【作者】 王斌；

【导师】 王春生；

【作者基本信息】 复旦大学 ， 外科学（专业学位）， 2013， 博士

【摘要】 二叶式主动脉瓣(bicuspid aortic valve, BAV)是常见先天性心脏畸形之一人群患病率在0.9-2.0%,男性女性好发比为3：1,而其中年龄达到15岁以上的54%出现主动脉瓣狭窄。二叶式主动脉瓣常与主动脉瓣狭窄、返流、主动脉夹层及感染性心内膜炎等疾病相关,使得这一疾病成为临床医师的又一挑战。二叶式主动脉瓣由一大一小两叶瓣膜组成,最常见的融合瓣叶为左-右冠瓣叶,这种融合方式与主动脉缩窄有关(约50-75%主动脉缩窄患者合并有BAV)；其余均为右-无冠瓣融合,与瓣尖病变相关。研究显示二叶式主动脉瓣伴随基因或遗传异常。Emanuel等发现在BAV家族中发病率达到14.6%,且在一代亲属关系的成员中BAV的发病率达到9.1%,远高于人群患病率。10q的ACTA2(编码平滑肌细胞α-肌动蛋白)突变被发现可导致胸主动脉瘤,且与BAV相关。BAV的诊断主要依靠心超,主动脉瓣出短轴位切面可见二叶式结构和假脊结构,另外还可见瓣膜增厚钙化、二叶瓣膜接合缘偏心等,舒张期呈“鱼嘴”样结构,长轴上可见融合瓣膜开放不全形成的顶盖结构。经食道超声可提高诊断准确性。同时建议无症状患者每两年检查一次TTE,有症状患者需每年检查一次。BAV最常见病变是主动脉瓣狭窄,成人主动脉瓣狭窄主要源于瓣叶钙化(可能源于长期的瓣叶边缘血流剪切力、内皮功能不全及继发炎症反应、脂质沉积),且钙化多出现于40岁年龄段。主动脉关闭不全也是常见病变,在手术行瓣膜置换患者中有13%是因为关闭不全。瓣膜手术方式包括：球囊扩张、瓣膜置换、ROSS手术(由于肺动脉中层与主动脉同样异常,术后移植动脉进行性增宽)及瓣膜修补,且BAV患者需要手术治疗年龄早于三叶瓣患者手术年龄。约50%的BAV患者可出现瓣膜以外部位的病变,以主动脉根部扩张最常见。近30%的BAV换瓣手术需要同时进行主动脉根部手术,包括根部加固或者根部置换。虽一定程度上认为主动脉增宽是血液动力学异常引起的主动脉瓣狭窄后扩张,但越来越多的文献指示其分子水平的改变也是其重要成因,病变主动脉壁病理可见原纤维蛋白减少、弹性蛋白断裂及细胞凋亡,原纤维蛋白-1的缺乏可引起中层平滑肌细胞的分离、基质溶解及细胞坏死,基质金属蛋白酶可能在此过程中起作用。手术是目前升主动脉瘤样扩张及夹层的主要治疗手段,包括主动脉成形术、窦上升主动脉置换、升主动脉置换合并根部成形、保留瓣膜的根部置换术、带瓣管道置换术。一般认为>50mm者需行动脉手术,而同期行瓣膜手术,>45mm也可考虑行动脉手术,另外主动脉直径每年增长>5mm者也考虑手术。然而动脉手术却是风险较高的手术,主动脉瓣置换术(AVR)合并升主动脉置换术死亡率是单纯AVR的2.78倍,主动脉夹层手术死亡率在不同中心达7%-30%,而且BAV患者仅行单纯AVR后发展主动脉病变的概率并不高。目前针对合并根部扩张>45mm的二叶式主动脉瓣患者多选择行Bentall术,同时置换扩张的根部和升主动脉；而对于根部内径<45mm而升主动脉>45mm的二叶式主动脉瓣患者,手术选择仍存在一定争议,是选择相对简单、手术危险低的Wheat术还是按照指南的建议选择行Bentall术,各个心脏中心和主刀医师都有不同的看法和习惯。本研究通过回顾性研究主动脉瓣置换同时行动脉手术(包括主动脉成形术、Bentall术和Wheat术)的二叶式主动脉瓣患者病例病史信息,通过统计分析研究根部扩张的影响因素、不同术式风险对比和不同术式随访情况,并探讨行Wheat术患者随访过程中根部扩张情况。第一部分二叶式主动脉瓣合并根部扩张的影响因素目的：二叶式主动脉瓣合并升主动脉扩张常起始于升主动脉近段,本文旨在通过回顾性研究已发生的升主动脉近段扩张的患者病案信息,探索相关影响根部扩张的因素。方法：收录我院2003年1月1日至2011年5月4日间出院的所有二叶式主动脉瓣并升主动脉扩张而行手术治疗的患者的所有病案信息,排除合并夹层和信息不完整者。按根部内径是否>45mm分为增宽组和非增宽组。应用SPSS20进行相关统计分析。结果：单因素分析提示：增宽组较非增宽组,男性比例高、年龄小、身高高、症状持续时间短、横裂式畸形比例高、瓣膜返流程度高、狭窄程度低、左室舒张末／收缩末内径大、LVEF值低、WBC低、TB/CB/BUN高。longistic多因素分析提示狭窄程度小、左室舒张末内径大为根部扩张显著危险因素。ROC曲线分析提示：左室舒张末内径和收缩末内径对根部增宽诊断价值最大,LVDd>60.00mm或LVDs>45.50mm时诊断灵敏度为0.93和0.79,特异度为0.83和0.89。结论：多因素分析提示狭窄程度小、左室舒张末内径大为根部扩张显著危险因素,左室收缩末、舒张末内径可有效诊断根部增宽与否。第二部分Wheat、Bentall和成形术在二叶式主动脉瓣患者中风险对照研究目的：通过回顾性资料分析探讨手术方式选择策略并研究Wheat术、Bentall术和成形术的手术难度和风险。方法：通过回顾性收集2003年1月1日至2011年5月4日间出院的所有因先天性二叶式主动脉瓣畸形合并升主动脉手术(包括Wheat术、Bentall术、成形术)的患者病案信息,并收集有关手术并发症情况,利用SPSS20进行统计分析。结果：Bentall组年龄小于Wheat组(p=0.017)和成形组(p=0.056),但体外循环时间和主动脉阻断时间均显著大于Wheat组和成型组；术后使用呼吸机支持时间方面,Bentall组显著大于成型组；ICU使用时间在三组见无明显差异；Bentall组总胆红素、直接胆红素和肌酐在术后一天升高值均明显大于Wheat组和成型组,而后两组之间均不存在差异。成型组术后总引流量显著低于Wheat组和Bentall组,且血浆使用量也最低(p=0.102, p=0.013),Bentall组所有患者均需输血液制品。三组间术后并发症发生情况无明显差异。所有患者均存活,且术后住院时间无明显差异。结论：虽然Bentall术手术难度较高且更加需要血制品的支持,但三组手术并发症和住院时间无明显差异,总体安全性基本一致。第三部分二叶式主动脉瓣合并升主动脉扩张手术治疗的随访研究目的：本文旨在回顾性研究二叶式主动脉瓣合并升主动脉扩张行手术干预患者的信息,通过电话、心超系统的随访、资料采集了解术后生存率和血管事件发生情况。方法：收录我院2003年1月1日至2011年5月4日间出院的所有因先天性二叶式主动脉瓣畸形行手术治疗83例。随访了解：是否有死亡事件及其时间点和主因,是否有主要不良心血管事件,是否有血管再次扩张(主要通过院内心超操作系统)。结果：所有83例患者,80例患者得到随访资料,随访率为96.4%。随访时间为术后38.14±23.65月,其中有4例出现死亡,主要不良心血管事件7例,出现血管事件6例,生存函数分析提示：术后1年生存率为97.3±1.9%,6年生存率为85.2±10.3%。术后13月无MACE概率为96.0±2.3%,73月无MACE概率为80.2±11.1%。术后33月无血管事件概率为94.9±2.9%,65月无血管事件概率为86.2±6.7%。结论：二叶式主动脉瓣合并升主动脉扩张行动脉手术远期死亡率、主要心血管不良事件和自身血管事件(动脉瘤、夹层等)发生率均在可接受范围,不同手术间不良事件的发生无明显差异。针对扩张升主动脉需要积极进行主动脉干预。更多还原

