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: 8011422
• 负责人: Pirooz Eghtesady
• 金额: $ 7.02万
• 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 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8011422
• 关键词: Accounting; Accreditation; Affect; Antibodies; Antigens; Aortic Valve Stenosis; 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; 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; Inflammatory; Injury; Institutes; Interleukin-4; Intervention; Lead; Left; Left ventricular structure; Lesion; 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）：左心发育不全综合征 (HLHS) 是一种严重且毁灭性的心脏缺陷，每年影响出生儿童的万分之一。导致 HLHS 发病机制和相关左侧心脏病的机制仍不清楚。该提案的目的是检验一项新假设，即 HLHS 是胎儿风湿性心脏病 (RHD) 的一种表现。在 RHD 中，除其他免疫过程外，抗链球菌抗体是响应链球菌感染而产生的。在遗传易感宿主中，这些抗体随后通过一种称为分子拟态的机制与左侧心肌和瓣膜抗原发生“交叉反应”。我们提出了 HLHS 发病机制的类似机制，即针对先前（和复发）链球菌感染而产生的母源抗体，穿过胎盘并损害易感宿主的胎儿心脏。我们的初步数据表明，与三个对照组相比，HLHS 不仅与母亲既往链球菌感染之间存在很强的相关性，而且 HLHS 婴儿的母亲的抗人心肌肌球蛋白血清滴度（如风湿热患者中发现的）升高。为了扩展这些研究，我们将比较转诊进行胎儿超声心动图 (echo) 并发现妊娠受到 (1) HLHS 影响的孕妇群体； (2) HLHS以外的先天性心脏病； (3)什么也没有（即正常胎儿回声，“参考”对照）。第四组（“随机”对照）是从怀孕早期（<18 周）的普通人群中招募的，以克服“参考”对照中明显的选择偏差。在目标 1 中，我们通过问卷工具、审查孕产妇医疗记录和测量抗链球菌抗体 (ASO) 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，使用从目标 1 中的 4 组受试者获得的样本库中的血清，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；然后将这些样本与从婴儿出生后获得的匹配血清样本进行比较。在目标 3 中，我们确定从 HLHS 婴儿（新生儿手术干预时）获取的心肌组织标本中是否也存在与 RHD 瓣膜病变有关的心脏反应性抗体和炎症标记物（TNF-α、INF-γ 和 IL-4）。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记物。候选人：Eghtesady 博士是一名儿科心胸外科医生，长期以来对 HLHS 的发病机制及其内科/外科治疗很感兴趣。关于拟议的研究，他的长期职业目标是改善受这种严重且毁灭性的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) 致力于通过完全整合、全球认可的研究、教育和创新来改善儿童健康并转变护理服务。 CCHMC 的使命是为社区、国家和世界的患者实现最佳的医疗和生活质量结果、患者和家庭的体验和价值。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，并做出了巨大承诺，以确保一个繁荣的环境，允许广泛的合作安排，如本研究所示。 Eghtesady 博士的临床日程安排为他提供了 50% 的受保护时间用于研究。 2007 年，CCHMC 获得人类研究保护项目认证协会的全面认证，证实了其对临床研究项目的实力和承诺。最后，2008 年，HI 临床研究核心成立，旨在通过严格监督和提供额外资源，专门监督正在进行的临床研究的成功。相关性：每年，每 100 个出生的儿童中就有 1 个患有先天性心脏病。其中，HLHS 可能是最严重和最具破坏性的，对受影响家庭的生活产生了重大影响。其医疗管理投入了大量资源。因此，了解 HLHS 发生的原因，所提出的研究目标对于公共卫生具有重大意义和相关性。 公共健康相关性：拟议的项目有可能通过预防和/或确定左心发育不全综合征（HLHS）（一种毁灭性的先天性心脏缺陷）婴儿的替代治疗来改善公共健康。我们提议测试一项新理论，即母亲的咽部链球菌感染或“链球菌性咽喉炎”与其婴儿发生 HLHS 之间存在潜在关联。如果被证明属实，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。