一个先天性主动脉瓣上狭窄家系的分子遗传性分析

目的 检测一个临床诊断为先天性升主动脉狭窄家系患者的基因组拷贝数变异,明确其发病的遗传学基础.方法 以一个先天性升主动脉狭窄家系为研究对象,收集患儿及其患病父亲、正常母亲外周血标本,常规提取基因组DNA.应用Affymetrix人类全基因组SNP 6.0芯片对患儿及1例正常健康对照个体进行检测,应用实时定量PCR(real-time quantitative polymerase-chain-reaction,qPCR)方法对芯片分析结果进行验证.结果 经Affymetrix SNP 6.0 芯片分析显示患儿染色体7q11.23区域内弹力蛋白基因(elastin,ELN)5′端大部分及基因上游区域共约80 kb发生杂合性缺失.在ELN基因内设计4对qPCR引物,在家系内进行验证,结果显示ELN的缺失向下游至少累及至第22外显子,且患儿父亲携带与患儿相同的杂合性缺失.结论 ELN 基因部分杂合性缺失为该患儿及其父亲发病的原因,二者之先天异常为主动脉瓣上狭窄(supravalvular aortic stenosis,SVAS).

Abstract：

Objective To detect the copy number variations(CNVs)in a family with congenital narrowing of the ascending aorta,and to explore the underlying genetic causes of the disease.Methods Peripheral blood samples were collected from an affected boy,his affected father and his apparently normal mother.Genomic DNA Was extracted and genotyped using Affymetrix Genome-Wide Human SNP Array 6.0.CNVs were confirmed by real-time quantitative PCR(qPCR).Results Our SNP Array 6.0analysis showed in the boy an about 80kb heterozygous deletion affecting part of the elastin gene(ELN).Further qPCR assays for four confirmed the presence of the deletion in the boy and his father,and indieated that the deletion involved at least the first 22 ELN exons.Conclusion A heterozygous deletion affecting part of the ELN gene has been identified in the boy and his father, A diagnosis of supravalvular aortic stenosis(SVAS)could he made based on the molecular finding.     

一例表现为主动脉瓣狭窄的非典型Williams-Beuren综合征患儿的遗传学诊断及分析

目的对1例主动脉瓣狭窄的患儿进行遗传学诊断,分析其发病机制。方法采用常规G显带染色体分析、微阵列比较基因组杂交(array comparative genomic hybridization,aCGH)及多重连接探针扩增(multiplex ligation-dependent probe amplification,MLPA)技术分析患儿及其父母的染色体核型和基因组拷贝数变异。结果患儿及其父母的外周血染色体核型均未见异常。aCGH检测显示患儿7q11.23区存在278 kb杂合缺失,与Williams-Beuren综合征(Williams-Beuren syndrome,WBS)关键区部分重叠,涉及WBS的关键致病基因之一ELN。MLPA检测证实患儿存在上述缺失,患儿父母未发现染色体微重复/微缺失。结论患儿7q11.23区杂合缺失为新发突变。ELN基因单倍剂量不足可能是其发生主动脉瓣狭窄的原因,诊断为非典型WBS。     

Concurrence of supravalvular aortic stenosis and peripheral pulmonary stenosis in three generations of a family: A form of arterial dysplasia

Isolated supravalvular aortic stenosis (SVAS) commonly is an autosomal dominant trait; it may also occur in the Williams syndrome (WS). While peripheral pulmonary stenosis (PPS) can occur in the same individual with familial isolated SVAS, concurrence of these lesions in different relatives of a family is uncommon. We describe five affected individuals in one family; three had isolated SVAS, one had isolated PPS, and one had SVAS and PPS. Based on this family and review of literature, we suggest that SVAS is a form of arterial dysplasia encompassing PPS in its spectrum. It is developmentally distinct from other left heart obstructive lesions that are hypothesized to be related to blood flow abnormalities in the developing embryo. We also conclude that the clinical disorder in this family represents one that is distinct from WS. © 1993 Wiley-Liss, Inc.     

