Cardiac allograft rejection remains a leading cause of morbidity and mortality affecting longevity in adult and pediatric heart transplant recipients. Early detection and treatment of rejection before overt graft dysfunction develops is paramount to ensuring long-term symptom-free survival. Current practices rely on endomyocardial biopsies (EMB) which limit surveillance and are both invasive and costly. However, no single echocardiographic parameter has had sufficient predictive power for rejection detection. ECHO, a non-invasive computer-assisted analysis algorithm with standardized risk scoring for deviations of multiple m-mode and tissue Doppler imaging (TDI) parameters, has been clinically validated for EMB-based acute cellular rejection (ACR) detection in single centers. However, widespread use of ECHO has been limited primarily because of technical factors. Recently ECHO has been enhanced (ECHO-E) with migration to the MatLab language, which supports every major operating system, native DICOM support and b-splines for tracking LV wall movement. This removes the need for a digitizer and creates program flexibility for beta testing emerging echocardiographic parameters that could also detect early antibody-mediated rejection (AMR). Specific aim 1 of this pilot study is to provide a preliminary test of the primary hypothesis that ECHO-E will be equivalent, or non-inferior, to EMB in detecting both ACR and AMR.

Cardiac allograft rejection remains a leading cause of morbidity and mortality affecting longevity in adult and pediatric heart transplant recipients. Early detection and treatment of rejection before overt graft dysfunction develops is paramount to ensuring long-term symptom-free survival. Current practices rely on endomyocardial biopsies (EMB) which limit surveillance and are both invasive and costly. However, no single echocardiographic parameter has had sufficient predictive power for rejection detection. ECHO, a non-invasive computer-assisted analysis algorithm with standardized risk scoring for deviations of multiple m-mode and tissue Doppler imaging (TDI) parameters, has been clinically validated for EMB-based acute
cellular rejection (ACR) detection in single centers. However, the widespread use of ECHO has been limited primarily because of technical factors. Recently ECHO has been enhanced (ECHO-E) with migration to the MatLab language, which supports every major operating system, native DICOM support and b-splines for tracking LV wall movement. This removes the need for a digitizer and creates program flexibility for beta testing emerging echocardiographic parameters that could also detect early antibody-mediated rejection (AMR). Specific aim 1 of this pilot study is to provide a preliminary test of the primary hypothesis that ECHO-E will be equivalent, or non-inferior, to EMB in detecting both ACR and AMR.

This will be the first prospective multi-center study comparing ECHO-E to EMB with power-optimized by a minimum of approximately 360 EMB + ECHO-E with 18 ACR and/or AMR episodes in an estimated 60 pediatric heart transplant recipients. This project will also be the first prospective multi-center testing of additive predictive values to ECHO-E of including emerging echocardiographic and laboratory markers of rejection. As a pilot, this study will also test the performance characteristics and capabilities of the specific multi-center study design including its implementation processes, metrics, limited standardization of immunosuppression and surveillance, and multiple equipment vendors that would germane for planning and funding a larger multi-center study.

When properly validated, ECHO-E optimized with GLS could offer a standardized echocardiographic strategy for rapid, non-invasive patient-centric screening and detection of early allograft ACR and AMR in pediatric heart recipients. With enhancements, ECHO-E is more user-friendly permitting wider access by other pediatric transplant centers. With validation, ECHO-E guidance could result in fewer EMBs for rejection surveillance of pediatric recipients.