To identify genes related to the heart developments, a total of 92 CHD families from Kaohsiung Veteran General Hospital, including 290 individuals with 95 affected, were genotyped in this study. Among these CHDs families, 54 were diagnosed as VSDs, accounted for 56.8% of all CHDs. Ten highly polymorphic markers, D22S420, D22S427, D22S1638, D22S941, D22S1648, D22S944, D22S1623, D22S264, D22S303 and D22S315, from centromere to the HSA22q telomere, covering HSA22q11 were genotyped by using a semi-quantitative fluorescent PCR. LOH at loci on 22q11 have been identified in 31 VSDs affected individuals. Candidate genes in HSA22q11 region was identified by bioinformatic methods firstly based on Ensembl (EMBL-EBI and the Sanger Institute), Genome browser (UCSU) and Map viewer (NCBI), and then FatiGO Data mining with Gene Ontology and Swiss-Prot annotations. In order to narrow down more specific cardiac development-related candidate genes within HSA22q11, TUBA8, DGCR2, DGCR14, CLTCL1, HIRA, TBX1 and GNB1L, from the centromere to telomere, were further subjected to dosage analyses by quantitative PCR. Results indicated the most frequent LOH region was localized on D22S1648. There are 48.3% and 38.7% of 31 VSDs patients with one copy deletion in TUBA8 and HIRA, respectively. Two VSDs patients were deleted in all seven candidate genes. Furthermore, there are one CAVC and one VSD patient were deleted in five consecutive genes, TUBA8, DGCR2, DGCR14, CLTCL1 and HIRA.

Objective. Congenital heart disease (CHDs) in Taiwan cause twice as many children die each year comparing with childhood cancers. Prevalent CHDs are ventricular septal defects (VSDs) which accounted for ~40% Taiwanese population averagely. Studies on heart development-related genes on the human genome will provide valuable information for early diagnosis/prevention in eugenics and the development of therapeutic strategies. Methods. A total of 239 CHD families from Kaohsiung Veteran General Hospital, including 713 individuals with 245 affected, participated in this study. Among these CHDs families, 83 were diagnosed as VSDs, accounted for 34.7% of all CHDs. We initiated using a semi-quantitative fluorescent PCR method applying ten highly polymorphic markers that located within 22q11, genotyping analysis for deletion or loss of heterozygosity. In those cases that are identified as chromosome 22q11-independent VSDs, cardiac development-related candidate genes TBX5, CSX and JAG1 analyses were performed by Single-Strand Conformation Polymorphisms (SSCPs) and Temporal Temperature Gradient Gel Electrophoresis (TTGE) analyses to identify whether any genomic mutation/deletion exists. Results. So far, there are twenty-five VSD affected individuals have been identified as loss of heterozygosity (LOH) at loci D22S264, D22S303, D22S420, D22S427,D22S941, D22S944, D22S1638 and D22S1648. Candidate gene approaches will therefore be carried out within chromosome 22q11 subregion in these individuals. Conclusions. The frequency of CHD necessitating intervention in patients referred for cardiovascular evaluation after diagnosis of a chromosome 22q11 deletion. Routine screening for CHDs, including VSD and other imaging studied to identify the any microdeletion(s) or LOH.