Supravalvular aortic stenosis cosegregates with a familial 6;7 translocation which disrupts the elastin gene

Supravalvular aortic stenosis (SVAS) is an autosomal dominant disorder characterized by abnormalities of development of the great vessels. SVAS is also commonly part of Williams syndrome. Linkage to the elastin gene on chromosome 7q11 has recently been reported in two kindreds with SVAS. Previous reports of patients with 7q11 deletions have noted great vessel abnormalities in some. We report on a family in which SVAS is cosegregating with a balanced reciprocal translocation, t(6:7) (p21.1;q11.23), providing further evidence that SVAS is the result of mutation of elestin at 7q11.23 region. The propositus of the translocation family has some minor anomalies which occur in Williams syndrome, Suggesting that elestin abnormalities may cause some of the abnormalities found in Williams syndrome. © 1993 Wiley-Liss, Inc. © 1993 Wiley-Liss, Inc.     

Novel mutations in the human elastin gene (ELN) causing isolated supravalvular aortic stenosis

Supravalvular aortic stenosis (SVAS), an inherited vascular disease, is caused by mutations in the elastin gene (ELN). Our aim was to identify novel mutations of ELN and to determine the expression of ELN in patients with SVAS. For screening mutations in ELN, we performed PCR-directed sequence analysis with genomic DNA isolated from SVAS patients and control subjects. Expression of ELN at the mRNA and protein levels were assessed by real-time PCR and Western blot analyses, respectively, using primary skin fibroblast cultures established from SVAS patients and control subjects. We identified two novel mutations of ELN, G297_A308del and Q700X, in two unrelated Korean patients with isolated SVAS. G297_A308del occurred de novo while Q700X was derived maternally. In the patient with G297_A308, elastin expression was not significantly altered at the mRNA level, but was reduced to approximately 50% of the normal control at the protein level. The elastin expression levels in the patient with Q700X were reduced to <50% of the normal controls at both the mRNA and protein levels. Our findings confirm that functional haploinsufficiency of elastin is responsible for the pathogenesis associated with isolated SVAS across different ethnic backgrounds.     

颅内宽颈动脉瘤合并载瘤血管重度狭窄的血管内治疗

目的:探讨颅内宽颈动脉瘤合并载瘤动脉重度狭窄血管内治疗的安全性及疗效。方法:回顾性研究。纳入郑州大学人民医院脑血管病科2017年1月—2019年12月采用血管内治疗颅内宽颈动脉瘤合并载瘤血管重度狭窄的患者14例,共14个动脉瘤。14例中,男5例、女9例,年龄45～76(61.07±10.43)岁;8例为破裂动脉瘤,6例...     

Abdominal aortic aneurysm and cytomegalovirus infection

Cytomegalovirus (CMV) has been implicated in the pathogenesis of atherosclerosis. Abdominal aortic aneurysm is regarded traditionally as a consequence of atherosclerosis. Several microorganisms have been suggested as possible contributing factors for the development of abdominal aortic aneurysm. The relevance of CMV in the processes underlying the development, expansion, and rupture of abdominal aortic aneurysm is unknown. The aim of the present study was to investigate whether CMV infection is related to abdominal aortic aneurysm rupture. One hundred nineteen patients with abdominal aortic aneurysm and 36 matched controls without abdominal aortic aneurysm were investigated prospectively by CMV serology. Patients with ruptured abdominal aortic aneurysm have similar levels of IgG antibodies against CMV as patients with nonruptured abdominal aortic aneurysm, small abdominal aortic aneurysm, and controls without abdominal aortic aneurysm. In conclusion, this study fails to demonstrate a connection between CMV infection and abdominal aortic aneurysm rupture.     

症状性颅内动脉粥样硬化性狭窄支架置入术治疗的长期疗效观察

目的 探讨支架置入术治疗症状性颅内动脉粥样硬化性狭窄(ICAS)的长期安全性及有效性。方法 回顾性研究。纳入2014年9月—2015年8月陆军军医大学第一附属医院神经内科行颅内动脉支架置入术的31例症状性ICAS患者的临床资料,其中男21例、女10例,年龄36~73(57.00±9.87)岁。依据置入支架的类型将患者分为自膨式支架组16例和球扩式支架组15例。对患者进行5年以上随访,观察和记录终点事件:术后30 d内的终点事件包括卒中、短暂性脑缺血发作和死亡,术后30 d~5年的终点事件包括同侧缺血性卒中、出血性卒中、血管性死亡。结果 31例患者获随访1～77(62.7±15.5)个月,5年内发生终点事件4例(死亡3例):术后30 d内发生终点事件(出血性卒中)2例,其中死亡1例;术后30 d~5年的终点事件2例。术后第1~5年每年累积发生终点事件分别为2、2、4、4、4例,其中第3年终点事件增加2例,分别为同侧缺血性卒中1例、出血性卒中1例(均死亡)。自膨式支架组和球扩式支架组患者各项终点事件比较,差异均无统计学意义(P值均＞0.05)。结论 支架置入术治疗症状性ICAS的围手术期及远期观察显示手术方式安全有效。     