【Abstract】 Bicuspid aortic valve (BAV) is one of the most common congenital heart diseases. Incidence rate is about0.9%-2%, ratio of male/female approximately reaches3:1,54%of patients aged over15come out with aortic stenosis (AS). Due to relationship between BAV and AS, aortic regurgitation (AR), aortic dissection and bacterial endocarditis (BE), BAV becomes a challenge of clinical physicians.BAV is structured of two leaflets, and the larger one could be charactered as fusion of right-left coronary cusps (BAV RL) and right-non coronary cusps (BAV RN). The BAV RL is associated with aortic coarctation (50%-75%of aortic coarctation accompanied by BAV), and the BAV RN is correlated with cuspal pathology.Series of studies have demonstrated that BAV is associated with abnormal gene and heredity. Emanuel et al found that incidence rate of BAV was14.6%in BAV families, and9.1%in first generation of relatives, which both exceeded that of population. Mutation of ACTA2in lOq, which encodes a-actin in smooth muscle cell, could induce generation and development of aneurysm of thoracic aorta and BAV.Diagnosis of BAV mainly depends on transthoracic echocardiographic (TTE) manifestation, including bicuspid construction, pseudo-raphe in the larger cusp, valvular thickening and calcification and eccentric commissure. But the most valuable findings are fish-mouth construction at diastole at short-axis view and doming of leaflet at systole at long-axis view. Furthermore, transesophageal echocardiography (TEE) could improve diagnostic accuracy. It is recommended that carry TTE for asymptomatic patients every two years and every year for symptomatic patients.The most common pathology of BAV is aortic stenosis, which deteriorates due to calcification, which mostly come out after40years old and is induced by long-term shear stress of free margin, dysfunction of endothelium, lipid deposition and secondary inflammation. Aortic regurgitation is the second common pathology.13% of BAV patients who underwent surgical aortic valve replacement suffered from aortic regurgitation. Interventions on dysfunctional aortic valve include balloon valvularplasty, surgical valve replacement, ROSS procedure and valvular repairment. The age of BAV patients who needed surgical interventions is younger than that of tricuspid aortic valve patients.Almost50%of BAV patients were accompanied by pathologies other than valve dysfunction, ascending aorta dilation is the most common one. Almost30%of BAV patients who underwent AVR should be given aortic interventions simutaneously, including aorta reinforcing or replacement. Aorta dilation is partially induced by abnormal hameodynamics, and due to molecular alterations which were detected in recent several researches. These alterations contained decreased fibrillin, fractured elastin and cellular apoptosis. It is reported that lack of Fibrillin-1could facilitate dissection of smooth muscle cell, lysis of extracellular matrix and apoptosis, in advantage of matrix metalloproteinases.Surgical interventions are effective for ascending aorta dilation and aortic dissection, and include reduction