Primary Investigators: Dr. James Reynolds, PhD
Institution: Case Western Reserve University
Funding began in 2019.
Pediatric heart transplantation is an accepted intervention to correct major congenital cardiac anomalies and end-stage heart failure. However, a successful outcome is highly dependent upon the physiologic status of the donor. Stressors placed upon organs, particularly brain death (BD), are believed to affect recipient survival rates and are also significant contributors to the poor procurement rate (< 50%) for the heart from consented donors – a disheartening figure when one considers there are over 14,000 pediatric heart failure hospitalizations annually in the US yet the actual pediatric heart transplants that occur number in the hundreds. As a result, many children die before their transplant need is met. We propose a new research focus is the effect of BD on S-nitrosothiols (SNOs), small molecules that act in the body to control oxygen delivery, cellular activity, and organ function. In fact SNO interactions (called protein Snitrosylation) is the major mechanism through which the cellular influence of nitric oxide (NO) is exerted. We have determined that SNO activity in adults is impaired following BD. Furthermore, we have preliminary evidence that, after BD, restoration of SNOs preserves adult cardiac status. Maintenance of a normal level of SNO activity thus provides an attractive drug target to improve pediatric donor heart status both in vivo and during ex vivo storage. However, to support conducting such a pediatric clinical trial it is important to first characterize the disruptions in S-nitrosylation in conjunction with the systemic cardiac impairments that occur following BD and during donor support.
While the waitlist mortality for children listed for heart transplantation is unacceptably high, the number of pediatric organ donors has declined in the recent era. This is compounded by the rejection of over 40% of pediatric donor hearts offered for transplantation. While the reasons for this are multifactorial, there is significant variability in donor acceptance practices across centers and heart transplant providers and limited evidence to guide clinical practices regarding optimal donor selection and donor-to-recipient matching. In addition, we have a limited understanding of how to optimize transport conditions or other novel preservation to improve the longevity and/or quality of donor hearts.
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