after TOF repair, increased circulating PICP and PIIINP levels were associated with worse subpulmonary RV and left ventricular (LV) function. In particular, these propeptides correlated positively with LV mechanical dyssynchrony, implicating a possible role of increased collagen synthesis in its pathogenesis. Increased plasma levels of hs-cTnT were further found in 30% of female, but not male patients. Female patients with elevated hs-cTnT levels compared to those without had greater RV volumes and LV mechanical dyssynchrony. Independent correlates of hs-cTnT in patients as determined from multivariate analysis were sex and RV ejection fraction. MicroRNA profiling following validation confirmed alteration of circulating levels of miR-99b and miR-766 in repaired TOF patients, a pattern distinct from that reported for left heart diseases. The miRNA expression was, however, not related to the cardiac functional indices. Patients after atrial repair for TGA had significantly higher circulating AnxA5 and TNF-αlevels, but similar PICP, PIIINP levels, compared with controls. Elevated AnxA5 level was associated with impaired systemic RV myocardial deformation, increased subpulmonary ventricular eccentricity, and increased TNF-αlevel. Elevation of hs-cTnT is found in 39% of the patients. The positive correlation between hs-cTnT level and systemic RV volume may suggest a role of hs-cTnT in reflecting RV remodeling. Circulating microRNA expression profiling and further validation identified 11 upregulated microRNAs (miR-16, miR-106a, miR-144*, miR-18a, miR-25, miR-451, miR-486-3p, miR-486-5p, miR-505*, let-7e and miR-93). Among them, miR-18a and miR-486-5p correlated negatively with systemic ventricular myocardial acceleration during isovolumic contraction, a relatively-load independent measure of systemic RV contractility. To conclude, these biomarkers reflect in varying extent the structural, functional, biological alteration of the subpulmonary and systemic right ventricles of the CHD patients late after surgical repair. These data may provide new perspectives in the understanding of progressive RV dysfunction in the adult CHD population and hopefully shed more lights on novel therapeutic interventions.
published_or_final_version
Paediatrics and Adolescent Medicine
Doctoral
Doctor of Philosophy

Objective - to assess possibilities and specific characteristics of pediatric cardiology in treatment of congenital heart diseases (CHD), to evaluate efficacy of curative per-catheter procedures by means of analysis of immediate and long-term results. Retrospective study. The data of 422 patients who underwent 467 CHD palliative-curative procedures during the period since 1971 till 2007 were analyzed. It was postulated that balloon atrial septostomy resulted in statistically significant increase of atrial septal defect, increase of arterial blood oxygen saturation and decrease of interatrial preasure gradient (PG). Balloon pulmonary valvulotomy (BPV) is one of the most common curative procedures; this procedure has an effect of marked decrease of pressure gradient between the right ventricle and right atrium; development of pulmonary artery valve insufficiency is the most common complication of this procedure. The long - term results of BPV are less positive when higher PG prior the procedure is present and residual PG after the procedure is 36mmHg and higher. It was postulated, that closure of small (less than 3 mm) persistent ductus arteriosus using Cook coils may compete with surgical treatment successfully. It was stated, that the efficacy of balloon angioplasties of aorta, caval veins and pulmonary artery branches is transient; treatment using stents is more effective. It was postulated, that closure of congenital and postsurgical anomalies connections using coils is... [to full text]
Disertacijos objektas yra nustatyti intervencinės pediatrinės kardiologijos galimybes ir ypatumus, gydant įgimtas širdies ydas (ĮŠY), įvertinti gydomųjų perkateterinių procedūrų efektingumą, remiantis ankstyvųjų ir vėlyvųjų rezultatų analize. Tai retrospektyvus tyrimas. Analizuoti 422 ligonių duomenys, kuriems 1971 - 2007 m. buvo atliekamos 467 įgimtų širdies ydų paliatyvinės - gydomosios procedūros. Nustatyta, kad po balioninės tarpprieširdinės pertvaros septostomijos, statistiškai reikšmingai padidėja prieširdžių pertvaros defektas, didėja arterinio kraujo įsotinimas deguonimi ir mažėja spaudimų skirtumas (SS) tarp prieširdžių. Balioninė plaučių arterijos valvuloplastika (BPV) yra viena iš dažniausiai taikomų gydomųjų procedūrų, jos efektas – ryškus SS tarp dešiniojo skilvelio ir plaučių arterijos (PA) sumažėjimas, o pagrindinė komplikacija – PA vožtuvo nesandarumo vystymasis. BPV vėlyvieji rezultatai blogesni, kai yra didelis SS prieš procedūrą, o po procedūros liekamasis SS ≥ 36mmHg. Nustatyta, kad mažų iki 3mm AAL kimšimas Cook spiralėmis gali sėkmingai konkuruoti su operaciniu gydymu. Rasta, kad aortos, tuščiųjų venų ir plaučių arterijos šakų balioninės plastikos efektas trumpalaikis, o gydymas stentais daug sėkmingesnis. Nustatyta, kad anomalinių įgimtų ir pooperacinių kraujagyslinių jungčių užkimšimas spiralėmis yra saugus ir efektyvus gydymo metodas.

Congenital Heart Defects (CHDs) are the most common type of human congenital anomaly, representing 0.8~1.2% of infants at birth and accounting for over 40% of prenatal deaths. Although the exact aetiology remains a significant challenge, epigenetic modifications, such as Deoxyribonucleic Acid (DNA) methylation, are thought to contribute to the pathogenesis of CHDs. We aimed to investigate the value of machine learning (ML) in enhancing CHDs diagnosis, particularly for identifying susceptive genes by exploring high-throughput DNA methylation data. The Illumina Human Methylation EPIC BeadChip was used to screen the genome-wide DNA methylation profiles of 24 infants diagnosed with CHDs and 24 healthy infants without heart diseases. Primary preprocessing was conducted by using RnBeads and limma packages. The significantly differentially-methylated CpG sites in top 660 genes with the lowest p-value were selected and further investigated by using a random forest (RF) algorithm. After training the algorithm, the RF classifiers were applied to a validation dataset of the testing samples with an accuracy rate of 100%. Three genes (MIR663, FGF3 and FAM64A) were identified not only for diagnosing CHDs, but also for predicting CHDs by RF model, with an average sensitivity and specificity of 85% and 95%, respectively. This finding highlights that aberrant DNA methylation plays a significant role in the pathogenesis of CHDs, which may provide us with a potential approach in understanding CHDs. The sample size is limited in the current study. Future research works may consider replicating and refining our key findings in large-scale studies.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior
Os cuidados de enfermagem para crianÃas com cardiopatia congÃnita devem ser estabelecidos e executados tÃo logo se suspeite do diagnÃstico de defeito cardÃaco congÃnito, voltados sempre para a detecÃÃo precoce de sinais de descompensaÃÃo e manutenÃÃo de condiÃÃes Ãtimas para a cirurgia. Objetivou-se caracterizar o quadro de diagnÃsticos de enfermagem apresentados por crianÃas com cardiopatias congÃnitas. Estudo de natureza observacional, longitudinal desenvolvido nos meses de julho a novembro de 2004. A amostra foi composta por 45 crianÃas internadas em um hospital da rede pÃblica do municÃpio de Fortaleza-CearÃ. Para a coleta, foram utilizados entrevista e exame clÃnico de enfermagem. As crianÃas foram acompanhadas durante quinze dias de internamento desde a data de sua admissÃo. No perÃodo efetivaram-se seis avaliaÃÃes diagnÃsticas com intervalo de 48 horas. O processo de elaboraÃÃo e inferÃncia dos diagnÃsticos e problemas colaborativos seguiu as etapas de coleta, interpretaÃÃo / agrupamento das informaÃÃes e nomeaÃÃo de categorias. Foram encontrados 22 diagnÃsticos de enfermagem, 34 fatores relacionados e 13 problemas colaborativos diferentes nas 270 avaliaÃÃes realizadas. Observou-se associaÃÃo estatisticamente significante entre os diagnÃsticos Troca de gases prejudicada, PadrÃo respiratÃrio ineficaz, IntolerÃncia à atividade, Crescimento e desenvolvimento retardados e PerfusÃo tissular ineficaz. Estes diagnÃsticos apresentaram associaÃÃo com os fatores relacionados: DesequilÃbrio da ventilaÃÃo-perfusÃo, HiperventilaÃÃo, ReduÃÃo mecÃnica do fluxo sangÃÃneo, SecreÃÃes brÃnquicas e SecreÃÃes retidas. Os diagnÃsticos IntolerÃncia à atividade e Crescimento e desenvolvimento retardados mostraram associaÃÃo com o sexo feminino. Nos diagnÃsticos Troca de gases prejudicada, PadrÃo respiratÃrio ineficaz, IntolerÃncia à atividade, Crescimento e desenvolvimento retardados e DÃbito cardÃaco diminuÃdo, identificaram-se diferenÃas de mÃdia de sobrevida entre crianÃas atà 4 meses e acima de 4 meses. Os diagnÃsticos Troca de gases prejudicada, PadrÃo respiratÃrio ineficaz, IntolerÃncia à atividade e Risco para infecÃÃo ocorreram precocemente no perÃodo de internamento. Entre os diagnÃsticos, seis evidenciaram maiores oscilaÃÃes em suas trajetÃrias de ocorrÃncia no tempo: PadrÃo respiratÃrio ineficaz, IntolerÃncia à atividade, DesobstruÃÃo ineficaz das vias aÃreas, Hipertermia, PadrÃo de sono perturbado e Risco para intolerÃncia à atividade. Foram construÃdos cinco modelos paramÃtricos no domÃnio tempo, com vistas a predizer a ocorrÃncia desses diagnÃsticos de enfermagem. O ajustamento das equaÃÃes para os diagnÃsticos PadrÃo de sono perturbado e Hipertermia denotou grande dispersÃo entre os dados e a linha de tendÃncia, indicando que, alÃm do tempo, outras variÃveis determinam a proporÃÃo de crianÃas que manifestarÃo esses diagnÃsticos. Considera-se a importÃncia de se realizar pesquisas de caracterizaÃÃo do quadro de diagnÃsticos para determinaÃÃo das necessidades de assistÃncia de enfermagem à crianÃa cardiopata. O conhecimento da evoluÃÃo temporal das respostas do indivÃduo pode direcionar os cuidados de enfermagem para as reais necessidades do cliente, facilitando, assim, a escolha de intervenÃÃes mais adequadas

