摘要:背景先天性心臟病是兒童最常見心臟疾患,單一心室疾病是其中長期預後最差,且常伴隨併發症需反覆住院的問題。Fontan式手術(包括開窗式完全腔靜脈肺動脈循環 TCPC)是目前能夠達到長期存活的標準手術療程。由於Fontan手術的獨特循環,由腔靜脈至肺動脈至心室的血流是完全被動式的,也因此整個循環系統比起一般人須保持更低的阻力,即使肺動脈壓微幅增高也會造成Fontan手術循環不良。已知危險因子包括高的術前肺動脈壓或阻力,心室功能不良,在台灣,藉由上述因子做術前評估,仍有許多病人在手術後或長期追蹤有Fontan循環不良甚至死亡。藉由精準醫療來評估手術納入條件可能可以改善存活率:包括以新的極譜分析評估氧氣消耗法估算肺血管阻力,生物指標,及適當肺血管擴張劑治療。肺高壓的致病機轉,內皮細胞的功能不良(表現為血循內皮細胞及內皮前驅細胞增加)及胞外基質影響(表現為基質金屬蛋白酶1及2的增加)在原發及次發的肺高壓都證實扮演重要角色。最近微小RNA被認為參與肺高壓致病機轉,並可做為臨床生物指標。在Fontan氏手術病人的肺血管重塑上這些生物指標的影響仍未知。目標回溯研究部分: 我們將評估最近27年Fontan式手術病人的存活情形。前瞻研究部分,我們藉由精準醫學(包括生物指標),建構Fontan式手術術後短期及長期預後的預測指標,另外也將檢測生物指標在TCPC開窗關閉,以及肺血管擴張劑反應的風險評估工具的角色。方法回溯部分評估最近27年所有單一心室病人,手術以及長期存活,及其風險因子評估。此外,也將研究接受開窗關閉次族群的長期結果。前瞻部分1.前瞻性評估所有單一心室病人預備手術前心導管評估及臨床資料,並做生物指標分析,持續追蹤病人臨床及生物指標變化。主要的試驗終點為心血管死亡,TCPC拆卸及心或心肺移植。次發終點為蛋白流失腸病變併發症,以及反覆心臟衰竭住院。2.所有上述回溯性研究且定期追蹤病人,評估臨床指標,六分鐘走路測試,以及生物指標分析,以建構新的精準風險評估工具。3.所有單一心室合併肺高壓病人,我們分析臨床參數及生物指標,並評估肺血管擴張劑的反應及有效的預測因子。基礎部分我們將由周邊血或肺動脈抽取5-10西西全血,我們會藉由四色流式細胞儀偵測血循內皮細胞及內皮前驅細胞,由ELISA方式偵測基質金屬蛋白酶-1, 2。另外以逆轉錄聚合酶鏈式反應方式偵測微小RNA
Abstract: Background Congenital heart disease (CHD) is the most common heart disease in children. Among them, single ventricle disease is the most severe form. Fontan type operation (including total cavopulmonary circulation TCPC) is the standard operative procedure. As the special physiology of Fontan operation, the flow from systemic vein through lungs to the ventricle is entirely passive. Therefore low resistance through the whole pathway is mandatory. The perioperative failure rate and long term outcome of TCPC is not low, and these patients often suffer from repeat admission for heart failure control and protein losing enteropathy, with which admission every month is necessary. A more comprehensive patient selection criterion through precision medicine including polarographic method for pulmonary vascular resistance (PVR) measurement, biomarkers analysis, and appropriate pulmonary vasodilators therapy may be beneficial. For the pathogenesis of pulmonary hypertension (PAH), endothelial dysfunction (with increasing circulating endothelial cell, CEC, and endothelial progenitor cell, EPC) and involvement of extracellular matrix (increase of matrix metalloproteinase (MMP)-1 and 2) in pulmonary vessel remodeling are important in idiopathic and secondary PAH. Recently, microRNA (miRNA) was found to be also involved in the pathogenesis of idiopathic PAH, and can be used as a biomarker of clinical condition. However, the role of pulmonary vascular remodeling and the application of these biomarkers on Fontan operation are still unknown.Aim Retrospectively, we will analyze the short term and long term outcome of these patients. Prospectively, through precision medicine, we will analyze the predictors (including biomarkers) of good perioperative outcome and construct new risk assessment tools for long term outcome, fenestration closure, and responder to pulmonary vasodilators therapy. Method Retrospective In these 27 years, all patients with single ventricle disease will be analyzed for perioperative and long term outcome. Besides, the subgroup of those received fenestration closure will be compared to those without closure by matched analysis. Prospectively 1. All patients who admit to cardiac catheterization for preoperative assessment prior to Fontan type operation will be analyzed for clinical parameters, cardiac catheterization data and biomarkers analysis. We will regularly follow the patients including biomarkers analysis. The primary endpoint of the prospective study includes cardiovascular death, TCPC takedown, and heart or heart-lung transplantation. The secondary endpoint includes protein losing enteropathy documented and repeat admission for heart failure control.2. All patients with single ventricle disease, enrolled in retrospective study, will be invited for clinical evaluation, 6 minute walk distance, and biomarker analysis. We will then construct a risk assessment tool in predicting long term outcome of these single ventricle disease patients.3. From 1990 Jan to 2021 Jun, all patients with single ventricle disease and PAH will be analyze for clinical parameters and biomarkers. We will evaluate the response and the predictors of responder to pulmonary vasodilators therapy.Basic part We will sample 5-10 cc whole blood from pulmonary artery or peripheral blood. CEC and EPC will be analyzed using 4-color flow cytometery analysis. The plasma MMPs will be measured using ELISA method. The circulating miRNA analysis will be performed using reverse transcription-polymerase chain reaction.