BACKGROUND: The ventricular septal defect (VSD), a hole between the ventricles of the heart, is the most common birth defect. Despite its commonality, little is known about related in utero functional deficits. Furthermore, although about 80% of clinical VSD resolve within a year, the long-term effects after their resolution are unknown due to lack of clinical follow-up. Chemical treatment was used to induce VSD in the rat and to investigate their functional consequences both in utero and postnatally. METHODS: Pregnant Sprague-Dawley rats were administered six 300mg/kg doses of dimethadione (DMO) by oral gavage every 12 hours beginning at 19h00 on gestational day (GD) 8 (Weston et al., 2011). DMO is the N-demethylated metabolite of the anticonvulsant trimethadione, a potent inducer of VSDs clinically and in laboratory animals. Fetal heart structure and function were examined with high-resolution ultrasound on GD 14, 15, 16, 17, and 21. A separate cohort of rats was dosed using the described paradigm, but offspring were allowed to reach parturition and mature naturally. Postnatal heart structure and function were assessed using telemetry (70 days postnatally), high-resolution ultrasound, and electrocardiography (ECG) (one year postnatally). RESULTS: Relative to controls, DMO-treated fetal rats had structural defects including VSD, an increased incidence of bradycardia (23 vs. 45%) and dysrhythmia (1.2 vs. 11%), and a reduction in cardiac output, stroke volume, and mean heart rate. Adult rats exposed to DMO in utero were more physically active, had elevated blood pressure, and had a higher incidence of dysrhythmia associated with ECG disturbances compared to controls. Both in utero and postnatal functional deficits occurred independent of septum patency. CONCLUSIONS: Gestational exposure to DMO disrupted cardiac function both in utero and postnatally, even in the absence of gross structural defects, indicating chemical exposures in utero may have permanent pathophysiological consequences on the heart. / Thesis (Master, Pharmacology & Toxicology) -- Queen's University, 2012-05-30 17:19:35.529

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13331号 / 論医博第2199号 / 新制||医||1044(附属図書館) / (主査)教授 湊谷 謙司, 教授 横出 正之, 教授 戸口田 淳也 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Doenças cardíacas congênitas são as mais frequentes entre as malformações congênitas graves, afetando de duas a três crianças por 100 nascidos vivos, sendo o defeito do septo atrioventricular (DSAV) responsável por 5% desses, e atingindo cerca de 50% dos pacientes portadores de Síndrome de Down. Caracteriza-se essencialmente por vários graus de desenvolvimento incompleto do tecido septal ao redor das valvas atrioventriculares, bem como de anormalidades na formação das mesmas. Recomenda-se a correção cirúrgica ao redor de 4 meses de vida, no intuito de prevenir o surgimento de hipertensão pulmonar (HP) irreversível devida ao hiperfluxo pulmonar, no entanto a despeito disso, identifica-se a presença de hipertensão pulmonar em pacientes já submetido ä correção do defeito cardíaco. O presente estudo teve por objetivo analisar a prevalência de hipertensão pulmonar diagnosticada através do ecocardiografia e identificar dos fatores de risco em pacientes submetidos à correção cirúrgica de DSAV nos últimos 16 anos no Hospital das Clínicas da Faculdade de Medicina de Ribeirão preto da Universidade de São Paulo (HCFMRP - USP). Foram selecionados pacientes portadores de DSAV, submetidos à correção cirúrgica no HCFMRP - USP, no período de janeiro de 1999 a janeiro de 2016, em seguimento no Ambulatório de Cardiologia Infantil do HCFMRP-USP, considerados portadores de hipertensão pulmonar os pacientes que apresentaram à ecocardiografia valores estimados de pressão sistólica de artéria pulmonar (PSAP) superiores a 30 mmHg. Foram analisadas variáveis clínicas pré e pós-operatórias. Não foi encontrada correlação entre peso e idade na data da correção cirúrgica e presença de HP na avaliação ecocardiográfica pós-operatória; no entanto esta se relacionou com tempo prolongado de circulação extra-corpórea e ventilação mecânica. Houve aumento significativo na sobrevida nos últimos oito anos analisados, refletindo a melhoria na qualidade de atendimento clinico e cirúrgico dos pacientes. A alta perda de seguimento ambulatorial causa preocupação, porém reflete as dificuldades próprias de serviços de saúde de países em desenvolvimento. / Congenital heart diseases are the most common serious congenital malformations, affecting two of three children per 100 newborns, the atrioventricular septal defect (AVSD) is responsible for 5% of these cases, reaching almost 50% of bearers of Down\'s Syndrome. It has been characterized essentially by many incomplete development degrees of de septal tissue around the atrioventricular valves, as well as its formation abnormalities. The actual recommendation is to proceed surgical correction nearly 4 months of age, in order to prevent irreversible pulmonary hypertension (PH) due to the pulmonary overflow. Despite of the surgical correction, patients may present pulmonary hypertension. This research aimed to analyze the prevalence of pulmonary hypertension diagnosed by transthoracic echocardiogram and identify risk factors for this outcome in patients undergoing surgical correction of AVSD in the last 16 years at the Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (HCFMRP - USP). All patients diagnosed with AVSD, submitted to surgical correction and followed at the HCFMRP - USP in the last 16 years and were selected. Those who had systolic pulmonary arterial pressure above 30 mmHg in the echocardiogram evaluation were considered to have pulmonary hypertension. Clinical variables before and after surgery were analyzed. Anthropometric and age data at the surgery had no influence in the presence of PH in the follow up. Although prolonged cardiopulmonary bypass and pulmonary mechanical ventilation had significantly affected that outcome. The survival had increased significantly in the last eight years of our study, reflecting the improvement of assistance. A high loss of follow up was detected and made us very concerned, however shows the difficulties and low investment in the public health system in developing countries.