Cardiovascular diseases are the leading cause of morbidity and mortality worldwide. Congenital heart disease (CHD) is a risk factor for premature cardiovascular complications. Great advances have occurred in the past years leading to the identification of several genes essential for proper cardiac formation such as GATA4/5/6 mutated in some individuals with CHD. GATA6 is a zinc finger transcription factor whose presence is crucial for early embryonic development. GATA6 is expressed in many cell types of the heart including myocardial, endocardial, neural crest, and vascular smooth muscle. In human, mutations in GATA6 result in variable cardiac phenotypes. The objective of this thesis was to determine the roles that GATA6 play in the different cell types of the heart and to elucidate the molecular basis of the cardiac defects associated with Gata6 haploinsufficiency. For this, a combination of cell and molecular techniques were used in vitro and in vivo. First, we show that Gata6 heterozygozity leads to RL-type bicuspid aortic valve (BAV)- the most common CHD affecting 2% of the population. GATA6-dependent BAV is the result of disruption of valve remodeling and extracellular matrix composition in Gata6 haploinsufficient mice. Cell-specific inactivation of one Gata6 allele from Isl-1 positive cells, but not from endothelial or neural crest cells, recapitulates the phenotype of Gata6 heterozygous mice revealing an essential role for GATA6 in secondary heart field myocytes during valvulogenesis. We further uncovered a role for GATA6 as an important regulator of the cardiac conduction system and revealed that GATA6 expression regulates the activity of the cardiac pacemaker. GATA6 exerts its role via regulation of the cross-talk among the different cell types of the SAN. Lastly, some CHDs are characterized by abnormalities of both the limbs and the heart such as the Holt Oram syndrome (caused by mutation in TBX5 transcription factor). The molecular basis for limb-heart defects remain poorly understood. In the course of this work, we discovered that Gata6 haploinsufficiency resulted in a partially penetrant polysyndactyly (extra digits fused together) phenotype. Together, the data provide novel molecular and cellular insight into GATA6 role in normal and pathologic heat development. Our results also suggest that GATA6 should be added to the list of genes whose mutations are potentially associated with heart and limb abnormalities. Better knowledge of the molecular basis of CHD is a prerequisite for the development of diagnostic and therapeutic strategies to improve care of individuals with congenital heart disease.

Heterotaxy refers to the abnormal arrangement of internal organs in relation to each other. Model organism studies have shown that functions of more than eighty genes are required for normal asymmetric left-right organ development. CRELD1 has been shown to be necessary for proper heart development and mutations in CRELD1 are known to increase risk of cardiac atrioventricular septal defects (AVSD). AVSD is the most common form of heart defect associated with heterotaxy, and we have previously shown that some individuals with heterotaxy-related AVSD have mutations in CRELD1. Therefore, we propose to examine the CRELD1 gene in a large sample of patients with heterotaxy syndrome. Our goal was to determine if mutations in CRELD1 are associated with other manifestations of heterotaxy or if they only coincide with AVSD. To achieve this aim, a sample size of 126 patients with heterotaxy collected by Dr. Belmont, Baylor college of Medicine, Texas, with approximately 66% of the heterotaxy population with different types of heart defects, were used for this study. Ten exons, promoter regions, and regulatory elements in the introns of CRELD1 gene were sequenced and analyzed. In this study three different heterozygous missense mutations in CRELD1 were identified in three unrelated individuals. These three individuals were diagnosed with different forms of heart defects in addition to AVSD. All three mutations were identified in highly conserved regions of CRELD1 possibly altering the CRELD1 properties. This demonstrates that mutations in CRELD1 may increase the susceptibility of AVSD in heterotaxy population. This information can help us to find factors effecting disease susceptibility in heterotaxy patients since the heart defects are a complex trait with incomplete penetrance.

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Developing countries have been dealing with several difficulties concerning congenital heart diseases. Among them is lack of control of results through some specific database. The participation in the International Quality Improvement Collaborative Database for Congenital Heart Disease (IQIC) - Improving care in low- and middle-income countries provides an opportunity to improve quality of care targeting morbidity and mortality reduction, facilitated by the establishment of parameters and objective data to evaluate treatment offered. Objective: To analyze factors in the International Quality Improvement Collaborative Database for Congenital Heart Disease (IQIC) database of a single center of cardiology and pediatric cardiovascular surgery that influenced the quality of care to patients with congenital heart disease. Casuistic and Methods: Data collection from January 2011 to December 2017 independently and with external audit by IQIC database partnership. Data included preoperative information such as demographic data, nutritional status, associated chromosomal abnormalities, Risk Adjustment for Congenital Heart Surgery (RACHS-1) score, as well as postoperative information such as infections, complications in the first 30 days or until hospital discharge and / or patient death. Results: In the preoperative period, there was a clear trend of increasing newborn patient cases, in detriment of those 1 to 18 years of age. There was a reduction in cases of malnutrition from 70% in 2013 to 55% in 2017. The postoperative period reveled significant variation between groups’ surgical procedures in RACHS-1 risk category (P= 0.003), prevalence of risk categories 2 and 3, as well as an increase in cases of risk categories 4,5 and 6, mainly in the last two years. Infection and mortality showed favorable results for reduction, with statistical significance for surgical site infection (P= 0.03), bacterial sepsis and other infections (both P <0.001). The 30-day postoperative follow-up showed a satisfactory evolution for discrete reduction in mortality, but not statistically significant difference in both in-hospital death (P=0.16) and 30 days (P=0.14). Conclusion: The analysis of the seven years of the IQIC database showed significant decrease in infection, increase in complexity of cases and reduction of mortality of patients with congenital heart disease in our environment.
Países em desenvolvimento enfrentam diversas dificuldades em relação às cardiopatias congênitas, dentre elas a falta de controle de resultados por meio de banco de dados específico. A participação no banco de dados International Quality Improvement Collaborative for Congenital Heart Disease (IQIC) - Improving care in low- and middle-income countries forneceu oportunidade de melhoria da qualidade na assistência para a redução de morbidade e mortalidade infantil, facilitada pelo estabelecimento de parâmetros e dados objetivos para avaliação de tratamentos oferecidos. Objetivo: Analisar os fatores do banco de dados International Quality Improvement Collaborative for Congenital Heart Disease (IQIC) – Improving care in low and middle income countries de um centro único de cardiologia e cirurgia cardiovascular pediátrica que influenciaram a qualidade de atendimento aos pacientes com cardiopatias congênitas. Casuística e Método: Coleta de dados no período de Janeiro de 2011 a Dezembro de 2017 de forma independente e com auditoria externa em parceria com banco de dados IQIC. Os dados incluíram informações pré-operatórias, tais como: dados demográficos, estado nutricional, síndromes associadas e categoria de risco cirúrgico (Risk Adjustment for Congenital Heart Surgery - RACHS-1), assim como, informações pós-operatórias como infecções, complicações nos primeiros 30 dias até a alta hospitalar e ou óbito do paciente. Resultados: No período pré-operatório, observou-se nítida tendência de aumento de casos de pacientes recém-nascidos em detrimento aos de 1 a 18 anos. Encontrou-se redução de casos com desnutrição de 70% em 2013 para 55% em 2017. No período pós-operatório os procedimentos cirúrgicos classificados na categoria de risco RACHS-1 revelaram variação significante entre os grupos (P=0,003), prevalecendo as categorias de grau 2 e 3, assim como, aumento de casos de categorias de risco 4,5 e 6, principalmente nos dois últimos anos do estudo. A infecção e mortalidade demonstraram resultados favoráveis para a redução, com significância estatística para infecção de sítio cirúrgico (P=0,03), sepse bacteriana e outras infecções (P<0,001). O acompanhamento de 30 dias de pós-operatório mostrou evolução satisfatória para discreta redução dos óbitos, porém sem diferença estatística tanto para morte intra-hospitalar (P=0,16) como em 30 dias (P=0,14). Conclusão: A análise dos sete anos do banco de dados IQIC permitiu demonstrar a diminuição significante de infecção, aumento da complexidade das doenças e redução da mortalidade dos pacientes com cardiopatias congênitas em nosso meio.

Congenital heart disease is the most common congenital anomaly, affecting approximately 1% of all live births each year. Although clinical interventions are improving, many affected infants do not survive to adulthood. Congenital cardiac defects originate from disturbances during development, making the study of mammalian cardiogenesis critical to improving outcomes for infants with congenital heart disease. Development of the mammalian heart involves epigenetically-driven specification and commitment of a diverse landscape of cardiac progenitors. Recent studies determined that chromatin modifying enzymes play a previously underappreciated role in the pathogenesis of congenital heart defects. This thesis investigates the functions of Hdac1 and Hdac2, highly homologous Class I histone deacetylases, during early murine cardiac development. We establish that Hdac1 and Hdac2 cooperatively regulate cardiogenesis in distinct cardiac progenitor populations during development. Together, our findings demonstrate that Hdac1 and Hdac2 are critical mediators of the earliest stages of mammalian cardiogenesis through a variety of spatiotemporally specific, redundant, and dose-sensitive roles and indicate they may play important roles in the pathogenesis of human congenital cardiac defects.

