本文選題：內(nèi)臟異位　切入點(diǎn)：先天性心臟病　出處：《復(fù)旦大學(xué)》2013年博士論文

【摘要】：先天性心臟病(以下簡稱先心病)是常見的出生缺陷之一,在新生嬰兒中發(fā)病率約7.5‰～-9‰,是1歲以內(nèi)嬰兒死亡的主要原因。世界衛(wèi)生組織資料顯示,全球每年約有150萬先心病患兒出生,其中,我國每年約有15萬到20萬先心病患兒出生。內(nèi)臟異位常合并復(fù)雜先心病,研究提示,合并內(nèi)臟異位先心病患者的術(shù)后呼吸道并發(fā)癥和死亡率較高,一直以來都被歸于心臟畸形的復(fù)雜和手術(shù)難度高。但是,近年的研究證實(shí),內(nèi)臟的左右模式發(fā)育和氣道粘液清除機(jī)制都需要?jiǎng)恿w毛；內(nèi)臟異位、先心病和原發(fā)性纖毛運(yùn)動障礙(Primary Ciliary Dyskinesis,PCD)之間存在密切關(guān)系。我們推測,氣道纖毛功能障礙(Ciliary Dysfunction, CD)可能是導(dǎo)致先心病合并內(nèi)臟異位患者術(shù)后呼吸道并發(fā)癥高發(fā)的重要原因。本研究內(nèi)容包括：1.通過臨床病例對照研究,觀察先心病合并內(nèi)臟異位患者呼吸道并發(fā)癥和預(yù)后情況；2.測定先心病合并內(nèi)臟異位患者鼻竇一氧化氮濃度(Nasal Nitric Oxide, nNO)、氣道纖毛運(yùn)動,觀察CD的發(fā)生率；3.探討先心病家系成員和內(nèi)臟異位核心家庭成員的CD。本研究旨在闡明纖毛功能障礙對先心病合并內(nèi)臟異位患者呼吸道并發(fā)癥的影響,揭示纖毛功能障礙在內(nèi)臟異位中的作用機(jī)制,將有助于改善先心病的臨床預(yù)后。 第一部分合并內(nèi)臟異位的先心病患者術(shù)后死亡率和呼吸道并發(fā)癥的回顧性研究 目的 以合并先心病的內(nèi)臟異位患者為研究對象,將不合并內(nèi)臟異位的先心病患兒作為對照組,探究內(nèi)臟異位患者的術(shù)后死亡率和呼吸道并發(fā)癥發(fā)生率。 方法 對從2000年1月1日到2011年12月31日期間,在我院心血管中心接受心臟外科手術(shù)的患兒,進(jìn)行一項(xiàng)回顧性病例對照分析；一共納入了107例合并內(nèi)臟異位的先心病患者作為研究組。同時(shí)納入了876例僅患有先心病,而未患有內(nèi)臟異位的患兒作為對照組。采用先天性心臟病手術(shù)風(fēng)險(xiǎn)校正評分(Risk Adjustment in Congenital Heart Surgery-1, RACHS-1)評分系統(tǒng)來確保兩個(gè)組的手術(shù)復(fù)雜程度是相當(dāng)?shù)?兩組的RACHS-1評分的中位數(shù)均為3.0。 結(jié)果 相比于不合并內(nèi)臟異位的先心病患兒,內(nèi)臟異位的患兒的術(shù)后病死率明顯升高(16.8%相比于4.7%；OR：3.0)。平均住院時(shí)間(12.7天對比9.1天),機(jī)械通氣時(shí)間(57小時(shí)對比42小時(shí))和ICU時(shí)間(93小時(shí)對比71小時(shí))要明顯延長。此外,研究組的延長的機(jī)械通氣(6.5%對比2.1%；OR：3.1),病危通知書(13.1%對比5.8%；OR：2.4),搶救(11.2%對比5.1%；OR：2.3),發(fā)熱(66.4%對比34.9%；OR：37)和Up音(30.0%對比18.9%；OR：1.8)的發(fā)生率都高于對照組。 小結(jié) 在中國人群中,與具有RACHS-1評分相當(dāng)?shù)膶φ战M患兒相比,合并內(nèi)臟異位的先心病患兒的術(shù)后病死率和呼吸道并發(fā)癥的發(fā)生率顯著增高,提示內(nèi)臟異位患者可能存在的呼吸道缺陷如纖毛活動障礙。 第二部分合并內(nèi)臟異位的先心病患者的呼吸道纖毛功能障礙研究 目的 研究CD對內(nèi)臟異位患者術(shù)后高死亡率和呼吸道并發(fā)癥的影響。 方法 招募共計(jì)32例合并內(nèi)臟異位的先心病患者,同時(shí)納入51例不合并內(nèi)臟異位的先心病患者作為先心病對照組,100例健康受試者作為健康對照組。利用配有微分干涉差(Differential Interference Contrast, DIC)系統(tǒng)和高頻攝像頭的顯微鏡,對取自鼻粘膜的呼吸道表皮細(xì)胞的纖毛運(yùn)動進(jìn)行評估,并測量這些患者的nNO；并進(jìn)行觀察內(nèi)和觀察者間一致性檢驗(yàn)。最后,對所有懷疑異常的鼻粘膜樣本進(jìn)行體外細(xì)胞培養(yǎng),排查繼發(fā)性CD。 結(jié)果 1、32例內(nèi)臟異位患者中有13例(40.6%)出現(xiàn)了CD,并且CD患者的nNO顯著降低,其中有8例患者(61.5%)的nNO低于或接近PCD的臨界值。 2、觀察內(nèi)和觀察者間的一致性檢驗(yàn)證實(shí)了利用顯微攝像評估纖毛運(yùn)動方法的可靠性。 3、共計(jì)9例CD的鼻粘膜樣本培養(yǎng)成功,其中2例樣本(22.2%)在培養(yǎng)后證實(shí)為繼發(fā)性CD。 小結(jié) 1、內(nèi)臟異位患者的CD發(fā)生率高,CD伴有nNO值的降低。 2、利用顯微攝像動態(tài)評估纖毛運(yùn)動的方法是可靠的。 3、鼻粘膜細(xì)胞培養(yǎng)有助于CD病因的分析。 第三部分先心病家系成員和內(nèi)臟異位核心家庭成員的呼吸道纖毛功能障礙研究 目的 評估先心病家系成員和內(nèi)臟異位核心家庭成員的CD分布情況,探討CD的遺傳特點(diǎn) 方法 招募了5個(gè)完整的先心病家系,評估家系成員的纖毛運(yùn)動和nNO值；統(tǒng)計(jì)33個(gè)已知先心家系中的內(nèi)臟異位患者數(shù)量；調(diào)查53個(gè)已知內(nèi)臟異位患者的先心病家族史；分析CD在22個(gè)內(nèi)臟異位核心家庭成員中的分布。 