Intermountain Pediatric Heart Disease Research Center

描述(由申请人提供)： 越来越多的婴儿正在接受完全修复而不是姑息先天性心脏缺陷，这需要在肺位置放置冷冻保存的同种带瓣移植物。同种异体移植会导致产生人类白细胞抗原抗体，从而导致管道狭窄和反流的发展，最终需要进行替换。事实上，60%-100%的婴儿植入物在5年内失败，抵消了早期完全修复的成功，因为需要后续手术。此外，这些儿童中的一些会发展为终末期心脏病，并可能被列入心脏移植的名单，如果群体反应性抗体(PRA)为10%，则需要前瞻性的交叉配型，限制了供体池，增加了发病率和死亡率。此外，尽管成功地进行了前瞻性交叉配型，但致敏儿童的移植物排斥反应发生率高于没有人类白细胞抗原抗体的儿童。因此，消除抗体的产生和延长同种异体移植物的寿命将减少管道替换手术的数量，以及相关的手术发病率和死亡率、经济负担、家庭压力以及多次住院对生长和发育的负面影响。它还将降低患有终末期心脏病的儿童的移植风险。在一项涉及少数首次接受低温保存的带瓣同种异体移植的先导性研究中，通过使用霉酚酸酯(MMF)进行短暂的免疫抑制，从药理上消除抗体反应似乎是成功和安全的。然而，在推荐广泛使用之前，需要一项具有足够功率的随机试验。这项前瞻性随机试验的总体目标是评估接受MMF治疗的组与只接受标准治疗的组中PRA&lt；10%的受试者的比例。此外，还将评估同种异体移植失败的超声心动图终点及其与PRA的关系。药物安全性将通过监测不良事件和特定的血液测试来确定。这项研究之所以被提交给儿科心脏网络，是因为它需要几个中心提供足够数量的受试者，而且由于所需的测试和程序在临床实践中被广泛使用，因此每个中心都将拥有执行方案所需的设备和人员，并获得核心实验室评估所需的研究和样本。总结：患有心脏缺陷的婴儿需要在他们右侧的心泵和通往肺部的血管之间放置一条管道，他们的管道会早期衰竭，每次失败时都需要额外的手术来更换。这项研究将确定在第一次插入导管后短期内给予的药物(霉酚酸酯)是否会安全地减少身体对导管的反应，并使其持续更长时间，这样孩子就不需要做那么多的手术。(摘要结束)。

DESCRIPTION (provided by applicant): Increasing numbers of infants are undergoing complete repair rather than palliation of congenital heart defects that requires placement of a cryopreserved valved allograft in the pulmonary position. Allograft implantation results in the production of HLA antibodies that contribute to the development of conduit stenosis and regurgitation and ultimately the need for replacement. In fact, 60 -100% of infant implants fail within 5 years, offsetting the success of an early complete repair since subsequent surgeries are needed. In addition, some of these children develop end-stage heart disease and may be listed for heart transplantation, If panel reactive antibodies (PRA) are >10%, prospective cross matching is required, limiting the donor pool and increasing both morbidity and mortality. Furthermore, despite successful prospective cross-matching, the incidence of graft rejection is higher in sensitized children than in children who do not have HLA antibodies. Thus, abrogating antibody production and prolonging the durability of the allograft would reduce the number of conduit replacement surgeries along with the associated surgical morbidity and mortality, economic burden, family stress, and negative effect of multiple hospitalizations on growth and development. It would also decrease the transplantation risk in the subset of children who develop end-stage heart disease. Pharmacological abrogation of the antibody response with a brief course of immunosuppression using mycophenolate mofetil (MMF) appeared successful and safe in a pilot study involving a small number of children who received a first time cryopreserved valved allograft. Before widespread use can be recommended, however, a randomized trial with adequate power is needed. The overall goal of this prospective randomized trial is to evaluate the proportion of subjects with PRA <10% in a group receiving MMF compared with a group receiving standard therapy only. In addition, echocardiographic endpoints of allograft failure will be evaluated along with their association with PRA. Drug safety will be determined by monitoring adverse events and specific blood tests. This study is being proposed to the Pediatric Heart Network because it requires several centers to provide an adequate number of subjects and because the required tests and procedures are widely used in clinical practice so each center will have the needed equipment and personnel to implement the protocol and obtain the studies and samples required for evaluation by core laboratories. Lay summary: Infants with heart defects who need a conduit placed between their right-sided heart pump and the blood vessel that goes to the lungs have early failure of that conduit and need additional surgeries to replace it each time it fails. This research will determine if a drug (mycophenolate mofetil) given for a short time after the conduit is first put in will safely decrease the body's reaction to the conduit and make it last longer so the child will not need as many operations. (End of Abstract).