Abstract Organogenesis involves precursor cells proliferation, differentiation along with their coordinated organization into precise multicellular arrangements by planar cell polarity (PCP) pathways. The beta-catenin independent/non-canonical type of Wnt-11 signaling has been known as a PCP modulator during development. In this thesis were analyzed the roles of Wnt-11 in heart and kidney development by using in vivo functional genomics technologies. We show that the Wnt-11 gene is important for murine ventricular myocardium development, since Wnt-11 deficiency in early cardiogenesis leads to impaired organization and maturation of mouse ventricular cardiomyocytes, causing primary cardiomyopathy with in utero lethality. Wnt-11 coordinates the co-localized expression of the cell adhesion molecules N-cadherin and β-catenin, which are critical for the spatially specific organization of cardiomyocytes. We show that Wnt-11 deficiency causes primary hypertrophic and noncompaction cardiomyopathy in adult mice, with consequences for regional myocardium function. The Wnt family of secreted signals has been implicated in kidney tubule development and tubular cystic diseases such as polycystic kidney disease. We show here that Wnt-11 is expressed in mature nephrons and is involved in late steps of nephrogenesis, since the kidney tubule organization is deregulated in Wnt-11 deficient kidneys, to enlarged lumen with increased convolution. These tubule abnormalities are associated with glomerular microcyst formation and kidney failure. Wnt-11 deficiency reduced significantly Wnt-9b expression, a critical signal for PCP-mediated kidney tubule elongation. In the cortical region this associated with reduced expression of nephron and stromal progenitor cell marker. The results in this thesis point out that Wnt-11 function is required for proper myocardium organization and maturation as well as proper morphogenesis of the kidney tubules during the embryonic and postnatal developmental stages. Wnt-11 knockout phenotypes depend on the genetic background, similarly to human congenital disease. This data may be relevant for human congenital cardiomyopathy and glomerulocystic kidney disease studies
Tiivistelmä Alkion sisäelinten kehityksen aikana esisolut lisääntyvät ja erilaistuvat muodostaen tarkoin määriteltyjä monisoluisia rakenteita. Muodostuvan kudosrakenteen määrittelyssä erilaiset solusignaalit ovat keskeisessä asemassa. Yksi näistä on nk. Wnt signaali perhe. Wnt perheeen jäsen Wnt-11 tehtävät on huonosti tunnettu. Wnt-11 viestittää ilmeisesti nk. planaaristen solupolariteettireittien (PCP) avulla, joka on beeta-kateniinista riippumattoman nk. ei-kanonisen Wnt signaali. Väitöskirjatyössä selvitettiin Wnt-11:n vaikutuksia sydämen ja munuaisten kehitykseen in vivo funktionaalisten genomisten menetelmien avulla. Ihmisen synnynnäiset kardiomyopatiat ovat sydänlihaksen ensisijaisia vaurioita, joiden taustalla on sydänlihaksen kehityshäiriö. Tutkimuksessa osoitetaan, että Wnt-11-geenillä on tärkeä merkitys hiiren sydänkammion kehitykselle, koska Wnt-11-geenin puute sydämen varhaisen kehityksen vaiheessa johtaa sydänlihassolujen järjestäytymisen ja kypsymisen häiriintymiseen, jolloin seurauksena on ensisijaisesta kardiomyopatiasta johtuva sikiökuolema. Wnt-11 koordinoi kahden solukiinnitysmolekyylin, N-kadheriinin ja β-kateniinin, samanaikasta ilmentymistä. Kyseiset molekyylit ovat keskeisen tärkeitä sydänlihasssolujen spatiaalisen järjestäytymisen kannalta. Tutkimuksessa osoitetaan, että Wnt-11-puutos aiheuttaa aikuisilla hiirillä ensisijaista sydänlihaksen liikakasvua ja trabekuloivaa kardiomyopatiaa, mikä vaikuttaa sydänlihaksen toimintaan. Tuloksilla voi olla merkitystä tutkittaessa ihmisen synnynnäisiä kardiomyopatioita. Wnt-signaaliperheen on osoitettu olevan yhteydessä munuaisputken kehitykseen ja sen sairauksiin, kuten munuaisten monirakkulatautiin. Väitöstutkimuksessa osoitetaan, että Wnt-11 ilmentyy kypsissä nefroneissa ja että se osallistuu nefrogeneesiin myöhempiin vaiheisiin, koska munuaisputken kehityksen säätely on poikkeavaa niissä munuaisissa, joista Wnt-11 puuttuu. Seurauksena on laajentunut, normaalia poimuttuneempi luumen. Munuaisputken poikkeavuuksilla oli yhteyttä munuaiskerästen mikrokystien muodostumiseen sekä munuaisten vajaatoimintaan. Wnt-11 -puute vähensi huomattavasti Wnt-9b-ilmentymistä, joka on PCP-välitteisen munuaisputken pidentymisen kannalta keskeisen tärkeä signaali. Kortikaalialueella Wnt9b:n vaimennussäätely liittyi poikkeavaan solujen lisääntymiseen, apoptoosiin ja kypsymiseen sekä vähentyneeseen nefroni- ja stroomakantasolujen merkkiaineen ilmentymiseen. Väitöskirjatutkimuksen tulokset viittaavat siihen, että Wnt-11 -toiminto on välttämätön sydänlihaksen normaalin muodostumisen ja kypsymisen sekä munuaisputken normaalin morfogeneesin kannalta sikiövaiheen ja syntymän jälkeisen kehityksen aikana. Wnt-11 -poistogeenisen hiiren fenotyypi riippuu geneettisestä tausta, samaan tapaan kuin ihmisen synnynnäisissä sairauksissa. Väitöstutkimuksesta saatavalla tiedolla voi olla merkitystä tutkittaessa ihmisen synnynnnäistä kardiomyopatiaa ja munuaisten monirakkulatautia

Disruptions in cardiac development cause congenital heart disease, the most prevalent and deadly congenital malformation. Genetic and environmental factors are thought to contribute to these defects, however molecular mechanisms remain largely undefined. Recent work highlighted potential roles of chromatin- modifying enzymes in congenital heart disease pathogenesis. Histone deacetylases, a class of chromatin-modifying enzymes, have developmental importance and recognized roles in the mature heart. This thesis aimed to characterize functions of Hdac3 in cardiac development. We found loss of Hdac3 in the primary heart field causes precocious progenitor cell differentiation, resulting in hypoplastic ventricular walls, ventricular septal defect, and mid- gestational lethality. In primary heart field progenitors, Hdac3 interacts with, deacetylates, and functionally suppresses transcription factor Tbx5. Furthermore, a disease-associated Tbx5 mutation disrupts this interaction, rendering Tbx5 hyperacetylated and hyperactive. By contrast, deletion of Hdac3 in second heart field progenitors bypasses these defects, instead causing malformations in the outflow tract and semilunar valves, with lethality prior to birth. Affected semilunar valves and outflow tract vessels exhibit extracellular matrix and EndMT defects and activation of the Tgfβ1 signaling pathway. In normal second heart field development, Hdac3 represses Tgfβ1 transcription, independent of its deacetylase activity, by recruiting the PRC2 methyltransferase complex to methylate the Tgfβ1 promoter. Importantly, knockouts of Hdac3 in differentiated cardiac cells do not fully recapitulate the progenitor-specific knockout phenotypes. These results illustrate spatiotemporal roles of Hdac3, both deacetylase-dependent and deacetylase-independent, in cardiac development, suggesting that dysregulation of Hdac3 in cardiac progenitor cells could be a contributing factor in congenital heart disease pathogenesis.

Disruptions in cardiac development cause congenital heart disease, the most prevalent and deadly congenital malformation. Genetic and environmental factors are thought to contribute to these defects, however molecular mechanisms remain largely undefined. Recent work highlighted potential roles of chromatin- modifying enzymes in congenital heart disease pathogenesis. Histone deacetylases, a class of chromatin-modifying enzymes, have developmental importance and recognized roles in the mature heart. This thesis aimed to characterize functions of Hdac3 in cardiac development. We found loss of Hdac3 in the primary heart field causes precocious progenitor cell differentiation, resulting in hypoplastic ventricular walls, ventricular septal defect, and mid- gestational lethality. In primary heart field progenitors, Hdac3 interacts with, deacetylates, and functionally suppresses transcription factor Tbx5. Furthermore, a disease-associated Tbx5 mutation disrupts this interaction, rendering Tbx5 hyperacetylated and hyperactive. By contrast, deletion of Hdac3 in second heart field progenitors bypasses these defects, instead causing malformations in the outflow tract and semilunar valves, with lethality prior to birth. Affected semilunar valves and outflow tract vessels exhibit extracellular matrix and EndMT defects and activation of the Tgfβ1 signaling pathway. In normal second heart field development, Hdac3 represses Tgfβ1 transcription, independent of its deacetylase activity, by recruiting the PRC2 methyltransferase complex to methylate the Tgfβ1 promoter. Importantly, knockouts of Hdac3 in differentiated cardiac cells do not fully recapitulate the progenitor-specific knockout phenotypes. These results illustrate spatiotemporal roles of Hdac3, both deacetylase-dependent and deacetylase-independent, in cardiac development, suggesting that dysregulation of Hdac3 in cardiac progenitor cells could be a contributing factor in congenital heart disease pathogenesis.

Les gènes Hox sont essentiels à la mise en place de l’identité des cellules le long de l’axe antéropostérieur des embryons et pourraient agir en aval de l’acide rétinoïque pendant la formation du cœur. Nous montrons que les gènes Hoxb1, Hoxa1 et Hoxa3 définissent des sous-domaines du second champ cardiaque. L’analyse de lignage génétique révèle que les progéniteurs cardiaques Hoxb1+ contribuent aux oreillettes et à la partie inférieure de la voie efférente, futur myocarde sous-pulmonaire. Les progéniteurs Hoxa1+ contribuent à la partie distale de la voie efférente, suggérant un rôle de ces gènes Hox antérieurs dans sa régionalisation proximo-distale. Alors qu’aucune anomalie cardiaque n’avait été décrite chez les mutants Hoxb1, notre étude détaillée des fœtus Hoxb1-/- révèle des défauts d’alignement des gros vaisseaux ainsi que des communications interventriculaires. L’utilisation d’un marqueur du myocarde sous-pulmonaire, montre une contribution anormale des cellules du second champ cardiaque à cette région chez les mutants. Nous montrons que ces défauts sont la conséquence de la dérégulation des voies de signalisation présentes dans le second champ cardiaque. En accord avec ces observations, les embryons ont une voie efférente plus courte. L’étude des mutants Hoxa1 révèle des malformations des arcs pharyngés puis des anomalies de la crosse aortique chez les fœtus. L’analyse des doubles mutants, montre une augmentation de la pénétrance et de la sévérité de ces défauts, suggérant une interaction synergique entre Hoxa1 et Hoxb1 lors de la formation des gros vaisseaux. Ces résultats révèlent un rôle crucial des gènes Hox antérieurs dans le développement du cœur
Hox genes are known to be involved in the establishment of cell position and identity along the anterior-posterior axis in embryos and could act as key downstream effectors of retinoic acid during heart development. In situ hybridization experiments show that Hoxb1, Hoxa1 and Hoxa3 define sub-domains within the second heart field (SHF). Our genetic lineage analysis reveals the contribution of Hoxb1+ cardiac progenitors to the atria and to the inferior wall of the outflow tract (OFT), which then gives rise to the myocardium at the base of the pulmonary trunk. Interestingly, Hoxa1+ progenitors contribute to the distal part of the OFT suggesting that these anterior Hox genes could play a role in its proximo-distal patterning. No cardiac anomalies had been reported so far in Hoxb1 mutant mice. However, our detailed study shows that mutant fetuses exhibit OFT misalignment and ventricular septal defects associated or not with ventricular wall and epicardium anomalies. Using a marker of the sub-pulmonary myocardium, we observe an abnormal contribution of SHF cells in Hoxb1-/- hearts. This defect is the consequence of the dysregulation of the signaling pathways controlling SHF regulation. Accordingly, those embryos exhibit a shorter OFT. The study of Hoxa1 mutant embryos reveals pharyngeal arch arteries patterning defects causing anomalies of the aortic arch and right subclavian artery at fetal stages. Using compound mutants, we show an increase in the penetrance and severity of these defects, suggesting a synergistic interaction between Hoxa1 and Hoxb1 during aortic arch patterning. Together, these data support a crucial role for anterior Hox genes in cardiac development