結(jié)果 1、5個(gè)先心病家系中共計(jì)招募了35例先心病家系成員,CD共有13例(37.1%)其中有5例成員(38.5%)的nNO值低于或接近PCD的臨界值。 2、在已取得聯(lián)系的33個(gè)家系共計(jì)78例的先心病患者中,內(nèi)臟異位患者7例(9.0%)。 3、53例已取得聯(lián)系的內(nèi)臟異位患者中,有7例(13.2%)患者具有先心病家族史。 4、22例內(nèi)臟異位核心家庭成員共計(jì)有49人,其中11人為CD,分布在7個(gè)核心家庭中,其中有3例成員(27.2%)的nNO值低于或接近PCD的臨界值。 小結(jié) 1、先心病家系成員中CD的發(fā)生率顯著增高,且部分CD成員nNO低于或接近PCD的臨界值。 2、具有先心病家族史的先心病患者人群中,內(nèi)臟異位發(fā)病率高,而內(nèi)臟異位患者中先心病家族史多見。 3、內(nèi)臟異位核心家庭成員CD的發(fā)生率顯著增高,且部分CD成員nNO低于或接近PCD的臨界值,提示CD具有明顯的遺傳傾向。
[Abstract]:Congenital heart disease (CHD) is one of common birth defects in newborn babies, the incidence rate of about 7.5 per 1000 ~ -9%, is a major cause of infant death within 1 years. The WHO data shows that about 1 million 500 thousand of children with congenital heart disease was born, which is about 150 thousand per year worldwide, 200 thousand children with congenital heart disease born in China every year. Heterotaxy is often associated with complex congenital heart disease in patients with congenital heart disease, research suggests that patients with visceral ectopic postoperative respiratory complications and high mortality rate, has been attributed to the complex heart malformation and operation difficulty is high. However, recent studies confirmed that the mode of development and visceral about airway mucus clearance mechanism need to dynamic cilia; visceral ectopic, congenital heart disease and primary ciliary dyskinesia (Primary Ciliary, Dyskinesis, PCD) there is a close relationship between. We speculate that airway cilia dysfunction (Ciliary Dysfunction, CD) may be the cause of congenital heart disease with high incidence of ectopic important causes of respiratory complications in postoperative patients with visceral. The research contents include: 1. through the clinical case-control study, observation of congenital heart disease with respiratory tract in patients with ectopic visceral complications and prognosis; 2. measured CHD patients with heterotopic sinus (Nasal Nitric Oxide, the concentration of nitric oxide nNO), airway ciliary movement, the incidence of CD was observed; 3. of CHD pedigrees and Heterotaxis core family members CD. the present study aimed to elucidate the effect on ciliary dysfunction in congenital heart disease complicated with visceral complications in patients with respiratory tract ectopic, mechanism of ciliary dysfunction in visceral ectopic, will help to improve the clinical prognosis congenital heart disease.
A retrospective study of postoperative mortality and respiratory complications in patients with congenital heart disease with visceral heterotopic heart disease
objective
The patients with congenital heart disease with heterotopic heart disease were selected as the control group.
