Hypoplastic Left Heart Syndrome: Expression of RHD in the Fetus?

左心发育不全综合征：RHD 在胎儿中的表达？

• 批准号: 7771616
• 负责人: Pirooz Eghtesady
• 金额: $ 38.77万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-15 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7771616
• 关键词: Accounting; Accreditation; Affect; Antibodies; Antigens; Autoantibodies; Award; Birth; Blood; Blood flow; Cardiac; Cardiac Myosins; Case-Control Studies; Child; Child health care; Childhood; Clinical; Clinical Research; Communities; Complex; Congenital Heart Defects; Control Groups; Cross Infection; Data; Development; Disease; Echocardiography; Education; Ensure; Environment; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Epitopes; Exhibits; Family; Fetal Heart; Fetus; General Population; Genetic; Goals; Heart; Heart Diseases; Human; Hypoplastic Left Heart Syndrome; Immunoglobulin Deposition; Immunoglobulin G; Immunohistochemistry; Immunologic Markers; Immunologics; In Situ; Infection; Inflammatory; Injury; Institutes; Interleukin-4; Intervention; Lead; Left; Left ventricular structure; Lesion; Life; Longitudinal Studies; Maternal antibody; Measurement; Medical; Medical Records; Mission; Mitral Valve; Mitral Valve Stenosis; Molecular; Molecular Mimicry; Morbidity - disease rate; Mothers; Myocardial; Myocardial tissue; Neonatal; Obstruction; Operative Surgical Procedures; Outcome; Pathogenesis; Pathology; Patients; Pharyngeal structure; Placenta; Pregnancy; Pregnant Women; Prevention; Process; Public Health; Quality of life; Questionnaires; Reaction; Recording of previous events; Recruitment Activity; Recurrence; Reporting; Research; Resources; Rheumatic Fever; Rheumatic Heart Disease; Sampling; Schedule; Selection Bias; Serum; Side; Specimen; Stenosis; Streptococcal Infections; Streptococcus; Structure; Support System; Surgeon; Surgical Management; Testing; Time; Tissues; Tumor Necrosis Factor-alpha; Ventricular; Western Blotting; alternative treatment; aortic valve; care delivery; career; congenital heart disorder; cytokine; experience; fascinate; fetal; human TNF protein; improved; in utero; inflammatory marker; innovation; interest; maternal serum; neonatal death; novel; operation; palliation; prevent; programs; public health relevance; repository; response; statistics; stem; streptolysin O; success; theories; tool

DESCRIPTION (provided by applicant): Hypoplastic Left Heart Syndrome (HLHS) is a severe and devastating heart defect that affects ~ 1 in 10,000 children born each year. The mechanism(s) leading to pathogenesis of HLHS and associated left-sided cardiac pathology remain unknown. The goal of this proposal is to test a novel hypothesis that states HLHS is an expression of rheumatic heart disease (RHD) in the fetus. In RHD, among other immunologic processes, anti-streptococcal antibodies are generated in response to strep infection. In genetically susceptible hosts these antibodies then "cross-react" with left-sided myocardial and valvular antigens through a mechanism known as molecular mimicry. We propose similar mechanism for the pathogenesis of HLHS in which maternal antibodies produced in response to antecedent (and recurrent) strep infection, cross the placenta and damage the fetal heart in the susceptible host. Our preliminary data suggest not only a strong association between HLHS and prior maternal strep infection, but also elevated anti-human cardiac myosin serum titers in mothers of HLHS babies (as found in patients with rheumatic fever), compared with three control groups. To extend these studies, we will compare groups of pregnant women referred for fetal echocardiography (echo) and found to have a pregnancy affected by (1) HLHS; (2) congenital heart disease other than HLHS; and (3) nothing (i.e., normal fetal echo, "referred" controls). A fourth group ("random" controls) are recruited from the general population early in pregnancy (<18 weeks) to overcome the obvious selection biases in the "referred" controls. In Aim 1 we determine if mothers of babies with HLHS have a significant history of strep infections through a questionnaire tool, review of maternal medical records and measurements of blood titers of an anti-streptococcal antibody (ASO). In Aim 2, using serum from the repository of samples obtained from the 4 groups of subjects in Aim 1, we will also compare antibody reactivity with a variety of valvular/myocardial antigens (shown to be involved in RHD lesions); these are then compared to matched serum samples obtained from the babies after birth. In Aim 3, we determine if heart reactive antibodies and inflammatory markers (TNF-alpha, INF-gamma and IL-4) implicated in valvular lesions in RHD are also present in myocardial tissue specimens obtained from HLHS babies (at the time of neonatal surgical intervention). Immunohistochemical analysis of neonatal heart tissues will be performed to assess for the presence of immunoglobulin deposition and other immune markers. The candidate: Dr. Eghtesady is a pediatric cardiothoracic surgeon who has had long standing interest in the pathogenesis of HLHS and its medical/surgical management. Pertaining to the proposed studies, his long-term career goal is to improve the quality of life for the children and families affected by this severe and devastating ongenital heart disease. The research environment: CCHMC and The Heart Institute (THI) of CCHMC are dedicated to improve child health and transform delivery of care through fully integrated, globally recognized research, education and innovation. The mission of CCHMC is to achieve the best medical and quality of life outcomes, patient and family experiences and value, for patients from the community, the nation and the world. For this reason, the success of studies such as proposed is of high priority to CCHMC and the HI. Significant resources are provided for this purpose with great commitment to ensure a thriving environment that allows for extensive collaborative arrangements, as in this study. Dr Eghtesady's clinical schedule has been structured to afford him 50% protected time for research. In 2007, CCHMC was awarded full accreditation by the Association for the Accreditation of Human Research Protection Programs confirming the strength and commitment to clinical research programs. Finally, in 2008, the HI Clinical Research Core was established to specifically see through the success of ongoing clinical studies, through rigorous oversight and provision of additional resources. Relevance: Each year, 1 out of 100 children born is affected by a congenital heart disease. Among these, HLHS is perhaps the most severe and devastating, significantly impacting the lives of affected families. Tremendous resources are devoted to its medical management. Therefore, understanding why HLHS happens, the goal of the proposed research would have great significance and relevance to public health. PUBLIC HEALTH RELEVANCE: The proposed project has the potential to improve public health by preventing and/or defining alternative treatments for babies with Hypoplastic Left Heart Syndrome (HLHS), a devastating congenital heart defect. We propose to test a novel theory that there is a potential association between pharyngeal streptococcal infection or "strep throat" in mothers and the development of HLHS in their babies. If proven true, the findings will have a profound impact on this disease and the lives of many mothers and their affected babies.