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Introduction- The prevalence of congenital cardiovascular disease is of 7 to 10 children in every 1000 live births. The reasons that lead to the referral of a child by primary care physicians are very varied, with cardiac heart murmur being the most common. Amongst other reasons one can find precordial pain, arrhythmia, fatigue, dyspnea, cyanosis, abnormal chest x-ray, abnormal electrocardiogram, medical examination for physical exercise. The present challenge for pediatricians, family physicians and pediatric cardiologists is to develop accurate diagnosis strategies in a cost-effective manner, with the aim of improving the treatment and save resources. Objectives- The objective is to strengthen the network of health care in its primary and secondary levels using cases of Pediatric Cardiology as the strategic condition and develop an interdisciplinary work proposal with the support of a matrix, which optimize the referral system. Material and methods- It is about the exploratory study with descriptive documental analysis from 433 referral letters of patients seen at the Pediatric Cardiology Ambulatory of Policlinic of Sorocaba from January to June 2012, along with the study of the patients medical records. The data collected is quantified using descriptive statistics when relevant. Results- One hundred and sixty-six patients (38,3%) were discharged, 93 with feedback letter of referral (56,0%). Ninetysix (22,2%) missing follow up, 9 of which had confirmed cardiovascular disease, 29 with absence of cardiovascular disease and 58 without a definitive diagnosis of cardiovascular disease. One hundred and seventy-one patients (39,5%) attend follow-ups. Conclusion- With the aim of strengthening the network of health care using recent medical advances, such as telemedicine and the concept of matrix support, as means of exchange, improvement and to save resources and knowledge
Introdução - A prevalência das cardiopatias congênitas está entre sete a dez crianças por 1000 nascidas vivas. Os motivos que levam o médico da atenção primária a encaminhar uma criança ao cardiologista pediátrico são bastante variados, sendo o sopro cardíaco a causa mais frequente. Dentre outros motivos frequentes encontram-se dor precordial, arritmias, cansaço, dispneia, cianose, radiografia de tórax anormal, eletrocardiograma alterado, avaliação para atividade física. O desafio atual dos pediatras, médicos de família e cardiopediatras é desenvolver estratégias de diagnósticos precisos e financeiramente adequados, com o intuito de melhorar o tratamento e racionalizar os recursos. Objetivos - O objetivo é fortalecer a rede de atenção à saúde em seus níveis primário e secundário, utilizando-se dos casos de Cardiologia Pediátrica como condição estratégica e desenvolver uma proposta de trabalho interdisciplinar e de interação com apoio matricial, otimizando o sistema de referência e contrarreferência. Material e método - Trata-se de estudo exploratório com análise documental descritiva das 433 guias de referenciamento de pacientes atendidos no ambulatório de Cardiologia Pediátrica da Policlínica Municipal de Sorocaba, no período de janeiro a junho de 2012, acompanhado do estudo dos prontuários. Os dados obtidos foram quantificados e utilizada a estatística descritiva quando pertinente. Resultados - Cento e sessenta e seis pacientes (38,3%) tiveram alta, 93 com contrarreferência (56,0%) preenchida. Noventa e seis pacientes (22,2%) perderam o seguimento, sendo nove com doença cardiovascular presente, 29 com doença cardiovascular ausente e 58 sem diagnóstico definitivo de doença cardiovascular. Cento e setenta e um pacientes (39,5%) pacientes mantêm seguimento. Conclusão A fim de se fortalecer a rede de atenção à saúde, a utilização de recentes avanços, como a telemedicina e o conceito de apoio matricial se colocam como meios de troca, otimização e racionalização do conhecimento e dos recursos

Introdução: Previamente, demonstramos que o remodelamento histológico do miocárdio à época da correção da tetralogia de Fallot (TF) influenciou na função do ventrículo direito (VD) no pós-operatório (PO) precoce. O impacto da fibrose miocárdica na função ventricular no PO tardio ainda é desconhecido. O objetivo deste estudo foi avaliar ecocardiograficamente na mesma coorte de pacientes a função do VD no PO tardio, comparando com dados anteriormente obtidos por ecocardiografia convencional e morfometria miocárdica. Métodos: Estudamos 20 pacientes no PO da TF (tempo de seguimento = 96,6 ± 13,3 meses), 15 homens (75%), idade média no PO tardio (PO2) 128,3 ± 25,7 meses. As velocidades miocárdicas do VD diastólica precoce (e´), tardia (a\') e sistólica (S\') foram avaliadas pelo Doppler tecidual no pré-operatório, três dias após a cirurgia, entre 30º-90º dia e no PO2. Parâmetros convencionais, como a excursão sistólica do anel da valva tricúspide (TAPSE), variação fracional da área (FAC), volume do átrio direito indexado, pico da velocidade de enchimento diastólico precoce (E) do fluxo transvalvar tricúspide e da deformação miocárdica global e regional, strain longitudinal sistólico (GLS), strain rate sistólico (GLSRs) e o strain no pico do tempo de relaxamento isovolumétrico (GLSTRIV), foram analisados apenas no PO2. Também, nesta fase, realizamos a análise tridimensional da fração de ejeção, e dos volumes diastólico e sistólico finais do VD. Resultados: A velocidade a\' diminuiu nas avaliações iniciais e persistiu anormal no PO2 (RM ANOVA p < 0,001). Houve correlação negativa significante entre a velocidade e\' no PO2 e a fração de área de fibrose miocárdica (FIBR) (p = 0,02; r = -0,54), e correlação positiva entre FIBR e a relação E/e\' (p= 0,0002; r= 0,787). No PO2, o TAPSE (1,50 ± 0,19cm) foi reduzido e FAC normal (47,51± 7,56%). O valor do GLS global foi 18,48 ± 2,97%, com Z score < -2 em 16 pacientes e diferiu regionalmente no segmento médio do septo (Z score < -2 em 5 pacientes) e no segmento médio da parede lateral (Z score < -2 em 1 paciente). Houve correlação negativa entre FIBR e GLS no segmento médio septal (p = 0,0376; r = -0,493), entretanto sem influência no GLS global. No PO2, a insuficiência pulmonar residual foi moderada ou acentuada em 15 pac (75%), sem diferença quanto à FIBR miocárdica em relação ao grau leve (p = 0,58). Estavam aumentados os volumes indexados: diastólico final médio (89,5 ± 34,3ml/m²; Z score > 2DP em 12 pacientes) e sistólico (40,6 ± 9,1ml/m²; Z score > 2DP em 14 pacientes). A fração de ejeção média foi normal 51,8 ± 6,9% e não houve correlação com a FIBR. Conclusões: A avaliação ecocardiográfica tardia identificou alterações evolutivas e adaptativas das funções sistólica e diastólica do VD, com função sistólica preservada e função diastólica anormal e associada ao grau de FIBR avaliado em amostras operatórias; o estudo da deformação miocárdica revelou alterações globais e regionais, possivelmente relacionadas à arquitetura do miocárdio nessa malformação e às adaptações decorrentes da interposição de retalhos e suturas cirúrgicas; a avaliação pelo modo tridimensional correlacionou-se positivamente com as medidas obtidas no modo bidimensional; a insuficiência pulmonar foi lesão residual altamente prevalente
Introduction: We have previously demonstrated that the myocardial remodeling at the time of corrective surgery in tetralogy of Fallot (TF) patients influenced the right ventricular (RV) function in the early post-operative period (PO). The impact of myocardial fibrosis in late follow up (LFU) has not been investigated so far. Our objective was to analyze in the same cohort of patients in LFU, the RV function, comparing the obtained results with echocardiographic data from the early PO and with myocardial morphometry. Methods: 20 patients in the late FLU of TF correction were studied (time of follow up = 96.6 ± 13.3 months), 15 men (75%), mean age at LFU 128.3 ± 25.7months. The early (e\') and late (a\') diastolic and the systolic (S\') myocardial velocities were evaluated through tissue Doppler in the pre-operative period, three days after surgery, between the 30o-90o days and in LFU. We analyzed conventional echocardiographic parameters like the tricuspid annular plane systolic excursion (TAPSE), the fractional area change (FAC), the indexed right atrial volume, the peak early diastolic filling velocity (E) and of myocardial deformation: global longitudinal strain (GLS), global longitudinal systolic strain rate (GLSRs) and global longitudinal strain at the peak of the isovolumetric relaxation time (GLSTRIV) in the LFU. Also in LFU we analyzed by tridimensional echocardiography the ejection fraction and the final RV diastolic and systolic volumes. Results: The a\' velocity decreased in the initial evaluations and persisted abnormal in LFU (RM ANOVA, p < 0.001). There was a significant and negative correlation between e\' in LFU and the area fraction of myocardial fibrosis (FIBR) (p = 0.02; r = -0.54) and a positive correlation between FIBR and E/e\' ratio (p = 0.0002; r = 0.787). In the LFU TAPSE decreased (1.50 ± 0,19cm) and FAC was normal (47.51 ± 7.56%). The GLS value was 18.48 ± 2.97%, with Z score <- 2 SD in 16 patients, and was significantly different in the mid ventricular septum (Z score <- 2 in 5 patients) and in the mid segment of the lateral wall (Z score < -2 in 1 patient). There was a negative correlation between FIBR and GLS in the mid ventricular segment of the septum (p = 0.0376; r = -0.493), however without influence in GLS. In LFU pulmonary regurgitation was considered moderate or severe in 15 patients (75%), with no difference relative to the group with mild regurgitation regarding FIBR (p = 0.58). The final indexed RV volumes were increased: diastolic (89.5 ± 34.3ml/m2; Z score > 2SD in 12 patients) and systolic (40.6 ± 9.1ml/m2; Z score > 2SD in 14 patients). The mean RV ejection fraction was normal (51.8 ± 6.9%), and did not correlate with FIBR. Conclusions: The LFU echocardiographic evaluation identified evolutive and adaptative alterations in RV function, with preserved systolic and abnormal diastolic function, associated with the degree of FIBR assessed in myocardial samples; the study of myocardial deformation indexes revealed regional and global alterations, possibly related to the abnormal myocardial architecture specific for the cardiac malformation and/or to post-surgical adaptation to patches and sutures; the tridimensional echocardiography data correlated positively with those obtained through bidimensional echo; pulmonary regurgitation was a highly prevalent residual lesion

