Predictive modeling of acute rejection in pediatric heart transplant recipients

项目摘要/摘要 尽管在儿科心脏移植(PHTx)患者的护理方面取得了重大进展，但急性排斥反应(AR) 仍然是导致死亡的主要原因之一。心内膜心肌活检(活组织检查)的心导管置入术是 诊断变应性鼻炎的标准护理，当临床怀疑有变应性鼻炎时或在常规情况下 监视系统。不幸的是，活检是侵入性的，并与潜在的风险相关，包括： 麻醉或镇静，瓣膜损伤，传导系统损伤，血管损伤或闭塞，以及 心脏穿孔。这些潜在的并发症在儿科人群中被放大。非侵入性 检测AR的方法，如血液生物标记物和心脏磁共振成像(CMR)，可以 减少活检率。血液生物标记物，如具有供体部分的无细胞DNA和微RNA， 已显示出诊断AR的潜力，但尚未在PHTx中得到广泛采用。进阶 CMR参数标测序列量化心肌纤维化和水肿，以及我们的初步数据 提示这些序列有可能用于AR的诊断。而CMR参数映射具有重要的意义 承诺，只关注整个左心室平面或区域的平均特性，而忽略 疾病的空间模式，导致信息丢失和使用成像数据的能力受损 直接护理。在这里，我们提出了比平面分析更精细的高级图像分析方法， 包括纹理分析，作为客观分析不同心肌疾病模式的手段 开发预测模型，以改善临床决策。这一点的中心假设是 格兰特认为，无创性心脏磁共振和血液生物标志物可以检测到心肌梗死 与儿童心脏移植受者急性排斥反应相一致的异常可以预测需要 做心内膜心肌活检。为了解决这一假设，目标1将开发和验证一个全面的 用于识别可疑AR和需要心导管的PHTx接受者的预测模型。 Aim 2将评估血液生物标记物是否改进了在Aim 1中开发的CMR模型。SubAims将 包括成本评估，以确定最具成本效益的筛查方案。AIM 3将扩展建模 以确定组织学定义的AR的严重程度。这项多PI方案是一项前瞻性的多中心研究 对同时接受临床活检的PHTx合并AR和不合并AR患者进行CMR检查。它的创新之处在于 研究是使用先进的CMR、质地分析和血液生物标志物进行非侵入性检测 阿。这项建议充分利用了美国儿科学会先天性/儿科研究委员会的支持 心血管磁共振(SCMR)检查。将这些数据应用于临床实践可能会改善 生活质量和降低相关发病率，通过确保只有高概率的患者 对排异反应进行活检。

PROJECT SUMMARY/ABSTRACT Despite significant advances in the care of pediatric heart transplant (PHTx) patients, acute rejection (AR) remains one of the leading causes of death. Cardiac catheterization with endomyocardial biopsy (biopsy) is the standard of care for diagnosing AR and is performed when there is a clinical suspicion for AR or during routine surveillance. Unfortunately, biopsy is invasive and associated with potential risks, including: complications from anesthesia or sedation, valve damage, injury to the conduction system, vascular damage or occlusion, and cardiac perforation. These potential complications are magnified in the pediatric population. Non-invasive methods of detecting AR, such as blood biomarkers and cardiac magnetic resonance imaging (CMR), could decrease the frequency of biopsy. Blood biomarkers, such has donor fraction cell-free DNA and microRNA, have shown potential for diagnosis of AR but have not yet gained widespread adoption in PHTx. Advanced CMR parametric mapping sequences quantify myocardial fibrosis and edema, and our preliminary data suggest a potential for these sequences to diagnose AR. While CMR parametric mapping has significant promise, focusing simply on the average properties across an entire left ventricular plane or region ignores the spatial patterns of disease, resulting in a loss of information and an impaired ability to use the imaging data to direct care. Here we propose advanced image analysis methods that are more granular than plane analysis, including texture analysis, as a means for objectively analyzing different patterns of myocardial disease and developing predictive models that would allow improved clinical decision making. The central hypothesis of this grant is that non-invasive cardiac magnetic resonance and blood biomarkers can detect myocardial abnormalities consistent with acute rejection in pediatric heart transplant recipients and can predict the need for endomyocardial biopsy. To address this hypothesis, Aim 1 will develop and validate a comprehensive predictive model for identifying PHTx recipients having suspected AR and requiring cardiac catheterization. Aim 2 will evaluate whether blood biomarkers improve the CMR model developed in Aim 1. SubAims will include assessment of cost to determine the most cost-efficient screening protocol. Aim 3 will expand modeling to determine severity of AR as defined histologically. This multi-PI proposal is a prospective, multicenter study to perform CMR in PHTx with and without AR who are also undergoing clinical biopsy. The innovation of this study is the use of advanced CMR, texture analysis, and blood biomarkers for the non-invasive detection of AR. This proposal leverages the support of the Congenital/Pediatric Research Committee within the Society of Cardiovascular Magnetic Resonance (SCMR). Application of these data to clinical practice could improve quality of life and decrease associated morbidity by ensuring that only patients with a high probability of rejection undergo biopsy.