Method
From January 1, 2000 to December 31, 2011 period, undergoing cardiac surgery in the cardiovascular center of our hospital were conducted a retrospective case-control analysis; a total of 107 cases with congenital heart disease in patients with heterotaxy. At the same time as the study group included 876 cases with congenital heart disease, without visceral endometriosis patients as control group the risk of congenital heart disease. Surgical correction score (Risk Adjustment in Congenital Heart Surgery-1, RACHS-1) scoring system to ensure that the two group is the complexity of the surgery, the median RACHS-1 score of two groups were 3.0.
Result
Compared to the patients without heterotaxy in children with congenital heart disease heterotaxic children postoperative mortality rate was significantly increased (16.8% compared to 4.7%; OR:3.0). The average hospitalization time (12.7 days vs. 9.1 days), mechanical ventilation time (57 hours compared to 42 hours) and ICU time (93 hours to 71 hours) to obviously prolonged. In addition, prolonged mechanical ventilation group (6.5% vs. 2.1%; OR:3.1), notice (13.1% vs. 5.8%; OR:2.4), rescue (11.2% vs. 5.1%; OR:2.3), fever (66.4% vs. 34.9%; OR:37) and Up (30% vs. 18.9%; OR:1.8.) the incidence is higher than that of control group.
Summary
In Chinese population, the incidence of postoperative mortality and respiratory complications of children with congenital heart disease with heterotopic heterotopic heart disease is significantly higher than that of children with RACHS-1 score. This suggests that there may be respiratory defects such as ciliary dyskinesia in patients with heterotopic viscera.
The study of respiratory cilium dysfunction in the second part of patients with congenital heart disease with visceral heterotopic heart disease
objective
The effect of CD on postoperative high mortality and respiratory complications in patients with visceral heterotopic surgery was studied.
Method
Recruit a total of 32 cases of patients with visceral ectopia in patients with congenital heart disease, also included 51 cases of congenital heart disease with heterotaxy patients with congenital heart disease as control group, 100 cases of healthy subjects as healthy control group. The use of a differential interference contrast (Differential Interference, Contrast, DIC) system and the high frequency camera microscope, ciliary movement of epidermis the cells of the respiratory tract from the nasal mucosa was assessed and measured in these patients were observed in nNO; and the inter observer consistency test. Finally, all suspected of nasal mucosa samples were abnormal in vitro, the investigation of secondary CD.
Result
In 13 cases (40.6%) of 1,32 heterotopic patients, CD appeared, and nNO in CD patients decreased significantly, of which 8 patients (61.5%) had nNO below or near the critical value of PCD.
2, the consistency test between observation and observer confirmed the reliability of using microphotography to evaluate ciliary movement.
3, a total of 9 cases of CD's nasal mucosa samples were cultured successfully, of which 2 cases (22.2%) were identified as secondary CD. after culture.
Summary
1, the incidence of CD in patients with visceral ectopia was high, and CD was accompanied by a decrease in the nNO value.
2, the method of dynamic evaluation of cilium motion by microphotography is reliable.
3, the cell culture of the nasal mucosa is helpful to the analysis of the cause of CD.
The study of respiratory cilium dysfunction in third part of the family members of congenital heart disease and the members of the visceral heterotopic core family
objective
The CD distribution of members of the family members of congenital heart disease and the members of the visceral heterotopic core family was evaluated and the genetic characteristics of CD were discussed.
Method
The recruitment of 5 complete congenital heart disease pedigrees, assessment of family members of ciliary movement and nNO value; counting the number of 33 known congenital heart disease in a family with congenital heart disease in patients with heterotaxy; investigation of 53 known Heterotaxis with family history; analysis of CD distribution in the 22 Heterotaxis core in the family members.
Result
A total of 35 cases of congenital heart disease family members were recruited in the 1,5 family of congenital heart disease, and CD had 13 cases (37.1%). Among them, 5 patients (38.5%) had nNO value below or near the critical value of PCD.
2, of the 33 families with a total of 78 cases of congenital heart disease, 7 cases of visceral ectopia (9%).
Of the 3,53 cases, 7 (13.2%) had a family history of congenital heart disease (13.2%).
The total number of visceral ectopic family members in 4,22 was 49, of which 11 were CD and distributed in 7 core families. 3 of the 3 members (27.2%) had nNO value below or near the critical value of PCD.
Summary
1, the incidence of CD in the members of the CHD family was significantly higher, and some of the CD members nNO were lower or close to the critical value of PCD.
2, among the patients with a family history of congenital heart disease, the incidence of ectopic ectopic disease is high, and the family history of congenital heart disease is common in the patients with visceral ectopia.
3, the incidence of CD in the family members of the visceral heterotopic family was significantly higher, and some of the CD members nNO were lower or close to the critical value of PCD, suggesting that CD has an obvious genetic tendency.

【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2013
【分類號】：R725.4

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