Improved heart function from older donors using pharmacologic conditioning strategies

Gayathri Kumarasinghe; Ling Gao; Mark Hicks; Jeanette Villanueva; Aoife Doyle; Padmashree Rao; Min Ru Qiu; Andrew Jabbour; Arjun Iyer; Hong Chee Chew; Christopher S Hayward; Peter Macdonald

doi:10.1016/j.healun.2015.12.020

Improved heart function from older donors using pharmacologic conditioning strategies

J Heart Lung Transplant. 2016 May;35(5):636-46. doi: 10.1016/j.healun.2015.12.020. Epub 2016 Jan 6.

Authors

Affiliations

¹ Cardiac 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.
² Cardiac Transplantation Laboratory, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia.
³ Cardiac 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; Department of Clinical Pharmacology and Toxicology.
⁴ Department of Anatomical Pathology.
⁵ Cardiac 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; Heart and Lung Transplant Unit, St. Vincent's Hospital, Sydney, New South Wales, Australia.
⁶ Cardiac 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; Heart and Lung Transplant Unit, St. Vincent's Hospital, Sydney, New South Wales, Australia. Electronic address: peter.macdonald@svha.org.au.

PMID: 26899770
DOI: 10.1016/j.healun.2015.12.020

Abstract

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.

Keywords: aging; extended criteria hearts; ischemia-reperfusion injury (IRI); myocardial preservation; pharmacologic conditioning.

MeSH terms

Animals
Heart Transplantation
Heart*
Organ Preservation
Organ Preservation Solutions
Rats
Rats, Wistar

Substances

Organ Preservation Solutions