Increasing Quality, Quantity and Longevity of Donor Hearts

Heart transplant remains the only curative treatment for children and adults with end-stage heart failure. But because the number of patients awaiting donor hearts continues to increase, and both the quality and quantity of available hearts remain inconsistent, these patients don’t always have meaningful hope for long-term survival. 

Clinician scientists are interested in the immunologic and inflammatory injury that results from ischemia (lack of blood flow to the donor heart following organ procurement) and reperfusion (when blood flow is restored during the transplant surgery). Despite knowledge gained, limited progress has been made in developing therapeutics to limit organ injury, expand the number of donor hearts and improve the quality of organs available for transplantation.

Faced with these challenges, transplant teams have begun to explore options that differ from the traditional approach, called cold static preservation. Instead, they’re exploring a more novel technology called ex vivo heart perfusion (EVHP), which allows for donor heart perfusion, an approach that keeps a retrieved heart beating and functioning with warm, oxygenated blood outside the body during transport. While there are advantages to this strategy, clinical trials have not yet shown significant advantages of EVHP over standard static cold storage preservation when it comes to increasing the quality, quantity and longevity of donor hearts.

To study the differences between ex vivo heart perfusion and cold static preservation methods, Matthew Stone, MD, PhD, and his research team developed murine models for heart perfusion and transplant. These models were purposefully designed to provide opportunities for genetic knockouts (the intentional disabling of specific genes) and the ability to increase the scale on which studies can be conducted on the specific immunogenic and inflammatory injury pathways.

Understanding the role of heart injury and perfusion

This research is important because once a donor heart is placed into a recipient and reperfused with oxygenated blood, the body reacts with inflammatory and immunologic processes that cause injury to the heart. This is called ischemia reperfusion injury, or IRI. 

When it comes to IRI, transplant surgeons are most concerned about the possibility of primary graft dysfunction (PGD). This happens when IRI is severe enough to impact the heart’s function. PGD occurs in as many as one-third of transplant recipients and has important implications for both short- and long-term survival following transplant.

“Our belief is that all hearts undergo a period of injury inherent to the transplant process, yet respond in different ways,” Dr. Stone says. “Our focus in the lab has been to understand the different mechanisms of injury to provide a foundation on which to build therapeutic interventions that may limit IRI and PGD.”

Donor heart preservation

The team’s hypothesis is that the hypothermia induced as part of EVHP, along with targeted immunologic therapy using sphingosine-1-phosphate (S1P), provides a potential strategy for limiting ischemia reperfusion injury and primary graft dysfunction during the preservation period.

While researchers around the world are exploring hypothermic perfusion systems, they have yet to use EVHP as a platform for direct immunologic treatment.

Dr. Stone and his team seek to approach this with a methodology that focuses on defining mechanisms of organ injury to guide delivery of targeted therapies.

By using both in vivo (living) models and in vitro (in glass) models to study ischemic injury, the team has identified potential advancements that could reduce ischemic injury after transplant. Having multiple reproducible models provides validation to mechanistic study. Showing the same things happening to two different models provides more accuracy than showing it in a single model and minimizes the potential for confounding variables.

If successful, EVHP combined with S1P promises to improve the quality of donor hearts for children and adults awaiting heart transplantation .

Preventing injury during transplant and extending longevity of donor hearts

The heart has a sharp inflection point for injury at four hours of ischemia, limiting how far a donor heart can travel to a recipient. "Within congenital heart surgery where additional vascular reconstructions are commonly needed, it takes us about an hour to sew a donor heart in prior to reperfusion. That gives us about three hours to get the heart out of the donor and fly it back here,” Dr. Stone says. “We are hopeful that these novel preservation strategies, in addition to preventing injury, will also have a role in the extension of ischemic times, which would make more hearts available to an increasing number of people awaiting transplant.”

Current research has begun to define important immunologic targets of heart injury inherent to transplantation. As the research continues, it will demonstrate the ability to limit this injury and improve graft function following transplantation.

“It is my opinion that meaningful, translational science is dependent upon the design and testing of a clinically relevant and reproducible model,” Dr. Stone adds.

The ultimate goal: Higher quality hearts, higher quality transportation and a higher number of hearts available.

“As a pediatric heart surgeon, my primary motivation for this research is to make more hearts available for more children. And second, to make them perform better and longer once they are transplanted,” Dr. Stone says.