描述（由申请人提供）：左心发育不良综合征（HLHS）是一种严重和毁灭性的心脏缺陷，每年影响约1/10，000的新生儿。导致HLHS发病机制和相关左侧心脏病理学的机制仍未知。该提案的目的是测试一个新的假设，即HLHS是胎儿风湿性心脏病（RHD）的一种表达。在RHD中，在其他免疫过程中，抗链球菌抗体是对链球菌感染的反应。在遗传易感的宿主中，这些抗体然后通过称为分子模拟的机制与左侧心肌和瓣膜抗原“交叉反应”。我们提出了类似的机制HLHS的发病机制，其中母体抗体产生的响应于先前（和复发）链球菌感染，穿过胎盘和损伤胎儿心脏的易感主机。我们的初步数据表明，HLHS和先前的母亲链球菌感染之间不仅有很强的关联，而且与三个对照组相比，HLHS婴儿的母亲（如风湿热患者）的抗人心肌肌球蛋白血清滴度也升高。为了扩展这些研究，我们将比较接受胎儿超声心动图（echo）检查的孕妇组，这些孕妇被发现患有（1）HLHS;（2）除HLHS外的先天性心脏病;（3）无任何影响（即，正常胎儿回声，“参考”对照）。第四组（“随机”对照）是在怀孕早期（<18周）从一般人群中招募的，以克服“参考”对照中明显的选择偏差。在目标1中，我们通过问卷调查工具、审查母亲病历和测量抗链球菌抗体（阿索）的血液滴度来确定HLHS婴儿的母亲是否有明显的链球菌感染史。在目标2中，使用目标1中4组受试者样本库中的血清，我们还将比较抗体与各种瓣膜/心肌抗原（显示与RHD病变有关）的反应性;然后将这些与出生后婴儿的匹配血清样本进行比较。在目标3中，我们确定是否心脏反应性抗体和炎症标志物（TNF-α，INF-γ和IL-4）牵连在RHD瓣膜病变也存在于心肌组织标本从HLHS婴儿（在新生儿手术干预时）。将对新生儿心脏组织进行免疫组织化学分析，以评估是否存在免疫球蛋白沉积和其他免疫标志物。候选人：Eghtesady博士是一名儿科心胸外科医生，长期以来一直对HLHS的发病机制及其内科/外科治疗感兴趣。关于拟议的研究，他的长期职业目标是改善受这种严重和毁灭性先天性心脏病影响的儿童和家庭的生活质量。研究环境：CCHMC和CCHMC心脏研究所（THI）致力于通过完全一体化的、全球公认的研究、教育和创新来改善儿童健康并改变护理提供方式。CCHMC的使命是为来自社区、国家和世界的患者实现最佳的医疗和生活质量结果、患者和家庭体验和价值。因此，CCHMC和HI高度重视所提议的研究的成功。为此目的提供了大量资源，并作出了巨大承诺，以确保一个蓬勃发展的环境，使广泛的合作安排，如本研究报告。Eghtesady博士的临床时间表已经被安排好，为他提供了50%的研究时间。2007年，CCHMC获得了人类研究保护计划认证协会的全面认证，证实了其对临床研究计划的实力和承诺。最后，在2008年，成立了HI临床研究核心，通过严格的监督和提供额外的资源，专门观察正在进行的临床研究的成功。相关性：每年，每100名出生的儿童中就有1名患有先天性心脏病。其中，HLHS可能是最严重和最具破坏性的，严重影响了受影响家庭的生活。大量资源用于其医疗管理。因此，了解HLHS发生的原因，提出的研究目标将对公共卫生具有重要意义和相关性。 公共卫生关系：拟议的项目有可能通过预防和/或定义患有左心发育不良综合征（HLHS）的婴儿的替代治疗来改善公共卫生，HLHS是一种毁灭性的先天性心脏缺陷。我们建议测试一个新的理论，即有一个潜在的关联之间的咽链球菌感染或“链球菌咽喉”的母亲和发展HLHS在他们的婴儿。如果被证实是真的，这些发现将对这种疾病以及许多母亲及其受影响婴儿的生活产生深远的影响。