Para avaliar a hipótese da presença de inflamação em artérias pulmonares periféricas de pacientes com hipertensão pulmonar (HP) decorrente de cardiopatias congênitas, foram quantificadas células inflamatórias através de marcação imunohistoquímica em biópsias de 26 pacientes e comparadas com 11 controles sem cardiopatia. Detectou-se quantidades semelhantes de células inflamatórias nos dois grupos, mas com predomínio de linfócitos T no grupo controle e de macrófagos jovens no grupo HP. Esses achados podem estar relacionados com a redução do estímulo dependente de macrófagos para diferenciação e maturação de linfócitos T nos cardiopatas e/ou a deficiência imunológica primária nesses pacientes
To evaluate the hypothesis of increased inflammation in peripheral pulmonary arteries from patients with pulmonary hypertension secondary to congenital cardiac shunts, we quantified the inflammatory cells with the aid of immunohystochemistry in 26 biopsies (HP group), comparing them to 11 patients with no cardiac disease. Similar quantities of inflammatory cells were observed in the two groups, with a predominance of T-lymphocytes in the controls and of young macrophages in the HP group. These findings could be related to a reduction of macrophagic stimulus to the differentiation and maturation of T-lymphocytes and/or to a primary immunological deficiency in patients with congenital cardiac shunts

Les cardiopathies congénitales (CC) représentent la première cause d’anomalie malformative à la naissance. Les progrès considérables des années 80 (CEC néonatale, diagnostic prénatal) en ont modifié l’épidémiologie, avec un transfert de la mortalité de la pédiatrie à l’âge adulte. Dans ce contexte, l’évaluation de la qualité de vie liée à la santé (QdV) des enfants et adultes porteurs de CC devient un critère de jugement important, en recherche clinique comme dans les soins. Nous avons mené 4 études prospectives de QdV chez des patients avec CC: une étude chez 282 enfants de 8 à 18 ans avec CC comparés à 180 enfants contrôles; une étude sur 202 enfants avec CC corrélant QdV et VO2; une étude de QdV sur 208 adolescents et adultes porteurs d'HTAP sur CC; et une étude sur l’évolution de la QdV de 111 enfants sous AVK participant à un programme d’éducation thérapeutique. Les patients avec CC simple ont manifesté une QdV similaire à celle de la population générale. Ceux avec une cardiopathie complexe ont été préférentiellement impactés sur leur bien-être physique mais ont développé aussi des mécanismes de coping. En pédiatrie, l’évaluation de la QdV par les parents était plus péjorative mais parfois plus pertinente que celle des enfants. Nous avons mis en évidence le lien entre QdV et VO2 chez l’enfant cardiaque. Les résultats de nos travaux devraient permettre d’aider les cardiologues, cardiopédiatres et chirurgiens cardiaques dans leurs annonces diagnostiques, en particulier lors des moments cruciaux de notre sur-spécialité médico-chirurgicale: diagnostic prénatal, réanimation, transition vers l’âge adulte, prise en charge palliative d’une cardiopathie sévère
Congenital heart diseases (CHD) are the leading cause of birth malformations. The tremendous progress since the 80’s (neonatal bypass, prenatal diagnosis) have changed the epidemiology, transferring mortality from pediatrics to adulthood. Therefore assessing the health-related quality of life (QoL) of children and adults suffering from CHD has become an important issue, in both clinical research and patients’ follow-up. We carried out 4 prospective QoL studies in patients with CHD: a study in 282 CHD children aged 8 to 18 compared with 180 controls; a study among 202 CHD children correlating their QoL scores to VO2; a QoL study among 208 adolescents and adults with PAH-CHD; and a study among 111 children in a therapeutic anticoagulation education program aiming to measure the evolution of their QoL. Patients with simple CHD showed a similar QoL to that of the control population. Those with complex heart diseases were preferentially affected in their physical well-being but also developed mechanisms of coping in other dimensions. In pediatrics, the evaluation of the QoL by parents is essential, sometimes more accurate than that of children themselves. As in previous studies in adults with heart failure, we found a significant relationship between QoL and physical performance during exercise in CHD children. The results of our work should help cardiologists, cardiac surgeons and pediatric cardiologists in their diagnostic announcement, especially during crucial moments of this medical and surgical subspecialty: prenatal diagnosis, intensive care, transition of care from adolescence to adulthood, palliative treatment of a complex CHD

Les cardiopathies congénitales cyanogènes (CCC) sont des malformations cardiaques qui entraînent une désaturation en oxygène à la naissance. Des progrès majeurs réalisés ces vingt dernières années dans la prise en charge médico-chirurgicale des nouveau-nés atteints de CCC ont permis de considérablement améliorer la survie et le pronostic cardiaque à long terme de cette population. Cependant, ces enfants sont exposés à un risque accru d’accidents neurologiques dû au caractère cyanogène de la cardiopathie et à certaines techniques de chirurgie à cœur ouvert. En conséquence, les troubles neurocognitifs font partie des principales morbidités résiduelles. Malgré l’augmentation exponentielle du nombre de patients qui atteignent dorénavant l’âge adulte, à ce jour très peu d’études ont investigué le devenir neuropsychologique des adultes opérés de CCC. Cette thèse a pour objectif principal d’évaluer le devenir neuropsychologique et psychosocial d’adultes ayant été opérés à cœur ouvert en période néonatale pour corriger une CCC. L’évaluation, qui repose sur des outils validés, est menée auprès de 67 patients âgés de 18 à 31 ans. Les résultats mettent en évidence qu’une proportion substantielle de patients présente des troubles cognitifs et émotionnels susceptibles de réduire leur qualité de vie et d’entraver leur réussite scolaire et leur insertion professionnelle. Ce travail offre des résultats pionniers concernant le devenir à long terme de cette population. D'autres études sont nécessaires pour mieux comprendre la trajectoire développementale des adultes opérés de CCC afin de mettre en place des stratégies préventives et thérapeutiques adaptées aux besoins de cette population
Cyanotic congenital heart diseases (CHD) are heart defects which cause oxygen desaturation at birth. In the last twenty years, the major progress in the medical and surgical care of newborns with cyanotic CHD has resulted in a considerable improvement of the survival and the long-term cardiac prognosis of this population. However, these children are at an increased risk of neurological injuries due not only to the cyanotic nature of their CHD but also to certain open-heart surgery techniques. Consequently, neurocognitive disorders are among the major remaining morbidities in this population. Despite the exponential increase in the number of patients who can now reach adulthood, to date very few studies have investigated the neuropsychological outcomes of adults with cyanotic CHD. The main objective of the present thesis is to evaluate the neuropsychological and psychosocial outcomes of adults who had undergone an open-heart surgery during the neonatal period in order to correct a cyanotic CHD. The assessment, based on validated tools, is conducted among 67 patients aged from 18 to 31 years. The results show that a substantial proportion of patients with TGA presents a number of cognitive deficits and emotional impairments which may reduce their quality of life and hinder their academic success and their professional integration. This thesis offers original results on the long-term neuropsychological and psychosocial outcomes of this population. Further studies are needed so as to better understand the developmental trajectory of adults with cyanotic CHD in order to develop preventive and therapeutic strategies adapted to the specific needs of this population