aortaplasty (with or without wrap augmentation), supra-sinus ascending aorta replacement, ascending aorta replacement with sinus resection and remodeling, valve-sparing root replacement, aortic root replacement with a valved conduit. As recommended, aorta with a diameter over50mm should be replaced, and45mm is the threshold if valve replacement is carried meanwhile. Yearly increase of diameter over5mm is also indication of surgical intervention. Anyway, aortic interventions possess higher risk, it was reported that ratio of mortality of AVR with ascending aorta replacement to mortality of simple AVR is2.78, and mortalities of surgeries on aortic dissection ranged from7%to30%. Furthermore, the secondary aortic incidences are rare after simple AVR for BAV patients.It is commonly accepted that Bentall procedure is essential for BAV patients with dilated aortic sinus (diameter>45mm), but is it essential for BAV patients with dilated ascending aorta without dilated sinus, there are different opinions in cardiac surgery centers. In this retrospective study, we are prone to review the medical records of BAV patients who underwent AVR and aortic surgeries, including Wheat procedure, Bentall procedure and reduction aortaplasty. With the help of SPSS20, we would try to find out risk factors of aortic sinus dilation, compare the prognosis of these three surgeries. If possible, follow up the development of aortic sinus in patients who underwent Wheat procedure and reduction aortaplasty. PART1Study on risk factors of aortic sinus dilation with bicuspid aortic valveObjective:Aortic dilation usually begins at the proximal tubular ascending aorta. This part, we investigate the risk factors of sinus dilation, in advantage of reviewing medical records of BAV patients with dilated ascending aorta.Methods:Include all the BAV patients with dilated ascending aorta who need surgical intervention from Jan1,2003to May4,2011. We exclude patients accompanied by aortic dissection and without echocardiographic report. Divide these patients into Group Dilation (>=45mm) and Group Non-Dilation (<45mm) according to sinus diameters and proceed statistical analysis in SPSS20.Outcomes:in univariate analysis, Group Dilation are younger and higher, and possess higher proportion of male and fusion of right-left coronary cusps, more severe aortic regurgitation, larger left ventricular diameters and higher elevation of total bilirubin, conjugated bilirubin and creatinine, but shorter duration of symptoms, less aortic stenosis, lower ejection fraction and lower elevation of white blood cell. In multivariate analysis with logistic regression model, less aortic stenosis and larger left ventricular end-diastolic diameter are the significantly risks of sinus dilation. It’s demonstrated in ROC curve analysis, that left ventricular systolic diameter and diastolic diameter are the two most valuable parameters indicating sinus dilation, the sensitivity and specificity is0.93,0.83while left ventricular diastolic diameter>60mm and0.79,0.89while systolic diameter>45.50mm.Conclusion:multivariate analysis demonstrates that less aortic