Comprehensive Cardiac Structure-Function Analysis in Heart Transplantation

总结/摘要 心脏移植（HTx）是一种成熟的挽救生命的手术，但与严重的并发症有关。 目前的临床监测算法依赖于频繁的侵入性程序，包括肌内膜活检 和导管血管造影术。为了解决这些局限性，PI开发了非侵入性的全面 心脏MRI，可以量化心肌组织和功能的局部变化。我们的努力集中在 关于HTx的2种主要并发症：1）急性心脏排斥反应（ACR），这是HTx的第一个死亡原因， 移植后1年; 2）心脏移植物血管病变（CAV），5年死亡率的最大风险因素 在Tx后的第一年。我们的心脏MRI研究已经确定了HTx的新成像生物标志物。我们 是第一个建立异常心脏MRI测量和潜在同种异体移植之间的生理联系的人 失败：心肌T2和细胞外容积分数（ECV）作为ACR的非侵入性组织生物标志物。我们 表明心肌瘢痕形成、T2和ECV的自然史可预测不良临床事件， HTx接收者。此外，我们的研究表明，捐赠者和接受者不匹配（年龄、性别、体重等）是 与心脏MRI衍生的心肌水肿/炎症、纤维化和 收缩和舒张功能障碍。在过去的五年里，PI已经建立了一个独特的研究数据库， 超过450次全面的心脏MRI检查，包括超过110，000张带注释的心脏MRI图像。 对于这一更新申请，我们确定需要进行进一步的长期随访研究， 减缓HTx的疾病进展，以确定多参数MRI指标和预测因子随时间的变化 HTX的结果。其次，关于儿童HTx人群中移植物组织和功能的数据很少， 需要在这一弱势群体中改进捐助者-受援者匹配战略， 有效利用有限的儿童供体心脏。因此，心脏MRI需要更好地解释 患者体质和生理学的年龄和性别相关差异，对于HTx的广泛年龄范围至关重要， 小儿到成人本研究的更新申请旨在：1）开发多参数心脏MRI， 评估从儿童到成人的移植物组织（T2、T1、ECV）和功能障碍（心肌速度、应变）， 2)利用现有的大型心脏MRI数据库（110，000个标记的心脏MRI图像）， 用于自动心脏MRI分析的基于学习的分析流水线， 评估者间变异性，3）识别不良结局的预测因素，并评估供体-受体的影响 在对儿童HTx患者的前瞻性研究中，移植物组织、功能和血流不匹配，以及4）确定 通过利用我们的HTx数据库（>145）预测长期（> 5年）HTx患者结局的心脏指标 在初始资助周期内获得现有基线心脏MRI的HTx接受者）。心脏随访 MRI将为移植物组织随时间的变化提供独特的见解，并作为潜在机制发挥作用 不同的HTx患者轨迹（非进展vs.晚发vs.缓慢进展vs.快速进展）。

SUMMARY / ABSTRACT Heart transplant (HTx) is a well-established life-saving procedure but is associated with severe complications. Current clinical monitoring algorithms rely on frequent invasive procedures including endomyocardial biopsies and catheter angiography. To address these limitations, the PIs have developed non-invasive comprehensive cardiac MRI, which can quantify regional changes in myocardial tissue and function. Our efforts have focused on the 2 major complications of HTx: 1) acute cardiac rejection (ACR), the leading cause of death in the first year after transplant; and 2) cardiac allograft vasculopathy (CAV), the greatest risk factor for 5-year mortality beyond the first post-Tx year. Our cardiac MRI studies have identified new imaging biomarkers in HTx. We were the first to establish a physiologic link between abnormal cardiac MRI measures and potential allograft failure: myocardial T2 and extracellular volume fraction (ECV) as non-invasive tissue biomarkers for ACR. We demonstrated that the natural history of myocardial scarring, T2, and ECV predicts adverse clinical events in HTx recipients. In addition, our studies showed that donor and recipient mismatch (age, sex, weight, etc.) was significantly associated with cardiac MRI-derived measures of myocardial edema/inflammation, fibrosis, and systolic and diastolic dysfunction. Over the past five years, the PIs have assembled a unique study database with over >450 comprehensive cardiac MRI exams comprising >110,000 annotated cardiac MRI images. For this renewal application, we identified the need to conduct further long-term follow-up studies tailored to the slow disease progression in HTx to identify changes over time in multiparametric MRI measures and predictors of HTx outcome. Second, data on graft tissue and function in the pediatric HTx population are scarce and improved strategies for donor-recipient matching in this vulnerable population are needed to make most efficient use of the limited availability of donor hearts in children. Thus, cardiac MRI needs to better account for age and sex related differences in patient habitus and physiology, critical for the wide age range in HTx from pediatric to adult. The renewal application for this study aims to 1) develop multiparametric cardiac MRI for the assessment of graft tissue (T2, T1, ECV), and dysfunction (myocardial velocities, strain) from pediatric to adult, 2) leverage the existing large cardiac MRI database (110,000 labeled cardiac MRI images) to establish deep learning based analysis pipelines for automated cardiac MRI analysis with improved efficiency and reduced inter-rater variability, 3) to identify predictors of adverse outcomes and to evaluate the impact of donor-recipient mismatch on graft tissue, function, and flow in a prospective study with pediatric HTx patients, and 4) to identify cardiac metrics predictive of long-term (> 5 years) HTx patient outcome by leveraging our HTx database (>145 HTx recipients with existing baseline cardiac MRI acquired during the initial funding cycle). Follow-up cardiac MRI will provide unique insights in changes over time in graft tissue and function as mechanism underlying different HTx patient trajectories (non-progression vs. late onset vs. slow progression vs. fast progression).