Tese de doutoramento, Ciências Biomédicas, Departamento de Ciências Biomédicas e Medicina, Universidade do Algarve, 2017
The majority of congenital heart disease (CHD) is sporadic, with a minority of cases associated with a known genetic abnormality. Combinations of geneticenvironmental factors are implicated in the etiology of the disease. Recently, several studies, using mostly animal models, unraveled that perturbations in the molecular processes that precede the beginning of heart development might also be at the origin of CHD. In fact, some of the most complex CHDs are found associated with laterality defects, a disorder resulting from abnormal Left-Right axis formation. In our laboratory, the identified mouse Cerberus-like2 (Cerl2 – human DAND5), a protein that inhibit Nodal signaling, prompt us to study cardiac and laterality diseases, since the generated Cerl2 KO mice display a wide range of laterality defects and CHD. Considering the high conservation of genetic pathways regulating cardiac development in mouse and human, the main objective of the present thesis was the study of human genes involved in the Nodal pathway, focusing mostly in DAND5, in a CHD and/or laterality defects patients cohort. The sequence analysis of DAND5 revealed two patients displaying the same p.R152H variant, resulting in a substantial decreased in the function of the protein. We propose that p.R152H acts as a risk allele for CHD and/or laterality defects. In addition, we found two alterations in NODAL, two alterations in PITX2C and one alteration in CFC1. We hypothesized that the NODAL p.H165R variant can act as a common modifier and the intronic variants in NODAL and PITX2C might cause alterations in the splicing pattern of the mRNA molecules. Moreover, we generated patient-specific iPSCs to understand the molecular mechanisms of disease behind the DAND5 nucleotide variant. Although we cannot make a clearly genotype-phenotype correlation, the variants here identified probably increase the disease susceptibility due to the resulting abnormal Nodal signaling. Because most of the patients presented more than one alteration, the cumulative effect of each variant within the pathway seems to enhance even more these risk. Therefore, the imbalance in dosage-sensitive Nodal signaling is a common denominator for laterality defects and associated CHDs.
Uma das questões fulcrais da biologia do desenvolvimento continua a ser como é que uma única célula, o oócito fecundado, se desenvolve num ser tão complexo e especializado, com os tecidos e órgãos diferenciados e organizados em torno de três eixos, o anterior-posterior (AP), dorso-ventral (DV) e esquerdo-direito (LR). De um modo geral, o desenvolvimento embrionário humano pode ser dividido em três períodos: o primeiro, chamado de período zigótico, inicia-se com a fusão dos gametas masculino e feminino, formação do zigoto e termina com a implantação do blastocisto na parede do útero duas semanas após a fecundação. Durante o segundo período, ou período embrionário, que vai desde a terceira até à oitava semana de gestação, ocorre a gastrulação, com a formação e diferenciação dos folhetos embrionários (ectoderme, mesoderme e endoderme), e a formação dos órgãos e sistemas fisiológicos. O ultimo período, chamado fetal, vai desde o terceiro mês de gestação até ao nascimento e é caracterizado pelo crescimento do embrião, maturação e funcionalização das estruturas e órgãos. Durante o desenvolvimento do embrião, o coração é o primeiro órgão interno a ser formado e a tornar-se funcional de modo a bombear sangue por volta das três semanas de gestação, suprindo as necessidades do embrião e garantindo a sua sobrevivência. Na maioria dos vertebrados o desenvolvimento cardíaco segue o mesmo padrão de formação. O coração forma-se a partir de duas regiões cardíacas bilaterais que advêm de uma região progenitora comum na gastrulação, a mesoderme cardíaca. A mesoderme cardíaca recebe informação posicional dos três eixos embrionários, porém o efeito do eixo Esquerda-Direita (ED) tem recebido particular atenção. Os dois “pools” bilaterais de células precursoras cardíacas mesodermais migram para a linha média onde se juntam e dão origem ao crescente cardíaco. Este crescente cardíaco vai formar posteriormente um tubo cardíaco linear primordial. De seguida, este tubo alonga e sofre um processo de “looping” para a direita levando à formação dos ventrículos e aurículas. Subsequentemente, ocorre a diferenciação, especialização e septação das quatro camaras cardíacas e válvulas proporcionando as paredes necessárias para a separação física da circulação sistémica e pulmonar de sangue. Por último a formação do sistema de condução cardíaco e maturação dos cardiomiócitos, culminam na formação de um coração inteiramente funcional. As doenças cardíacas congénitas (DCC) são a manifestação clínica de problemas durante o desenvolvimento embrionário do coração. Esta doença é a forma mais comum de defeito à nascença, ocorrendo em cerca de 8 em 1000 nados vivos, bem como a principal causa não-infeciosa de morte no primeiro ano de vida. Na maioria dos casos (80%), esta doença tem origem desconhecida e manifesta-se isoladamente em doentes não sindrómicos e não seguindo os padrões de hereditariedade definidos por Mendel, sendo considerada uma doença complexa com origem multifatorial. Esta complexidade advém do facto de a doença em muitos casos se apresentar geneticamente heterogenica, com penetrância reduzida e expressividade genética variável. Para além disso, fatores de risco ambientais foram também identificados como contribuído para o risco de desenvolver a doença. Nos dias de hoje, um modelo envolvendo tanto fatores genéticos como a interação genes-ambiente, é a explicação mais plausível para as altas frequências verificadas para a doença cardíaca congénita. Nos últimos anos, vários esforços foram feitos de modo a se compreender os mecanismos moleculares que levam a uma má formação do coração. Estes estudos, usando principalmente animais modelo e genética molecular humana, da morfogénese do coração e dos primeiros passos da determinação do eixo de simetria esquerdo-direito durante a embriogénese, indicam que na maioria dos casos de distúrbios de lateralidade é observada uma malformação cardíaca complexa, sugerindo que as DCC podem dever-se a defeitos de lateralidade na morfogénese do coração. Uma das redes regulatórias por detrás do estabelecimento do eixo esquerdodireito é a via de sinalização Nodal, um fator de crescimento da família TGF-b, que é expresso assimetricamente do lado esquerdo do nó e placa lateral esquerda da mesoderme de ratinho. Os fenótipos cardíacos de ratinhos geneticamente modificados para desativar a sinalização de nodal ou a sua regulação, demonstraram que o desenvolvimento cardíaco depende vivamente do estabelecimento do eixo E-D embrionário. Para além disso, foram identificadas variantes genéticas em genes envolvidos na via de sinalização Nodal em doentes com DCC. O nosso laboratório identificou um membro da família Cerberus/DAN, o gene Cerberus-like2 (Cerl2), que é assimetricamente expresso no lado direito do nó em ratinho. O gene Cerl2 codifica para uma proteína secretada capaz de se liga diretamente a Nodal, inibindo a sua via de sinalização. Na presença de Cerl2 a atividade da via de sinalização Nodal restringe-se apenas ao lado esquerdo do embrião, o que culmina com uma morfogénese normal dos órgãos do abdómem. Ratinhos knock-out para o gene Cerl2, em que o gene Nodal passa a poder ser expresso e induzir a sua cascata de sinalização em ambos os lados da placa lateral da mesoderme, revelaram uma ampla gama de defeitos de lateralidade - situs inversus, isomerismos e heterotaxia - e malformações cardíacas - formação incompleta das aurículas, defeitos no septo ventricular, falha na rotação das principais artérias (transposição das grandes artérias, ventrículo direito de dupla saída), looping cardíaco anormal (randomizado), posicionamento do ápex cardíaco e hipertrofia ventricular - o que nos levou a suspeitar que alterações neste gene poderiam estar associadas a doenças de lateralidade e/ou casos isolados de doenças cardíacas congénitas. Dado que as vias genéticas que regulam o desenvolvimento cardíaco em ratinhos e humanos são conservadas, o principal objetivo desta tese foi o estudo de alguns dos genes homólogos humanos envolvidos na via de sinalização Nodal, com principal foco no gene DAND5, homólogo humano de Cerl2, mapeado no cromossoma 19, região 19p13.2, mas também verificando a existência de variantes nos genes NODAL, PITX2C e CFC1 numa cohort de doentes com defeitos cardíacos congénitos com origem em perturbações do eixo esquerdo-direito. A análise dos resultados da sequenciação de DNA do gene DAND5 permitiunos identificar dois doentes com a mesma variação. Clinicamente, um dos doentes apresenta um fenótipo de defeito no septo ventricular com aorta conectada aos dois ventrículos, atresia pulmonar e isomerismo esquerdo. O outro doente apresenta um caso extremo de tetralogia de Fallot (defeito no septo ventricular com aorta conectada aos dois ventrículos, hipertrofia do ventrículo esquerdo e atresia pulmonar). A variante, identificada nos dois doentes como heterozigótica, leva à substituição de um nucleótido guanina por uma adenina na posição 455 do exão 2, resultando na substituição de um aminoácido arginina por uma histidina (p.R152H) numa região altamente conservada e funcionalmente importante da proteína DAND5. De modo a entendermos o potencial efeito da alteração p.R152H na proteína DAND5, fizemos um estudo in silico recorrendo a vários programas bioinformáticos. Os resultados dessas predições foram inconclusivos uma vez que 3 programas apontam para um possível efeito nefasto enquanto que outro programa sugere que a variante não tem qualquer efeito na proteína. Para clarificarmos a função desta proteína variante, avaliámos o seu efeito na regulação da via de sinalização Nodal recorrendo a um ensaio funcional de luciferase. O resultado obtido mostra uma diminuição substancial da função da proteína mutante comparada com a proteína wild-type. Embora os fenótipos dos doentes sejam muito semelhantes, não podemos fazer uma clara correlação do genótipo com o fenótipo pois a variante c.455G>A foi reportada em bases de dados publicas como variante de nucleótido único (rs45513495). Além disso, a mãe de um dos doentes é portadora da variante sem apresentar indícios de doença, sugerindo uma penetrância incompleta, expressividade genética variável ou o efeito de fatores ambientais. Estas observações estão de acordo com a complexidade das doenças cardíacas congénitas e/ou defeitos de lateralidade e podem refletir a acção de variantes modificadoras ou outras variantes genéticas na via de sinalização que podem exacerbar ou atenuar o efeito da variante p.R152H na proteína DAND5 e nos fenótipos dos doentes. Portanto, nós propomos que esta variação no gene DAND5 pode ser um alelo de risco para o desenvolvimento de DCC e/ou defeitos de lateralidade. Por esta razão, decidimos levar a cabo uma busca de possíveis alterações em genes que fazem parte desta cascata Nodal. Foram assim identificadas uma nova alteração na zona codificante do gene CFC1, sem efeito funcional aparente, e quatro polimorfismos, um na zona codificante e outro no intrão do gene NODAL e dois na zona não codificante do gene PITX2C em doentes com uma vasta gama de defeitos. Tendo em conta a análise levada a cabo por um programa bioinformático que permite analisar se alterações genéticas podem afetar o processo de splicing, nós verificamos que de facto, as variantes genómicas encontradas fora das zonas codificantes dos genes NODAL e PITX2C podem resultar em moléculas de RNA mensageiro anormais, principalmente devido à criação ou disrupção de locais para a ligação da maquinaria de splicing. Quanto à variante na zona codificante do gene NODAL, esta encontra-se no exão 2, e leva à substituição do aminoácido Histidina por uma Arginina na posição 165 (p.H165R). Esta variante já tinha sido reportada em dois estudos de 2008/2009 nos quais os autores verificaram, recorrendo a um ensaio funcional de lucifarese, que a variante leva à redução da atividade da proteína NODAL e parece atuar como variante modificadora e como fator de risco quando associada a outras possíbeis alterações em genes da via Nodal, com os quais este normalmente interage. Para além disto, e com o objetivo de modelar a doença e estudar os mecanismos moleculares por de trás de uma simples variação num nucleótido, geramos células estaminais induzidas de um dos doentes com a variante no gene DAND5. Estas células foram caracterizadas, apresentado uma morfologia, expressão de marcadores pluripotentes e cariotipo normais. Em conclusão, embora não possamos fazer uma correlação dos genótipofenótipo, nem classificar as alterações identificadas neste estudo como alelos associadas a doença por si, estas variantes, podem, no entanto, aumentar a suscetibilidade para o desenvolvimento de DCC e/ou defeitos de lateralidade. Uma vez que a maioria dos doentes apresenta mais do que uma das variantes no seu genoma, o efeito cumulativo de cada variante na via parece aumentar ainda mais o risco para desenvolver doença. Portanto, o desequilíbrio dos níveis adequados da via de sinalização Nodal, em ambos os lados da placa lateral da mesoderme, devido a uma ou várias variantes nos seus componentes, é um denominador comum para defeitos de lateralidade e/ou doenças cardíacas congénitas.