Paraganglioma presenting with an aortic aneurysm

The concurrence of a paraganglioma of the organ of Zuckerkandl and an abdominal aortic aneurysm is reported in a 72-year-old caucasian male. Computerized tomography scan confirmed the aneurysm and noted a well-circumscribed tumour of the aneurysmal wall. At operation, the tumour was identified and excised with part of the aneurysmal wall. The tumour exhibited all the features of a paraganglioma while the vessel wall showed atherosclerosis and secondary degenerative changes. The features of the aortico-sympathetic group of paragangliomas are discussed.     

Phenotypic delineation of the retinal arterial macroaneurysms with supravalvular pulmonic stenosis syndrome

Retinal arterial macroaneurysms with supravalvular pulmonic stenosis (RAMSVPS), also known as Familial Retinal Arterial Macroaneurysms (FRAM) syndrome, is a very rare multisystem disorder. Here, we present a case series comprising ophthalmologic and systemic evaluation of patients homozygous for RAMSVPS syndrome causative IGFBP7 variant. New clinical details on 22 previously published and 8 previously unpublished patients are described. Age at first presentation ranged from 1 to 34 years. The classical feature of macroaneurysms and vascular beading involving the retinal arteries was universal. Follow up extending up to 14 years after initial diagnosis revealed recurrent episodes of bleeding and leakage from macroaneurysms in 55% and 59% of patients, respectively. The majority of patients who underwent echocardiography (18/23) showed evidence of heart involvement, most characteristically pulmonary (valvular or supravalvular) stenosis, often requiring surgical correction (12/18). Four patients died in the course of the study from complications of pulmonary stenosis, cerebral hemorrhage, and cardiac complications. Liver involvement (usually cirrhosis) was observed in eight patients. Cerebral vascular involvement was observed in one patient, and stroke was observed in two. We conclude that RAMSVPS is a recognizable syndrome characterized by a high burden of ocular and systemic morbidity, and risk of premature death. Recommendations are proposed for early detection and management of these complications.     

Biomechanical characterization of ascending aortic aneurysm with concomitant bicuspid aortic valve and bovine aortic arch

Studies have shown that patients harboring bicuspid aortic valve (BAV) or bovine aortic arch (BAA) are more likely than the general population to develop ascending aortic aneurysm (AsAA). A thorough quantification of the AsAA tissue properties for these patient groups may offer insights into the underlying mechanisms of AsAA development. Thus, the objective of this study was to investigate and compare the mechanical and microstructural properties of aortic tissues from AsAA patients with and without concomitant BAV or BAA. AsAA (n = 20), BAV (n = 20) and BAA (n = 15) human tissues were obtained from patients who underwent elective AsAA surgery. Planar biaxial and uniaxial failure tests were used to characterize the mechanical and failure properties of the tissues, respectively. Histological analysis was performed to detect medial degenerative characteristics of aortic aneurysm. Individual layer thickness and composition were quantified for each patient group. The circumferential stress–strain response of the BAV samples was stiffer than both AsAA (p = 0.473) and BAA (p = 0.152) tissues at a low load. The BAV samples were nearly isotropic, while AsAA and BAA samples were anisotropic. The areal strain of BAV samples was significantly less than that of AsAA (p = 0.041) and BAA (p = 0.004) samples at a low load. The BAA samples were similar to the AsAA samples in both mechanical and failure properties. On the microstructural level, all samples displayed moderate medial degeneration, characterized by elastin fragmentation, cell loss, mucoid accumulation and fibrosis. The ultimate tensile strength of BAV and BAA sampleswere also found to decrease with age. Overall, the BAV samples were stiffer than both AsAA and BAA samples, and the BAA samples were similar to the AsAA samples. The BAV samples were thinnest, with less elastin than AsAA and BAA samples, which may be attributed to the loss of extensibility of these tissues at a low load. No apparent difference in failure mechanics among the tissue groups suggests that each of the patient groups may have a similar risk of rupture.     