Doenças cardíacas congênitas são as mais frequentes entre as malformações congênitas graves, afetando de duas a três crianças por 100 nascidos vivos, sendo o defeito do septo atrioventricular (DSAV) responsável por 5% desses, e atingindo cerca de 50% dos pacientes portadores de Síndrome de Down. Caracteriza-se essencialmente por vários graus de desenvolvimento incompleto do tecido septal ao redor das valvas atrioventriculares, bem como de anormalidades na formação das mesmas. Recomenda-se a correção cirúrgica ao redor de 4 meses de vida, no intuito de prevenir o surgimento de hipertensão pulmonar (HP) irreversível devida ao hiperfluxo pulmonar, no entanto a despeito disso, identifica-se a presença de hipertensão pulmonar em pacientes já submetido ä correção do defeito cardíaco. O presente estudo teve por objetivo analisar a prevalência de hipertensão pulmonar diagnosticada através do ecocardiografia e identificar dos fatores de risco em pacientes submetidos à correção cirúrgica de DSAV nos últimos 16 anos no Hospital das Clínicas da Faculdade de Medicina de Ribeirão preto da Universidade de São Paulo (HCFMRP - USP). Foram selecionados pacientes portadores de DSAV, submetidos à correção cirúrgica no HCFMRP - USP, no período de janeiro de 1999 a janeiro de 2016, em seguimento no Ambulatório de Cardiologia Infantil do HCFMRP-USP, considerados portadores de hipertensão pulmonar os pacientes que apresentaram à ecocardiografia valores estimados de pressão sistólica de artéria pulmonar (PSAP) superiores a 30 mmHg. Foram analisadas variáveis clínicas pré e pós-operatórias. Não foi encontrada correlação entre peso e idade na data da correção cirúrgica e presença de HP na avaliação ecocardiográfica pós-operatória; no entanto esta se relacionou com tempo prolongado de circulação extra-corpórea e ventilação mecânica. Houve aumento significativo na sobrevida nos últimos oito anos analisados, refletindo a melhoria na qualidade de atendimento clinico e cirúrgico dos pacientes. A alta perda de seguimento ambulatorial causa preocupação, porém reflete as dificuldades próprias de serviços de saúde de países em desenvolvimento. / Congenital heart diseases are the most common serious congenital malformations, affecting two of three children per 100 newborns, the atrioventricular septal defect (AVSD) is responsible for 5% of these cases, reaching almost 50% of bearers of Down\'s Syndrome. It has been characterized essentially by many incomplete development degrees of de septal tissue around the atrioventricular valves, as well as its formation abnormalities. The actual recommendation is to proceed surgical correction nearly 4 months of age, in order to prevent irreversible pulmonary hypertension (PH) due to the pulmonary overflow. Despite of the surgical correction, patients may present pulmonary hypertension. This research aimed to analyze the prevalence of pulmonary hypertension diagnosed by transthoracic echocardiogram and identify risk factors for this outcome in patients undergoing surgical correction of AVSD in the last 16 years at the Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (HCFMRP - USP). All patients diagnosed with AVSD, submitted to surgical correction and followed at the HCFMRP - USP in the last 16 years and were selected. Those who had systolic pulmonary arterial pressure above 30 mmHg in the echocardiogram evaluation were considered to have pulmonary hypertension. Clinical variables before and after surgery were analyzed. Anthropometric and age data at the surgery had no influence in the presence of PH in the follow up. Although prolonged cardiopulmonary bypass and pulmonary mechanical ventilation had significantly affected that outcome. The survival had increased significantly in the last eight years of our study, reflecting the improvement of assistance. A high loss of follow up was detected and made us very concerned, however shows the difficulties and low investment in the public health system in developing countries.