BACKGROUND: Researchers recently created a new scoring system for characterizing organ dysfunction in critically ill pediatric patients, named the pSFOA (pediatric sequential organ failure assessment). Support for applying this scoring system in pediatric patients who suffer from cyanotic and acyanotic congenital heart diseases has not been evaluated. OBJECTIVES: To compare the pSOFA scores between pediatric patients with acyanotic and cyanotic congenital heart disease (CHD). Exampine the pSOFA results of CHD patients with pediatric patients who underwent hematopoietic stem cell transplantations. METHODS: A retrospective case-study of pediatric patients with congenital heart disease admitted to the CICU at Boston Children’s Hospital in 2018. Patients were included if between 1 and 5 years of age, neonates of less than a month old were excluded. A total of 101 patients were reviewed, 50 with cyanotic CHD and 51 with acyanotic CHD. Patient vital signs were assessed using the pSOFA scoring system, with scores assigned based on indices of respiratory, coagulation, hepatic, cardiovascular, neurologic, and renal system function. Scores were analyzed using two-tailed nonparametric Mann-Whitney tests with an alpha of 0.05. The pSOFA scores of CHD patients were then compared to patients who were admitted to the ICU at Boston Children’s Hospital after they received a hematopoietic stem cell transplantation (HSCT). Dunn’s multiple comparisons tests were performed for the two CHD groups and the HSCT patients. An alpha value of 0.05 was also used for these tests. RESULTS: Parameters determined to be statistically significant between the cyanotic and acyanotic CHD patients were, Total High Direct score, Total Average Direct score, Total Low Indirect Score, Total High Indirect score, Neurologic High score, Average Neurologic score, Renal High score, Average Renal score, and Hepatic Low Indirect score. The parameters that were statistically different between the CHD groups and the HSCT group were Age, Maximum Coagulation, Maximum Renal, Maximum Hepatic, and Maximum Total pSOFA scores. Parameters that were significantly different only between cyanotic CHD and HSCT were Maximum Cardiovascular and Maximum Respiratory. Scores that were significantly different between acyanotic CHD and HSCT were Maximum Neurologic. CONCLUSIONS: There were significant differences in pSOFA scores between children with cyanotic CHD and acyanotic CHD, specifically regarding total direct, total indirect, neurologic, and renal scores. Additional research is required to explain these scores differences and validation of these scores in predicting morbidity and mortality outcomes in these patient populations.
2022-06-02T00:00:00Z

博士
國立陽明大學
生物醫學影像暨放射科學系
106
Prenatal ultrasound screening is widely employed for detecting fetal congenital malformations and structural defects. In previous studies, the prevalence of fetal congenital anomaly ranged from 19.8/1000 to 23.9/1000 total live births. In the presence of fetal congenital anomaly, fetal congenital heart disease (CHD) are highly prevalent in newborns. The incidence of fetal CHD is 3 to 10 per 1000 live births. The leading causes of mortality and morbidity in the perinatal and infant population are related to congenital heart diseases. In some studies, the chromosomal anomalies associated with CHD were trisomy 21, trisomy 13, trisomy 18, and so on. Nowadays, the standard screening of fetal CHD depends on the prenatal sonography. Several screening images for CHD developed to increase the detecting rates in different cases of CHD. Four-chamber view is the basic view used for the screening of two atrioventricular valves, ventricular septum, and right or left atrium and ventricle anomaly. In outflow tract views, assessment of the left ventricular outflow tract (LVOT) and right ventricular outflow tract (RVOT) is the routine method. Three-vessel and trachea (3VT) view and three-vessel view (3VV) could increase the detection rate up to 89% in two great vessel abnormality. In the series of my studies, the objectives are mainly focusing on using prenatal ultrasound for examination of fetal congenital malformations. The study results analysis were compared with traditional screening method in fetal CHD. The trend of fetal NBL, UA PI, and MCA PI in VSD’s fetuses were also compared with non-VSD’s fetuses. 1. Length to Width Ratio of the Ductus Venosus in Simple Screening for Fetal Congenital Heart Diseases in the Second Trimester： From September 2012 to September 2013, the length and width of the fetal ductus venosus were measured sonographically in 1006 singleton fetuses, and the ratio of length to width was calculated. Of the 1006 singleton fetuses between 19 and 28 weeks' gestation, 36 had CHD. The ductus venosus length/width ratio (DVR) for the first CHD screening was extremely sensitive at 88.90%, with a specificity of 99.10% for the cardiac abnormalities included in this study. The DVR differed significantly between fetuses with CHD and normal fetuses during the second trimester. 2. Prenatal Ultrasonography and Doppler Sonography for the Clinical Investigation of Isolated Ventricular Septal Defects in a Late Second-Trimester Population Fetal echocardiogram, Doppler ultrasound and biometry were measured by well-trained technicians for 2661 singleton fetuses between August, 1, 2006 and May, 31, 2010. The results show that 124 out of 2661 singleton fetuses between 19 and 24 weeks' gestation had isolated VSD. Using multiple logistic regression analysis, in addition to short fetal NBL (OR=0.691, 95%CI: 0.551-0.868), PI of the umbilical artery (UA) (OR=8.095, 95%CI: 4.309-15.207) and the middle cerebral artery (MCA) (OR=0.254, 95%CI: 0.120-0.538) were the significant factors associated with isolated VSD. Late second-trimester fetal NBL, UA PI, and MCA PI are useful in detecting isolated VSD and may be used to adjust the a priori risk of both high- and low-risk women for isolated VSD. 3. The Association Between Tricuspid Regurgitation and Low AFI in the Late Second Trimester Clinical data on tricuspid reverse flow (TR) cases were extracted from two large regional medical centers from May 2014 to April 2015. A total of 209 cases of pregnant women were studied. Our data showed the RA-PI increased and RA-VTI significantly decreased, which lead to a reduction in urine production. For the AFI below 5.0 cm group, the right heart function and the renal blood flow dynamics are worse than the AFI above 15.0 cm groups. The result indicated that the blood volume of fetal blood circulation is closely associated with the fetal urine production. In clinical practice, we might need to be concerned about and conduct further examinations of the right heart function or kidney blood-flow dynamics when AFI is less than 10 cm. In our series of studies on the use of prenatal ultrasound examination to assess the risk of fetal defects, compared with the traditional methods in the past, this series of simple and rapid methods is mainly used to provide the first choice for clinical prediction of the risk of fetal defects.

Οι καρδιαγγειακές παθήσεις αποτελούν την κύρια αιτία θανάτου στις αναπτυγμένες χώρες. Η στένωση σε μία αρτηρία, είτε αυτή προκαλείται από μία πάθηση όπως το ανεύρυσμα, είτε προκαλείται από μία περίδεση, όπως στις περιπτώσεις των συγγενών καρδιοπαθειών, μπορεί να μεταβάλλει σε σημαντικό βαθμό τα χαρακτηριστικά της ροής του αίματος. Η μελέτη της φυσιολογικής παλλόμενης ροής μέσα από στένωση είναι ιδιαίτερα σημαντική για τη διάγνωση και αντιμετώπιση των αγγειακών νόσων. Το ιατρικό πρόβλημα το οποίο εξετάζουμε στην παρούσα εργασία, είναι η στένωση της πνευμονικής αρτηρίας από περίδεση. Η περίδεση γίνεται προφανώς για να μειωθεί η υψηλή αρτηριακή πίεση και τελικά η ροή του αίματος προς τους πνεύμονες. Πρόκειται για μία χειρουργική μέθοδο αντιμετώπισης συγγενών καρδιοπαθειών. Η περίδεση της πνευμονικής αρτηρίας (pulmonary artery banding - PAB) είτε με συμβατικό τρόπο, ή με την πλέον σύγχρονη μέθοδο μέσω της συσκευής FloWatchTM προκαλεί τη στένωσή της. Με τον συμβατικό τρόπο η στένωση μπορεί να θεωρηθεί αξονικά συμμετρική, ωστόσο με τη χρήση του FloWatchTM είναι μη αξονικά συμμετρική. Έχει αποδειχθεί ότι τόσο η αξονικά συμμετρική, όσο και η μη συμμετρική περίδεση δημιουργεί διαφόρου βαθμού ίνωση του τοιχώματος της πνευμονικής αρτηρίας. Η αναδόμηση της πνευμονικής αρτηρίας είναι πολύ ηπιότερη στην περίπτωση της περίδεσης με το FloWatchTM. Η διαφοροποίηση αυτή έγκειται κυρίως στο ότι η συμβατική περίδεση προκαλεί για συγκεκριμένη μείωση της διατομής ισχυρότερη μείωση της περιμέτρου της διατομής από εκείνης της περίδεσης με το FloWatchTM. Στην παρούσα εργασία γίνεται αναφορά και ανάλυση των διαφόρων περιπτώσεων ροής σε στενώσεις αρτηριών, των συγγενών καρδιοπαθειών και των τεχνικών περίδεσης της πνευμονικής αρτηρίας. Επιπρόσθετα, μελετήθηκαν και υπολογίστηκαν η μόνιμη και η παλλόμενη ροή σε αξονικά συμμετρική 25% στένωση προκαλούμενη από συμβατική περίδεση, καθώς και η μόνιμη και παλλόμενη ροή σε μη συμμετρική 25% στένωση της πνευμονικής αρτηρίας όπως προκαλείται από το FloWatchTM, μέσω των πακέτων Fluent και Gambit. Η υπολογιστική μελέτη του πεδίου ροής περιλαμβάνει την κατανομή ταχυτήτων, τον προσδιορισμό των περιοχών ανακυκλοφορίας, την κατανομή των πιέσεων και την σύγκριση των παραπάνω μεγεθών με τα αντίστοιχα αποτελέσματα της βιβλιογραφίας. Τέλος, με βάση τα αποτελέσματα γίνεται η σύγκριση των δύο μελετούμενων μεθόδων περίδεσης. Αριθμητικά ρεαλιστικά δεδομένα ελήφθησαν από την καρδιοχειρουργική κλινική του νοσοκομείου Παίδων «Αγία Σοφία».
Cardiovascular diseases are the leading cause of death in developed countries. A stenosis in an artery , caused either by a disease such as an aneurism or by a banding (such as in congenital diseases) can change the characteristics of the blood flow very seriously. The study of the physiological pulsatile flow through a stenosis is very important for the diagnosis and treatment of the arterial diseases. The medical problem which is examined in this study is pulmonary artery stenosis caused by a banding. The banding takes place to reduce the high arterial pressure and finally the blood flow from the heart to the lungs. It is a surgical method used for treatment of congenital heart diseases. The pulmonary artery banding either with the use of the conventional method or the most modern with the use of the FloWatchTM technology causes stenosis of the artery. With the conventional method, stenosis can be considered axially symmetrical while with the use of FloWatchTM it is asymmetrical. It has been proven that both the axially symmetrical and asymmetrical banding cause fibrosis of the pulmonary artery walls of different degrees. The reconstruction of the pulmonary artery is milder where there is banding with FloWatchTM. This differentiation is based mainly on the fact that the conventional banding causes, for a specific decrease of the cross-section, a decrease in the perimeter of the cross-section higher than that of banding with FloWatchTM. In this assignment there is a report of different cases of flow in arterial stenosis, in congenital heart diseases and pulmonary banding techniques. In addition what was studied and appreciated was the steady and pulsatile flow in axially symmetrical 25% stenosis caused by the conventional banding, as well as the steady and pulsatile flow in asymmetrical 25% stenosis of pulmonary artery caused by FloWatchTM with the use of Fluent and Gambit. The numerical study of flow distribution includes velocity distribution, designation of back flow area, distribution of pressure and comparison of these quantities with the results in bibliography. Finally, based on the results, there is a comparison of the two banding methods under study. The numerical realistic data were received from the cardio-surgical clinic of children’s hospital “Aghia Sophia”.

