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

描述(由申请人提供)：左心发育不全综合征(HLHS)是一种严重的破坏性心脏缺陷，每年出生的儿童中约有1人受到影响。高位高血压病的发病机制(S)和相关的左侧心脏病理尚不清楚。这项提议的目的是测试一种新的假设，即HLHS是风湿性心脏病(RHD)在胎儿中的表现。在风湿性心脏病中，在其他免疫过程中，链球菌感染会产生抗链球菌抗体。在遗传易感的宿主中，这些抗体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。对于HLHS的发病机制，我们提出了类似的机制，即母体抗体对先前(和反复)的链球菌感染做出反应，穿过胎盘，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不仅与既往的母体链球菌感染有很强的相关性，而且HLHS婴儿的母亲(风湿热患者中发现的)抗人心肌肌球蛋白血清效价也升高。为了扩展这些研究，我们将比较被转诊进行胎儿超声心动图(ECHO)的孕妇组，这些孕妇被发现有(1)HLHS；(2)HLHS以外的先天性心脏病；和(3)没有任何影响(即正常的胎儿超声，“转诊”对照)。第四组(“随机”对照)是从怀孕早期(18周)的普通人群中招募来的，以克服“参照”对照中明显的选择偏见。在目标1中，我们通过问卷调查工具、母体病历回顾和抗链球菌抗体(ASO)血液滴度的测量来确定患有HLHS的婴儿的母亲是否有显著的链球菌感染史。在目标2中，使用从目标1中的4组受试者获得的样本储存库中的血清，我们还将比较抗体与各种瓣膜/心肌抗原(被证明与风湿性心脏病病变有关)的反应性；然后将这些抗体与出生后从婴儿身上获得的匹配血清样本进行比较。在目标3中，我们确定了心脏反应性抗体和炎症标志物(肿瘤坏死因子-α、干扰素-γ和白介素4)是否也存在于风湿性心脏病瓣膜病变中(在新生儿手术干预时)从HLHS婴儿获得的心肌组织标本中。将对新生儿心脏组织进行免疫组织化学分析，以评估免疫球蛋白沉积和其他免疫标志物的存在。候选人：Eghtesady博士是一位儿科心胸外科医生，长期以来一直对HLHS的发病机制及其内外科治疗感兴趣。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的生殖器官心脏病影响的儿童和家庭的生活质量。研究环境：CCHMC和CCHMC的心脏研究所(THI)致力于通过完全整合的、全球公认的研究、教育和创新来改善儿童健康和改变护理提供方式。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、患者和家庭的体验和价值。因此，这类研究的成功对CCHMC和HI来说是高度优先的。为此目的提供了大量资源，并作出了极大的承诺，以确保一个繁荣的环境，以便作出广泛的协作安排，如本研究所述。Eghtesady博士的临床时间表经过精心设计，为他的研究提供了50%的受保护时间。2007年，CCHMC获得了人类研究保护计划认证协会的完全认证，确认了其对临床研究计划的实力和承诺。最后，在2008年，HI临床研究核心成立，通过严格的监督和额外资源的提供，专门监督正在进行的临床研究的成功。相关信息：每年，每100名出生的儿童中就有一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，对受影响家庭的生活产生了重大影响。巨大的资源被投入到它的医疗管理上。因此，了解HLHS发生的原因，拟议研究的目标将对公共卫生具有重大意义和相关性。 公共卫生相关性：拟议的项目有可能通过预防和/或定义患有先天性心脏病的先天性心脏缺陷发育不良综合征(HLHS)的婴儿的替代治疗来改善公共健康。我们建议测试一种新的理论，即母亲的咽链球菌感染或“链球菌咽喉”与其婴儿的HLHS的发展之间存在潜在的联系。如果被证实属实，这一发现将对这种疾病以及许多母亲和她们受影响的婴儿的生活产生深远的影响。

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.