Characteristics of circulating monocytes at baseline and after activation in patients with intracranial aneurysm

Intracranial aneurysm (IA) is a bulging of blood vessels around the brain that is often asymptomatic but may cause severe complications and death if ruptured. Macrophage-mediated immune responses can contribute to the development of IA. During homeostasis and inflammation, circulating monocytes can infiltrate the vasculature, where they develop into macrophages, and modulate immune responses. Based on the expression of CD14 and CD16, total circulating monocytes can be distinguished into three main subsets, including the CD14⁺CD16⁻ classical monocytes, the CD14⁺CD16⁺ intermediate monocytes, and the CD14^loCD16⁺⁺ non-classical monocytes. In this study, we found that frequencies of CD14⁺CD16⁻ classical monocytes were significantly lower in IA patients than in healthy controls, while the frequencies of CD14⁺CD16⁺ intermediate monocytes and CD14^loCD16⁺⁺ non-classical monocytes were significantly higher in IA patients than in healthy controls. The frequencies of CD14⁺CD16⁺ intermediate monocytes were further elevated in IA-ruptured patients compared to those in IA-unruptured patients. Compared to classical monocytes, intermediate monocytes and non-classical monocytes presented higher TNF-α and IL-1β expression. When cocultured with autologous naive CD4 T cells, intermediate and non-classical monocytes preferentially promoted the expression of TBX21 and RORC over the expression of FOXP3 in CD4 T cells. Inhibition of TNF-α and IL-1β slightly reduced TBX21 expression and markedly reduced RORC expression, and at the same time significantly increased FOXP3 expression in CD4 T cells. Overall, this study demonstrated that the monocytes were dysregulated in IA patients in a manner that favored the development of proinflammatory responses.     

Association analyses confirming a susceptibility locus for intracranial aneurysm at chromosome 14q23

Previous linkage analyses of intracranial aneurysm (IA) have proposed several genetic susceptibility loci; however, some loci remain contradictory. The objective of this study was to confirm these loci in a Japanese population using allelic and haplotype association analyses. We set high-density single nucleotide polymorphism markers in previously suggested IA loci and conducted an association analysis in 29 cases and 35 controls from a small community in Akita, Japan. Genotyping was carried out using the GeneChip 10 K mapping array, and the association analysis was performed using GeneSpring GT2 software. The result was confirmed in a replication cohort consisting of 237 cases and 253 controls from all over Japan. Only one variant, rs767603, at chromosome 14q23, was significantly associated with IA, both in allelic analysis (p = 0.00017, Bonferroni-corrected p = 0.021) and haplotype analysis (p = 0.00178, Bonferroni-corrected p = 0.048). This association was confirmed in the replication cohort (p = 0.0046 for allelic association, p = 0.0060 for haplotype association). Our findings confirm 14q23 to be a susceptibility locus for intracranial aneurysm.     

David手术在主动脉根部瘤合并主动脉瓣二叶畸形治疗中的应用

目的 探讨David手术在治疗主动脉根部瘤合并主动脉瓣二叶畸形中应用的临床效果。方法 回顾性研究。纳入南京大学医学院附属鼓楼医院心胸外科2016年1月—2019年1月行David手术治疗主动脉根部瘤合并主动脉瓣二叶畸形的11例患者临床资料。其中男8例、女3例,年龄18～60(35±13)岁;主动脉瓣轻度反流7例、轻中度反流4例,心功能Ⅱ级5例、Ⅲ级5例、Ⅳ级1例。观察患者围术期指标;术后定期复查心脏超声,观察人工血管通畅情况及主动脉瓣反流情况,包括左室射血分数、主动脉瓣反流程度、平均跨瓣压差、峰值跨瓣压差及最大血流速度。结果 11例患者均成功实施手术。围术期观察指标:体外循环时间(246.1±27.2)min,主动脉阻断时间(207.5±21.5)min,术后机械通气时间4.5(3.25,9.25)h,重症监护时间(2.8±1.5)d,术后24 h引流量(418.2±299.0)mL。所有患者术后随访18~30个月,平均22.5个月,未见死亡及二次手术病例。随访期间心脏超声显示患者人工血管血流均通畅,主动脉瓣轻微反流8例、轻度反流3例,平均跨瓣压差均＜10 mmHg(1 mmHg=0.133 kPa),末次随访时,患者心功能Ⅰ级8例、Ⅱ级3例,较术前明显改善。结论 采用David手术结合主动脉瓣修复技术治疗主动脉根部瘤合并中度以下反流的主动脉瓣二叶畸形,其临床疗效满意。     