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.

碩士
國立中山大學
醫務管理研究所
95
Objective: Since its implication, case payment system prevailed and increased cases number in the following years. Hospitals in Taiwan face continous challenge with emerging policies such as global budget and TW-DRG system, which is soon on the way. Remarkable medical resource comsuption is seen in patients with congenital heart deseases, with presence of structural heart defects at birth. The corrective treatment of congenital heart diseases, surgical and transcather, is usually undertaken in large-scale Hospitals in Taiwan.Congenital heart diseases. Items of case payment for congenital heart diseases treatment were implented years ago. However, in the literature there is yet no research about the results of its implentation. This study focus on three objectives: 1.To study of medical resource consumption of case payment system with congenital heart diseases. 2.To study the effect of patient and provider attributes on medical resource consuption in the case payment with congenital heart diseases. 3.To provide the evidence-based information for forcoming NHI policies. Materials and Methods: Retrospectively, claims data from Bureau of National Health Research Insurance (BNHI) for resource utilization of case payment for congenital heart diseases was analyzed. The data includes DD(Inpatient expenditures by admissions) and HOSB(Registry for contracted medical facilities) files ranged from 1997 to 2005. Data items meeting the criteria of both CHD and case payment were extracted. The relationships between patient factors (age, sex, DRG code), healthcare provider (contract type, accreditation type, ownership, area) and resource utilization (length of stay, expenditure) were studied. Results: A total of 4,366 admissions for CHD case payment was enrolled. The mean patients’ age is 14.56 years. Female accounts for 55.46 % of the admissions. Among them there are 3954 open heart surgeries and 412 transcatheter treatments. Average hospital day is 11.6 and 3.37 days respectively. Average payment per case is NT$215,355 and NT$61,819 respectively. Different degrees of resource utilization occur with different patient or hospital characteristics, with statistical signifcance. More resource utilization tends to occur in extremes of age groups, e.g., newborn and elderly populations, regardless open heart surgery or transcatheter treatment cases. Also more hospital fee occurred in private hospital than public hospital, but less in medical centers when compared to metropolitian hospitals. For regression analysis of dependence of resource consumption on patient and hospital factors, the overall power of explanation is higher in transcather treatment cases. Among the factors influencing medical resource utilization, age_group and ownership are respectively the most significant factors. Conclusion: We have verify the hypothesis in this study, which emphasize that resource utlization differs by different patient and hospital factors. The pattern of resource utilization for this unique disease (CHD) and its discrepancy with concurrent payment criteria are evaluated in this study. Based on our results, adjustment of payment criteria should be reasonable to ensure early and adequate treatment for these patients. Thus this study provides strong insight for implication of TW-DRG for disease management. Further study will include aspects of resource utlization such as direct, indirect costs, tangle and intangle, and related complication and comorbidities.

碩士
弘光科技大學
護理研究所
104
Background: Congenital heart diseases (CHD) were a gross structural abnormality of the heart or intra-thoracic great vessels that is present at birth. Due to of progress made in cardiovascular surgery, most children with CHD were expected to survive to adolescence , even to adulthood. if the adolescents with congenital heart disease have enough knowledge of their disease , they can develop a positive adjustment capability and bring up their own health-promoting behaviors, master and create their own health state to extend their life to adulthood. This will be an important issue for adolescents with congenital heart disease. Objective: This study aimed to explore and analyze the relationship between congenital heart disease adolescent's and their parents for Congenital Heart Diseases knowledge and their related factors for adolescents with congenital heart disease. Methods: This study was a cross-sectional and descriptive correlation research design. Convenience sampling method was used by selecting 89 adolescents between ages 12-18 and their parents with the research requirements from the outpatient departments of pediatric congenital cardiology of the medical centers in Central Taiwan. The data collected by this method was through a constructive questionnaire composed of Leuven Knowledge Questionnaire for Congenital Heart Disease (LKQCHD). The collected data was SPSS version 20.0 then analyzed through the numerical and descriptive statistics, Pearson’s product-moment and independent sample t test, Chi-square test, analysis of variance (ANOVA), and multiple linear regression analysis. Results: In this study, from 89 families to participate in a total of 178; 40 adolescents, adolescent girls have 49, the average age was 15.33 ± 3.03 years. To participate in this study father 16, mother 73, the average age was 44.73 ± 6.17 years. Level of education, the adolescents junior (including) in the following occupy to 56.18% majority, with parents who graduated from high school level occupy to 47.19 percent majority. Self-rated health , adolescents have overall score of 21.12 ±3.52points, parents overall score of 21.47 ± 3.73 points. In aspects of knowledge of the source of the disease, the parents most of the information from the medical staff occupy to 94.38%, newspapers and magazines, While mostly from parents, adolescents with congenital heart disease (67.42%).The congenital heart disease knowledge awareness level rating, CHD adolescents average score of 16.61 ± 3.61 points.The overall rate of 53.57% of correct answers; parental average score of 18.58 ± 3.17 points, the overall rate of 59.95% of correct answers. The study patients had adequate knowledge (>80% correct answers) about the need for regular follow-up, required diet, past treatment, and dental practices. They had moderate knowledge (50-80% correct answers) about the frequency of follow-up, medication regimen, the effects of competitive sports, and the impact of alcohol on their heart disease . However, the patients had poor knowledge (<50% correct answers) of the name of their heart defect; the reasons for follow-up; the effects of competitive sports; the symptoms that reflect deterioration of their heart disease, the definition, characteristics, and risk factors of endocarditis, the possibility of recurrent episodes of endocarditis during their lifetime; the impact of smoking on their heart disease; the hereditary nature of their condition; the suitability of intrauterine devices as contraceptives; the appropriateness of oral contraceptives; and the risks of pregnancy. CHD overall level of understanding, self-health status, educational attainment, and family socioeconomic status level, the differences were statistically significant (p <.001), CHD knowledge cognitive factors also affected. Conclusion: The study found although the adolescents parents than CHD significantly better disease knowledge awareness, and the overall level of understanding of CHD The the better, the more adequate cognitive knowledge of the disease.But parents knowledge correctness, it will affect the accuracy of adolescents The CHD knowledge, knowledge of cognitive disease better, better able to realized in the future how to prevent heart disease risk, future prevention of complications. However, clinical Nursing staff in providing sufficient knowledge The CHD is very limited.Therefore, this study may provide Nursing staff care in the implementation of health education, according to the knowledge of the disease than the lack of adolescents CHD part to provide comprehensive plan, measure, and the connecting, and follow-up care of cooperation and to reach the complete model of care.

博士
中臺科技大學
醫學影像暨放射科學系暨研究所
105
ABSTRACT Taguchi's analysis was adopted to optimize the various factors referring to cardioangiography used to delineating the ductus arteriosus. The purpose of this study was to optimizate the cardioangiography for congenital heart diseases via Taguchi methodology and accompanied radiation doses. Thirty-six patients with PDA (type A) were enrolled from 2004 to 2005 in this study. A Taguchi’s L9 array was used to generate nine different designs of angiographic levels. Four controllable factors were selected and there were three levels for each as the following combinations. The optimal levels combination obtained by the S/N ratio to get the highest image quality for PDA was at (A) BSA <0.65m2, (B) projection angles: RAO 30O plus Cr15O and LAT view, (C) catheter locations: T 2.5 and (D) volumes of contrast medium: 1.0cc/kg. Further, the S/N ratio was 15.11 much better than conventional program 10.61 and the projection angle was found to be the most significant factor and not interacted by others, to delineate the ductus using the ANOVA test. Finally, the verification experiment was performed by setting the design with 12 PDA patients and S/N ratio was 14.25 revealing the better reproducibility. Otherwise, the dose evaluation was investigated through the TLD and farmer ion-chamber in five PMMA phantoms and the phantom was exposed to exposure and fluoroscope to obtain either effective or skin dose according to the ICRP-60 report. The derived effective dose and skin dose according to various BMI and dose-area product (DAP) were further reassembled into Statistica 7 program to derive several semi-empirical formulas in this work. There were four r2 values : r2 = 0.9767；r2= 0.9860；r2= 0.9520 and r2= 0.8875 for effective doses and skin doses during fluoroscope and exposure, respectively. Finally, 30 patients were performed using the verification experiments and demonstrated the advantages of the effective doses and skin doses only reassembling the BMI and DAP. The semi-empirical formula obtained in this study can be applied to estimate the effective and skin doses given by the examination.