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Improved heart function from older donors using pharmacologic conditioning strategies
Gayathri Kumarasinghe1, Ling Gao2, Mark Hicks3
1Cardiac Transplantation Laboratory, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia; Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
Insights
Supplementing Celsior solution with glyceryl trinitrate, erythropoietin, and zoniporide protects older donor hearts from ischemia-reperfusion injury, improving graft function for transplantation.
Area of Science:
- Cardiology
- Transplantation Medicine
- Organ Preservation
Background:
- Increasing use of older donor hearts for transplantation.
- Older donor hearts exhibit heightened susceptibility to ischemia-reperfusion injury (IRI).
- Higher rates of primary graft dysfunction are observed with older donor hearts.
Purpose of the Study:
- To evaluate a pharmacologic conditioning strategy for older donor hearts.
- To assess the protective effects of supplemented Celsior solution against IRI.
- To improve donor heart preservation and graft function.
Main Methods:
- Utilized Wistar rats aged 3, 12, and 18 months to model donor age.
- Hearts were subjected to brain death and stored in Celsior or supplemented Celsior (GTN+EPO+ZON).
- Assessed cardiac function, lactate dehydrogenase, Western blots, and histopathology post-storage.
Main Results:
- 18-month-old hearts showed impaired function post-storage compared to 3-month-old hearts.
- Supplemented Celsior significantly improved functional recovery in 18-month-old hearts.
- Reduced IRI markers (lactate dehydrogenase, edema) and activated survival pathways (p-ERK1/2, p-Akt) were observed.
Conclusions:
- Older donor hearts are vulnerable to IRI from brain death and storage.
- Supplemented Celsior enhances cell survival signaling in older hearts.
- This strategy effectively reduces IRI and improves donor heart preservation.
Background:
Hearts from older donors are increasingly being referred for transplantation. However, these hearts are more susceptible to ischemia-reperfusion injury (IRI), reflected in higher rates of primary graft dysfunction. We assessed a strategy of pharmacologic conditioning, supplementing Celsior (Genzyme, Naarden, The Netherlands) preservation solution with glyceryl trinitrate (GTN; Hospira Australia Pty, Ltd, Mulgrave, VIC, Australia), erythropoietin (EPO; Eprex; Janssen-Cilag, North Ryde, NSW, Australia), and zoniporide (ZON; Pfizer, Inc., Groton, CT), to protect older hearts against IRI and improve graft function.
Methods:
Wistar rats, aged 3, 12, and 18 months old, were used to represent adolescent, 30-year-old, and 45-year-old human donors, respectively. Animals were subjected to brain death (BD) and hearts stored for 6 hours at 2° to 3°C in Celsior or Celsior supplemented with GTN+EPO+ZON. Cardiac function and lactate dehydrogenase before and after storage were assessed during ex vivo perfusion. Western blots and histopathology were also analyzed.
Results:
After BD, 18-month hearts demonstrated impaired aortic flow, coronary flow, and cardiac output compared with 3-month hearts (p < 0.001 to p < 0.0001). After storage in Celsior, the recovery of aortic flow, coronary flow, and cardiac output in 18-month BD hearts was further impaired (p < 0.01 vs 3-month hearts). Percentage functional recovery of 18-month BD hearts stored in Celsior supplemented with GTN+EPO+ZON was equivalent to that of 3-month hearts and significantly improved compared with 18-month hearts stored in Celsior alone (p < 0.01 to p < 0.001), with reduced lactate dehydrogenase release (p < 0.01) and myocardial edema (p < 0.05) and elevated phosphorylated extracellular signal-related kinase 1/2 (p < 0.05) and phosphorylated Akt (p < 0.01).
Conclusions:
Older hearts are more susceptible to IRI induced by BD and prolonged hypothermic storage. Supplemented Celsior activates cell survival signaling in older hearts, reduces IRI, and enhances donor heart preservation.
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