“Novel Cardiac Biomarkers & Echocardiographic Modalities for Rejection Surveillance after Pediatric Heart Transplantation”

Doctor's Name: 
Steven Colan, M.D.
Boston Children’s Hospital, Boston

The medical problem and its magnitude: For many children with end-stage hear failure, heart transplantation is a dramatic step in their lives, but the only option for survival. In spite of progress in the medical management of the about 10,000 children and young adults who have received a new heart, rejection of the new organ remains a common, potentially fatal problem: about 25% of them still experience a rejection episode during the first year after HT.

Background and research gap: The standard of monitoring children after HT for rejection is a biopsy, which requires an invasive heart catheterization and clipping out a piece of heart tissue to study it under the microscope: Children and their families have to undergo this procedure numerous times after a heart transplantation, and they fear it, because each biopsy requires yet another hospital admission for kids who have already been through a tremendous ordeal, is painful, requires sedation or anesthesia, and might be associated with complications – let alone costing several thousands of health care dollars each time.

One strategy to reduce the number of invasive procedures for children after heart transplantation is to transition monitoring for rejection to non-invasive modalities such as modern echocardiography with tissue Doppler imaging (TDI) or novel blood biomarkers; these methods, found to be promising for that purpose in adults, have not yet been established as safe accurate for rejection surveillance in children.

Specific aim I (1-20 months): To assess whether a decline in TDI echocardiographic measures and a significant increase in serum biomarkers concentration from baseline is associated with biopsy findings and can thus predict rejection without the need for a heart catheter.

Hypothesis: Children after HT who experience a biopsy-proven rejection will show a significant decline in TDI echocardiographic measures from baseline, and a significant increase in serum biomarkers concentration, compared to rejection-free baseline, using each patient as their own control.

Specific aim II (21-24 months): To develop non-invasive TDI - and biomarker-based criteria, i.e., determine thresholds at which we can accurately exclude rejection, without missing cases that need treatment.

Hypothesis: Monitoring of cardiac allograft function using these TDI- and biomarkers-based criteria will reliably exclude rejection in children after HT, therefore reduce the need for invasive procedures and thus reduce health care costs.

Study design: This is a prospective observational study, which we propose to conduct between January 1, 2014 and December 331, 2015 specifically to address the above questions.

Study population or sample material: All children and young adults under 21 years of age who underwent heart transplantation and who present to our institution for heart biopsy (routinely scheduled or due to symptoms) will be eligible and approached to be included in this study following informed consent. The statistical assessment will analyze paired comparison of selected TDI indexes and biomarker serum levels using patients’ baseline as control values (primary outcomes); health care spending per patient annually (secondary outcome); and time of measurement, i.e., baseline biopsy (non-rejection) vs. follow-up biopsy (non-rejection or rejection) (predictor variable), with rejection defined by biopsy findings according to the ISHLT-2004 (the current international standard) as grade ≥2R cellular or antibody-mediated rejection.

Sample size/power of primary endpoint: Based on preliminary studies we conducted in a limited number of children using existing TDI data, we estimate that we will need to look at 270 biopsies to detect statistically significant effects, based on state-of-the-art calculations.

Next steps: This is a proof-of-concept study towards developing a non-invasive rejection-surveillance protocol, which will develop a less invasive monitoring regimen  and lay the ground for the validation of this less invasive novel non-rejection screening approach in a larger sample of children after HT (multicenter trial), including comparisons across various institutions of clinical adverse events, frequency and duration of treatment for rejection, and annual patient care costs after transplantation

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