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).

PROJECT NARRATIVE Our goal is to develop multiparametric cardiac MRI and automated deep learning based cardiac MRI analysis workflows for improved assessment for complications after heart transplantation, the treatment of choice for many patients with end-stage heart failure. Cardiac MRI will be developed to allow for efficient application from pediatric to adult patients in order to evaluate its diagnostic value for non-invasively detecting complications and to investigate the impact of differences in heart donor and recipient characteristics on the performance of the transplanted heart. In addition, we will leverage an existing large cardiac MRI database to allow for long-term 5-year follow-up to establish new measures for improved outcome prediction and therapy management in heart transplant recipients.