Darbe išnagrinėti mažiau invazinės įgimtų prieširdžių pertvaros defektų (PPD) ir skilvelių pertvaros defektų (SPD) ydų chirurgijos galimybės ir ypatumai. Standartinį šių ydų operavimo būdą per išilginę vidurinę sternotomiją galima pakeisti mažiau invaziniu su geresniu kosmetiniu rezultatu. Darbe parodoma, kad mažiau invazinių PPD ir SPD korekcijų rizika iš esmės nesiskiria nuo standartinės metodikos per vidurinę išilginę sternotomiją. Mažiau invazinių širdies pertvarų defektų uždarymo operacijų metodika įgalina jas saugiai atlikti su įprastiniais širdies chirurgijos instrumentais be papildomų išlaidų. Mažiau invazinių įgimtų širdies ydų operacijų indikacijos yra siauresnės. / The study defines the possibilities and peculiarities of the less invasive congenital atrial septal defect (ASD) and ventricular septal defect (VSD) surgery. A standard median sternotomy approach in some cases is possible to replace with more cosmetic friendly and less invasive access. The study demonstrates that the risk of less invasive ASD and VSD closure doesn’t differ from the standard median sternotomy surgery risk. Less invasive operations methodic used in our centre enables it with conventional instrumentary set. Indications for less invasive congenital heart defects surgery are narrower.

Ce mémoire par article est une étude des différences hémodynamiques entre la dextro-transposition des gros vaisseaux (TGV) avec communication interventriculaire (CIV) et la TGV avec septum intact (SI) pendant la période fœtale et périopératoire. Il est à noter que SI fait référence au septum inter ventriculaire et non au septum inter auriculaire. La présence d’une communication inter auriculaire étant, comme nous le verrons dans ce travail, un élément important de la physiologie des fœtus/nouveau-nés porteur de TGV. Le document est divisé en deux parties importantes. La première partie est composée du chapitre 1 qui présente une revue de littérature détaillant les notions importantes à la compréhension de la problématique et du chapitre 2 qui décrit la méthodologie utilisée pour répondre à la question de recherche. On détaille d’abord les méthodes d’acquisition des échocardiographies fœtales ainsi que les principales mesures effectuées à partir de celles-ci. Ensuite, on y décrit les technologies de la spectroscopie proche infrarouge avancée et de la spectroscopie à corrélation diffuse (NIRS-DCS) permettant de recueillir les données hémodynamiques sur la microvascularisation cérébrale des nouveau-nés. La seconde partie est constituée du chapitre 3 qui est le manuscrit accepté au journal Ultrasound in Obstetric & Gynecology pour publication. Celui-ci décrit les différences hémodynamiques entre les patients ayant une TGV&CIV et les TGV&SI et présente les différences retrouvées en échocardiographie fœtale et en hémodynamie cérébrale périopératoire étudiée à l’aide de la NIRS avancée. Ensuite, nous présentons dans le chapitre 4 une discussion sur les principaux impacts cliniques et sur d’éventuelles améliorations. / This master’sthesis is composed of an article and a study. They present hemodynamic differences between patients with transposition of the great arteries (TGA) and ventricular septum defect (VSD), and TGA with intact ventricular septum (IVS) during fetal and perioperative periods. This document is divided into two principal sections. The first section includes Chapter 1 that presents a review of literature detailing important notions to understand the problematic, and Chapter 2, that describes the methodology used to answer our research question. First, we detailed acquisition data and measured parameters of the fetal echocardiography exams. Then, we describe advanced near infrared spectroscopy (NIRS-DCS) technology that allowed hemodynamic data acquisition on the cerebral microvascularization of neonates. The second section is composed of Chapter 3, the manuscript accepted in Ultrasound in Obstetric & Gynecology journal for publication. The aim of this article is to describe hemodynamic differences between patients with TGA&VSD and TGA&IVS. It describes fetal echocardiography and cerebral perioperative hemodynamic differences studied with advanced NIRS. Next, we present in Chapter 4 a more detailed discussion with principal impacts on the clinical field and future improvements.