stenosis and larger left ventricular end-diastolic diameter are the significantly risks of sinus dilation. The left ventricular systolic and diastolic diameters are the valuable parameters indicating sinus dilation. PART2Risk comparison of Wheat, Bentall procedure and reduction aortaplasty in bicuspid aortic valveObjective:in this retrospective study, we would discuss the protocol of surgeries selection and investigate difficulties and risk of Wheat, Bentall procedure and reduction aortaplasty.Methods:Include all the BAV patients with dilated ascending aorta who need surgical intervention from Jan1,2003to May4,2011. We exclude patients accompanied by aortic dissection and without echocardiographic report and divide accepted patients into Group Wheat, Group Bentall and Group Aortaplasty. We contein all the related complications and carry statistical analysis in SPSS20.Outcomes:Compared to Group Wheat and Group Aortaplasty, Group Bentall were younger but needed longer extracorporeal circulation and cross clamp time. Group Bentall need longer ventilator support than Group Aortaplasty. There’s no difference on ICU consumption among three groups. Elevations of total bilirubin, conjugated bilirubin and creatinine one day after surgery in Group Bentall are significantly more than those in the other two groups. Group Aortaplasty possess significantly less total drainage than the other two groups along with the least blood plasma consumption, while every member in Group Bentall has a history of blood products consumption. Anyway, all the patients survived the surgeries and there’s no difference in complication and length of stay among these three groups.Conclusion:Although Group Bentall expend more operation time and blood products consumption, there is no significantly more complication and longer length of stay, securities in these group are mainly coincident. PART3Follow-up study of aortic intervention on patients of biscuspid aortic valve and aortic dilationObjective:we retrospectively reviewed the information of bicuspid aortic valve patients with aortic dilation who underwent aortic intervention. Follow up the cardiac death and aortic incidences.Method:Include all the BAV patients with dilated ascending aorta who need surgical intervention from Jan1,2003to May4,2011. Follow up and get information on survival, major adverse cardiac events and aortic incidences.Outcomes:96.4%of the patients followed up and the last follow-up time was38.14±23.65months after operation. There were4deaths,7major adverse cardiac events and6aortic incidences. Kaplan-Meier analysis suggested that survival rate was97.3±1.9%at1year after operation,85.2±10.3%at6years; freedom from major adverse cardiac events was96.0±2.3%at13months,80.2±11.1%ar73months; freedom from aortic incidences was94.9±2.9%at33months,86.2±6.7%at65months.Conclusion:survival rate, freedom from major adverse cardiac events and aortic incidences after aortic interventions on bicuspid aortic valve patients with aortic dialtion are acceptable, there’s on significant diffenrence among different surgeries. We suggest active aortic interventions.更多还原