Autosomal dominant inheritance of a predisposition to thoracic aortic aneurysms and dissections and intracranial saccular aneurysms

A genetic predisposition for thoracic aortic aneurysms and dissections (TAAD) can be inherited in an autosomal dominant manner with decreased penetrance and variable expression. Four genes identified to date for familial TAAD account for approximately 20% of the heritable predisposition. In a cohort of 514 families with two or more members with presumed autosomal dominant TAAD, 48 (9.3%) families have one or more members who were at 50% risk to inherit the presumptive gene causing TAAD had an intracranial vascular event. In these families, gender is significantly associated with disease presentation (P < 0.001), with intracranial events being more common in women (65.4%) while TAAD events occurred more in men (64.2%,). Twenty‐nine of these families had intracranial aneurysms (ICA) that could not be designated as saccular or fusiform due to incomplete data. TGFBR1, TGFBR2, and ACTA2 mutations were found in 4 families with TAAD and predominantly fusiform ICAs. In 15 families, of which 14 tested negative for 3 known TAAD genes, 17 family members who were at risk for inheriting TAAD had saccular ICAs. In 2 families, women who harbored the genetic mutation causing TAAD had ICAs. In 2 additional families, intracranial, thoracic and abdominal aortic aneurysms were observed. This study documents the autosomal dominant inheritance of TAADs with saccular ICAs, a previously recognized association that has not been adequately characterized as heritable. In these families, routine cerebral and aortic imaging for at risk members could prevent cerebral hemorrhages and aortic dissections. © 2011 Wiley‐Liss, Inc.     

Active cytomegalovirus infection in aortic smooth muscle cells from patients with abdominal aortic aneurysm

Cytomegalovirus (CMV) is associated with atherosclerosis and transplant vascular sclerosis. The aim of this study was to explore the hypothesis that active CMV infection in the vessel wall could be associated with abdominal aortic aneurysm (AAA). We examined the prevalence of CMV in AAA specimens from 22 patients undergoing surgery and, in five cases, characterized the function of smooth muscle cells (SMCs) from the aneurysm in vitro. Twenty-one (95%) of the 22 AAA specimens were CMV positive by a polymerase chain reaction assay, in situ hybridization, or a highly sensitive immunohistochemical staining technique. No positive cells were found in aortas from three CMV-seronegative organ donor cadavers. CMV immediate-early and late antigens were expressed in SMCs in the lesions and were associated with 5-lipoxygenase (5-LO) expression. CMV-positive intimal SMCs migrated 6.6 ± 1.5 times more efficiently than CMV-negative medial SMCs (p < 0.05). In vitro CMV infection of medial SMCs resulted in a 3.2 ± 1.2 times increase in migration (p < 0.05). The intimal migration was significantly inhibited by antibodies against basic fibroblast growth factor (bFGF; p < 0.05) in a dose-dependent fashion. Antibodies against platelet-derived growth factor (PDGF)-AB, insulin-like growth factor 1, vascular endothelial growth factor (VEGF), RANTES, monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein (MIP)-1α, or interleukin-1β did not significantly affect intimal SMC migration. However, intimal and medial SMCs secreted similar amounts of bFGF, MCP-1, MIP-1α, RANTES, PDGF-AB, PDGF-BB, epidermal growth factor, and VEGF. CMV infection in vitro of intimal and medial cells did not result in significant changes of bFGF or MCP-1 secretion. Since CMV infection can affect several functional parameters in SMCs, including several key factors in infected SMCs, our findings provide support for the hypothesis that CMV contributes to the pathogenesis of abdominal aortic aneurysm. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. Sara Gredmark-Russ and Mensur Dzabic contributed equally to this work and share first co-authorship.